Transcript for the March 9, 2015 Meeting of the Dermatologic and Ophthalmic Drugs Advisory ...
October 30, 2017 | Author: Anonymous | Category: N/A
Short Description
, FAAD. 2. Professor of Dermatology and Janet Evans-Watkins 03-09-15 FDA DODAC AM Session _Revised 04 ......
Description
1
1
FOOD AND DRUG ADMINISTRATION
2
CENTER FOR DRUG EVALUATION AND RESEARCH
3 4 5 6
DERMATOLOGIC AND OPHTHALMIC DRUGS
7
ADVISORY COMMITTEE (DODAC)
8 9 10
Monday, March 9, 2015
11 12
Morning Session
13 14
8:05 a.m. to 12:10 p.m.
15 16 17 18
FDA White Oak Campus
19
White Oak Conference Center
20
Building 31, The Great Room
21
Silver Spring, Maryland
22
A Matter of Record (301) 890-4188
2
Meeting Roster
1 2
ACTING DESIGNATED FEDERAL OFFICER (Non-Voting)
3
Jennifer Shepherd, RPh.
4
Division of Advisory Committee and Consultant
5
Management
6
Office of Executive Programs, CDER, FDA
7 8
DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY
9
COMMITTEE MEMBER (Voting)
10
Lynn A. Drake, MD
11
(Chairperson)
12
Lecturer
13
Harvard Medical School
14
Department of Dermatology
15
Massachusetts General Hospital
16
Boston, Massachusetts
17 18
Mary E. Maloney, MD
19
Professor of Medicine
20
Division of Dermatology
21
UMass Memorial Medical Center
22
Worcester, Massachusetts
A Matter of Record (301) 890-4188
3
1
DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY
2
COMMITTEE MEMBER (Non-Voting)
3
Gavin R. Corcoran, MD, FACP
4
(Industry Representative)
5
Chief Medical Officer
6
Actavis plc
7
Jersey City, New Jersey
8 9
TEMPORARY MEMBERS (Voting)
10
Mural Alam, MD, MSCI
11
(Morning Session Only)
12
Professor of Dermatology, Otolaryngology, and
13
Surgery
14
Chief, Section of Cutaneous and Aesthetic Surgery
15
Department of Dermatology
16
Northwestern University
17
Chicago, Illinois
18 19 20 21 22
A Matter of Record (301) 890-4188
4
1
TEMPORARY MEMBERS (Voting) (cont.)
2
Wilma F. Bergfeld, MD, FAAD
3
Professor of Dermatology and Pathology
4
Senior Dermatologist & Co Director
5
Dermatopathology
6
Departments Of Dermatology and Pathology
7
Cleveland Clinic
8
Cleveland, Ohio
9 10
Warren B. Bilker, PhD
11
Professor of Biostatistics
12
Department of Biostatistics and Epidemiology
13
Perelman School of Medicine
14
University of Pennsylvania
15
Philadelphia, Pennsylvania
16 17
Danielle Boyce, MPH
18
(Patient Representative)
19
(Afternoon Session Only)
20
Philadelphia, Pennsylvania
21 22
A Matter of Record (301) 890-4188
5
1
TEMPORARY MEMBERS (Voting) (cont.)
2
Erica Brittain, PhD
3
Mathematical Statistician and Deputy Branch Chief
4
Biostatistics Research Branch
5
National Institute of Allergy and Infectious
6
Disease (NIAID)
7
National Institutes of Health (NIH)
8
Bethesda, Maryland
9 10
Julie Cantatore-Francis, MD
11
(Afternoon Session Only)
12
Dermatologist/Pediatric Dermatologist
13
Dermatology Physicians of Connecticut
14
Norwalk, CT/Shelton, CT
15
Voluntary Faculty, Department of Dermatology
16
Yale New Haven Hospital
17
New Haven, Connecticut
18 19
Cynthia Chauhan
20
(Patient Representative)
21
(Morning Session Only)
22
Wichita, Kansas
A Matter of Record (301) 890-4188
6
1
TEMPORARY MEMBERS (Voting) (cont.)
2
Bernard A. Cohen, MD
3
(Afternoon Session Only)
4
Professor, Pediatrics and Dermatology
5
Johns Hopkins University School of Medicine
6
Baltimore, Maryland
7 8
John J. DiGiovanna, MD
9
Staff Clinician
10
Dermatology Branch
11
Center for Cancer Research
12
National Cancer Institute (NCI), NIH
13
Bethesda, Maryland
14 15
Anthony A. Gaspari, MD
16
Professor, Department of Dermatology and
17
Microbiology/Immunology
18
University of Maryland Baltimore
19
Baltimore, Maryland
20 21 22
A Matter of Record (301) 890-4188
7
1
TEMPORARY MEMBERS (Voting) (cont.)
2
Brian Green, DO, FAAD
3
(Afternoon Session Only)
4
MAJ, MC, USA
5
Staff Dermatologist
6
Chief, Pediatric Dermatology
7
Associate Program Director
8
National Capital Consortium Dermatology
9
Residency
10
Walter Reed National Military Medical Center
11
Bethesda, Maryland
12 13
Kimberly A. Horii, MD
14
(Afternoon Session Only)
15
Associate Professor of Pediatrics
16
University of Missouri, Kansas City
17
Children's Mercy Hospital Division of Dermatology
18
Kansas City, Missouri
19 20 21 22
A Matter of Record (301) 890-4188
8
1
TEMPORARY MEMBERS (Voting) (cont.)
2
Ken Katz, MD, MSc, MCSE
3
(Afternoon Session Only)
4
Dermatologist
5
Kaiser Permanente
6
Pleasanton, California
7 8
Loretta Kopelman, PhD
9
(Afternoon Session Only)
10
Professor Emeritus
11
Department of Bioethics & Interdisciplinary Studies
12
Brody School of Medicine
13
East Carolina University
14
Greenville, North Carolina
15
Professor, Practice of Family Medicine and
16
Faculty Affiliate, Kennedy Institute of Ethics
17
Georgetown University
18
Washington, District of Columbia
19 20 21 22
A Matter of Record (301) 890-4188
9
1
TEMPORARY MEMBERS (Voting) (cont.)
2
Alan Matarasso, MD, FACS
3
(Morning Session Only)
4
Private Practice
5
Clinical Professor of Plastic Surgery
6
Albert Einstein College of Medicine
7
New York, New York
8 9
Delora L. Mount, MD, FACS
10
(Morning Session Only)
11
Associate Professor of Surgery, Pediatrics and
12
Neurological Surgery
13
Division of Plastic Surgery
14
University of Wisconsin School of Medicine and
15
Public Health
16
Madison, Wisconsin
17 18
Vesna Mrzljak, MD
19
(Morning Session Only)
20
Otolaryngologist in Private Practice
21
Alexandria, Virginia
22
A Matter of Record (301) 890-4188
10
1
TEMPORARY MEMBERS (Voting) (cont.)
2
Robert X. Murphy, Jr., MD, MS, CPE
3
(Morning Session Only)
4
Associate CMO
5
Attending Plastic Surgeon
6
Lehigh Valley Health Network
7
Professor of Surgery
8
Morsani College of Medicine
9
Allentown, Pennsylvania
10 11
Lisa A. Orloff, MD, FACS
12
(Morning Session Only)
13
Director of Endocrine Head & Neck Surgery
14
Professor of Otolaryngology/Head & Neck Surgery
15
Stanford University School of Medicine
16
Stanford, California
17 18
Sharon S. Raimer, MD
19
Professor, Dermatology and Pediatrics
20
Chair, Department of Dermatology
21
University of Texas Medical Branch
22
Galveston, Texas
A Matter of Record (301) 890-4188
11
1
TEMPORARY MEMBERS (Voting) (cont.)
2
Elaine Siegfried, MD
3
(Afternoon Session Only)
4
Professor, Pediatrics and Dermatology
5
Director, Division of Pediatric Dermatology
6
Saint Louis University
7
St. Louis, Missouri
8 9
Maral Kibarian Skelsey, MD
10
(Morning Session Only)
11
Director, Dermatology and Clinical Assistant
12
Professor
13
Department of Dermatology
14
Georgetown University
15
Washington, District of Columbia
16 17
Kenneth E. Towbin, MD
18
(Afternoon Session Only)
19
Chief, Clinical Child & Adolescent Psychiatry
20
Emotion and Development Branch
21
National Institute of Mental Health, NIH
22
Bethesda, Maryland
A Matter of Record (301) 890-4188
12
1
TEMPORARY MEMBERS (Voting) (cont.)
2
Carmen Myrie Williams, MD
3
Clinical Professor of Dermatology and Pathology
4
George Washington University Medical Center
5
Dermatopathologist
6
Bethesda Dermpathology Lab
7
Bethesda, Maryland
8 9
FDA PARTICIPANTS (Non-Voting)
10
Julie Beitz, MD
11
(Afternoon Session Only)
12
Director
13
Office of Drug Evaluation III (ODE III)
14
Office of New Drugs (OND), CDER, FDA
15 16
Amy Egan, MD, MPH
17
(Morning Session Only)
18
Deputy Director
19
ODE III, OND, CDER, FDA
20 21 22
A Matter of Record (301) 890-4188
13
1
FDA PARTICIPANTS (Non-Voting) (cont.)
2
Jill Lindstrom, MD
3
(Afternoon Session Only)
4
Clinical Team Leader
5
DDDP, ODE III, OND, CDER, FDA
6 7
Kendall A. Marcus, MD
8
Director
9
Division of Dermatology and Dental Products (DDDP)
10
ODE III, OND, CDER, FDA
11 12
David Kettl, MD
13
(Morning Session Only)
14
Acting Deputy Director
15
DDDP, ODE III, OND, CDER, FDA
16 17
Michelle Roth-Cline, MD, PhD
18
(Afternoon Session Only)
19
Pediatric Ethicist
20
Office of Pediatric Therapeutics (OPT)
21
Office of the Commissioner (OC), FDA
22
A Matter of Record (301) 890-4188
14
C O N T E N T S
1 2
AGENDA ITEM
3
Call to Order
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
PAGE
Lynn Drake, MD
16
Conflict of Interest Statement Jennifer Shepherd, RPh
21
FDA Introductory Remarks Kendall Marcus, MD
24
Sponsor Presentations – Kythera Introduction Frederick Beddingfield
27
ATX-101 Administration Derek Jones, MD, FAAD
32
Pivotal Clinical Study Design Todd Gross, PhD
37
Efficacy Frederick Beddingfield
46
Safety Paul Lizzul, MD, PhD, FAAD
51
Education/Training and Summary Frederick Beddingfield Clarifying Questions
A Matter of Record (301) 890-4188
58 61
15
C O N T E N T S (continued)
1 2
AGENDA ITEM
3
FDA Presentations
4
Background
5 6 7 8 9 10 11
PAGE
Milena Lolic, MD, MS
112
Efficacy Endpoints Elektra Papadopoulos, MD, MPH
117
Summary of Efficacy Kathleen Fritsch, PhD
123
Summary of Safety Milena Lolic, MD, MS
129
12
Clarifying Questions
132
13
Open Public Hearing
136
14
Questions to the Committee and Discussion
166
15
Adjournment
221
16 17 18 19 20 21 22
A Matter of Record (301) 890-4188
16
1
P R O C E E D I N G S
2
(8:05 a.m.)
3
Call to Order
4
Introduction of Committee DR. DRAKE:
5
Good morning.
Hi.
Welcome to
6
this meeting.
I'm delighted that all of you are
7
here on time concerning the early morning that we
8
all had to get up, so thank you. What I want to do initially is I'd like to
9 10
remind everybody to please silence your
11
cell phones, your smartphones, and any other
12
devices if you've not already done so.
13
like to identify the FDA press contact, Andrea
14
Fischer. Andrea, would you wave at everybody?
15 16 17
I'd also
you.
Thank
She's here. So if you have any questions or if you have
18
anybody who wants to talk to you, please work with
19
Andrea because she's the official representative to
20
speak to the press from this committee.
21 22
I'm going to ask everybody to go around. I'll start.
I'm Lynn Drake, and I'm at Harvard
A Matter of Record (301) 890-4188
17
1
Medical School at Massachusetts General Hospital.
2
I'm a dermatologist and dermatopathologist by
3
training.
4
have a really great committee.
5
We got a really good program, and we
I must take a minute to compliment the FDA
6
on putting together such two terrific panels today.
7
I was just stunned with the quality of the members
8
of the panel, so I want to thank everybody for
9
thanking time to come.
10 11
And I want to thank the FDA
for doing such a good job.
It's a great panel.
So I'd like to start.
Gavin, how about I
12
start with you?
13
everybody -- please identify your name, your
14
institution, and your role at this committee.
15
Let's go around the table and have
DR. CORCORAN:
Good morning.
My name is
16
Gavin Corcoran.
17
Actavis, and I'm the industry representative.
18
I'm the chief medical officer at
DR. MURPHY:
Good morning.
I'm Bob Murphy.
19
I'm the immediate past president of the American
20
Society of Plastic Surgeons at Lehigh Valley.
21 22
DR. MRZLJAK:
I'm Vesna Mrzljak, and I'm an
otolaryngologist in private practice in Alexandria,
A Matter of Record (301) 890-4188
18
1 2
Virginia. DR. ALAM:
I'm Mural Alam.
I'm a
3
dermatologist at Northwestern University in
4
Chicago.
5
DR. SKELSEY:
I'm Maral Skelsey.
I'm a
6
dermatologist and Mohs surgeon in Washington at
7
Georgetown University.
8 9 10 11
DR. BERGFELD:
I'm Wilma Bergfeld.
I'm a
dermatologist and dermatopathologist from the Cleveland Clinic, Cleveland, Ohio. DR. RAIMER:
Sharon Raimer, I'm a
12
dermatologist at the University of Texas Medical
13
Branch in Galveston, Texas.
14
MS. CHAUHAN:
15 16 17
Cynthia Chauhan, Wichita,
Kansas, patient representative. DR. MALONEY:
Mary Maloney, I'm the chief in
dermatology at the University of Massachusetts.
18
DR. DRAKE:
19
LCDR SHEPHERD:
20 21 22
Jennifer? Jennifer Shepherd,
designated federal officer. DR. WILLIAMS:
I'm Carmen Myrie-Williams.
I'm a dermatologist/ dermatopathologist on staff
A Matter of Record (301) 890-4188
19
1
for George Washington University and
2
dermatopathologist here in town at Bethesda
3
Dermpath Lab.
4 5 6
DR. BILKER:
I'm Warren Bilker.
I'm a
biostatistician at the University of Pennsylvania. DR. BRITTAIN:
I'm Erica Brittain.
I'm a
7
statistician at the National Institute of Allergy
8
and Infectious Diseases.
9
DR. GASPARI:
I'm Tony Gaspari.
I'm a
10
dermatologist from the University of Maryland
11
Baltimore.
12
DR. DiGIOVANNA:
I'm John DiGiovanna.
13
dermatologist at NCI NIH.
14
DR. MOUNT:
15 16
I'm Delora Mount.
I'm a
I'm a plastic
surgeon at the University of Wisconsin in Madison. DR. ORLOFF:
Hi.
I'm Lisa Orloff.
I'm an
17
otolaryngologist head and neck surgeon at Stanford
18
University.
19 20 21 22
DR. KETTL:
Dave Kettl, acting deputy
director in Derm and Dental Products. DR. EGAN:
Amy Egan, deputy director Office
of Drug Evaluation III.
A Matter of Record (301) 890-4188
20
1 2 3
DR. MARCUS:
Kendal Marcus, director of
Division of Dermatologic and Dental Products. DR. DRAKE:
Thank you.
For topics such as
4
those being discussed at today's meeting, there are
5
often a variety of opinions, some of which are
6
quite strongly held.
7
meeting will be a fair and open forum for
8
discussion of these issues and that individuals can
9
express their views without interruption.
Our goal is that today's
10
Thus, as a general reminder, individuals
11
will be allowed to speak into the record only if
12
recognized by the chairperson, me, and we look
13
forward to a productive meeting.
14
So in the spirit of the Federal Advisory
15
Committee Act and the government in the Sunshine
16
Act, we ask that the advisory committee members
17
take care that their conversations about the topic
18
at hand take place on the open forum of the
19
meeting.
20
We are aware that members of the media are
21
anxious to speak with the FDA about these
22
proceedings.
However, FDA will refrain from
A Matter of Record (301) 890-4188
21
1
discussing the details of this meeting with the
2
media until its conclusion.
3
reminded to please refrain from discussing the
4
meeting topic during breaks or lunch.
5
Also, the media is
Thank you.
Now, I'm going to ask our Lieutenant
6
Commander Jennifer Shepherd, to read the Conflict
7
of Interest Statement.
8 9
Conflict of Interest Statement LCDR SHEPHERD:
Good morning.
The Food and
10
Drug Administration is convening today’s meeting of
11
the Dermatologic and Ophthalmic Drugs Advisory
12
Committee under the authority of the Federal
13
Advisory Committee Act of 1972.
14
of the industry representative, all members and
15
temporary voting members of the committee are
16
special government employees or regular federal
17
employees from other agencies and are subject to
18
federal conflict of interest laws and regulations.
19
The following information on the status of
With the exception
20
this committee's compliance with federal ethics and
21
conflict of interest laws, covered by but not
22
limited to those found at 18 U.S.C. Section 208, is
A Matter of Record (301) 890-4188
22
1
being provided to participants in today's meeting
2
and to the public.
3
and temporary voting members of this committee are
4
in compliance with federal ethics and conflict of
5
interest laws.
6
FDA has determined that members
Under 18 U.S.C. Section 208, Congress has
7
authorized FDA to grant waivers to special
8
government employees and regular federal employees
9
who have potential financial conflicts when it is
10
determined that the agency's need for a particular
11
individual's services outweighs his or her
12
potential financial conflict of interest.
13
Related to the discussions of today's
14
meeting, members and temporary voting members of
15
this committee have been screened for potential
16
financial conflicts of interest of their own as
17
well as those imputed to them, including those of
18
their spouses or minor children, and, for purposes
19
of 18 U.S.C. Section 208, their employers.
20
interests may include investments, consulting,
21
expert witness testimony, contracts, grants,
22
CRADAs, teaching, speaking, writing, patents and
A Matter of Record (301) 890-4188
These
23
1 2
royalties, and primary employment. This morning, the committee will discuss new
3
drug application 206333, deoxycholic acid
4
injection, a cytolytic drug submitted by Kythera
5
Biopharmaceuticals, proposed for the improvement in
6
the appearance of moderate-to-severe convexity or
7
fullness associated with submental fat in adults.
8
This is a particular matters meeting during which
9
specific matters related to Kythera's deoxycholic
10 11
acid injection will be discussed. Based on the agenda for today's meeting and
12
all financial interests reported by the committee
13
members and temporary voting members, no conflict
14
of interest waivers have been issued in connection
15
with this meeting.
16
To ensure transparency, we encourage all
17
standing committee members and temporary voting
18
members to disclose any public statements that they
19
have made concerning the product at issue.
20
With respect to FDA's invited industry
21
representative, we would like to disclose that
22
Dr. Gavin Corcoran is participating in this meeting
A Matter of Record (301) 890-4188
24
1
as a nonvoting industry representative acting on
2
behalf of regulated industry.
3
at this meeting is to represent industry in general
4
and not any particular company.
5
employed by Actavis.
Dr. Corcoran's role
Dr. Corcoran is
We would like to remind members and
6 7
temporary voting members that if the discussions
8
involve any other products or firms not already on
9
the agenda for which an FDA participant has a
10
personal or imputed financial interest, the
11
participants need to exclude themselves from such
12
involvement, and their exclusion will be noted for
13
the record. FDA encourages all other participants to
14 15
advise the committee of any financial relationships
16
that they may have with the firm at issue.
17
you.
18 19 20
DR. DRAKE:
Thank you.
Thank
I'd like to now ask
Dr. Marcus for some opening remarks. FDA Introductory Remarks – Kendall Marcus
21
DR. MARCUS:
Good morning, and welcome
22
everybody to the FDA today.
I'm looking forward to
A Matter of Record (301) 890-4188
25
1
productive discussions, both this morning and this
2
afternoon.
3
I'd like to take a moment to thank my
4
colleagues, Jill Lindstrom, Jane Liedtka, and
5
Dave Kettl for their extraordinary efforts in
6
identifying qualified committee members.
7
that their hard work paid off and will contribute
8
to productive discussions.
9
I think
This morning's session, we will be talking
10
about the marketing application for deoxycholic
11
acid for the improvement in the appearance of
12
moderate-to-severe convexity or fullness associated
13
with submental fat in adults.
14
This application represents a first-in-class
15
of a product for this indication that DDDP has
16
reviewed.
17
Milena Lolic and Electra Papadopoulos, will walk
18
you through the process of endpoint development for
19
this indication that FDA undertook through
20
interactions with the applicant.
21
Fritsch and Milena Lolic will then provide a
22
summary of the efficacy and safety of this product
This morning, FDA presenters,
A Matter of Record (301) 890-4188
Doctors Kathleen
26
1
based on their review of the marketing application.
2
As a woman, I can tell you I understand the
3
impact that appearance can have on a person's
4
self-perception and emotional well-being.
5
spent countless hours with friends and colleagues
6
discussing diet, exercise, weight, and appearance.
7
If the risk-benefit evaluation of this application
8
is found to be favorable, this product could
9
represent an alternative to surgical interventions
10 11 12
for appearance. With that, I will turn the podium over to Dr. Milena Lolic for our first presentation.
13
Oh, I'm sorry --
14
DR. DRAKE:
15
I have
this morning.
That's okay.
We're doing fine
It's still early.
16
(Laughter.)
17
DR. DRAKE:
The next part of this is to go
18
to the sponsor's presentation, and I'd like to
19
thank -- I didn't do this in my introduction.
20
There are two other people I want to thank, two
21
other groups.
22
In addition to the FDA and this wonderful
A Matter of Record (301) 890-4188
27
1
panel, I wanted to thank the sponsor for coming
2
forward with a new potential product for our
3
consideration.
4
I think it's terrific that everybody is here paying
5
attention to the business of the FDA.
6
just wanted to welcome you and thank you.
7
I'd like to turn the presentation over to the
8
sponsor.
9
And I want to thank the audience.
And so, I And now,
Sponsor Presentation – Frederick Beddingfield
10
DR. BEDDINGFIELD:
11
Good morning.
Thank you.
My name is Frederick
12
Beddingfield.
13
Kythera Biopharmaceuticals.
14
dermatologist and a clinical associate professor of
15
medicine and dermatology at UCLA.
16
Kythera, I'd like to thank the panel and the FDA
17
for reviewing the scientific information on
18
ATX-101.
19
I'm the chief medical officer for I'm a practicing
On behalf of
ATX-101 was developed for the treatment of
20
convexity or fullness associated with submental
21
fat, commonly referred to as double chin.
22
Submental fat can be caused by genetics, lifestyle,
A Matter of Record (301) 890-4188
28
1
and aging, and it can be resistant to weight loss
2
measures such as dieting and exercise.
3
Currently, the only available treatment
4
options are traditional aesthetic surgical
5
procedures, targeted liposuction, and/or unlicensed
6
and/or compounded lipolytic drugs.
7
FDA sent warning letters to several clinics who
8
were promoting compounded lipolytic drugs that
9
included deoxycholate and phosphatidylcholine.
10
In 2010, the
Because these products are not FDA-approved,
11
not made to pharmaceutical standards, have no
12
approved label, no pharmacovigilance monitoring,
13
they pose a potential risk to public health.
14
The availability of an approved product such
15
as ATX-101 could provide healthcare practitioners
16
and patients with a less invasive,
17
rigorously-tested, and clinically-proven
18
alternative to unregulated products.
19
Also, an approved product would have
20
established quality standards that fulfill good
21
manufacturing practices, and this is further
22
supported by safety monitoring that would be
A Matter of Record (301) 890-4188
29
1 2
reported to the FDA. To provide some background, in contrast to
3
compounded, animal-derived deoxycholic acid or DCA,
4
ATX-101 contains a synthetic version of naturally
5
occurring DCA.
6
It emulsifies fats for the absorption in the
7
intestinal tract.
8 9
And DCA is an endogenous molecule.
The homeostasis of bile acids is tightly regulated through several mechanisms, and its
10
biology is well-documented and understood.
11
Exogenous DCA, administered as ATX-101, is
12
biologically indistinguishable from endogenous DCA,
13
and evidence suggests that both are regulated in
14
the same homeostatic mechanisms.
15
Treatment with ATX-101 temporarily increases
16
DCA exposure, but levels remain within the typical
17
endogenous range, and they return to baseline
18
within 24 hours.
19
DCA, has been used as a solubilizing excipient from
20
more than 20 years in global-approved drug
21
products, including intravenously administered
22
amphotericin B.
Sodium deoxycholate, a salt of
It's also found in influenza
A Matter of Record (301) 890-4188
30
1
vaccines.
And in Europe, in several countries,
2
sodium deoxycholate, at a concentration of
3
4.75 percent, was used as a solubilizing excipient
4
in an approved drug product for the intravenous
5
treatment of fat emboli. ATX-101 presents a less invasive treatment
6 7
to available surgical options.
Patients receive
8
acute intermittent exposure to ATX-101,
9
administered via subcutaneous injections.
Patients
10
may receive up to 6 treatments with at least
11
4 weeks between treatments. Submental fat reduction occurs gradually
12 13
with each treatment session, and the number of
14
sessions and the number of injections per session
15
are tailored to the individual patient based on the
16
size and the distribution of the submental fat and
17
the desired outcome. Once ATX-101 is injected into the
18 19
subcutaneous fat, DCA physically disrupts the cell
20
membrane of adipocytes causing destruction of fat
21
cells.
22
releases fat droplets consisting of triglycerides,
The destruction of adipocytes predominantly
A Matter of Record (301) 890-4188
31
1
and the exposure of triglycerides to the extra
2
cellular environment leads to the formation of free
3
fatty acids, which elicits a predictable tissue
4
response, including a local attraction of
5
macrophages that eliminates cellular debris.
6
Macrophage infiltration leads to the
7
appearance of fibroblasts and observed thickening
8
of fibrous septa and an increase in total collagen
9
or neocollagenesis.
10
A phase 1 study evaluated the systemic
11
effects and suggests that ATX-101 does not
12
adversely affect total triglycerides, free fatty
13
acids, diacylglycerol, cholesterol, or adiphokines.
14
And as we'll demonstrate today, the efficacy and
15
safety data on ATX-101 support our requested
16
indication for the improvement in the appearance of
17
moderate-to-severe convexity or fullness associated
18
with submental fat in adults.
19
With this background in mind, I'd like to
20
review our agenda and introduce our presenters.
21
Dr. Derek Jones from Los Angeles will review how
22
ATX-101 is administered.
Following Dr. Jones,
A Matter of Record (301) 890-4188
32
1
Dr. Todd Gross from Kythera will speak on the
2
clinical study design.
3
I will then present the efficacy results,
4
and Dr. Paul Lizzul from Kythera will present the
5
safety profile of ATX-101.
6
with some concluding remarks.
7
Finally, I'll follow up
In addition to our presenters, we have
8
invited other subject matter experts, all of whom
9
have been compensated for their time.
At this
10
time, I'd like to call Dr. Derek Jones to the
11
lectern.
12 13
Sponsor Presentation – Derek Jones DR. JONES:
Thank you, Dr. Beddingfield.
14
I'm Derek Jones.
15
Los Angeles and have been an investigator in
16
several ATX-101 clinical trials.
17
significant clinical experience in the treatment of
18
submental fat and, as an investigator in ATX-101
19
pivotal and other trials, have used the product
20
with great success.
21 22
I'm a practicing dermatologist in
I have
As Dr. Beddingfield mentioned, many patients are dissatisfied with their excess submental fat or
A Matter of Record (301) 890-4188
33
1
double chin and the impact it has on their
2
appearance.
3
corrective treatment to reduce their submental fat.
As a result, some patients will seek
The amount of the desired reduction will
4 5
also depend on the patient.
Some may seek maximum
6
reductions while others may seek a smaller but
7
noticeable reduction that improves overall
8
appearance in proportion to their other features. Let's look at how ATX-101 is administered.
9 10
Prior to treatment, we perform a thorough
11
assessment of the patient from multiple vantage
12
points.
13
the patient is an appropriate candidate for
14
treatment and establish that there is sufficient
15
submental fat to treat and identify any
16
abnormalities that would preclude treatment.
17
During the assessment, we determine that
The assessment is also dynamic.
The patient
18
is asked to tense the platysma muscle to help
19
isolate the preplatysmal fat pad and smile and
20
swallow to rule out any asymmetry or
21
characteristics that could impact treatment or
22
outcome.
A Matter of Record (301) 890-4188
34
Next, we clean the cervicomental region
1 2
including the treatment area with an appropriate
3
topical antiseptic.
4
landmarks of the cervicomental region such as the
5
inferior border of the mandible, the
6
anterior borders of the sternocleidomastoid
7
muscles, and the thyroid cartilage.
8
of the submental fat compartment are then marked,
9
including the submental crease, the hyoid bone, and
We identify important external
The boundaries
10
the caudal continuations of the labiomandibular
11
folds.
12
It is also important to mark a no-treatment
13
zone around the probable location of the marginal
14
mandibular nerve as it courses superficially across
15
the mandible.
16
a 3 centimeter radius circle, centered at a point
17
that is 2 centimeters lateral and 2 centimeters
18
inferior to the oral commissure.
19
This may be accomplished by drawing
It is recommended not to inject within the
20
inferior arc of the circle or within a region
21
defined by a 1-1.5 centimeter line below the
22
inferior border of the mandible lateral to the
A Matter of Record (301) 890-4188
35
1
antegonial notch.
2
grid pattern to the treatment area, or we can use a
3
marking pen and ruler to draw a grid pattern with
4
1 centimeter spacing.
5
Then we apply a 1 centimeter
Next, we apply an ice or cold pack to the
6
treatment area for approximately 5 minutes while
7
preparing ATX-101 for administration.
8
procedure, oral analgesics and/or topical or an
9
injectable anesthetics could also be administered.
10
Using a large bore needle, we draw
11
1 milliliters of ATX-101 into the sterile syringe
12
and replace with a 30 gauge half-inch needle for
13
the injections.
14
fingers, pull it away from the underlying tissue,
15
and inject 0.2 milliliters of ATX-101 adjacent to
16
each grid marking perpendicular to the skin until
17
the needle is midway into the underlying
18
preplatysmal subcutaneous fat layer.
Prior to the
We pinch the fat between two
19
ATX-101 should not be injected too
20
superficially into the dermis or during withdrawal
21
of the needle, as this may result in skin
22
ulceration.
The actual injection procedure
A Matter of Record (301) 890-4188
36
1 2
normally takes less than 15 minutes. Upon completion of the injections, we have
3
the patient sit up and then smile to assess for
4
symmetry, and swallow to assure that any swelling
5
or edema is not impacting this function.
6
cold pack is applied to the treatment area for 5 to
7
15 minutes to reduce any discomfort.
8 9
An ice or
Next, the grid and surgical markings are gently removed.
We then discuss post-treatment
10
expectations and options for managing
11
post-treatment discomfort.
12
for an additional treatment after no less than
13
4 weeks.
14
The patient may return
Not all patients are candidates for ATX-101.
15
Patients with prominent platysmal bands or
16
excessive skin laxity may not achieve ideal
17
aesthetic results.
18
procedures in the treatment area may make the
19
indication in the injections more challenging.
20
Scar tissue or prior surgical
Also, caution is advised in patients with a
21
history of dysphagia, with neuropraxia, and with
22
inflammation or induration in the treatment area.
A Matter of Record (301) 890-4188
37
1
Lastly, infection at the injection site is a
2
contraindication.
3
We are seeking an indication for patients
4
who have moderate-to-severe submental fat.
5
are representative photos of a typical ATX-101
6
patient.
7
the submental fat and improve appearance and
8
satisfaction with the treatment area.
9
Here
The goal of the treatment is to reduce
In summary, patients are currently seeking
10
treatment for submental fat, and they want less
11
invasive options.
12
a relatively straightforward procedure for
13
healthcare providers who are familiar with other
14
facial injectable products.
In my opinion, ATX-101 would be
15
Next, I would like to invite Dr. Todd Gross
16
to the lectern to present the design of the ATX-101
17
pivotal clinical studies.
18
Sponsor Presentation – Todd Gross
19
DR. GROSS:
Thank you, Dr. Jones.
20
Good morning.
I'm Todd Gross, vice
21
president of clinical development, biostatistics,
22
and data management for Kythera and also associate
A Matter of Record (301) 890-4188
38
1
professor of statistics at the University of
2
California at Santa Barbara.
3
The 2 pivotal phase 3 studies, known as
4
studies 22 and 23, are independent, identical,
5
double-blind, placebo-controlled, randomized
6
trials, each conducted in the U.S. and Canada.
7
be eligible for these trials, both the clinician
8
and patient had to judge the submental fat as
9
moderate to severe at baseline, and the patient had
10
to be dissatisfied with the appearance of their
11
face and chin.
12
To
Eligible patients must have been 18 and
13
65 years of age, have stable body weight, and a BMI
14
of 40 or less.
15
interventions for their submental fat and had to be
16
free of excessive skin laxity.
Patients could not have had prior
17
Following screening and baseline
18
assessments, patients were randomized to receive
19
either ATX-101 or placebo.
20
up to 6 treatments at 28-day intervals but would
21
receive fewer treatments if the investigator
22
determined that there was not sufficient submental
Patients could receive
A Matter of Record (301) 890-4188
39
1
fat to inject or if the patient was satisfied with
2
the outcome. Once treatment was complete, follow-up
3 4
assessments were performed at 4, 12, and 24 weeks
5
after the last treatment.
6
secondary endpoints were based on the change from
7
baseline to 12 weeks after the last treatment
8
regardless of the number of treatments received.
The primary and
Several elements were included in the
9 10
pivotal study design in order to implement these
11
double-blind trials.
12
of the inactive vehicle and was indistinguishable
13
from the active drug in both appearance and
14
injection characteristics.
First, the placebo consisted
The placebo and active study drug were
15 16
independently labeled with blinded kit codes prior
17
to being shipped to the investigational sites.
18
Subjects were randomized to placebo or
19
active treatment using an automated web-based
20
system.
21
collected independent of each other and without
22
knowledge of ratings from prior time points.
The clinician and patient ratings were
A Matter of Record (301) 890-4188
40
1
Finally, MRI was collected as an objective
2
measure to support the clinician and patient
3
efficacy ratings.
4
Because there were no existing measures for
5
assessing submental fat and related convexity,
6
Kythera developed and validated new scales.
7
ongoing dialogue with the FDA during the
8
development program to identify the appropriate
9
primary and secondary endpoints for evaluating
10 11
We had
efficacy. It was agreed that the primary assessment
12
would be based on a composite of clinician and
13
patient quantitative ratings of submental fat and
14
convexity.
15
ratings and patient impact scale were developed and
16
validated in accordance with the FDA guidance on
17
patient-reported outcomes and with industry best
18
practices.
19
with patients and input from clinical experts.
20
The clinician and patient submental fat
These scales were based on interviews
The reliability and validity of these scales
21
were established in our phase 2 clinical trials and
22
in non-treatment studies, and then confirmed in the
A Matter of Record (301) 890-4188
41
1 2
pivotal trials. I'll now present the details of each of
3
these scales.
4
Clinician-Reported Submental Fat Rating Scale or
5
CR-SMFRS.
6
5-point photometric guide with representative
7
photographic images and verbal descriptions for
8
each rating grade.
9
or absence of submental convexity, to 4 or extreme
10 11
First, we have the
This validated scale consists of a
Ratings could range from zero
submental convexity. After a live comprehensive examination of
12
the patient, physicians used this scale to rate the
13
patient's submental fat without reference to
14
ratings from previous time points.
15
patients must have had moderate-to-severe submental
16
fat at baseline, which corresponds to a score of 2
17
or 3 on this scale.
Eligible
18
Patient ratings of SMF were also obtained.
19
Using a mirror, patients categorized the amount or
20
size of their chin fat by selecting 1 of 5
21
descriptors on the Patient-Reported Submental Fat
22
Rating Scale or PR-SMFRS.
A Matter of Record (301) 890-4188
42
The patient's response could range from "no
1 2
chin fat at all" to "a very large amount of chin
3
fat."
4
themselves with a moderate or large amount of chin
5
fat at baseline.
6
ratings were obtained independent of the clinician
7
ratings.
8 9
Enrollment was limited to patients who rated
At each visit, all patient
Now, let's review how these scales were combined to define our primary endpoints.
To be
10
successful, each pivotal trial had to show
11
statistical significance on two primary efficacy
12
endpoints, each a composite of the clinician and
13
patient ratings of submental fat.
14
The first primary endpoint was the
15
percentage of patients who demonstrated at least a
16
2-grade improvement on both the clinician rating of
17
SMF and the patient rating of SMF.
18
were referred to as composite 2-grade responders.
These patients
19
The second primary endpoint was the
20
percentage of patients who demonstrated at least a
21
1-grade improvement on both the clinician and
22
patient ratings.
These patients are known as
A Matter of Record (301) 890-4188
43
1 2
composite 1-grade responders. The more difficult to attain, 2-grade
3
composite response, was included consistent with
4
FDA's evaluations of prior dermatologic therapies.
5
The 1-grade endpoint was also included because
6
scale validation results show this change to be
7
clinically meaningful to patients and because not
8
every patient desires a 2-grade change.
9
In addition to the co-primary efficacy
10
endpoints, there were two secondary endpoints.
11
first secondary endpoint was a magnetic resonance
12
image assessment of submental volume.
13
substudy included 449 randomized patients at
14
34 centers.
15
The
The MRI
The MRI secondary endpoint was defined as
16
the percentage of patients who achieved at least a
17
10-percent reduction in their submental volume
18
following treatment.
19
objective measure of SMF change that supports the
20
clinician and patient ratings.
21 22
This endpoint provides an
Here, we see an example of the profile MRI images used to assess submental fat in the
A Matter of Record (301) 890-4188
44
1
protocol-defined region of interest.
2
submental volume consists of preplatysmal fat,
3
post-platysmal fat, and associated submental
4
structures.
5
The measured
In the follow-up MRI example on the right,
6
one can see the change in the preplatysmal fat,
7
which is the target area for treatment.
8
because both pre- and post-platysmal fat are
9
measured, the percent change in MRI submental
But
10
volume tends to underestimate the actual percent
11
change to the target preplatysmal fat area.
12
The other secondary efficacy endpoint was a
13
total scale score on the patient-reported submental
14
fat impact scale or PR-SMFIS.
15
how submental fat impacts patient's visual and
16
emotional self-perceptions.
17
endpoint measures what the change in submental fat
18
actually means to the patient.
19
This scale measures
In other words, this
The patient impact score uses an 11-point
20
scale ranging from zero, or no negative impact, to
21
10, or extreme negative impact.
22
Patients were asked to look at the area
A Matter of Record (301) 890-4188
45
1
under their chin to help them answer specific
2
questions.
3
responses could range from "not bothered at all" to
4
"extremely bothered."
For example, on this item, patients'
Patients responded to six individual
5 6
questions listed here, using similar 11-point
7
scales.
8
bothered, self-conscious, and embarrassed patients
9
were with the appearance of their chin fat, as well
10
as how much older or overweight they looked because
11
of their chin fat.
12
questions were then averaged to generate an overall
13
or total impact score on the PR-SMFIS.
The scale items assessed how unhappy,
Responses to these six
Now, let's review the disposition and
14 15
demographics of the studies.
16
patients were enrolled in the pivotal phase 3
17
studies or approximately 250 in each arm of each
18
study.
19
completed the primary endpoint visit.
20
missing on the primary or secondary endpoints was
21
imputed prior to analysis.
22
A total of 1,022
Between 86 and 93 percent of the patients Any data
The most common reasons for study
A Matter of Record (301) 890-4188
46
1
discontinuation were subject convenience and loss
2
to follow-up.
3
patients discontinued the studies due to adverse
4
events.
5
A total of 1 to 2 percent of the
The study sample was representative of the
6
target population of aesthetic patients and subject
7
characteristics were evenly balanced between the
8
two treatment groups in each study and between the
9
two pivotal trials.
10
The typical patient was a middle-aged white
11
female with a BMI of 29.
12
types were adequately represented, and baseline SMF
13
severity was equally distributed between moderate
14
and severe.
15
I'd like to turn the presentation over to
16
Dr. Beddingfield who will review the effectiveness
17
data for ATX-101.
18
All Fitzpatrick skin
With this information as background,
Sponsor Presentation – Frederick Beddingfield
19
DR. BEDDINGFIELD:
Thank you, Dr. Gross.
20
During this portion of the presentation, I
21
will review the primary and secondary endpoints
22
followed by additional analyses.
A Matter of Record (301) 890-4188
And I'll conclude
47
1
with a series of before and after photos. All prespecified endpoints demonstrated
2 3
statistically significant results in both studies.
4
There were two co-primary endpoints, which were
5
both based on a composite of the clinician and the
6
patient rating scales. Both pivotal studies met their primary
7 8
efficacy endpoints based on the 2-grade composite
9
score.
To be a responder, both the clinician and
10
patient had to independently assess that there was
11
at least a 2-grade change. As you can see, for the greater-than or
12 13
equal-to 2-grade composite endpoint, the results
14
from both studies were statistically significant.
15
The ATX-101 responder rates were similar in both
16
studies at 13 percent and 19 percent versus placebo
17
responder rates of zero percent and 3 percent. One of the reasons for having a 2-grade
18 19
composite endpoint is to drive the placebo response
20
rate down, and this was clearly achieved in both
21
trials.
22
The 1-grade composite endpoint in both
A Matter of Record (301) 890-4188
48
1
trials was also statistically significant.
The
2
ATX-101 responder rates were 70 percent and
3
66 percent versus placebo responder rates of
4
19 percent and 22 percent.
5
two co-primary endpoints demonstrate a substantial
6
treatment effect of ATX-101.
Taken together, these
We also examined the individual components
7 8
of the endpoints over time.
On this chart, we've
9
plotted the clinician-reported SMFRS responder
10
rates for the ATX-101 patients, represented by the
11
blue line, and the results for the placebo patients
12
shown on the gray line.
13
for both studies, we pooled the studies for this
14
analysis.
Since the data was similar
15
As you can see, there's an early,
16
significant and sustained separation between the
17
groups.
18
1-grade improvement within two to four treatments.
19
Here, we've overlaid the patient ratings for each
20
group, and we see the same separation between
21
groups and, importantly, similar results between
22
the clinician and the patient-reported ratings.
The majority of patients achieved the
A Matter of Record (301) 890-4188
49
We also had two secondary endpoints:
1
MRI
2
assessment, which is a specific measure of
3
submental volume reduction, and the PR-SMFIS, a
4
patient-reported measure of the impact of submental
5
fat. Blinded MRI assessment was used to
6 7
objectively estimate the reduction in submental
8
volume.
9
reviewing site, and the assessor was masked to the
10 11
MRI images were evaluated at a central
treatment group and to the order of the images. The secondary endpoint achieved statistical
12
significance in both trials.
13
rates were 46 percent and 40 percent for studies 22
14
and 23 respectively, and the comparative placebo
15
responder rates were roughly eightfold lower at
16
5 percent.
17
The ATX-101 responder
As Dr. Gross mentioned, the other secondary
18
efficacy endpoint, the PR-SMFIS, measures how
19
submental fat impacts patients' visual and
20
emotional self-perceptions.
21
with ATX-101 reduced the total score by
22
approximately 50 percent from a baseline of 7.1 to
In study 22, treatment
A Matter of Record (301) 890-4188
50
1
a post- value of 3.6 on an 11-point scale, while
2
placebo only decreased 15 percent from 7.3 to 6.2.
3
Study 23 shows statistically significant and
4
similar results.
5
Let me now share with you some
6
representative examples of 2-grade and 1-grade
7
improvements in the composite primary endpoint.
8
Here, we see a 2-grade improvement as scored by
9
both the clinician and the patient.
This resulted
10
in a change from extreme dissatisfaction to extreme
11
satisfaction following 6 treatment sessions with
12
ATX-101.
13
Here, we see a 1-grade improvement as scored
14
by both the clinician and the patient.
15
resulted in a change from dissatisfaction to
16
slightly satisfied following 5 treatment sessions
17
with ATX-101.
18
And this
This patient did not go undergo a sixth
19
treatment due to insufficient submental fat.
20
these pictures show how the visual scale and the
21
perceptual scales demonstrate a clinically
22
meaningful effect.
A Matter of Record (301) 890-4188
And
51
For completeness' sake, we also show here a
1 2
nonresponder.
This patient was rate as moderate by
3
both the clinician and patient and had no change
4
after treatment.
5
dissatisfied to slightly dissatisfied.
Her satisfaction rating went from
In conclusion, both pivotal studies met
6 7
their primary efficacy endpoints, the 1-grade and
8
2-grade composite clinician- and patient-reported
9
submental fat scores.
The secondary endpoints were
10
met with high statistical significance in both
11
trials.
12
Thank you for your attention.
13
Dr. Paul Lizzul will review our safety data.
14
And now,
Sponsor Presentation – Paul Lizzul
15
DR. LIZZUL:
Thank you, Dr. Beddingfield.
16
I'm Paul Lizzul, a practicing dermatologist
17
and senior medical director for Kythera.
18
overview of our safety presentation.
19
Here's an
First, we'll look at how adverse events were
20
collected.
Next, we'll review vitals, lab results,
21
and adverse events.
22
of serious adverse events, followed by adverse
Then, I'll present an overview
A Matter of Record (301) 890-4188
52
1
events of special interests.
2
our longer term safety data.
Finally, we'll review
A list of potential adverse events were
3 4
included in the protocol and investigator's
5
brochure, including injection site-related adverse
6
events such as pain, bruising, and swelling.
7
collected traditional spontaneous adverse event
8
reports observed or elicited at each study visit.
9
Clinical evaluations of the submental area,
We
10
physical exams, and the evaluation of a laboratory
11
test result could also generate an adverse event
12
report. For the purposes of today's presentation, we
13 14
will present pooled data in 1,019 patients who
15
received at least one treatment in the two pivotal
16
studies. Next, let's take a look at an overview of
17 18
vital signs, laboratory results, and adverse
19
events.
20
with any clinically meaningful changes in vital
21
signs and clinical chemistry, including serum lipid
22
concentrations, liver or renal function tests, or
Treatment with ATX-101 was not associated
A Matter of Record (301) 890-4188
53
1 2
hematology results. As anticipated with an injectable aesthetic
3
procedure, most patients reported adverse events
4
related to the injection such as pain, bruising, or
5
swelling.
6
moderate in nature.
7
events in ATX patients were reported as mild and 18
8
percent as moderate in severity.
9
The majority of all events were mild or Eighty-one percent of the
Shown here are the adverse events reported
10
by at least 10 percent of patients at any time
11
during the course of the studies.
12
patients experienced treatment area events, which
13
were related to either the procedure, the
14
pharmacologic activity of the drug, and/or the
15
local tissue response.
16
Nearly all
Let me provide more detail on the severity
17
of adverse events.
18
bars, the majority of adverse events associated
19
with the treatment area are mild.
20
As shown here by the green
Now, we'll look more closely at the
21
90 severe adverse events with ATX-101.
22
occurred in 55 patients.
These
We've grouped the severe
A Matter of Record (301) 890-4188
54
1
adverse events by preferred terms.
2
events, there were 52 events of bruising, pain,
3
numbness, edema, and swelling.
4
events occurred after the first treatment session.
5
The median duration was 4 days and importantly,
6
100 percent of these events resolved without
7
sequelae.
8 9
Of the 90
Thirty-six of these
In addition, there were a total of 7 events with preferred terms of induration, tingling,
10
dysphagia, or hypersensitivity.
11
duration of these events was 8 days, and all events
12
resolved without sequelae.
13
The median
Within the group of severe adverse events,
14
there were 31 events in 18 patients with various
15
preferred terms that suggest no relationship to
16
study drug or the treatment area, ranging from
17
abdominal abscess to vertigo.
18
recorded that these events were unrelated to
19
treatment.
20
Investigators
Next, I'll review the serious adverse events
21
and then adverse events of special interest.
22
order to more fully characterize less common
A Matter of Record (301) 890-4188
In
55
1
events, we assessed all patients who received at
2
least one treatment of the proposed dose of ATX-101
3
from all of our submental fat studies.
4
First, let's look at serious adverse events.
5
In this table, we've listed serious adverse events
6
by system organ class.
7
adverse events was low and generally similar
8
between the ATX-101 and placebo groups.
9
The incidence of serious
Twenty-eight patients in the placebo group
10
and 27 patients in the ATX-101 group reported SAEs.
11
Only one SAE in the clinical development program
12
was considered to be related to study drug by the
13
investigator.
14
injury, which resolved without sequelae.
15
This was an injection site nerve
We carefully evaluated adverse events of
16
special interest, which are those that may be
17
potentially related to the procedure, mechanism of
18
action, or tissue response.
19
present reports of motor nerve injury, as these may
20
be related to injection technique.
21 22
In particular, we will
Based on our findings from our clinical trials, we have provided a detailed description of
A Matter of Record (301) 890-4188
56
1
injection technique in the proposed label. Injection site motor nerve injury was
2 3
reported by 0.3 percent of patients in the placebo
4
group and 2.9 percent of patients in the ATX-101
5
group.
6
injury had a median duration of 45 days, and all
7
cases resolved without sequelae.
8
occur because the marginal mandibular nerve
9
traverses the mandibular region adjacent to the
10
In the ATX group, injection site nerve
Nerve injury can
target treatment area.
11
Here's a dynamic photo of a patient who
12
experienced nerve injury, which was reported as
13
moderate in severity.
14
mandibular nerve results in a weakening of the lip
15
depressor muscles on one side of the mouth and
16
typically presents as an asymmetric smile, as shown
17
on the left.
18
of the event and a normal smile.
19
injury events in the trial were mild.
20
Injury to the modular
On the right, we can see resolution Most of the nerve
To mitigate the potential for motor nerve
21
injury, clear instructions on proper injection
22
placement and technique will be communicated via
A Matter of Record (301) 890-4188
57
1
our label and physician training programs, which
2
Dr. Beddingfield will discuss shortly.
3
Finally, I'll summarize data from patients
4
who have long-term follow-up.
5
long-term, post-treatment follow-up studies, two of
6
which have been completed.
7
up to four years of long-term adverse event data in
8
374 patients.
9
There were four
This provides us with
Thirty-six patients reported adverse events
10
during this post-treatment period, and none of
11
these adverse events were severe.
There were no
12
study drug-related SAEs reported.
Importantly, no
13
unexpected findings have been identified from our
14
long-term follow-up.
15
In summary, the safety profile of ATX-101 is
16
well-characterized.
ATX-101 is an acute, elective,
17
and safe treatment with mostly transient and mild
18
adverse events related to the treatment area that
19
resolve without intervention or sequelae and that
20
can be readily managed by the practitioner.
21
Moreover, the types of events observed are
22
consistent with the expectations of clinicians and
A Matter of Record (301) 890-4188
58
1
patients for such a product or procedure. Dr. Beddingfield will now provide additional
2 3
information on our education and training programs
4
as well as concluding remarks.
5
Sponsor Presentation – Frederick Beddingfield
6
DR. BEDDINGFIELD:
Thank you, Dr. Lizzul.
7
At Kythera, we want to ensure that patients
8
receive optimal outcomes as part of this treatment,
9
and we intend to have a robust training program
10
available in a variety of formats.
Healthcare
11
providers will be instructed on the relevant
12
submental anatomy; specific injection techniques
13
will be communicated; and comprehensive patient
14
evaluation and selection would be emphasized to
15
enhance the patient experience. Both providers and patients will be informed
16 17
about the adverse event profile.
18
will communicate these likely and unlikely adverse
19
events.
20
and tutorials for healthcare providers in order to
21
avoid unnecessary events such as nerve injury.
22
Patient materials
In addition, we will provide instructions
We will specifically highlight the relevant
A Matter of Record (301) 890-4188
59
1
submental anatomy and associated neuromuscular
2
structures.
3
participants on key internal anatomic structures,
4
including the platysma and SMF compartments.
Training programs will educate
5
For instance, injections should not be made
6
above the inferior border of the mandible or in the
7
hatch marked area below the inferior border of the
8
mandible.
9
injury to the marginal mandibular nerve of the
10 11
This reduces the potential for the
branch of the facial nerve. Now, I'd like to summarize our key findings.
12
Our pivotal studies demonstrate that ATX-101
13
provides statistically significant and clinically
14
meaningful reductions in submental fat compared
15
with placebo.
16
helps demonstrate a clear benefit over placebo.
17
The rigorous 2-grade improvement
Most ATX-101 patients experienced at least a
18
1-grade response on the clinician- and the
19
patient-rated scales, which aligns with patient
20
satisfaction measures.
21
support the clinician and patient-reported primary
22
endpoints, and patients also reported that the
The objective MRI results
A Matter of Record (301) 890-4188
60
1
improvement was impactful both on visual and
2
emotional self-perceptions.
3
to determine the impact of bias did not change our
4
interpretation of the efficacy.
5
Sensitivity analyses
So how does this translate to a patient
6
experience?
Most patients remain on treatment
7
until achieving their desired results.
8
this is an injectable treatment, patients can
9
expect to experience some swelling, bruising, pain
And because
10
and other treatment area events.
11
the adverse events were mild to moderate, transient
12
in nature, and they resolved without sequelae.
13
However, most of
Until now, patients who wanted their
14
submental fat treated had limited choices,
15
including the use of invasive techniques, or in
16
some instances, potentially risky unapproved
17
compounded products.
18
extensively and provides a minimally invasive
19
therapy with excellent efficacy results that can be
20
tailored to the patient's needs.
21 22
ATX-101 has been studied
Safety of the products has been thoroughly evaluated and confirms that ATX-101 is
A Matter of Record (301) 890-4188
61
1
well-tolerated with common and expected treatment
2
area related adverse events such as bruising, pain,
3
and swelling.
4
that treatment typically occurs over several
5
sessions, patients and healthcare providers can
6
have an ongoing dialogue about the benefit risk and
7
whether further treatments are warranted or
8
desired.
9 10 11 12
Because of this profile and the fact
Thank you.
We'd be happy to address your
questions. Clarifying Questions DR. DRAKE:
Well, thank you for a very
13
efficient and informative presentation.
14
compliment the sponsor because you initially
15
identified that your presenters or employees were
16
compensated, which I didn't really have to do the
17
traditional warnings, so that was really nice.
18
I want to
As we enter into the clarifying questions, I
19
want to remind anybody that maybe has not been at
20
the podium to please be sure, in the interest of
21
transparency, that you identify any financial
22
relationships that you might have that have not
A Matter of Record (301) 890-4188
62
1
been alluded to already.
2
choose not to, it will not preclude you from
3
speaking.
4
transparency that everybody understands if there's
5
any financial involvement.
6
And of course, if you
But it's helpful in the interest of
Now, having said all that, I'd like to move
7
into the clarifying questions to the sponsors.
And
8
please remember that if you have -- this is for the
9
committee.
For those of you who haven't been here,
10
remember, this is not a discussion of whether we're
11
going to vote or anything.
12
clarify with the sponsor any questions you might
13
have about their presentation.
14
This is really to
Also, my assistant -- I shouldn't say my
15
assistant -- the staff officer, lieutenant
16
commander by the way, Shepherd, will also capture
17
names and so will I.
18
something to say, raise your hand.
19
And we'll keep track of who's asking a question,
20
and we'll make sure that everybody gets included.
21 22
So please as you have She'll nod.
Please state your name also for the record because we're recording this.
A Matter of Record (301) 890-4188
So as you ask a
63
1
question, please state your name, so that we'll
2
have that for the record.
3
With that, I'd like to start
4
recognizing -- taking questions from -- Dr. Alam,
5
you're first.
6
DR. ALAM:
Thank you.
Mural Alam.
The
7
sponsor, I think, discussed this in detail, but in
8
the FDA summary, there was mention of a couple of
9
cases of malignancy that were specified.
I think
10
one was cholangiocarcinoma and one was pancreatic
11
cancer, but it was determined that those were not
12
related to study drug.
13
Would the sponsor be able to clarify the
14
circumstances of those which apparently preceded,
15
potentially, the use of the drug and, hence, were
16
not related?
17
Thank you.
DR. BEDDINGFIELD:
Yes, absolutely.
I'll
18
ask Dr. Lizzul to give additional details.
But
19
importantly, the overall rate was comparable on
20
ATX-101 and in placebo, and no event was considered
21
related to study drug.
22
of these events thoroughly, and Dr. Lizzul can give
We have investigated each
A Matter of Record (301) 890-4188
64
1
additional details.
2
DR. LIZZUL:
So at a high level overall,
3
there was comparable numbers of observed neoplasms
4
in the placebo and ATX groups, as you can see above
5
here.
6
about pancreatic carcinoma and bile duct cancer.
7
Just give us a moment to pull out those details. But the temporal relationship of these
8 9 10
I believe your questions were specifically
events to treatment -- sorry, we're having an issue with the slide here. Can I have that slide up, please?
11
There we
12
go.
13
47-year-old male.
14
session, they received a dose of 6.2 milliliters of
15
ATX-101.
16
50 days after treatment, so temporal nature was
17
quite proximal to treatment, and only one treatment
18
session.
19
So a cholangiocarcinoma occurred in a During the first treatment
The onset of the event was approximately
The second event was a placebo subject in
20
our earlier phase 2 study who had pancreatic
21
carcinoma.
22
DR. DRAKE:
Dr. Brittain?
A Matter of Record (301) 890-4188
65
1
DR. BRITTAIN:
Yes, I was interested in
2
your -- if you have any comments about the fact
3
that we know that there are certain differences in
4
the adverse events between the groups and whether
5
that could have led to lack of blinding.
6
primary endpoint is so subjective, it seems like
7
that's an important thing to consider, and I'm
8
wondering if you have any comments about that.
9
DR. BEDDINGFIELD:
Given the
I appreciate that
10
comment, and we certainly understand that
11
unblinding can occur in trials such as this if the
12
drug either has a very good efficacy or perhaps
13
there are certain discriminating AEs, which are
14
both potentially true in this case.
15
The data suggests, however, that the
16
treatment effect is real, and I'd like to go
17
through just several steps that we looked at as we
18
investigated this potential.
19
First, we did have steps in place to protect
20
the blind.
I'll talk about those in just a minute.
21
Perhaps most importantly, we had an objective
22
endpoint that is not subject to unblinding, and
A Matter of Record (301) 890-4188
66
1
that is the MRI.
2
then we did do an analysis of the potentially
3
unblinding AEs, and I'll describe that.
4
finally, we looked at whether active and placebo
5
groups stayed in the trial through several
6
treatment cycles, which might suggest they were
7
unsure which group they were in.
8 9
I'll describe those results.
And
And
So first, the steps to protect the blind, it was a randomized, controlled trial.
The placebo
10
and ATX-101 were indistinguishable visually, and
11
investigators were blinded to patient assessments
12
at the time of the evaluation, so they weren't in
13
the room as the patient was assessing themselves,
14
and the investigator didn't tell the patient their
15
assessment.
16
These are standards things, and certainly
17
alone might not mitigate unblinding.
18
though, was put into the trial specifically as a
19
measure that would be objective and not subject to
20
unblinding.
21 22
The MRI,
These are the results of the MRI data that we showed earlier.
You can see that on this
A Matter of Record (301) 890-4188
67
1
measure, which was done by assessors who were
2
removed from the clinical trial didn't know the
3
treatment group, and they were presented in a
4
random order, so they didn't actually know which
5
was before and after treatment.
6
You can see that on two separate trials,
7
there was an eightfold difference between ATX-101
8
and placebo.
9
results that argue against unblinding.
10
This is probably the strongest
The next analysis that we did was to look at
11
the AEs, which were common and potentially higher
12
in ATX-101 versus placebo.
13
analysis looking at the responder rates in those
14
who had what might be potentially unblinding AEs
15
and those who did not; because one might surmise
16
that if you could tell on the basis of AEs which
17
group they're in, it might affect your assessment
18
of efficacy.
And so we did an
19
What you can see here -- if you just focus
20
on the left-hand side, which is ATX-101 -- is very
21
comparable responder rates in those patients who
22
had these five most common and discriminating AEs
A Matter of Record (301) 890-4188
68
1
and those who did not have them, which would, I
2
think, also suggest that the data are robust. Then finally, looking at the number of
3 4
treatments patients received, if you're a placebo
5
patient and you believe you're getting placebo or
6
the doctor has somehow informed you due to the AE
7
profile that you might be getting placebo, you
8
might think you might not get all 6 treatments
9
since you would doubt there would be a positive
10
impact.
11
But you can actually see that 82 percent of
12
placebo patients got 6 treatments versus 60 percent
13
of the ATX-101.
14
would contend suggest that the treatment effect is
15
real.
16 17
So those are the data that we
DR. DRAKE:
I apologize.
last name?
18
DR. MRZLJAK:
19
DR. DRAKE:
20
DR. MRZLJAK:
21
DR. DRAKE:
22
How do I say your
Mine? Yes. Mrzlyak. Mrzljak, good.
Dr. Mrzljak, you're on.
Thank you.
A Matter of Record (301) 890-4188
Thank you.
69
1
DR. MRZLJAK:
Yes, Dr. Beddingfield.
These
2
instructions on where to inject the ATX-101, did
3
you design that before or after you had those few
4
temporary damages to the marginal mandibular nerve?
5
That's one question.
6
Another one is I read, in this material that
7
we had ahead of time, that the triglycerides were
8
released from the apoptotic adipose cells, yet
9
absorbed the local circulation.
And then they get
10
deposited in the nearby adipocytes, and whether
11
that would lead to the bumpiness.
12
DR. BEDDINGFIELD:
Thank you for those
13
questions.
14
There was an investigator meeting prior to the
15
pivotal trials, and the marginal mandibular nerve
16
was discussed.
17
The first was regarding the training.
I do not think it was emphasized to the
18
extent that we would now, having learned from the
19
development program, emphasize this issue.
20
go back and talk to every investigator who had a
21
marginal mandibular nerve injury to try to
22
understand some of the factors that might have
A Matter of Record (301) 890-4188
We did
70
1
precipitated that.
2
learning and some cadaver dissections that we did,
3
which Dr. Jones was involved in -- and I'd like to
4
ask him to perhaps discuss the training after I'm
5
done and whether you believe that would be adequate
6
to help with this situation.
7
And it's as a result of that
So we've now designed the training in
8
response to our increased knowledge through the
9
development program, through our work with experts
10
in the area of the marginal mandibular nerve
11
anatomy.
12
other products -- and I would -- what comes to mind
13
is the incidence of ptosis with botulinum toxin,
14
which was originally quite high, and then with
15
training became much lower.
16
And I do believe, as has been seen with
So having said that, I'd ask Dr. Jones to
17
comment on that, and then I'll come back to your
18
second question.
19
DR. JONES:
Derek Jones.
I agree with
20
Dr. Beddingfield that we investigators exist on a
21
learning curve when it comes to any new procedure
22
such as this.
And indeed although the marginal
A Matter of Record (301) 890-4188
71
1
mandibular nerve was pointed out as an area to
2
avoid at the investigator meeting, we have learned
3
a great deal more about that.
4
The sponsor has actually undertaken nice
5
cadaveric studies looking at this, and has come up
6
with this training program talking about how to
7
avoid the marginal mandibular nerve.
8
that the recommendations that the sponsor has are
9
quite effective.
10
DR. BEDDINGFIELD:
Thank you.
So I do think
And regarding
11
the question of triglycerides, we did do an
12
evaluation, a thorough evaluation of lipids.
13
of the important things to remember about this is
14
that the area of submental fat was chosen in part
15
because it is a small area.
16
of fat released as a result of this procedure
17
versus, say, a liposuction in which liters of fat
18
are taken out and sometimes a liter may be left in
19
to be absorbed -- so relative to something like
20
that, this is a small amount of fat.
21
obviously, it is a question that comes to mind, and
22
so we looked at carefully.
One
And the actual amount
A Matter of Record (301) 890-4188
But
72
If we look at the results of the AEs, we did
1 2
not see any patterns, any shifts, any changes in
3
mean values or changes in outliers in any of the
4
lipid parameters.
5
give you.
If you want those details, I can
We also did a study though where we looked
6 7
at the triglycerides before and after treatment
8
with DCA.
9
just like to show that one; if you'd give us just
And if I could pull that slide up, I'd
10
one second here.
I'm looking for the actual graph
11
of the triglycerides before and after treatment.
12
Here, we go. Now, what is graphed on this slide, this is
13 14
the triglyceride profile, and over time, if you
15
look at the off-yellow color, that's the baseline
16
value.
17
at the blue, which has been superimposed over the
18
same time period after treatment, you can see that
19
they basically overlie each other.
20
That's before treatment.
Now, if you look
The significant change in triglycerides that
21
you see is actually a result of a meal, and it
22
looks quite comparable in the ATX-101 and the
A Matter of Record (301) 890-4188
73
1
baseline.
2
the AE data and other investigations we've done,
3
just the fact that we're not releasing a lot of fat
4
because of the small area, that this is not a
5
significant issue.
6
DR. DRAKE:
7 8 9
And so, this would tell us, as well as
Dr. Gaspari.
Thank you.
Let's see.
You're on.
DR. GASPARI:
I had a question about the
quality of the outcome.
So you're injecting the
10
submental fat pad with a grid or a matrix.
11
curious whether you ever observed pebbling or
12
uneven resolution of the fat pad.
13
may have been reduced.
14
And I'm
So overall, it
Was there any banding or areas where there
15
was more fat pad resolution like directly over
16
where the injection was and the areas that weren't
17
injection; so like an uneven contour of the area
18
after the area had been treated?
19
Was that ever a complaint, and was that
20
reflected in the patient assessment scores?
21
wasn't addressed.
22
That
Also along the same lines, it appears that
A Matter of Record (301) 890-4188
74
1
you're replacing subcutaneous fat with fibrous
2
tissue, i.e. scar tissue.
3
that as well? DR. BEDDINGFIELD:
4
Can you also clarify
Absolutely.
So we did
5
not have reports in terms of adverse events of
6
unevenness.
7
Dr. Lizzul, please correct me.
8
that from the adverse event terms.
If there was a sporadic case, I do not recall
One of the benefits of the treatment
9 10
paradigm, and since it does typically occur over
11
multiple sessions, is if there was some unevenness,
12
you would have the opportunity to go back and touch
13
up.
14
no pebbling.
15
It just wasn't reported as an adverse event,
Dr. Jones, perhaps you could comment on your
16
experience in the trial.
17
standpoint, was that an issue?
18
you had to manage?
19
standpoint.
20
DR. JONES:
From a practical Was that something
It wasn't reported from an AE
At my side, I saw no cases,
21
especially in primary efficacy endpoint analysis,
22
of pebbling or unevenness.
There was an occasional
A Matter of Record (301) 890-4188
75
1
patient -- and I think we saw it in the
2
photograph -- who may have had a display of
3
platysmal banding, but that indeed was rare at my
4
site.
5
DR. BEDDINGFIELD:
I think your second
6
question had to do with the fibrous collagenous
7
being laid down afterwards.
8
of the -- probably the beneficial effect of the
9
product.
That is, in fact, part
If you notice from the photographs, that
10
there's more than just simply a removal of fat
11
because if one considered that you are taking fat
12
and removing it from the submental area and nothing
13
else was happening, you might expect a change in
14
skin laxity unless the skin just had a great skin
15
elasticity.
16
So we actually measured skin laxity, not so
17
much as an efficacy endpoint but as a safety
18
endpoint because in our discussions with the FDA,
19
we knew this was a parameter we wanted to monitor,
20
and we didn't see that.
21
hypothesize -- and this is a hypothesis -- that
22
part of that reason why we're not seeing that
But we can
A Matter of Record (301) 890-4188
76
1
laxity is due to some of the collagen that is being
2
laid down.
3
DR. DRAKE:
Dr. Bergfeld?
4
DR. BERFELD:
Yes.
I wanted clarification
5
of the mentioned briefly in the adverse events area
6
of hypersensitivity.
7
hypersensitivity to the injection material or
8
something else?
9 10 11
You rushed by that.
DR. BEDDINGFIELD:
Is this
I'm going to have
Dr. Lizzul give the details on those cases. DR. LIZZUL:
There were no cases of
12
hypersensitivity to ATX-101.
13
clinical trials, you collect all adverse events,
14
and the cases of drug hypersensitivity reported
15
were to other medications the subjects were taking.
16
DR. DRAKE:
17
DR. MALONEY:
As you know in
Dr. Maloney? Thank you.
Mary Maloney.
I
18
have three questions.
The first is, what do these
19
people look like at 24 hours and 1 week as far as
20
bruising and things go?
21
immediate post-op pictures.
22
huge dissuasion, it would be nice to know.
We didn't see any And while that isn't a
A Matter of Record (301) 890-4188
77
DR. BEDDINGFIELD:
1 2
Would you like me to
answer that now or wait for -- I can do that now.
3
DR. MALONEY:
Sure.
4
DR. BEDDINGFIELD:
So we did not routinely
5
collect photos of adverse events, so I can tell
6
you -- I think I would actually again call on
7
Dr. Jones who saw these patients after treating
8
them.
9
He might be able to describe that better. Because most of these adverse events, while
10
they're common, most of them were mild.
11
bruising was mild.
12
study protocol is that it did not significantly
13
impact their activities of daily living.
14
case of bruise, I would suggest that that probably
15
means that they could cover it with makeup.
16
weren't embarrassed to go outside in the mild case.
17
Moderate would suggest some impact on that,
18
so that would mean perhaps a more extensive bruise.
19
But the majority of them were mild, and severe ones
20
were rare.
21 22
The
And how that is defined in a
So in a
They
Dr. Jones, if you could add some more context to that as someone who saw and treated the
A Matter of Record (301) 890-4188
78
1
patients, I think that would be helpful. DR. JONES:
2
Great.
I think it is probably
3
helpful to put a photograph up as you asked, so I
4
will do that.
5
bruising.
6
after treatment and on day 1 some bruising there.
7
And on day 7, this is mostly resolved at this
8
point.
9
And we see a patient here with a
Pretreatment, you can see immediately
While bruising was common, it was not
10
anything that was any more than any other
11
injectable procedure that we see, and it occurred
12
both in the ATX and placebo groups.
13
events were mild and temporary, and resolved in all
14
cases without sequelae usually, in my experience,
15
by day 7.
16
DR. BEDDINGFIELD:
The majority
And I think the other
17
perhaps surrogate marker for how bad the AEs were
18
is that it was an uncommon reason for people to
19
discontinue from the study or to not get additional
20
treatments.
21
deciding not to get additional treatments, it was
22
typically in the first treatment or occasionally
And when it did result in them
A Matter of Record (301) 890-4188
79
1
the second treatment.
2
they made early on based on just not liking it.
3
DR. MALONEY:
So it was a decision that
Okay.
Thank you.
Then the
4
second question is that for the grade 1 responders,
5
you actually had a significant number of people who
6
saw a grade 1 in the placebo group, 20 percent,
7
which isn't so bad.
8
those people were responding?
9
across both their satisfaction and the
10 11
What is your thought about why Because it was
investigators'. DR. BEDDINGFIELD:
Yes.
One of the reasons
12
we included the 1- and the 2-grade was because we
13
knew the 2-grade would drive that placebo response
14
rate down.
15
20 percent -- and if I could find the core slide
16
that shows that.
17
can see it.
18
between the placebo and ATX-101.
19 20 21 22
But with respect to the 1-grade, the
Let's put those data up so people
We still do have a 50 percent delta
DR. MALONEY:
Oh, no question.
But
20 percent is great for saline. DR. BEDDINGFIELD:
It is great.
And we know
that in dermatology trials and aesthetic trials,
A Matter of Record (301) 890-4188
80
1
there is a placebo response.
2
trial; they do receive some tender loving care for
3
lack of a better term.
4
remember about this procedure is that the placebo
5
actually gets needling.
6
has some impact on the skin.
7
do a whole lot as seen by the MRI to submental fat,
8
but it might improve the quality of the skin.
9
perhaps that might impact their assessment in a
10
People get in a
Then the other thing to
And we know that needling It probably doesn't
And
positive fashion in some cases. But those would be the reasons I would
11 12
suggest.
13
if she has any additional thoughts on this related
14
to her experience as an investigator with the
15
product and relative to other trials you've been
16
in.
17
I would like to ask Dr. Dee Anna Glaser
DR. GLASER:
Hi.
I'm Dee Anna Glaser.
I'm
18
a professor of dermatology at St. Louis University.
19
I've been there for 20 years and run the aesthetic
20
division.
21
actually the placebo has a procedure being done,
22
and it is possible that, as Frederick mentioned,
I do think that this is a trial that
A Matter of Record (301) 890-4188
81
1
the needling component may have induced some skin
2
benefit over several treatments. But, Mary, you know that a placebo rate of
3 4
20 percent is pretty common with most of these
5
trials, so I think it's pretty consistent with
6
those that we see with Botox or other ones.
7
think the effect is real when you look at the MRI
8
data, the patient satisfaction, and the grade 1 and
9
grade 2 composites. DR. MALONEY:
10
Sure.
I
I just immediately
11
thought that it was a nice response rate.
For
12
people who can't afford drug, we can just stick
13
them with a needle.
14
(Laughter.)
15
DR. BEDDINGFIELD:
16
DR. MALONEY:
Very good point.
The last is something that I'm
17
sure that everyone in this room worries about, and
18
then that is going to be the training component.
19
You can lead a horse to water, but if they don't
20
choose to get the halter on, you may not get them
21
there.
22
training in their residency programs for anatomy
And we do know that people who do not have
A Matter of Record (301) 890-4188
82
1
and for worries might pick this up and really not
2
understand the danger areas and the difficulties. So this is sort of a theoretic question,
3 4
nothing that I think you are actually responsible
5
for.
6
training for the people who -- the dentists who are
7
going to pick this up?
8
have a good idea of the anatomy --
9 10 11
But how are you going to try and drive
DR. DRAKE:
Actually, the dentists may
I was just going to say.
That
might be -DR. MALONEY:
That might be okay, but how
12
about the OB, gynecologists, who are now working in
13
the cosmetics arena?
14
DR. DRAKE:
Actually, it's probably true not
15
just in any specific areas -- don't mind me, Mary.
16
I just say it's probably true across the board.
17
Your question is quite good about training.
18
DR. BEDDINGFIELD:
Well, I do appreciate the
19
question, and we are very committed to the
20
training.
21
who is going to use the product get trained, and
22
therefore, we do not intend to make the product
We do think it's important that everyone
A Matter of Record (301) 890-4188
83
1
available to people who have not gone through the
2
training.
3
can help.
So that's one way in which I think we
We've done an extensive outline of our
4 5
training, and we have several modules related to
6
the condition, the anatomy, the way the drug works,
7
the data, the injection technique, and the patient
8
experience.
And certainly, we think this can help.
9
It may not completely alleviate the issue
10
that you're referring to, but I think it's a good
11
start, and it's what we can do as a sponsor and
12
have control over.
13
that.
So we're certainly committed to
I do think in general, based on experience
14 15
that I and others from our company have had with
16
other products in the space of fillers and
17
botulinum toxins, that one nice thing is that, in
18
general, most people that will do this are very
19
interested in training, and they do sign readily
20
for it.
21
everybody might fall into that camp.
22
But I appreciate your point that not
DR. DRAKE:
I want to remind the panel
A Matter of Record (301) 890-4188
84
1
members that please -- even though I may call on
2
you by name, it would be very helpful if you would
3
identify yourself before you speak for the record.
4
And we have quite a few people who have questions
5
and stuff, so let's keep the questions focused and
6
on point if you can.
7
but I want everybody to have a chance to ask their
8
questions.
9 10
I want to answer all of it,
Dr. Bilker, you're next please, sir. DR. BILKER:
I have a question about some of
11
the groups who didn't complete the studies, for
12
instance the administrative decisions, the loss to
13
follow-up, and withdraw of consent due to patient
14
convenience.
15
treatments did they have on average at the time
16
they terminated, and how effective was the
17
treatment up until that point in time?
18 19 20
For those patients, how many
DR. BEDDINGFIELD:
Yes.
Dr. Gross, could I
get you to respond to that question, please? DR. GROSS:
For subjects that discontinued
21
during the adverse event, that was most often after
22
the first treatment and occasionally after the
A Matter of Record (301) 890-4188
85
1
second.
In terms of the other categories, we've
2
not done an analysis specifically of the
3
treatments, the number of treatments received.
4
can try and look at that and have it for you after
5
the break.
6
DR. DRAKE:
Dr. Chauhan?
7
DR. GROSS:
Actually, if I can revise my
We
8
answer.
9
something here.
Let's walk you through this this
10
slide actually.
So this is actually a breakdown of
11
the number of treatments received and the reason
12
for receiving fewer than 6 treatments.
13
My crack slide team actually has provided
We've broken these into three categories.
14
So the blue sections describe patients that had
15
therapeutic success that is insufficient SMF for
16
patient satisfaction, and you see that coming on
17
more and more as you go through the visits.
18
The red category is adverse events, and
19
there's an additional category of discomfort that
20
did not rise to the level of an adverse event, and
21
you see that quite clearly after the first
22
treatment session.
A Matter of Record (301) 890-4188
86
So the yellow bar is everyone else, loss to
1 2
follow-up, withdraw of consent, and you see that
3
fairly evenly with some decrease in the percentage
4
of subjects stopping treatment for that reason as
5
you go across treatment sessions.
6
DR. BEDDINGFIELD:
Dr. Jones, would this be
7
consistent with your experience as an investigator,
8
that those patients who withdrew from treatment due
9
to AEs or administrative reasons did so more
10
earlier?
11
treatments later, it was more often due to the fact
12
that they were satisfied or there was insufficient
13
SMF?
14 15
And when they decided not to get further
DR. JONES:
Indeed, that was exactly my
experience at my site.
16
DR. BEDDINGFIELD:
17
DR. DRAKE:
18
MS. CHAUHAN:
Thank you.
Ms. Chauhan. Cynthia Chauhan.
I want to
19
support Dr. Maloney on the training issue.
20
it's huge.
21
you in passing mentioning a or several
22
non-responders.
I think
Also, my question is I thought I heard
And if I did hear that, I'd like
A Matter of Record (301) 890-4188
87
1
to know more about the non-responder and whether
2
you're aware of any predictive factors that might
3
help people deal with that.
4
DR. BEDDINGFIELD:
Thank you for the
5
question.
6
you could walk us through the analyses you did of
7
the predictive factors for response and
8
non-response?
9
We have looked at that.
DR. GROSS:
Dr. Gross, if
So we looked at the demographic
10
and baseline characteristics and their potential to
11
predict response.
12
analysis.
13
impact on response rate.
14
severity.
15
tended to respond slightly higher than those who
16
are at moderate severity.
17
This was done in a multivariate
We found two predictors that had a small One was baseline
So subjects of severity at baseline
The second was BMI.
Patients that were in
18
the lower BMI categories had a slight benefit
19
compared to patients that were in higher BMI
20
categories.
21
baseline characteristics, did not have a
22
significant predictive ability for response rate.
The other demographic factors,
A Matter of Record (301) 890-4188
88
1
DR. BEDDINGFIELD:
The other factor I think
2
is important to mention is that these composite
3
endpoints do require that both the physician or the
4
clinician and the patient have assessed that
5
there's a change.
6
So someone who is categorized as a non-
7
responder may not be a complete non-responder.
And
8
actually, I've noticed in the FDA's analysis, they
9
had looked at that and actually showed the cases
10
where sometimes the clinicians said they were a
11
1-grade response, and the patient said they weren't
12
and vice versa.
13
So that is one other case.
That doesn't
14
mean they've completely been a non-responder, but
15
they didn't meet the threshold for a composite
16
1-grade response.
17
DR. DRAKE:
Thank you.
18
DR. ORLOFF:
Dr. Orloff?
Lisa Orloff.
One of the
19
adverse events that was described was dysphagia,
20
and I think there were 11 subjects, 10 of whom
21
were the study drug subjects who experienced
22
dysphagia, and a couple of them discontinued
A Matter of Record (301) 890-4188
89
1
therapy.
2
One was mentioned as not having had resolution of
3
dysphagia at the time of conclusion of the study.
4
I wondered if you could comment on that.
A second question is simply the
5
determination of 6 total treatments as the maximum
6
number of treatments, if you could address that.
7 8 9
DR. BEDDINGFIELD:
Yes.
I'd like to ask
Dr. Lizzul to go over the cases of dysphagia. DR. LIZZUL:
So dysphagia was a consequence
10
of injection volume as well as some associated
11
swelling or local inflammation.
12
reporting discomfort with swallowing.
13
you mentioned that was unresolved was actually a
14
subject who received ATX-101, and then
15
discontinued, withdrew consent, so there was no
16
ability to get resolution reporting because they
17
left the study.
So it was subjects The one case
18
The other event, which was stopping
19
treatment -- just give me a moment to pull up that.
20
Can I have the stopping treatment?
I'm
21
trying to remember the details of this one.
22
a mild case that resolved after several weeks, and
A Matter of Record (301) 890-4188
It was
90
1
the subject did not receive additional treatments. DR. DRAKE:
2
I'd like to take moment to
3
introduce -- Dr. Matarasso, would you introduce
4
yourself?
5
You were a little bit late as we went through the
6
introduction, so please introduce yourself and then
7
ask your question. DR. MATARASSO:
8 9 10 11
You got stuck in traffic this morning.
I'm Dr.
Thank you, and I apologize.
Alan Matarasso.
I'm from New York City.
I'm a plastic surgeon. Thank you for the presentation.
The results
12
that are shown were shown typically at 12 weeks.
13
have a number of questions related to the use and
14
the longevity.
15
beyond 12 or 24 weeks, any studies, or I wonder if
16
you can comment about the impact of prior surgery
17
or future surgery in a patient that's treated, and
18
if these have been biopsied.
19
Are there any studies showing
Finally, I wonder if you could comment on
20
the impact of concurrent treatment.
21
that if this were approved, we would see patients
22
that came in for neurotoxins and fillers,
A Matter of Record (301) 890-4188
I anticipate
I
91
1 2
simultaneously. DR. BEDDINGFIELD:
Yes, sir.
With respect
3
to your first question -- and then I will come back
4
to you, Dr. Orloff; I know you had a second
5
question -- the long-term follow-up studies, we
6
have four long-term follow-up studies.
7
respect to the design of the clinical trials, the
8
patients were treated up to their maximum number of
9
6 treatment sessions.
With
Then the primary endpoint
10
was at 12 weeks, and then they were followed for
11
any additional 12 weeks, so 24 weeks after their
12
last treatment; so 6 months.
13
Then we have had four long-term follow-up
14
studies where those people were not treated further
15
but they were simply followed for their effects and
16
for safety and other purposes.
17
have shown is that the longest day that we have
18
currently -- and some of those studies are ongoing.
19
But four years out, 88 percent of subjects who were
20
responding at the end of that 24 weeks after the
21
last treatment are still responding.
22
What those studies
We've seen no safety signals to suggest any
A Matter of Record (301) 890-4188
92
1
long-term untoward effects in the follow-up
2
studies.
3
long-term follow-up studies, is that obviously,
4
it's hard to keep people in studies for a long
5
time, so there's certainly a sample of patients who
6
would come back to you in such a study.
Our only caveat, the results of these
Your second question was regarding surgery
7 8
and concurrent treatments, and I believe I would
9
like to ask Dr. Steve Fagien to speak on this and
10
whether he has concerns about patients who might
11
come in for a treatment who have had prior
12
treatments or surgeries of other kind or are
13
requesting concurrent treatment with botulinum
14
toxins and fillers.
15
DR. FAGIEN:
16
Thank you, Frederick, and thank
you Dr. Matarasso. My name is Steve Fagien.
17
I'm an
18
oculoplastic surgeon in private practice in Boca
19
Raton, Florida.
20
ATX-101 has a purpose, and it reduces submental
21
fat.
22
indications, and they're usually aesthetically
As you have suggested, I agree.
But these patients will have other cosmetic
A Matter of Record (301) 890-4188
93
1
oriented, so they'll probably seek their aesthetic
2
physician for some sort of treatment. As was even suggested in the presentation
3 4
earlier, the drug does not treat platysmal band, so
5
other modalities to treat platysma bands, even
6
using some off-label usage, which we won't talk
7
about.
8
patients will probably be interested in other
9
procedures, other facial injectable agents.
10
But the fact is, as surgery included,
I don't think, again, that it treats
11
everything, obviously.
12
they're, again, usually aesthetically oriented and
13
interested in other treatments.
14
So they will have -- and
How it may impact future surgery, these
15
patients are all precluded from having any other
16
treatments during the study and shortly afterwards.
17
So we'll see how that matters in the future, but I
18
have no reason to believe in these patients who
19
have had other modalities, including liposuction or
20
other treatments of submental fat, that it
21
certainly has not precluded them from other
22
treatments in the future.
So I don't envision that
A Matter of Record (301) 890-4188
94
1
being a problem.
2
DR. BEDDINGFIELD:
Thank you, Dr. Fagien.
3
Dr. Orloff, your question was relating I
4
think to why 6 was the maximum number of
5
treatments.
6
looked at a variety of treatments.
7
no reason to believe that patients getting more
8
than 6 treatments will be put in harm's way, our
9
goal was to optimize the treatment.
10
We did do dose ranging studies and While we have
What one sees, if one looks at this data
11
that was shown, is while -- there is still an
12
increase in the responder rate.
13
to the fifth or sixth treatment, you're getting up
14
to that 70, 80 percent response rate.
15
slope is starting to change, which suggests we're
16
starting to plateau on the dose response.
17
When you get out
And the
So we think that this is the right paradigm,
18
but again, just to be clear, we don't have any
19
reason to believe those people would be put in
20
harm's way if they chose to get more treatments.
21
That would not be part of our intention, and in our
22
discussions with the FDA, we would be limiting it
A Matter of Record (301) 890-4188
95
1
to 6 treatments.
Thank you.
DR. DRAKE:
2
Dr. Orloff, I apologize.
I
3
forgot you had a second question before I called on
4
the next person.
5
being tuned into that.
Thank you, Dr. Beddingfield, for
6
Dr. Skelsey?
7
DR. SKELSEY:
Thank you.
Maral Skelsey.
My
8
question relates to, again, patient selection.
And
9
the caution advised by the sponsor states that they
10
recommend caution with prior surgical or aesthetic
11
procedures in the treatment area.
12
Dr. Matarasso alluded to, these patients are
13
generally people who like multiple procedures and
14
have undergone multiple aesthetic procedures.
And as
Has the sponsor done any work on clarifying
15 16
the quality and the timing of prior surgical
17
procedures and associated adverse events?
18
it's not particularly specific in terms of when
19
these prior procedures were and what kind they
20
were.
21 22
DR. BEDDINGFIELD:
Because
These were part of the
protocol-derived inclusion criteria.
A Matter of Record (301) 890-4188
They were, to
96
1
some degree, left to the investigator's discretion.
2
And I would ask Dr. Jones if you could perhaps
3
describe how you implemented that in the trials
4
with respect to the prior procedures and whether
5
that precluded you from enrolling certain patients
6
in the trial.
7
DR. JONES:
Derek Jones.
Inclusion criteria
8
was very well-specified in this trial, and included
9
everything that we had talked about.
It also
10
included prior types of surgical procedures such as
11
facelifts.
12
were no concomitant therapies allowed in the area
13
during the time of the trial.
14 15 16
Those patients were excluded, and there
DR. DRAKE:
Thank you.
Dr. DiGiovanna,
you're next. DR. DiGIOVANNA:
John DiGiovanna.
This is
17
an interesting new indication, and with new
18
indications measurement tools have to be developed.
19
So they don't have a history of a long experience
20
with time.
21 22
So actually I have two questions.
The first is that you have two co-endpoints: One is a patient-reported and one is a physician
A Matter of Record (301) 890-4188
97
1
assessment.
2
that these actually occur because the slide you
3
just showed, that's slide 40, shows the results of
4
the physician and the patient reports pretty
5
parallel.
6
they don't influence each other.
7 8 9
And I wonder how the protocols specify
So it would be really important that
So exactly what did the protocols specify with how this was to be done? DR. BEDDINGFIELD:
I'm going to ask
10
Dr. Gross to respond to exactly how it was
11
specified, and it was very specifically specified
12
in the protocol.
13
DR. GROSS:
Yes, the protocol specified that
14
the ratings must be done independently.
15
the patient would present for the office visit.
16
They would have the patient ratings collected, and
17
then the clinician assessment would be done
18
separate from that.
19
Typically,
So the clinician did not collect the patient
20
response because that was done by clinical staff
21
separately.
22
investigator training that this be done strictly
And there was emphasis at the
A Matter of Record (301) 890-4188
98
1
independently without knowledge of each other's
2
ratings. DR. DiGIOVANNA:
3
I had a second question,
4
and that is your grading scale showed pictures
5
going to the most extreme.
6
most extreme that I've ever seen, and I think there
7
are many people who have far more advanced
8
involvement. Are those individuals to not be treated or
9 10
However, that's not the
can they be treated, and how will you address that? DR. BEDDINGFIELD:
11
Well, our
12
indication -- sorry if we could go back to the
13
photo guide slide.
14
This was what you were referring to.
15
indication will be specifically for moderate to
16
severe.
17
I'd just like to put that up. Our
Now, the rating scale did include absent to
18
mild because patients would move in that direction
19
presumably with a positive treatment.
20
did not include the 4's, and we are seeking
21
indication for the extreme cases.
22
ongoing study.
Our studies
We do have an
It's a safety setting, where again,
A Matter of Record (301) 890-4188
99
1
we're not seeking that indication.
2
discussed with the FDA that patients like that
3
might come in to get treated.
4
But that was
While we have no reason to believe that it
5
would be harmful to them, we don't believe they are
6
the ideal candidates because, frankly, many of
7
those people might be better off with treatments of
8
obesity, treatments with liposuction or a neck lift
9
even perhaps.
10
Dr. Glaser, I know you do liposuction in
11
your practice.
12
if I'm off base or on target there with that
13
comment.
14
Perhaps you could comment on that
DR. GLASER:
Dee Anna Glaser.
I actually
15
also am an investigator in the ongoing trial with
16
the two extreme groups of the 1's and the 4's.
17
being in St. Louis, we have a lot of very large
18
necks, so I can say that it was not difficult to
19
recruit for that study at all.
20
And
Certainly, they had no problems undergoing
21
the treatments with those much larger necks.
22
was a little more challenging to see the degrees of
A Matter of Record (301) 890-4188
It
100
1
improvements that you could see with the more
2
moderate ones, but mechanistically, there shouldn't
3
be any problem. But I think to your point, it's important
4 5
for a physician to properly evaluate the patient
6
and to guide the patient as to what procedure would
7
be the best for them, and as you mentioned, whether
8
it's a facelift, neck lift, liposuction, or
9
something a little more extensive in those
10
individuals.
11
in the study.
But certainly, we didn't see problems
DR. BEDDINGFIELD:
12
I should mention also
13
from the standpoint of the study conduct, while it
14
is a blinded and placebo-controlled trial, safety
15
data comes in on all comers.
16
any new signals that have come in any treated
17
patient, so nothing that we haven't seen or
18
wouldn't have expected already from our data. DR. DRAKE:
19 20
There have not been
I'm going to call on Dr. Murphy
next.
21
DR. MURPHY:
Thank you, Dr. Drake.
22
Bob Murphy.
My question falls on
A Matter of Record (301) 890-4188
101
1
Dr. Orloff's earlier question and
2
Dr. Beddingfield's response about the current
3
recommendation for 6 maximum treatments.
4
about a patient who is a scale 3 who withdraws
5
early because they've gotten a 1-grade response but
6
comes back 6 months later and wants additional
7
enhancement or somebody who puts on 10 pounds, and
8
6 months to 12 months later comes back and wants to
9
be treated again?
What
10
What is the group thinking as far as this
11
modality being applicable under those conditions?
12
Are there any studies going on or are there any
13
guidelines going to be published?
14
DR. BEDDINGFIELD:
We have not evaluated
15
patients who might get a response perhaps and then
16
choose to come back at a later time.
17
our long-term follow-up study does suggest that
18
people who achieve are the responder status in a
19
select group of patients in those follow-up
20
studies, 88 percent of those are still responding
21
out to four years.
22
In general,
On the other hand, given the relatively
A Matter of Record (301) 890-4188
102
1
benign profile of the product, the relatively low
2
dose of DCA relative to endogenous levels, we have
3
no reason to believe that if somebody did come back
4
at a later time for treatment, that they would be
5
put in any harm's way based on a mechanistic or
6
biological rationale.
7
that, and we're not seeking a label for that type
8
of treatment. DR. DRAKE:
9 10
But we have not studied
Dr. Brittain, I think you're
next. DR. BRITTAIN:
11
Yes.
My question relates to
12
slide CO-34.
I just wanted to get some
13
clarification -- and maybe you mentioned this
14
earlier and I missed it -- in terms of how you're
15
handling the patients who did not complete the
16
primary endpoint visit.
17
about Cochran-Mantel-Haenszel method of imputation.
There's a little footnote
18
I certainly know about the Cochran-Mantel-
19
Haenszel, but I don't know it in terms of a method
20
of imputation, so I don't really know what that
21
means.
22
DR. BEDDINGFIELD:
I'm going to ask
A Matter of Record (301) 890-4188
103
1
Dr. Gross, our statistician, to answer that
2
question.
3
DR. GROSS:
Patients that did not attend the
4
primary time point visit or did not provide values
5
were imputed prior to analysis.
6
analysis used multiple imputation.
7
performed a sensitivity analysis of five additional
8
imputations -- or actually four additional
9
imputations and no imputation on observed case.
10
The primary We also
The most stringent of these would be a
11
post hoc analysis that we did, which was a tipping
12
point analysis, which starts with the worst case
13
assumption, which is that all missing placebo
14
patients are imputed as success, all missing
15
treatment subjects are imputed as failures.
16
Regardless of the method of imputation, the
17
results were the same.
18
significant difference between treatment and
19
placebo.
20
DR. BRITTAIN:
There was a statistically
Did you just say the worst
21
case scenario, the results remains significant?
22
that right?
A Matter of Record (301) 890-4188
Is
104
DR. GROSS:
1
We did, and I was about to add a
2
single exception.
3
endpoints to this:
4
were significant in both studies under the worst
5
case scenario; the 2-grade composite was
6
significant for the worst case scenario in study
7
22.
8
placebo subjects had to be imputed as success in
9
order to tip to non-significance.
10
There are three dichotomous 1-grade composite and the MRI
And in study 23, 82 percent of the missing
To remind the panel, the responder rate
11
among patients who did provide information was
12
roughly 16 percent.
13
in the placebo group would be somewhat unlikely.
14
So these results, we think, show that the method of
15
imputation is not a sensitive issue.
16
DR. DRAKE:
17
DR. GASPARI:
So an 82-percent response rate
Okay.
Dr. Gaspari?
Tony Gaspari.
In terms of the
18
demographics, mostly women, high BMIs, curious
19
about the range of the BMIs.
20
of increased BMIs, there's no mention of any
21
existing comorbidities:
22
hypertension, osteoarthritis, other kinds of health
And along those lines
type 2 diabetes,
A Matter of Record (301) 890-4188
105
1
problems of people that were enrolled in the trial.
2
So that's one question.
3
The second question related to demographics
4
also, is that about a quarter to a third of the
5
patients were dark-skinned individuals,
6
Fitzpatrick 4 through 6.
7
swollen, painful neck, any problems with
8
dyspigmentation after undergoing a round of
9
injections?
10
DR. BEDDINGFIELD:
And so if they have a
Okay.
I appreciate your
11
questions.
12
first was with respect to females, and we did
13
enroll roughly 85 percent females.
14
consistent with the population seeking aesthetic
15
treatments according to the ASAPS, which is the
16
American Society for Aesthetic Plastic Surgery,
17
survey in 2013.
18
patients seeking aesthetic treatments are women.
19
I'll try to answer these in order.
The
This is
And it's roughly 90 percent
So our demographics, while certainly skewed
20
towards women, is consistent with the population.
21
Having said that, when we look at the data by
22
gender, we saw efficacy in the male and female
A Matter of Record (301) 890-4188
106
1
subgroups.
2
Your second question was regarding BMI, and
3
I think you had specifically asked for the range of
4
BMI.
5
Dr. Gross, perhaps you can pull up that
6
information for us.
The average BMI was 29 in both
7
studies, in both groups in both studies.
8
amongst ATX-101 and placebo is 29, which is
9
overweight but not obese.
So
But there was a range,
10
and we did do some analyses along that line.
11
come back to your other questions.
12
DR. GROSS:
I'll
The inclusion criteria capped a
13
permissible BMI at 40.
We did have individuals
14
across a range of BMI that was a minimum of 20.
15
And maximum, we had maximums, 39.9 was the highest
16
that we saw.
17
Does that provide sufficient information?
18
DR. DRAKE:
19
DR. GASPARI:
Tony, is that okay? So the patients related to the
20
increased BMI and then associated comorbidities, so
21
I didn't hear a response to that.
22
DR. BEDDINGFIELD:
Yes.
A Matter of Record (301) 890-4188
I just asked
107
1
Dr. Gross about the BMI range, which I thought you
2
had asked about.
3
population that had what one would typically expect
4
in terms of comorbidities.
5
a listing of some of those.
But the comorbidities, we had a
Let's see if I can find
Here is an example of comorbidities from the
6 7
trial.
8
ATX-101 and placebo.
9
because there are three slides here.
10
You can see those are broken down by I'll keep going down the list
These would suggest that we enrolled a
11
population, that while they could participate in a
12
study, they did have the normal types of
13
comorbidities that people have walking around and
14
would be expected in a population of people who
15
would likely show up for treatment.
16
Then your final question was with respect to
17
darker skin types.
18
30 percent Fitzpatrick types 4, 5 and 6, and we do
19
know that in patients of skin color, two AEs are
20
important.
21 22
And we did enroll roughly
I will say overall, the adverse event profile in the darker skin types were actually
A Matter of Record (301) 890-4188
108
1
slightly lower than in the lighter skin types
2
across all the common AEs.
3
we know that of specific interest are keloids,
4
hypertrophic scarring and hyperpigmentation.
5
did not have any keloid or hypertrophic scarring in
6
the study.
7
as discoloration.
8
hypopigmentation and four of those were
9
hyperpigmentation.
10
But having said that,
We
We did have 8 cases of what we're coded Four of those were
We have Dr. Valerie Callender, who was one
11
of our investigators.
She had one case of
12
hyperpigmentation.
13
that case.
14
topical hydroquinone.
15
these cases did resolve, and hers was the only case
16
that actually required treatment.
I'd like to ask her to describe
That case she actually treated with a
17
Dr. Callender?
18
DR. CALLENDER:
Importantly though, all
My name is Valerie
19
Callender.
I am a practicing dermatologist in the
20
Maryland area, and I was one of the clinical
21
investigators for this trial.
22
very important question as far as pigmentary
A Matter of Record (301) 890-4188
And I think that's a
109
1
changes.
Any time we're injecting into the skin,
2
we are producing inflammation that is a concern for
3
patients with darker skin type. I thought it was very important to realize
4 5
that hyperpigmentation and hypopigmentation did
6
occur in 8 subjects.
7
1.6 percent, so that's pretty low as far as numbers
8
of dyspigmentation in a clinical trial, especially
9
one that involves injecting.
The relative risk was
So I will say that in my patient, I had one
10 11
who actually was a skin type 5 who developed
12
hyperpigmentation post the first treatment.
13
just watched her for about 6 weeks, did no
14
treatment.
15
own.
16
hydroquinone cream, which is a topical preparation,
17
4 percent, twice a day, for about another 6 weeks.
18
And it actually just totally resolved.
19
We
It started to fade and resolve on its
And then, we ended up actually giving her
So most of the patients in this study did
20
not require any treatment, and the
21
hyperpigmentation and hypo was mild and transient.
22
DR. BEDDINGFIELD:
Thank you, Dr. Callender.
A Matter of Record (301) 890-4188
110
1
DR. DRAKE:
I'm going to take the
2
prerogative of the chair to just have one last
3
question before we go to break because right now,
4
I'm in between you and your coffee and restrooms.
5
And so what we'll do is we'll have one more
6
question.
7
Remember during the -- then when we return,
8
I'm going to ask everybody to return promptly.
9
We'll return promptly for the FDA presentation, and
10
then we'll have the open public hearing
11
presentation.
12
for clarification and questions and discussion.
13 14 15
And then there'll still be more time
So with that, Dr. Orloff, I think you had the last question please. DR. ORLOFF:
Thank you.
Among the adverse
16
events, I did not see any mention of salivary gland
17
effects.
18
the proximity of the submandibular glands and the
19
sublingual glands to the region of injection,
20
whether these just didn't occur or whether they
21
were evaluated, and if you could comment on how you
22
would assess for a possible salivary gland side
And I just wanted to inquire because of
A Matter of Record (301) 890-4188
111
1
effects. I'll save my other comments for the next
2 3
session so thanks. DR. BEDDINGFIELD:
4
We did not have any cases
5
of glandular injury of any kind, salivary gland,
6
other submandibular glands or thyroid glands.
7
these were assessed in a normal fashion. Dr. Lizzul, do we have any cases of
8 9
And
salivation being adversely affected in the trial?
10
DR. LIZZUL:
No, there were no cases.
11
DR. BEDDINGFIELD:
12
DR. DRAKE:
Thank you.
Well, thank you very much,
13
committee, and the sponsor for a very good question
14
period.
15
take a break, a 10-minute break, please.
16
please reconvene promptly at 10:00 so that we may
17
continue with the FDA's presentation.
18
very much.
We will adjourn -- or not adjourn.
We'll
And
Thank you
19
(Whereupon, a recess was taken.)
20
DR. DRAKE:
May I have your attention,
21
please?
Just so that we may stay on time and have
22
plenty of opportunity for what is probably going to
A Matter of Record (301) 890-4188
112
1
be a nice, vigorous discussion, and we have lots of
2
people at the open session today, I'd like to
3
proceed.
4
presentation.
5
starting?
6 7
Coming up now is we have the FDA's Who is starting?
Dr. Lolic, welcome.
Dr. Lolic is Thank you.
FDA Presentation – Milena Lolic DR. LOLIC:
Good morning.
We will start the
8
FDA presentation with the background information on
9
endpoints development, followed by closer look on
10
efficacy endpoints used in pivotal trials; efficacy
11
and safety summaries; and we will have some time in
12
the end for the questions.
13
My name is Milena Lolic.
I'm medical
14
officer in the dermatology division, and we'll
15
start with an overview of endpoints development.
16
The challenge was to develop a reproducible and
17
clinically meaningful endpoints for aesthetic
18
indication.
19
As you have already heard, the proposed
20
indication is improvement in the appearance of
21
moderate-to-severe convexity or fullness associated
22
with submental fat in adults as it relates to
A Matter of Record (301) 890-4188
113
1
submental convexity contouring.
2
indication, it poses a minimal physical morbidity
3
with variable individual values.
4
currently no approved drug treatment for this
5
indication, and therefore, there are no established
6
endpoints to evaluate the efficacy of the drug.
7
As an aesthetic
There is
The diagram on the screen outlines a general
8
approach for new endpoints development, which was
9
applied for this aesthetic indication.
The agency
10
typically recommends that assessment of the concept
11
of interest for which the aesthetic treatment is
12
administered be conducted from the perspective of
13
both the investigator and the patient.
14
The concept of interest that will define the
15
treatment benefit in this case is submental
16
convexity contouring.
17
outcome is observable so both patient-reported
18
outcome and clinician-reported outcome can be used.
Obviously, the measurement
19
As for biomarker, in this case, we
20
considered that some type of objective measurement
21
with minimal human influence could be utilized
22
after taking into consideration that submental fat
A Matter of Record (301) 890-4188
114
1
represents a part of the continuous band of
2
subcutaneous fat and is deformable soft tissue.
3
In addition, to increase objectivity,
4
biomarkers should connect concept of measurement
5
with proposed adipocytolytic mechanism of action,
6
as the submental area besides fat contains other
7
types of tissues:
8
just a few.
lymphatic, vasculature, to name
9
As you will see, through multiple
10
collaborative exchanges between the applicant and
11
the FDA, we tried to refine each of the potential
12
endpoints.
13
primarily evaluated via clinician-reported outcome
14
using a 5-point Clinician-Reported Submental Fat
15
Rating Scale.
16
In early phase 2, efficacy was
For patient-reported outcome, two scales
17
were used, Subject Self-Rating Scale and the
18
Patients Global Impression of Change.
19
patient-reported outcome was not recorded
20
consistently throughout the studies and was focused
21
on satisfaction with the treatment and not directly
22
to the concept of interest.
A Matter of Record (301) 890-4188
However,
115
After discussing the reports of these two
1 2
studies, FDA advised the applicant to continue
3
developing clinician assessment using the same
4
tool.
5
should be done consistently throughout the study,
6
focused on the area of treatment and be comparable
7
to clinician's assessment.
8
suggested looking for a way to objectively quantify
9
the improvement by using a biomarker.
10
We also recommended that patient assessment
In addition, we
The applicant proposed endpoint model
11
consisted of primary endpoint assessing amount of
12
submental fullness using patient- and
13
clinician-reported instruments and submental fat
14
volume change as a secondary endpoint using MRI
15
measurement as a biomarker.
16
would be a different patient-reported outcome
17
focusing on impact of submental fullness.
Exploratory endpoint
18
The endpoint model was explored in
19
multicenter randomized controlled trial using the
20
battery of clinician and subject-reported
21
measurements and MRI as a biomarker.
22
Further discussion led to agreement that
A Matter of Record (301) 890-4188
116
1
clinician and one of the patient scales are
2
comparable and measured the same concept.
3
assessment of patient satisfaction with the
4
treatment had the potential to become supportive
5
endpoint.
6
Separate
As for fat volume reduction, assessed by
7
MRI, it was found that the technical aspect of
8
volume reduction in submental area was conceptually
9
acceptable and trending the right direction.
But
10
some limitations of the measurements were noticed.
11
For example, there was frequently discordance
12
between clinician and patients on perceived success
13
in a single patient, which could not be explained
14
only by subjective nature of the measurement.
15
To enhance the accuracy of the assessment,
16
improved standardized subject positioning and
17
assistance with patient assessment was recommended
18
as the path forward towards the composite endpoint
19
as the measure of success for a single patient,
20
based on the agreement of both patient and
21
clinician's assessment.
22
We concluded and agreed that the primary
A Matter of Record (301) 890-4188
117
1
endpoint would be based on responder definition,
2
which required same-grade improvement on both the
3
Clinician-Reported and the Patient-Reported
4
Submental Fat Rating Scales.
5
Assessment using Submental Fat Impact Scale could
6
be considered as one of the secondary efficacy
7
endpoints along with the fat volume reduction
8
assessed by MRI.
The Patient Impact
Dr. Elektra Papadopoulos will now present
9 10
the endpoints from phase 3 trials focusing
11
primarily on those that employed scales as tools
12
for the efficacy assessment. FDA Presentation – Elektra Papadopoulos
13
DR. PAPADOPOULOUS:
14
Good morning.
I'm
15
Elektra Papadopoulos, and I will present the FDA's
16
perspective on the key clinician-reported and
17
patient-reported efficacy outcome measures that
18
were used in the phase 3 studies. The clinician-reported outcome assessment
19 20
that was used as the primary efficacy outcome
21
provides a single rating score of the submental fat
22
size.
Using this scale, clinicians evaluate the
A Matter of Record (301) 890-4188
118
1
submental convexity or the extent to which the
2
submental chin is bulged or rounded outward.
3
Ratings are assigned using a 5-point scale
4
ranging from zero, or absent submental convexity,
5
to 4, or extreme submental convexity, each with
6
related verbal descriptors.
7
by a trained clinician following a clinical
8
evaluation of the patient, including palpation of
9
the chin and neck, anterior oblique and profile
Scores were assigned
10
views of the chin, and observation of pronation,
11
supination, and lateral movement of the head.
12
score is determined using the definitions in the
13
rating scale with representative photographs
14
associated with each score serving as a guide.
15
The
To reduce the potential impact of
16
variability and head and neck positioning on
17
scoring and to increase consistency across
18
clinician ratings, the applicant included a
19
positioning grid to help in determining head and
20
neck positioning vertically, as well as
21
horizontally, as shown in this slide.
22
The patients were horizontally positioned to
A Matter of Record (301) 890-4188
119
1
have the lower orbital arch of their eye in
2
parallel line with the cephalic margin of the
3
tragus of the ear.
4
positioned lining up the tragus of the patient's
5
ear with the front of the patient's shoulder and
6
aligning the back of the patient's head on a plane
7
slightly posterior to the back of the patient's
8
shoulder.
They were also vertically
The photo guide for use with the clinician
9 10
assessment displays differences in the appearance
11
of submental bulge among the grades, and included
12
two sets of three exemplar photos for each of the
13
five grades.
14
photos for grade zero, or absent submental
15
convexity, shown to the left, and grade 1, or mild
16
submental convexity, shown to the right.
This slide shows the representative
Here are the sets of photos for grades 2,
17 18
moderate submental convexity, to the left, and
19
grade 3 or severe submental convexity, to the
20
right.
21
the scale were eligible for inclusion in the
22
phase 3 studies.
Of note, only patients with grade 2 or 3 on
And finally, this slide shows
A Matter of Record (301) 890-4188
120
1
representative photos for grade 4 or extreme
2
submental convexity. Included as a primary outcome measure with
3 4
the clinician assessment was the Patient-Reported
5
Submental Fat Rating Scale or the patient-rating
6
scale.
7
of the amount or size of submental fat.
8
select one of the five descriptors to classify the
9
size of their chin fat.
10
This scale provides a single-score rating Patients
During the administration of the rating
11
scale, patients are given a copy of the instrument
12
and a standard non-magnifying mirror to assist in
13
the rating.
14
the submental chin area and to look in the mirror
15
to evaluate that area, positioning their heads in a
16
manner similar to that described for the
17
clinician-rating scale.
18
match to the corresponding 5-point scale, where
19
zero is no chin fat at all and a very large amount
20
of chin fat corresponds to a score of 4.
21 22
Patients are instructed to think about
The patients' responses
To evaluate the relationship between the clinician- and the patient-rating scales as a
A Matter of Record (301) 890-4188
121
1
separate assessment, not part of the
2
Patient-Reported Submental Fat Rating Scale,
3
patients were asked to look at 10 shuffled line
4
drawings shown in this slide, which included
5
profiles of faces with varying grades of submental
6
fat.
7
From these line drawings, patients were
8
asked to select the line drawing card that best
9
represented how they believed their profile to look
10
with respect to submental fullness at the time of
11
the assessment.
12
The Patient-Reported Submental Fat Impact
13
Scale was a questionnaire designed to evaluate the
14
degree of bothersomeness of the patient's perceived
15
submental fullness.
16
questionnaire based on qualitative research with
17
patients, and it includes six impacts resulting
18
from patients' perception of their submental
19
fullness.
20
The applicant developed the
Patients are asked to rate their happiness,
21
bother, embarrassment, and self-consciousness due
22
to their chin fat, as well as how much they
A Matter of Record (301) 890-4188
122
1
perceived their chin fat to make them look older or
2
more overweight.
3
Each item is rated on an 11-point numeric
4
rating scale where zero is "not bothered at all"
5
and 10 is "extremely bothered."
6
the impact scale, patients are given a copy of the
7
questionnaire and the standard non-magnifying
8
mirror to assist in the rating.
9
instructed to think about the submental chin fat
With administering
They are
10
area and to look into the mirror to evaluate that
11
area only.
12
The responder definition used as the primary
13
efficacy outcome was defined by a 1-grade
14
improvement from baseline on both the 5-point
15
submental fat rating scales, that is both the
16
clinician-reported and patient-reported submental
17
fat rating scales.
18
patient-reported submental fat impact scale, a key
19
secondary outcome measure, was defined as a 3-point
20
improvement from baseline on the 11-point scale.
21 22
A responder on the
Now, Dr. Fritsch will discuss these endpoints further as part of her presentation.
A Matter of Record (301) 890-4188
123
1
Thank you. FDA Presentation – Kathleen Fritsch
2
DR. FRITSCH:
3
Good morning.
My name is
4
Kathleen Fritsch, and I am the statistical reviewer
5
for this application, and I will be discussing the
6
efficacy results.
7
of the two phase 3 trials, study 22 and 23, which
8
were the identically designed, double-blind,
9
placebo-controlled trials with up to 6 treatment
10
I will be presenting the results
sessions. As previously mentioned, there were many
11 12
interactions between the agency and the sponsor to
13
come up with meaningful and useful endpoints for
14
assessing the effect of the treatment for submental
15
fat.
16
under a special protocol assessment, abbreviated
17
SPA, following which the agency provided a list of
18
agreements regarding the design, endpoints, and
19
analysis.
20
The sponsor submitted protocols to the agency
The sponsor's protocols included two
21
endpoints designated as co-primary endpoints, at
22
least 2-grade reduction on both the clinician-
A Matter of Record (301) 890-4188
124
1
reported and patient-reported scales and at least
2
1-grade reduction on both scales; so both endpoints
3
are alternate ways of defining a responder based on
4
the two same underlying scales.
5
In addition, the protocol defined two
6
secondary endpoints, at least 10-percent reduction
7
in MRI volume, which was conducted in a subset of
8
subjects, and a reduction in the mean total score
9
of the patient impact scale.
10
In the agreement letter issued in response
11
to the SPA request, the agency provided agreements
12
regarding one of the two co-primary endpoints, the
13
one with at least 2-grade reduction on both scales
14
and one of the secondary endpoints, the MRI volume
15
response endpoint.
16
that those endpoints could form the primary basis
17
of an efficacy claim.
18
The agency provided agreement
Based on the information available at the
19
time of the SPA assessment, the agency did not have
20
sufficient evidence about the other two endpoints
21
to provide agreement regarding their ability to
22
support an efficacy claim.
A Matter of Record (301) 890-4188
125
1
So at this time, I'll present the results of
2
the primary endpoints based on the two responder
3
definitions, and our analyses were the same as the
4
sponsor's.
5
endpoint, about 13 to 19 percent response rate for
6
the active arm and less than 3 percent for the
7
placebo arm.
8
endpoint, in the range of 67 to 70 percent response
9
for the active arm and 19 to 20 percent for the
We see, for the 2-grade improvement
And for the 1-grade improvement
10
placebo arm.
11
significant for both cases.
12
And the end point is statistically
This is the table again, the same table of
13
the two secondary endpoints, and all of our
14
analyses are consistent, and we have statistical
15
significance for both secondary endpoints with
16
appropriate multiplicity adjustments.
17
One of our concerns based on the review of
18
the phase 2 data was the concordance between the
19
clinician- and the patient-reported scales.
20
recognize that there's a lot of information packed
21
onto this slide, and so we can review this later,
22
if needed.
A Matter of Record (301) 890-4188
I
126
1
So in this table, I presented the
2
concordance of the levels of improvement seen on
3
both the patient and the clinician scales.
4
clinician scales go down the side, and the patient
5
scale across the top.
6
on these two assessments, are classified in
7
definitions of responder, either at least 2-grade
8
improvement, 1-grade improvement, or no change, or
9
worsening on each of the two scales.
10
So the
And all the subjects, based
The blue boxes represent the cases where the
11
ratings by the patient and the clinician, the
12
response ratings, were in agreement.
13
that for the DCA arm, which is on the top of the
14
chart, approximately 44 percent of subjects were
15
classified, both by themselves and the clinician,
16
as having the same level of improvement.
17
placebo arm, it was about 57 percent have
18
concordance.
19
We can see
For the
Most of the cases where the patient and the
20
clinician classifications differed on the DCA arm
21
were where 1 rater classified the subject as being
22
2 grades improvement while the other rater
A Matter of Record (301) 890-4188
127
1
classified the subject as being a 1-grade improver. So although the discordance can go either
2 3
way, we see that 23 percent of the subjects were
4
classified as 2 grades improvement by the clinician
5
in only 1-grade improvement by the subject
6
themselves, while 14 percent were rated by the
7
clinician as 1-grade improvement and 2 grades
8
improvement by the subject. So now that we've taken a look at the levels
9 10
of concordance on the individual subject level, I'd
11
like to take a look at just the trends over time
12
that were observed in the studies for all of the
13
three key assessments:
14
clinician assessment, and the MRI assessment as
15
well.
16
the patient assessment, the
So for this graph, I'm going to be looking
17
at just raw scores themselves, looking at the means
18
across all subjects, and so these are not
19
transformed into responders.
20
So here we have the clinician-reported
21
assessment scores, which is measured as we've noted
22
on a scale that runs from zero to 4, ranging from
A Matter of Record (301) 890-4188
128
1
absent up to extreme.
And we can see that
2
throughout the treatment period, the mean scores
3
for the subjects on the DCA arm decreased slightly
4
over time with a much smaller decrease for the
5
placebo subjects.
6
period, where they were followed up after all the
7
treatments were completed, the results are pretty
8
flat during that period.
And during the post-treatment
A typical DCA subject decreased by about
9 10
1.3 units on the clinician scale from baseline to
11
12 weeks post-treatment, which was the primary
12
efficacy time point. Here, I'm going to add the patient responses
13 14
on top of the clinician responses, so these
15
responses are also on a similar 5-point scale with
16
slightly different descriptors for each of the
17
levels.
18
similar based on the two scales, both the patient
19
and the clinician scale.
20
the post-treatment period, there's a fair amount of
21
agreement for the average response.
22
We see that the trends over time are very
And particularly during
So finally, I've added the MRI volume
A Matter of Record (301) 890-4188
129
1
assessments onto this chart as well.
The MRI
2
volumes are measured using the scale on the right,
3
which measures volumes in terms of cubic
4
centimeters.
5
was approximately a volume of roughly 7 cubic
6
centimeters and a decrease on the DCA arm from
7
baseline to 12 weeks post-treatment of
8
approximately 0.7 cubic centimeters, while the
9
placebo volumes were roughly flat and similar at
So we can see that at baseline, there
10
12 weeks post-treatment to what they were at
11
baseline.
12
Thus, we see that the three assessment
13
measures, although on different scales and
14
different types of measurements from three
15
different perspectives, all have changes over time.
16
Now, I'll turn the podium back to Dr. Lolic
17 18 19
for description of the safety. FDA Presentation – Milena Lolic DR. LOLIC:
A safety database for NDA
20
consists of over 2400 subjects with 1,019 from two
21
U.S. pivotal trials.
22
5 deaths in DCA development program, none of which
There were a total of
A Matter of Record (301) 890-4188
130
1
was considered treatment-related.
There were 75
2
serious adverse events reported in 58 trial
3
subjects.
4
investigator as treatment-related.
5
marginal mandibular nerve injury from European
6
phase 3 trial, and the patient recovered.
Only one was considered by principal That was
Presentation of safety will from this point
7 8
on focus on common adverse events and adverse
9
events of special interest from two U.S. pivotal
10
trials.
The most common adverse events were
11
injection site reactions.
12
The figure represents per arm distribution
13
of the injection site reactions that were reported
14
in more than 20 percent of subjects treated with
15
DCA presented in dark blue.
16
site edema reported in over 80 percent of subjects,
17
followed by hematoma, pain, numbness, erythema, and
18
induration in descending order.
Those were injection
Marginal mandibular nerve injury was one of
19 20
the adverse events of special interest and was
21
identified as adverse event in early development
22
stages.
Four percent of subjects treated with DCA
A Matter of Record (301) 890-4188
131
1
and less than 1 percent treated with placebo were
2
observed with this type of injury.
3
duration of paresis was 58 days, median 45 days,
4
and it fully and spontaneously resolved in all
5
subjects.
6
The average
Dysphagia, which occurred in the context of
7
administration site reactions, such as pain,
8
swelling, and induration of the submental area, was
9
observed in 2 percent of DCA-treated subjects in
10
comparison to less than 1 percent in
11
placebo-treated.
12
median 3 days.
13
after 32 days at the time when dysphagia was still
14
ongoing.
15
allergic reactions and limited urticarial events
16
completely resolved.
The average duration was 14 days, This subject discontinued the trial
There were no reported cases of severe
17
There were no differences between DCA- and
18
placebo-treated subjects in the number of elevated
19
liver function tests reported as more than 2 times
20
upper normal limit.
21 22
This last slide summarizes the time dependency for all adverse events per arm per
A Matter of Record (301) 890-4188
132
1
subject.
2
reported adverse events between DCA and placebo
3
occurred following the first cycle treatment, with
4
gradual decline throughout the next three
5
treatments after which it remained flat.
6 7
As presented, the biggest difference in
This concludes FDA presentation, and we will answer your questions now. Clarifying Questions
8 9
DR. DRAKE:
And we'll handle the questions
10
the same way we did with the sponsor.
And thank
11
you to the FDA for such a good presentation.
12
concise.
13
question and you'll be noted, and then we will ask
14
you the question.
Very
Please raise your hand if you have a
15
So who you have down first?
16
DR. BILKER:
Dr. Bilker.
There were multiple outcomes
17
looked at, for instance, the patient scale, and the
18
clinician scale, and the MRI.
19
which is great.
20
was done in the individual scales, the patient
21
scale and the clinician scale.
22
statistic or ICC done to look at the validity of
And they agreed,
I'm curious about if validation
A Matter of Record (301) 890-4188
Was the Kappa
133
1
the scale? DR. DRAKE:
2 3
You're going to do it at the mic
over there? DR. PAPADOPOULOS:
4
So as was mentioned,
5
there were no established scales, and so the
6
applicant developed scales, novel scales, working
7
closely with the agency during the course of drug
8
development.
9
evidence to support these instruments, as well,
And they did provide documentation of
10
defined and reliable tools for use in their drug
11
development program. So they have provided an evidence dossier,
12 13
as we call it, showing the evidence for validity,
14
reliability, and ability to detect change, which we
15
have reviewed. DR. DRAKE:
16 17
please identify yourself for the record. Dr. Beddingfield, did you have a comment on
18 19 20 21 22
And I remind all speakers to
that? DR. BEDDINGFIELD:
If you'd like additional
details -DR. DRAKE:
Let's do that during the
A Matter of Record (301) 890-4188
134
1
discussion.
Thank you very much.
Right now, I'm
2
going to reserve it for questions for the FDA.
3
thank you.
But
That's helpful.
4
Dr. Brittain?
5
DR. BRITTAIN:
In terms of the safety, I
6
guess I'm a little confused in terms of the long-
7
term follow-up.
8
or is it -- can you clarify that?
9
Is any of that placebo-controlled
DR. LOLIC:
The data that was presented by
10
FDA is based on the phase 3 trials.
11
seen, it was extended to 24 weeks, and those are
12
placebo-controlled.
13 14 15 16
DR. BRITTAIN:
And as you've
So the long-term data that
were noted in -DR. LOLIC:
The long-term were not
placebo-controlled.
17
DR. BRITTAIN:
18
DR. DRAKE:
19
DR. ALAM:
Okay.
Thank you.
Dr. Alam? Mural Alam.
As FDA knows,
20
previously an analogue of this drug that was not
21
approved, was compounded, and was used in many
22
parts of the U.S. for a similar indication of fat
A Matter of Record (301) 890-4188
135
1
dissolution. In those cases, I think FDA sent a warning
2 3
letter.
4
some of them were triggered by microbacterial
5
infections that were resistant to treatment and
6
required prolonged antibiotic treatment. Was anything like that or anything remotely
7 8
There was some concerns; in particular,
similarly seen in any of the pivotal trials?
9
DR. LOLIC:
Briefly, no.
10
DR. DRAKE:
That was a great answer.
11
(Laughter.)
12
DR. DRAKE:
13
DR. MRZLJAK:
Yes? Vesna Mrzljak.
I have again a
14
question about the schematic sketch of how avoid
15
injury to the marginal mandibular nerve.
16
wonder whether this proposed sketch met with FDA
17
approval, if anybody has looked at it and agreed
18
that this is the best way.
19
DR. LOLIC:
And I
This application is still under
20
review.
Therefore, we are still negotiating with
21
the applicant and looking into data that they are
22
submitting in order to enhance the application.
A Matter of Record (301) 890-4188
136
1
DR. MRZLJAK:
Open Public Hearing
2 3
Thank you.
DR. DRAKE:
Well, seeing no other questions,
4
all done as an auctioneer would say?
5
All right.
6
All done?
So what we're going to do now then -- and
7
this is great.
We've made up some time.
I think
8
now, it is time to proceed with the open public
9
hearing session.
Before we proceed, I want
10
to -- by the way, there's a lot of interest with
11
the open public hearing session, which is terrific.
12
But I want to note that both the FDA and the
13
public believe in a transparent process for
14
information-gathering and decision-making.
15
ensure such transparency at the open hearing
16
session of the advisory committee meeting, the FDA
17
believes it is important to understand the context
18
of an individual's presentation.
19
To
For this reason, the FDA encourages you, the
20
open public hearing speaker, at the beginning of
21
your written or oral presentation to advise the
22
committee of any financial relationships that you
A Matter of Record (301) 890-4188
137
1
may have with the sponsor, its product, and if
2
known, its direct competitors.
3
For example, the financial information may
4
include the sponsor's payment of your travel,
5
lodging, or other expenses in connection with your
6
attendance at the meeting.
7
encourages you at the beginning of your statement
8
to advise the committee if you do not have any such
9
financial relationships.
10
Likewise, FDA
If you choose not to address this issue of
11
financial relationships at the beginning of your
12
statement, it will not preclude you from speaking.
13
The FDA and this committee place great
14
importance in the open public hearing process.
15
insights and comments provided can help the agency
16
and this committee in their consideration of the
17
issues before them.
18
The
That said, in many instances and for many
19
topics, there will be a variety of opinions.
20
of our goals today is for this open public hearing
21
to be conducted in a fair and open way and where
22
every participant is listened to carefully and
A Matter of Record (301) 890-4188
One
138
1
treated with dignity, courtesy, and respect.
2
Therefore, speak only when recognized by the chair,
3
and I certainly thank you for your cooperation.
4
We have quite a few open public hearing
5
speakers today, which I think, the committee, if
6
you haven't gone through this before, will find
7
very enlightening because sometimes they bring the
8
most salient points forward for our consideration.
9
So I want to thank everybody who is participating
10
in the open public hearing.
11
here.
I thank you for being
12
With that, we'll start.
13
number 1 step up to the podium?
14
yourself.
15
organization you are representing for the record.
Introduce
Please state your name and any
16
Speaker number 1?
17
make your way to the mic.
18
in my sights now, yes.
19
Will speaker
MS. CERRO:
I think you're trying to I see you.
Good morning.
I have you
My name is
20
Elaine Cerro, and I'm from Toronto, Canada, and
21
next month, I will be 62.
22
travel here today, but I'm not being compensated
Kythera supported my
A Matter of Record (301) 890-4188
139
1
for my time. I teach yoga to all age groups, including
2 3
young college students, so my confidence and
4
self-image are very important to me.
5
the fitness staff at Humber College in Toronto, and
6
I'm mindful that my appearance is important as I do
7
tell my students that yoga helps us to stay fit
8
physically and mentally, and also helps us stay
9
young.
10
I am part of
It is, therefore, very important for me, to
11
me, that I present myself in a way that looks like
12
yoga has benefited me.
13
something I was not able to change.
14
weight down.
15
my goal to be an inspiration for my students to
16
continue coming to my classes.
17
Having a double chin was I keep my
I'm mindful of what I eat, and it is
Having a double chin was something that
18
weighed on my mind, and I felt it added years to my
19
appearance.
20
I used gadgets that claim to eliminate chin fat,
21
and I saw no results.
22
front of a mirror and stretch the fat away with my
I've tried various exercises, videos.
I would stand sideways in
A Matter of Record (301) 890-4188
140
1
hand, and as the double chin is gone, I think how
2
great it would be if it wasn't there. Prior to each treatment, there was a
3 4
preparation with a numbing cream.
5
injected into the fatty area, and the doctor
6
started out with one needle per each centimeter
7
that needed treatment. I could hardly feel the injections and
8 9
Needles were
afterwards held cold packs over the area.
In the
10
beginning, they kept me there for half an hour to
11
observe how my skin reacted.
12
skin, although there was minimal recovery time, and
13
I was still able to teach later that night.
I do have sensitive
None of us knew if I was getting the real
14 15
treatment or placebo, although it was evident that
16
I was getting the ATX injection after a couple of
17
visits.
18
after four visits, I had one chin.
19
The injections were effective enough that
It has made a major difference in my life,
20
and I feel more confidence as a yoga teacher and as
21
a person.
22
can only imagine how boring it is to listen to
And I also no longer talk about it.
A Matter of Record (301) 890-4188
I
141
1
someone talking about this on more than one
2
occasion.
3
anymore.
4
ago was when this was done, and I'm still enjoying
5
the results of the treatments.
6
And I also don't focus on this area And I'm happy to say that over two years
I believe this procedure should be made
7
available to the public because since this trial, I
8
have noticed how so many people, including my young
9
students, have double chins.
I would
10
wholeheartedly advise anyone to do this procedure,
11
not only for -- but also because it is safe and the
12
benefits are long term.
13 14 15
DR. DRAKE:
Thank you.
Thank you very much.
Speaker
number 2, would you please step forward? DR. COX:
Good morning.
My name is
16
Dr. Sue Ellen Cox.
17
my time.
18
UNC and at Duke, and I'm in private practice in
19
Chapel Hill, North Carolina.
20
primary investigators for the ATX-101 study.
21 22
My travel was supported but not
I'm an associate clinical professor at
And I was one of the
I thought the best way to bring my experience with ATX-101 to light was to discuss one
A Matter of Record (301) 890-4188
142
1
of my patients, so this is a little vignette. This was a 63-year-old female who came in,
2 3
referred from a plastic surgeon who she had seen
4
for evaluation for a facial rhytidectomy or
5
submental liposuction.
6
surgical candidate due to health concerns and
7
medical concerns that the physician had. I discussed with her enrolling in the
8 9
She was deemed not a
ATX-101 study, and she decided to proceed.
10
Initially, we did her first series of injections,
11
and she did excellently.
12
injections, she did have some numbness and some
13
fibrosis, so the second set of injections was
14
delayed.
Before her second set of
She ended up with five sets of injections,
15 16
and she felt her submental fat, as well as the
17
laxity of the skin, was greatly improved.
18
self-esteem, her self-confidence was manifestly
19
better.
20
thought of her as fat or overweight, and that they
21
would always look towards her; not towards the top
22
of her face.
Her
And she described to me that people always
A Matter of Record (301) 890-4188
143
1
She felt that this treatment greatly
2
improved her life, and she was very happy to be
3
enrolled in this study.
4
to speak.
5 6 7
DR. DRAKE:
Thank you for allowing me
Thank you very much.
specialty -- I didn't -- what department? DR. COX:
Sorry.
I'm a dermatologist.
8
I teach the residence at UNC and at Duke.
9
done that for 15 years.
10 11 12
What
DR. DRAKE:
Thank you.
Yes,
I've
Will speaker
number 3 please step forward? DR. ALSTER:
Good morning.
My name is
13
Dr. Tina Alster, and I am a board certified
14
dermatologist and clinical professor of dermatology
15
at Georgetown University with a busy cosmetic
16
dermatology practice in Washington, DC.
17
to thank the panel for giving me time to share my
18
perspectives about ATX-101.
19
I'd like
As disclosure, I have served as an advisor
20
to Kythera, but I'm here today as a private
21
practitioner without compensation.
22
never used ATX-101, I am at full support of its
A Matter of Record (301) 890-4188
While I have
144
1
approval because it is a unique treatment for a
2
very cosmetic problem.
3
consumer survey on cosmetic dermatologic
4
procedures, the American Society of Dermatologic
5
Surgery found that nearly 70 percent of consumers
6
are somewhat to extremely bothered by their
7
submental fullness.
8 9
In fact, in its 2014
I have seen this personally with my own patients, as well as myself, as many of them
10
identify the area under their chin as a chief
11
concern.
12
That's why I always wear a neck scarf.
It is a common misconception that submental
13
fullness only occurs in those who are overweight.
14
It actually occurs in a variety of body types.
15
Submental fat, which could be resistant to diet and
16
exercise, can manifest even in younger patients and
17
in those who have a normal body mass index.
18
For both men and women, submental fullness
19
can lead to a negative self-impression, even among
20
younger patients.
21
concern for many patients I see on a daily basis.
22
These patients are seeking minimally invasive or
Clearly, this is a significant
A Matter of Record (301) 890-4188
145
1
nonsurgical procedures.
2
treatments have been limited to surgical
3
interventions.
4
However, current
The few energy devices that are available to
5
treat fat via ultrasound or radiofrequency, which I
6
have at my office, are limited in their ability to
7
successfully contour subcutaneous fat in the
8
submental region.
9
It is my opinion that we cannot overlook the
10
submental area because it is a critical component
11
of facial aesthetics and contributes to overall
12
facial balance and harmony.
13
As you have heard from others today, ATX-101
14
has been tailored for this specific area and has a
15
very good safety profile.
16
and my patients to have an FDA-approved treatment
17
that is well-studied and effective.
18
definitely fill an unmet need.
19
alternative like it.
20
It is important to me
ATX-101 will
There is simply
As such, I and my patients will be most
21
grateful to have it available, and I will no longer
22
have to wear my scarf.
Thank you again for the
A Matter of Record (301) 890-4188
146
1 2 3
opportunity to present to you today. DR. DRAKE:
Thank you, Dr. Alster.
never boring.
4
(Laughter.)
5
DR. DRAKE:
6 7
You're
Would speaker number 4, please
step forward? DR. LAWRENCE:
Good morning.
I am
8
Naomi Lawrence.
I am director of procedural
9
dermatology at Cooper Medical Center, Rowan
10
University, and I have been in the full time
11
academic practice of dermatologic surgery for the
12
past 22 years.
13
I am here today in my role for the American
14
Society for Dermatologic Surgery Association, which
15
is an advocacy organization for dermatologic
16
surgeons and their patients.
17
ASDSA paid for my travel.
18
As a disclosure, the
The ASDSA represents over 6,000 dermatologic
19
surgeons and their patients and is purely an
20
advocacy organization.
21
we are active include banning tanning beds for
22
minors without parental support and skin cancer
Some of the issues in which
A Matter of Record (301) 890-4188
147
1
awareness.
2
As an advocacy organization, we are
3
interested in supporting the development of
4
products that are desired by our physician members
5
and the patients they serve.
6
such product, and this product fulfills the need
7
for a nonsurgical, non-device method to dissolve
8
fat.
9
We believe ATX-101 is
The ASDSA organization is purely supported
10
by physicians, and we regularly poll our members on
11
their needs and their patients' needs.
12
summary, the reasons why we support this particular
13
product include the fact that dermatologic surgeons
14
are looking to the FDA for a regulated procedure
15
for this indication.
16
So in
The ASDS survey on dermatologic procedures
17
has shown a steady increase in interest in body
18
contouring procedures.
19
polled and showed 143,500 body contouring
20
procedures.
21
had risen to 175,000 procedures.
22
In 2012, our members were
Only a year later in 2013, the number
We find that our members in our recent
A Matter of Record (301) 890-4188
148
1
consumer survey, as Dr. Alster pointed out,
2
68 percent of our respondents said that they were
3
somewhat to greatly bothered by the submental fat
4
on their neck.
5
trained dermatologists and other physicians in the
6
safe, effective use of any new product or any new
7
indication, and the ASDSA provides ongoing
8
education and training to support those procedures. Thank you and thanks for considering us
9 10
We believe in having appropriately
today.
11
DR. DRAKE:
Thank you very much.
12
Speaker number 5, please?
13
DR. WOLFE:
I'm Sid Wolfe.
I'm with the
14
Public Citizen and Health Research Group.
15
no financial conflict of interest.
16
I have
Similar to the FDA, our main two special
17
safety concerns were both the marginal mandibular
18
nerve damage without any adequate causal
19
explanation or data comparing its frequency to that
20
seen with submental surgical procedures, and
21
secondly, the increased incidents of dysphagia
22
lasting as long as 81 days.
A Matter of Record (301) 890-4188
149
As you all know, dysphagia sometimes is
1 2
associated with aspiration pneumonia, and it can be
3
a serious impairment to good health; and again,
4
without evidence that nerve damage is not also a
5
causal factor along with the local induration and
6
edema. This is from the FDA's briefing document
7 8
just highly statistically significant increase, 20
9
cases versus 1 of mandibular nerve injury, duration
10
from 1 to 298 days.
The concluding statement,
11
which is similar to what the company said, is the
12
marginal mandibular never injury is a well
13
recognized complication of surgical interventions.
14
Again, I don't know what the comparable numbers
15
are, but clearly in the group that got the placebo,
16
those complications were almost nonexistent, one
17
case as opposed to 20 cases. Kythera similarly said it's likely to be
18 19
related to incorrect injection procedure or
20
technique via injection placement outside the
21
submental region or failure to inject into the SC
22
fat.
A Matter of Record (301) 890-4188
150
1
So in both cases, what is being stated is
2
that it is not so much the problem of the
3
deoxycholate but it's the technique.
4
the technique is okay if you don't use deoxycholate
5
so it's clearly injecting this fairly cytotoxic
6
substance.
7
Conclusions.
Obviously,
For the proposed use, the
8
sponsors failed to demonstrate benefits outweigh
9
the risk.
And I say that despite the comments on
10
this that have been made.
11
what the cause of the nerve damage is.
12
compression because of induration?
13
neurotoxicity?
14
We do not know about Is it
Is it direct
A large number of tissues have been found to
15
be highly damaged by this chemical, including
16
multiple cells, muscle cells, and other things that
17
are involved in this kind of procedure.
18
Second, there will inevitably be significant
19
off-label use of DCA in Brazil.
There were studies
20
in 2007 during this.
21
approval, it's essential the adequate preclinical
22
investigations should be done to determine the
And again, finally, before
A Matter of Record (301) 890-4188
151
1
exact mechanism of the neurotoxicity.
2
and the company said the local effects were the
3
same across species, and maybe one of the species
4
is the human being as well.
5
DR. DRAKE:
6
appreciate your comments.
Both the FDA
Thank you very much.
Thank you, Dr. Wolfe.
We always
Would speak number 6 please step forward?
7 8
Speaker 6 apparently is not here today.
9
to speaker 7, please? MS. SIVERD:
10
Hello.
May I go
My name is Amy Siverd,
11
and I was a participant in the study before you
12
today.
13
to be here.
14
Kythera supported my travel but not my time
I'd like to share some personal information
15
about myself if I may.
16
mother of two children, 14 and 10, and have been
17
married 16 years.
18
child therapist and will complete my graduate
19
degree in clinical social work next month.
20
I am 42 years old and a
I work as an early intervention
I'm here to share my story because I believe
21
in this product as my results and experiences with
22
ATX-101 have been nothing but positive and beyond
A Matter of Record (301) 890-4188
152
1
my expectations.
2
Although it was something that has bothered
3
me most of my late adolescent and adult life, I did
4
not think my double chin was something I could
5
change without surgery.
6
related to our physical features, it came to my
7
attention in high school after seeing a profile
8
picture of myself.
9
Like most insecurities
After that, I've worn a not-so-flattering
10
habit of overcompensating for my chin in
11
photographs.
12
chinny roll, it was at the expense of the camera
13
having a straight shot up my nose, and I assure
14
you, it was not attractive.
15
While I was successful at hiding my
So it may be an understatement to say I was
16
beyond excited when I discovered my new
17
dermatologist was participating in a study to
18
reduce submental fat.
19
call about the study and was told it was quickly
20
filling up with qualified participants.
I was one of the last to
21
Upon meeting the doctor to see if I met the
22
requirements for the study, my nervous anticipation
A Matter of Record (301) 890-4188
153
1
quickly changed to relief when the doctor declared,
2
to his surprise, I possessed a moderate amount of
3
submental fat for a person of my physique. As expected, during the next four
4 5
treatments -- because that is all that I
6
needed -- the numerous tiny injections were painful
7
but were not unbearable.
8
controlled with over-the-counter pain relievers and
9
small ice packs.
Pain was easily
The swelling was minimal to
10
moderate and never lasted more than a couple of
11
days.
12
once, and a minimal redness never lasted more than
13
a few hours.
I believe I only experienced slight bruising
14
If there's one thing I want you to remember
15
from this short time before you today is that I got
16
exactly what I hoped for, and more, when I signed
17
on to be one of the subjects in Kythera's double
18
chin study.
19
opportunity, and I hope others have the chance to
20
decide if ATX-101 is right for them.
21 22
Looking back, I am so happy I had this
DR. DRAKE:
Thank you.
Thank you very much.
speaker number 8, please come forward?
A Matter of Record (301) 890-4188
Would
154
1
DR. JEWELL:
Good morning.
My name is
2
Mark Jewell.
3
from Eugene, Oregon.
4
clinical professor of plastic surgery at Oregon
5
Health Science University.
I have no conflict of
6
interest with the sponsor.
The Aesthetic Society
7
paid for my transportation and I'm not being
8
compensated otherwise.
9
I'm a board certified plastic surgeon I'm also an associate
I'm here to represent the American Society
10
for Aesthetic Plastic Surgery at this hearing on
11
ATX-101.
12
for Injectable Safety, a group of core trained
13
physicians numbering about 40,000 whose focus is
14
proper training, patient education, for the safe
15
use of cosmetic injectables.
16
brief oral statements this morning.
17
I also represent the Physicians Coalition
I will make some
For many patients, the presence of localized
18
fat in the chin and neck represents a cosmetic
19
deformity that impacts their lives and body image.
20
It is diet-resistant and often familial in
21
heritage.
22
lipolytic drug designed to thin fatty deposits
The option of having an FDA-approved
A Matter of Record (301) 890-4188
155
1
through direct injection is of interest to improve
2
this deformity.
3
Before ATX-101, the options for injectable
4
lipolysis were compounding pharmacies who elicit
5
importation of lipolytic drugs from offshore.
6
believe the FDA is well-aware of problems in this
7
area due to the lack of good manufacturing
8
practices and sterility control.
9
I
From what I heard, it appears the sponsor
10
has done an excellent job of conducting the pivotal
11
study in a rigorous scientific fashion to document
12
safety, science, and patient satisfaction.
13
A response of 80 percent of 1-grade
14
improvement in submental fat is excellent.
15
scientific evidence from this study demonstrates a
16
low level of adverse events when ATX-101 is used by
17
a properly trained injector.
18
most important issue regarding the approval of a
19
new compound for injectable lipolysis, which is
20
that of physician training and patient education.
21 22
The
This brings me to the
It behooves Kythera to offer robust physician education in the use of ATX-101.
A Matter of Record (301) 890-4188
156
1
Physicians who offer cosmetic injectables are not
2
knowledgeable about a standardized process for
3
injectable lipolysis or patient selection.
4
every candidate who has a full chin and jaw line
5
may be suitable for ATX-101.
Not
It is also important that this drug, once
6 7
injected, cannot be reserved; hence the need for
8
precise injection technique.
9
enough the role of physician training for ATX-101
10
And I can't emphasize
in order to achieve optimal outcomes. In speaking for the American Society for
11 12
Aesthetic Plastic Surgery, I believe the FDA
13
approval of ATX-101 will afford select patients the
14
opportunity for a safe and effective injection to
15
improve fullness in the chin and jaw line.
16
cannot emphasize enough the importance of having
17
the core trained injector as an integral part of
18
the treatment in order to maximize the outcomes and
19
to minimize the potential for adverse events
20
associated with injectable lipolytic drugs.
21
you.
22
DR. DRAKE:
But I
Thank
Thank you very much, Dr. Jewell.
A Matter of Record (301) 890-4188
157
1 2
Speaker number 9, please? DR. GOLDMAN:
Thank you for the opportunity
3
to be here.
4
have about 30 years' experience in liposuction and
5
dermatologic surgery.
6
dermatology at the University of California
7
San Diego and the immediate past president of the
8
American Society for Dermatologic Surgery.
9
My name is Dr. Mitchel Goldman.
I
I'm an a professor of
I have treated approximately 500 patients
10
with neck fullness over the last 30 years with
11
liposuction and about 50 people with the ATX-101
12
product.
13
time to be here by the Kythera Corporation, and I
14
was an investigator with the ATX-101 trial.
15
My coach airfare was paid here by not my
I'd like to address three points.
First is
16
side effect profile.
In performing liposuction and
17
other procedures on the neck, I can assure you that
18
the safety profile of the ATX-101 is similar, if
19
not much better than the adverse events that occur
20
with liposuction procedures.
21
addressing dysphagia and nerves palsy, these can
22
happen with many laser procedures as well as
Specifically
A Matter of Record (301) 890-4188
158
1
liposuction procedures.
2
procedures, as with the ATX-101, are temporary,
3
mild, and of short duration and should not be a big
4
concern to our group.
5
The results of those
Second is the need for an approved product.
6
I recognize and agree with Dr. Jewell and the
7
American Society for Plastic Surgery in that
8
training is extremely important.
9
having an FDA-approved product will we be able to
And only by
10
ensure that physicians and our residents-in-
11
training receive proper training to use this
12
product effectively.
13
Third, what was addressed by some of the
14
panel members was are there any long-term problems
15
and can you do other procedures after you've had
16
the ATX-101?
17
in the slide deck that was shown to you, and that
18
patient, although had great results, still had a
19
little bit of neck laxity.
20
One of my patients was actually shown
After completing the study and being
21
dismissed from the study, she then underwent an
22
additional procedure with a radiofrequency to
A Matter of Record (301) 890-4188
159
1
further tighten the skin.
So I do not believe that
2
there is any adverse effects, which can occur from
3
having additional procedures, if required, after
4
the ATX-101.
Thank you for your attention.
5
DR. DRAKE:
Thank you, Dr. Goldman.
6
number 10, please?
7
DR. GREEN:
Good morning.
Speaker
My name is
8
Larry Green.
I'm a board certified dermatologist
9
and an assistant clinical professor of dermatology
10
at George Washington University School of Medicine.
11
I practice at Montgomery County, Maryland for the
12
past 20 years.
13
My practice is equally, parts medical,
14
surgical and cosmetic in nature.
15
surgeon, nor can I say I specialize uniquely in
16
aesthetic medical procedures.
17
believe I represent the average board certified
18
dermatologist who commonly performs skin surgery
19
and cosmetic procedures but still sees a fair
20
amount of medical dermatology daily.
21 22
I'm not a Mohs
In this respect, I
As far as disclosures, I've not received any compensation nor had any transportation arranged or
A Matter of Record (301) 890-4188
160
1 2
paid for me by Kythera to be here today. In my medical, cosmetic, and surgical
3
dermatologic practice, people often do ask about
4
submental fat reduction and their submental fat.
5
As you heard, an ASDSA survey done last year show
6
that 68 percent of people ask about submental fat.
7
And also, as you've heard, there's really nothing
8
adequately to address this in a noninvasive way
9
currently.
10
So I'm here today before you, Committee,
11
because I have a significant amount of experience
12
with ATX-101 as a phase 3 investigator and would
13
like to share it.
14
At the investigator meeting, investigators
15
who participate in the phase 3 trials were shown
16
slides, videos, and had hands-on training prior to
17
initiating the trial and using ATX-101 on subjects.
18
This was training more than half a day.
19
We learned, not only how to perform the
20
procedure but also learned about proper patient
21
selection.
22
helpful, which you probably saw earlier.
And I especially found the grid tattoo
A Matter of Record (301) 890-4188
Using the
161
1
grid tattoo really makes it very difficult, if not
2
impossible, to inject something like that marginal
3
mandibular nerve.
4
So you've seen today that clinical trial
5
data from ATX-101 shows clearly high significant
6
p-values showing investigator and patient
7
preference over placebo.
8
corroborates this.
9
a visible and significant decrease in submental fat
My experience
Participants at my site showed
10
usually after three or four sessions.
11
this occurred without a change in skin laxity.
12
In general,
To manage the potential discomfort, I had
13
subjects place an ice pack on their chin for a few
14
minutes before and after injections.
15
did feel burning during injections.
16
did bruise, and when I say "most" I have to include
17
some placebo patients since it was 50-50 we assume.
18
Despite this discomfort in local injections
Some patients Most patients
19
given at each treatment session, none of my
20
patients wished to stop at any time.
21
did experience some induration erythema that lasted
22
up to a few weeks after injection with anesthesia
A Matter of Record (301) 890-4188
Some patients
162
1
confined to the treatment area that lasted up to
2
two to four weeks after injection.
3
experienced any dysphagia.
4
marginal mandibular nerve changes.
5
No one
No one experienced any
However -- and I want to stress this because
6
I feel the investigators were well-prepared for how
7
to use medication and its expected outcomes, the
8
subjects were also well-prepared.
9
events were not an issue for them with their
10 11
These adverse
experience during or after the treatment. Patient satisfaction rate was very high, and
12
I could also mention almost all my patients entered
13
the long-term trial.
14
and who has active, but all the patients who had
15
reduction in their chin fat maintained that
16
reduction up to 24 months up until today.
17
I don't know who has placebo
So I think ATX-101 therefore represents an
18
innovation to fill a void in treating a commonly
19
desired area of improvement and currently has no
20
noninvasive ways to achieve results.
21 22
So speaking as a general dermatologist, I feel that with proper training, any general
A Matter of Record (301) 890-4188
163
1
dermatologist or plastic surgeon in the core
2
specialties will be able to adequately discuss ATX-
3
101 with patients and prepare them for treatment
4
sessions, and treat their submental fat achieving
5
good outcomes.
6 7 8 9
Thank you.
DR. DRAKE: Appreciate it.
Thank you very much, Dr. Green.
Speaker number 11, please?
MS. FOSTER:
Good morning.
My name is
Danna Foster, and I want to thank you for having me
10
before your panel today.
11
rep for Retriever Merchant Solutions, and Kythera
12
supported my travel today to speak before you with
13
no compensation for my time or time away from work.
14
I am an executive sale
First off, I struggled for years with excess
15
fat under my chin, and I've tried creams and skin
16
tightening devices to no avail.
17
chin affected me personally, especially how others
18
viewed me and how I viewed myself.
19
a face-to-face meeting with customers, I found them
20
looking down at my double chin or people would feel
21
I was older than I was.
22
Having a double
If I was doing
And I am 56.
With this product, I had no side effects.
A Matter of Record (301) 890-4188
164
1
The product was fast with next-day results that I
2
noticed right away.
3
do come before this panel to express how important
4
it is to improve this product for other patients
5
struggling with the same concerns that I did.
I think it's important that I
6
I got really excited that even on the plane
7
coming over, I talked with people that were sitting
8
next to me who had trouble with double chins.
9
that was amazing because I just felt very excited
10
about the product and what it did for me, and how
11
it raised my self-esteem even more than it was. So I do thank you again, and thank you for
12 13
having me before you.
Thank you.
14
DR. DRAKE:
15
We appreciate you coming.
16
please?
17
And
Thank you very much, Ms. Danna.
DR. MAAS:
Speaker number 12,
Good morning.
I'm
18
Dr. Corey Maas, a facial plastic surgeon, board
19
certified in San Francisco.
I was a member of the
20
clinical trial for Kythera.
Our clinical trial
21
center conducted it, and I was reimbursed for my
22
travel here today.
A Matter of Record (301) 890-4188
165
1
A couple of comments that I think were not
2
addressed, one is that submental fat does not
3
necessarily correlate directly with BMI.
4
lot more change in facial fat loss when people gain
5
or lose weight, and as these patients were often
6
candidates for surgery and end up undergoing a
7
submental liposuction surgery, which, as
8
Dr. Goldman mentioned, has significantly more risks
9
and side effects.
10
We see a
In fact, in studies that are conducted
11
relative to the marginal mandibular nerve and neck
12
rejuvenation, surgically, the incidence of that
13
injury is somewhere between 1 and 5 percent, which
14
probably averaging about 2 percent according to a
15
study published by the late Dr. Owsley.
16
The other point that I'd like to make is
17
that, an important one too, many patients who are
18
heavy, if they do have surgical interventions in
19
this area, or in this case, the drug, it's a
20
motivation for them to lose further weight.
21
think this has a good addition to the options that
22
we're providing.
A Matter of Record (301) 890-4188
So I
166
Relative to an earlier discussion about
1 2
placebo effect, I think we all know in aesthetic
3
surgery, there is very high placebo effect rate
4
that this -- it's hard to explain, but it's been
5
reported in the literature as high as 30 percent,
6
so fairly consistent with what we see here in this
7
study.
8
Thank you.
Questions to the Committee and Discussion
9
DR. DRAKE:
10
We appreciate you coming.
11
Thank you very much, Dr. Maas.
So those were all our speakers.
First of
12
all, I want to thank all the speakers who took time
13
to come and share their opinions with us.
14
it's an essentially important part of this process.
15
I think
So the open public hearing portion of this
16
meeting has now concluded, and we'll no longer take
17
comments from the audience.
18
turn its attention to address the task at hand, the
19
careful consideration of the data before the
20
committee as well as the public comments.
21 22
The committee will now
I want to remind the public that I hope you'll stay because I think the participation of
A Matter of Record (301) 890-4188
167
1
all of us is what gets good products out the door.
2
So that's just an editorial comment from your
3
chair. The questions that we're going to consider
4 5
in your book -- if you haven't seen them there, the
6
questions for the committee are in your materials
7
in front of your desks.
8
of time, we will be using an electronic voting
9
system for this meeting.
A couple of comments ahead
And we're not going to
10
vote right now, but I just want to give you a heads
11
up.
12
flashing and will continue to flash even after
13
you've entered your vote.
Once we begin the vote, the buttons will start
When you get ready to vote, please press it
14 15
firmly.
And then if you're unsure of your vote and
16
wish to change it, you may press a corresponding
17
button until the vote is closed.
18
has completed the vote, the vote will be locked in,
19
and then the vote will be displayed on the screen.
20
So the designated federal officer,
21
lieutenant commander sitting here next to me, will
22
read the vote from the screen on to the record.
A Matter of Record (301) 890-4188
After everyone
168
1
And next, we'll go around the room, and each
2
individual who voted will state their name and will
3
vote into the record.
4
You can also state the reason you voted as
5
you did if you want to and will continue in the
6
same manner until all the questions have been
7
answered or discussed.
8 9
So I just wanted to give you -- because we're not going to head right into the voting.
I
10
just wanted to tell you how the process is going to
11
work as we move forward.
12
I'm going to read the question right now,
13
and then I'm going to open up the floor for
14
discussion.
15
don't state how you're going to vote during the
16
discussion, all right?
17
clarification questions.
18
themselves available if you have further questions
19
for them, or if you have questions for the FDA,
20
they're here; they're available.
21 22
During the discussion of this, please
The discussion is for more The sponsor has made
Please don't state your opinion for the vote -- I mean how you're going to vote, rather.
A Matter of Record (301) 890-4188
169
1
This process right now is for us to clarify and
2
elucidate any questions you might have before you
3
move into the vote if there's still pending issues,
4
so let's take this opportunity.
5
to do that.
6
be recognized by the chair.
We have some time
And again, raise your hand, and you'll
Well, before I do it, Dr. Matarasso, I want
7 8
to read the question into the record just so we
9
have it.
So the question for the
10
committee -- there are two questions.
11
question is, do the efficacy and safety data
12
provided to you today support the approval of the
13
deoxycholic acid injection for the improvement in
14
the appearance of moderate to severe convexity or
15
fullness associated with submental fat?
16
not, what additional studies or analysis are
17
needed?
18
The first
And if
I said in the background, as the question
19
states, we're asking the committee to weigh all the
20
risks and benefits in the vote for approval.
21
please note that a vote for approval, in general
22
terms -- now, this is important.
A Matter of Record (301) 890-4188
A vote for
And
170
1
approval in general terms does not mean that one
2
must agree with a proposed dosing recommendations
3
or the proposed labeling.
4
FDA and the sponsor to work out.
5
answer is no, please consider what additional
6
studies should be recommended.
That will be up to the However, if your
7
Then the second question that will come up
8
as the morning progresses is do the members of the
9
committee have any comments on the approach, which
10
was developed for evaluation of safety and efficacy
11
for this novel indication?
12
So those are the two things that are up for
13
discussion now.
With that, I'd like to open up
14
this session for discussion.
15
that I have is Dr. Matarasso.
16
DR. MATARASSO:
And the first name
Thank you.
This is a couple
17
of questions for the manufacturers.
18
to specifically answer the concurrent use of other
19
injectable products at the same time, such as
20
neurotoxins for platysma bands at the same time as
21
this product.
22
I'd like you
The additional question is, specifically in
A Matter of Record (301) 890-4188
171
1
relation to surgery, have any of these patients had
2
a surgical procedure that required opening of the
3
skin of this area after they've had the drug used?
4
And finally, any medical contraindications and any
5
agents that will reverse the effect of the drug?
6
Thank you.
7
DR. BEDDINGFIELD:
For your first question,
8
we would not advise concurrent treatment in the
9
same area with botulinum toxins or fillers in the
10
same treatment session with this product.
11
not advise that.
12
good thing to do.
We would
I would not think that would be a
13
DR. MATARASSO:
Time frame?
14
DR. BEDDINGFIELD:
Typically, in our studies
15
when we've looked at the effect for full resolution
16
of any inflammation, that would be 4 weeks.
17
why we have at least a 4-week treatment interval
18
between treatments.
19
time frame that we would recommend.
20 21 22
That's
So that would be the
Your second question, we're not aware of any patients needing surgery after this procedure. DR. MATARASSO:
So no patient required a
A Matter of Record (301) 890-4188
172
1
facelift or their thyroid operated on
2
post-treatment? DR. BEDDINGFIELD:
3
We're not aware of any
4
patient needing surgery after our treatment.
5
does not mean, however, that some patients may not
6
have elected to.
7
that one of his patients chose to get a
8
radiofrequency procedure after they were out of the
9
study.
10
That
And we heard from Dr. Goldman
We would not have any knowledge of that,
based on standard study follow-up. DR. MATARASSO:
11
So no other patients that
12
were included in the study had any surgery in this
13
area afterwards? DR. BEDDINGFIELD:
14 15 16
No, not as part of the
study. DR. MATARASSO:
So we don't have any
17
information on the impact of this on someone who
18
would require, for example, a non-cosmetic
19
operation?
20
DR. BEDDINGFIELD:
21
DR. MATARASSO:
22
DR. BEDDINGFIELD:
That's right.
Not radiofrequency. That's correct.
A Matter of Record (301) 890-4188
173
1
DR. MATARASSO:
And finally, medical
2
contraindications, and are there any agents that
3
could reverse the use of the drug?
4
DR. BEDDINGFIELD:
No agents would reverse
5
the use of this product, and there are no known
6
medical contraindications.
7
DR. DRAKE:
8
DR. SKELSEY:
9
Dr. Skelsey? Maral Skelsey.
Thank you.
I
wanted to give the sponsor the opportunity to
10
address the question that was raised by Dr. Wolfe,
11
I believe, on whether they're going to address
12
any -- perform any future studies to look at the
13
mechanism of action of the nerve injury.
14
DR. BEDDINGFIELD:
Just to make sure I
15
understand the question, you are wondering if we're
16
going to perform additional studies on the
17
mechanism around nerve injury?
18
DR. SKELSEY:
Yes.
The question was it's
19
likely that there's going to be off-label use of
20
this agent.
21
there is the marginal mandibular nerve injury.
22
Have you any plans to look into this mechanism?
And we don't understand exactly why
A Matter of Record (301) 890-4188
As
174
1
it was not something that occurred with the
2
placebo.
3
DR. BEDDINGFIELD:
Well, one of the
4
important things to remember about the nerve
5
injury, which we have seen and reported, is that in
6
all cases, it has resolved.
7
earlier in her comments that this is the experience
8
with liposuction as well.
9
it typically resolves, although I think in the
Dr. Glaser mentioned
When this injury occurs,
10
surgical literature, there are certainly reported
11
cases that it didn't.
12
So that's our understanding, is that this is
13
from inflammation and from the effect of the
14
deoxycholic acid on the nerve but it is temporary.
15
I'm not sure if that answered your question.
16
DR. SKELSEY:
It was a question raised about
17
what the complications might be in off-label use.
18
So I don't think that you have to address all of
19
those things, but it would important to know, I
20
think, in the future.
21 22
DR. BEDDINGFIELD:
Well, one of the
important things about this is that with an
A Matter of Record (301) 890-4188
175
1
approved product, one would have an approved label
2
with specific language around how it should be
3
used.
4
products and use them in any way, shape, or form,
5
and there are no instructions, and there's no
6
pharmacovigilance.
7
In the current setting, people can compound
So certainly, one of the benefits of an
8
approved product is that we would monitor for
9
adverse events regardless of whether they are used
10
on an on-label or off-label fashion, and we would
11
report this to the FDA.
12
signals, and we'd certainly be interested in
13
maximizing the outcomes.
14
We'd certainly look for
I think there has been -- several people
15
have mentioned the importance of training, and we
16
fully support that.
17
would want mandatory training.
18
to sell the product to people who have not been
19
trained.
20
would make as a company.
21
with specific training and instructions on the
22
label is another benefit.
And as I mentioned earlier, we We would not want
And that would be a commitment that we And again, having a label
A Matter of Record (301) 890-4188
176
1
DR. DRAKE:
Dr. DiGiovanna?
2
DR. DiGIOVANNA:
John DiGiovanna.
I have a
3
question about toxicity.
4
suggested, this is a product that will have
5
off-label use.
6
appropriately directed to Dr. Beddingfield or to
7
the FDA, or both.
8 9
As Dr. Skelsey has
And I don't know if this is
I would envision that not only for more extreme and severe submental fat, but for the same
10
material in other body locations, be they love
11
handles, or underarms, or other places, or the
12
abdomen, that there may be situations where massive
13
amounts of this product would be injected.
14
would help me if I got a sense as to what some of
15
the toxicities have been seen in various animal
16
studies or in other scenarios with injections of
17
large amounts.
18
And it
Then a second question would be, have you or
19
the FDA thought about a way to try to avoid the
20
outcomes that may have been seen with some other
21
agents with massive injections?
22
DR. DRAKE:
Please, Dr. Beddingfield.
A Matter of Record (301) 890-4188
177
DR. BEDDINGFIELD:
1
Yes.
With respect to the
2
off-label use, one of the reasons that the
3
submental fat area was chosen is because it's a
4
small area and because it has an important impact
5
on facial appearance.
6
place for use of the product.
We think it's the ideal
When one starts to get into larger areas,
7 8
treating at the abdomen, I would like to ask
9
Dr. Glaser.
I know she has a liposuction practice.
10
I think there are probably other procedures and
11
opportunities that are better, frankly.
12
settings, weight loss, liposuction, other
13
procedures are probably better.
14
bit impractical because of the number of injections
15
to use in larger areas.
In those
This is a little
16
I'll let Dr. Glaser speak to that.
17
DR. GLASER:
I think it's a very good
18
concern, but the likelihood of using this kind of
19
treatment for larger areas, I think, is relatively
20
small.
21
where you can get to large areas and large amounts
22
of fat removed at one time and contouring done, as
I think using something like liposuction,
A Matter of Record (301) 890-4188
178
1
well as the multitude of already FDA-cleared
2
devices like CoolSculpting and UltraShape and
3
others, which are really designed for those larger
4
areas.
5
love handle trying to do little injections.
I can't imagine every centimeter on a large
So I think the risk of that is relatively
6 7
low.
There are too many good procedures for those
8
areas, but we really haven't had a great procedure
9
for the submental area. DR. BEDDINGFIELD:
10
I'd also like to respond
11
to your question about the margin of safety as
12
well.
13
there's a large margin of safety.
14
reason for that is because this is an endogenous
15
molecule.
16
We're injecting 100 milligrams into the
17
subcutaneous space with an intermittent dosing of
18
at least one month apart.
19
were turned back to normal in that setting within
20
24 hours, mostly within 12 hours.
We have done preclinical models that show Part of the
The bio acid pool is roughly 3 grams.
We know that the levels
21
We have looked, though, at dosing of higher
22
amounts, and there is a less-than-dose proportional
A Matter of Record (301) 890-4188
179
1
increase in the exposure to deoxycholic
2
systemically because of the tight homeostatic
3
mechanisms for bio acids.
4
injecting twice as much doesn't give you twice as
5
much exposure systemically.
6 7 8 9
So in other words,
The other question you had -- I'm trying to remember.
I think there was one last one.
DR. DiGIOVANNA:
It really was not to what
alternative procedures are available.
It's what is
10
the toxicity of large amounts of this medication
11
should someone actually inject it in larger
12
amounts, which I think may happen.
13
DR. BEDDINGFIELD:
I think, from our
14
perspective, because this is an endogenous molecule
15
and we've studied it in larger doses than is
16
intended, and several multiples of that, I
17
think -- a QT study that we had, if you can pull up
18
the data on that.
19
In that study, we did go up to 200
20
milligrams, and that was the study where we did
21
find that there was a less-than-dose proportional
22
increase.
We also did a population PK modeling of
A Matter of Record (301) 890-4188
180
1
five studies, looking at the PK data.
2
ask Dr. Jaw-Tsai to comment on that.
3
DR. JAW-TSAI:
I'd like to
Sarah Jaw-Tsai, clinical
4
pharmacology staff from Regulatory Professionals.
5
So for the higher dose of the ATX-101, we only do,
6
as Dr. Beddingfield mentioned, up to 200 milligram.
7
At higher dose, we do modeling up to 500 milligram
8
of ATX-101, which is pretty much.
9
the number of injection you could do over in 1 hour
If you look at
10
of clinical unit, probably that's the maximum dose
11
you could deliver, is 500 milligram.
12
Then with that higher amount of ATX-101, as
13
Dr. Beddingfield mentioned, we see –non-dose
14
proportional increase in systemic exposure to DCA.
15
So with fivefold of the maximum intended dose, we
16
see twofold of additional increase in DCA level.
17
And this DCA is highly tightly regulated endogenous
18
molecule.
19
reduced to baseline level within 24 hours.
20
So it reduced, even at a high dose,
DR. BEDDINGFIELD:
Thank you.
And the other
21
piece of evidence that we have for safety comes
22
from the use of deoxycholic acid as a solubilizing
A Matter of Record (301) 890-4188
181
1
excipient.
2
excipient for phosphatidylcholine, 4.75 percent.
3
It was used intravenously in that case.
4
in the use of amphotericin, I believe it's in the
5
realm of 3 percent.
6
over months in that case.
7
of a security with respect to increasing dosing.
8 9
So in Lipostabil, it was a solubilizing
And then
And that is just chronically That also gives us some
Again, I think the most important thing is the use of an approved product with an approved
10
label, and training and pharmacovigilance
11
monitoring to look for safety signals would be
12
better than the alternative.
13
DR. DiGIOVANNA:
Do you envision having the
14
label indicate a maximum amount to be used or not
15
to be --
16
DR. BEDDINGFIELD:
Yes.
Our label obviously
17
is subject to the FDA's discussion and approvals.
18
But we are recommending a maximum of 100
19
milligrams.
20
DR. DRAKE:
Okay.
Now, I have four more
21
people that I have on my list that I want to ask
22
questions -- well, now, five, so if you could add
A Matter of Record (301) 890-4188
182
1
Dr. Matarasso.
2
some people sitting at the table that have not
3
commented, and I want to make sure that everyone at
4
this committee has an opportunity to make a
5
comment, insight, or concern, or ask a question.
6
But before I do that, there are
So for those of you who have been very
7
quiet, here I come.
Sharon Raimer, I'd like to
8
know what you're thinking about all this.
9
have comments, questions, concerns, insight?
Do you I
10
mean, you're here for a reason, because we value
11
your opinion.
12
DR. RAIMER:
I think my initial concerns
13
have all been answered.
14
concerns at this point.
15
DR. DRAKE:
16
DR. CORCORAN:
I don't have further
Thank you.
Gavin?
I have a couple of comments
17
that I wanted to make.
18
think we need to congratulate the FDA and Kythera
19
for working together on putting the endpoint scale
20
together.
21 22
I think, first of all, I
They've really done a great job of coming up with something that's meaningful, that's
A Matter of Record (301) 890-4188
183
1
reproducible, that really will give something
2
that'll be able to for clinicians that are going to
3
use the product to actually hang their hat on and
4
for future trials to be done.
5
So I think from that standpoint, I think
6
that's great data that's been put together, and I
7
think it's a nice collaboration between the FDA and
8
the company.
9
Secondly, I do think that the information
10
that's been provided certainly provides a
11
substantial amount of information that can guide
12
physicians going forward.
13
part is extremely important, and the company's
14
commitment to that is also extremely important;
15
obviously another piece of collaboration with the
16
FDA, not only on the pharmacovigilance piece but
17
also teaching physicians how to use this and making
18
sure that nobody uses it without being
19
well-trained.
20
I think the training
So all the things put together, those from
21
my standpoint, I think that there is a great amount
22
of data that's well put together and gives a nice
A Matter of Record (301) 890-4188
184
1
pathway to be able to use this product effectively.
2
DR. DRAKE:
Thank you.
3
DR. WILLIAMS:
Dr. Williams?
I think everybody would agree
4
that as physicians, our motto is do no harm.
5
think that's one of the things that we're all
6
thinking about, that it's nice that we have a new
7
product that's localized; it could do good for a
8
small area.
9
And I
But I think all of us in the background are
10
thinking we want to make sure that when this is
11
released, we've all said already that everybody
12
needs to be properly trained.
13
I think maybe a little bit more needs to be done
14
with regards to the nerve toxicity and what that
15
really means, and how that really comes into play.
16
And I think once those things are hammered out, I
17
think everybody will fill a little bit more
18
comfortable, including me.
19
DR. DRAKE:
Thank you.
Dr. Mount?
20
DR. MOUNT:
Thank you.
Actually, most of my
That's a given.
21
questions have already been addressed.
22
concern that I would have would be over the
A Matter of Record (301) 890-4188
The only
But
185
1
non-responders and particularly looking at the
2
profile of why they're not responding.
3
As we know from other areas of fat,
4
certainly gender plays a role in whether the fat is
5
more fibrous or more lipophilic.
6
if you could look into various attributes or
7
individual aspects on the people that do not
8
respond to the submental injections.
9 10 11
DR. DRAKE:
My suggestion is
Dr. Beddingfield, did you have a
comment? DR. BEDDINGFIELD:
I was just going to ask
12
Dr. Gross to discuss the non-responders, as we did
13
do an analysis to look at variables that predict
14
non-response.
15
DR. DRAKE:
Good.
16
DR. GROSS:
So very briefly, if I could have
17
the slide that compares CR, PR, and composite
18
response.
19
patients that may have dropped out of the study.
20
There's just a small percentage that do not make it
21
out to the visit time point.
22
The first category of non-responders are
Then there's actually a very small
A Matter of Record (301) 890-4188
186
1
percentage of patients where both the clinician and
2
the patient agreed that they were a non-responder.
3
This graph shows the composite endpoint on the
4
right, but it shows the clinician-rating responder
5
rate on the left and the patient-rating responder
6
rate in the middle. So you can see that 70 percent of the cases
7 8
both agreed that they were a responder.
An
9
additional 12 percent of the cases, the patient
10
thought they were a responder but the clinician did
11
not.
12
clinician thought they were a responder; the
13
patient did not.
And additional 9 percent of the cases, the
14
So these non-responders actually are quite
15
likely patients that experienced some benefit from
16
the therapy, but for one reason or another, one of
17
the raters did not give a rating that indicated a
18
1-grade improvement.
19
We also looked at age, sex, variety of other
20
demographic factors, BMI, baseline severity, and
21
again, we've only identified 2 predictors of
22
response, and of course the 2 predictors of
A Matter of Record (301) 890-4188
187
1
non-response, that is baseline severity to a slight
2
amount and then BMI.
3
a fairly consistent responder rate across those
4
categories. DR. MOUNT:
5
So in general, what we see is
And just for the follow-up
6
question, were the non-responders equally
7
represented in the MRI volumetric assessments, too?
8
I mean, was this true that the clinician and the
9
patient really weren't seeing a non-response that
10
was demonstrated via subjective or non-subjective
11
route?
12
DR. GROSS:
Inward, yes, and I'll show a
13
graphic here.
14
are the -- this is box and whiskers plot, so it
15
shows a distribution of MRI percent change within
16
various categories of subjects.
17
the placebo patients.
18
patients.
19
Here, we've got -- the gray boxes
The gray boxes are
The blue boxes are the ATX
The first category here on the left is
20
patients that are non-responders on the composite
21
endpoint.
22
reference to the blue box, is that even patients
And what you see, particularly with
A Matter of Record (301) 890-4188
188
1
that are not achieving a composite response are
2
still experiencing approximately a 5-percent
3
reduction in their MRI-based volume. So these are patients that the drug is
4 5
producing a reduction in their submental volume,
6
again simply did not rise to the level of
7
expectation of the patient and the clinician, and
8
so they fall out of the responder category.
9
you can see here by comparison and confirmation,
And
10
the placebo patients having a zero percent change,
11
which is what we've expected. DR. DRAKE:
12
Thank you.
So that I can get my
13
timing down, I have five people who still have a
14
question or comment.
15
add it to my list, so I can get my timing down
16
here?
Are there any others so I can
Who I have on the list is Brittain, Chauhan,
17 18
Gaspari, Maloney, and Matarasso.
Anybody else have
19
a comment, insight -- who else?
20
have plenty of time.
21
vote.
22
additional comments as to what you think may need
Okay.
So we'll
And then we'll go to the
And then after the vote, you can offer
A Matter of Record (301) 890-4188
189
1
to be done in the future that would really help the
2
FDA make their decisions and the sponsors address
3
your concerns. With that, I'm going to go with the order in
4 5
which they came in.
6
please. DR. BRITTAIN:
7
Dr. Brittain, you're next,
To help me understand the
8
context about the adverse events that have been
9
seen, I have two questions.
One, did you formally
10
question the patients at the end of the study about
11
their satisfaction with the treatment?
12
And B, can you show us a slide that has any hard
13
data that would compare between results and adverse
14
events comparing this treatment to surgery? DR. BEDDINGFIELD:
15
That's A.
We did ask a question on
16
satisfaction, and we're going to try to pull those
17
results up and we can show you.
18
specific questions about satisfaction.
19
regarding satisfaction with the face and chin, the
20
appearance of their face and chin.
21
SSRS.
22
itself.
We asked two One was
That was the
And the second was about the treatment
A Matter of Record (301) 890-4188
190
So I'd like to pull up the data on both of
1 2
those.
Here we have that information.
3
SSRS, at the very top, in the two studies, you can
4
see the satisfaction was 82 percent in 1 study, 75
5
in the other.
6
and chin.
7
that manner.
That is satisfaction with the face
They were specifically asked that in
The other question is about satisfaction
8 9
So the
with the treatment, and you can see we've separated
10
it there by -- that's the third question -- SGQ-3,
11
yes.
12
treatment was 77.8 percent and 75.3 percent.
And you can see the satisfaction with the
DR. BRITTAIN:
13
Were you asking them
14
essentially a risk-benefit question when you were
15
asked -- I mean about in terms of their -- I guess
16
what I'm trying to get at is if -- you know,
17
obviously a number of these patients had adverse
18
events.
19
they'd had the treatment?
20
DR. BEDDINGFIELD:
Were they still happy, overall happy that
Yes.
So this was a
21
question -- the SGQ-3 was specifically, how
22
satisfied are you with the treatment you received
A Matter of Record (301) 890-4188
191
1
in this study; whereas the first question was more
2
related to how satisfied are they with their chin.
3
So we tried to get at it in two ways.
4
data, whichever way you ask it, seems to be fairly
5
comparable.
6
But the
For many of the adverse events, we've looked
7
at the satisfaction and whether it seems to have
8
been affected.
9
high in those people with the various adverse
By and large, the satisfaction is
10
events and without it.
11
events with this treatment, while they are common,
12
they're mild, so people are generally coming back
13
for further treatments despite getting the adverse
14
event, and the satisfaction is remaining high.
15
DR. BRITTAIN:
And as you recall, adverse
And my other question was
16
about do you have a slide to show us about a
17
comparison to surgery?
18
DR. BEDDINGFIELD:
19
couldn't hear the last question.
20
DR. BRITTAIN:
I'm sorry.
I just
Do you have any hard data
21
that you can show us that would compare a surgical
22
intervention in terms of adverse events and perhaps
A Matter of Record (301) 890-4188
192
1
the outcome?
2
DR. BEDDINGFIELD:
3
comparative study versus surgery.
4
ask Dr. Glaser to come up.
5
liposuction in her practice.
6
her experiences, as well as some of the literature
7
on some of the adverse events.
8 9
We have not done a I'd just like to
I know she does do Maybe she can discuss
Some of these patients are different patients, though.
Some people don't want surgical
10
interventions, and they would like a less invasive
11
procedure.
12
Dr. Glaser?
DR. GLASER:
Dee Anna Glaser.
I do practice
13
liposuction and other procedures on the neck and
14
chin area.
15
But I think many patients are seeking noninvasive
16
procedures, and that's what this really offers
17
that's different than having to have a more
18
invasive procedure.
19
I don't do facelifts or rhytidectomies.
Even though liposuction is somewhat
20
minimally invasive.
There's a cannula going
21
through.
22
anesthetic; there's swelling; there's bruising;
The neck is hyperextended; there's an
A Matter of Record (301) 890-4188
193
1
there's numbness, very similar side effects to what
2
you might see with this.
3
experience, a little bit more.
4
patients are very excited about having an even less
5
invasive procedure.
6
Although, in my And certainly, my
I think the whole issue of the marginal
7
mandibular nerve injury has come up several times,
8
and it's an important one.
9
the collective literature on liposuction, as well
But when you look at
10
as rhytidectomies, there's a variety of ranges
11
depending on the surgical paper.
12
around 5 to 6 to 7 percent when you average them
13
all out, and this is less.
14
But it's all
Just like those procedures, when I do
15
liposuction, I warn the patient ahead of time that
16
it might happen.
17
temporary.
18
away usually within a few weeks.
19
isn't any different than what we would expect with
20
any procedure that we were doing there.
21
my patients are really looking forward to it.
22
I let them know that it's
It's generally very mild, and it goes
DR. DRAKE:
Dr. Chauhan?
A Matter of Record (301) 890-4188
So this really
So I know
194
1
MS. CHAUHAN:
I'd like to go back to
2
Dr. Matarasso's question about surgery,
3
post-treatment.
4
your study on were I think from 18 to 65, which is
5
a large age range.
6
some of those people are going to need surgery on
7
the frontal neck.
8 9
The range of people that you did
And it's highly probable that
I'm concerned about how this might interfere with healing or might not.
And you said you
10
haven't looked at it.
11
Did you look at it in your animal models?
12
it's an important thing going forward when you're
13
doing this procedure on women in their 20s or men
14
in their 20s or 30s, and they're going to live to
15
be 70 or 80.
16
Are you going to look at it?
DR. BEDDINGFIELD:
I think
We did not do studies
17
where patients did receive surgery after the
18
treatment.
19
patient could not get surgery after the procedure.
20
I'd like to ask Dr. Fagien, perhaps as a surgeon,
21
to give his opinion on that.
22
something that we specifically studied at this
We're not aware of a reason why a
But it's not
A Matter of Record (301) 890-4188
195
1
time.
We're just not aware of a reason why they
2
couldn't have surgery afterwards. MS. CHAUHAN:
3
After he speaks, I'd like to
4
know what you're planning if it's approved,
5
post-approval, to look at that or are you planning
6
to.
7
DR. FAGIEN:
Yes.
Steve Fagien again.
8
Dr. Matarasso kind of asked a similar question
9
earlier as you mentioned.
Take, for example, a
10
patient in their 20s or 30s, some of them which
11
presented today as the public with their
12
experiences.
13
We've all seen patients who have had even
14
surgery in the particular area.
15
surgery years late done well, it doesn't seem to
16
impact surgery.
17
When they have
So obviously, there's no direct experience
18
with this agent, but my guess would be -- and it
19
would be just a guess -- is that with time, there
20
will probably no significant effect on the ability
21
to have surgery at a later date.
22
We've seen the same kind of issues with
A Matter of Record (301) 890-4188
196
1
dermal fillers and neurotoxins, the concern of what
2
impact do they have on future treatment.
3
again, done appropriately in the right hands and
4
the appropriate patient, everything that we've done
5
so far with other agents suggests that future
6
surgery is not precluded.
7
would be similar to your young patient who has
8
cervical or neck liposuction who may, 10 years
9
later, decide they want a full facelift.
10
And
And I would imagine it
The effects seem to not, in most hands, be a
11
big problem, unless of course they've had a problem
12
related to a procedure.
13
completely out on that, but what we've learned with
14
other agents and other surgeries is that done well
15
in the appropriate patient doesn't seem to have an
16
impact on future surgery.
17
DR. DRAKE:
Okay.
So I think the jury is not
I'm going to interrupt
18
you a minute.
I'm very conscious of the time.
19
it's 20 until.
20
committee's indulgence to run over a little bit.
21
Is there anybody who has any objection?
22
think the discussion is quite important.
So
And I'm going to ask the
A Matter of Record (301) 890-4188
Because I
197
Does anybody have a problem if we go over
1 2
the 12 o'clock limit, say to 12:15 or something?
3
need to know that now.
4
(No response.)
5
DR. DRAKE:
6 7
that?
I
Okay, so you're all cool with
Thank you. Also, as the questioners, please ask your
8
questions in a concise manner, and just be mindful
9
that we're tight on time.
I really hate this part
10
of being the chair because I think this discussion
11
is the single most important thing we do.
12
will still come, so please feel free to ask your
13
questions, but just be mindful.
14
Next is Dr. Gaspari.
15
DR. GASPARI:
Tony Gaspari.
The vote
Many of the
16
local acting treatments of dermatologists use their
17
mechanism -- the way they work is by inducing
18
inflammation.
19
And so it's important for those two reasons,
20
understanding how the medicine works, how the
21
treatment works, and for patient counseling.
22
So we counsel patients about that.
My question is in terms of segregating the
A Matter of Record (301) 890-4188
198
1
responders and the non-responders.
2
the array of adverse events or the severity of the
3
adverse events, was there any correlation -- or did
4
you look at that, whether more pain and itching at
5
the application site was associated with a better
6
clinical response in terms of fat pad reduction?
7
DR. BEDDINGFIELD:
So in terms of
We did look at the issue
8
of whether adverse event severity or frequency
9
predicted response, and it wasn't correlated.
We
10
had the same thought that that might be related,
11
but in fact when we looked at the numbers, it
12
doesn't appear to be predictive.
13
DR. GASPARI:
It's kind of intuitive that
14
that if fat cells are sinks for inflammatory
15
mediators, the more fat cells you lyse, the more
16
release you would have.
17
FDA slide near the end, on page 22, the number of
18
AEs over time per subject seemed to go down, and
19
that kind of would support that idea.
20
correlations in your responders and non-responders
21
didn't support that idea or that line of reasoning.
22
DR. BEDDINGFIELD:
And along the lines, the
But your
Well, it didn't.
A Matter of Record (301) 890-4188
We
199
1
tried to look at it.
And here's just one of the
2
analyses that we did.
3
pain and subjects without pain, and looked at their
4
response rate.
5
whether or not they had pain.
We looked at subjects with
You can see that they're identical,
So you might guess, based on the logic that
6 7
you have, which we had the same thought, that more
8
pain might mean there's more effect going on, and
9
therefore those would be more likely to respond,
10
but it turns out it didn't work that way. But we also did the analysis as the FDA did,
11 12
and we did see that the rates of AEs do go down
13
over time.
14
treatment session and they go down over time after
15
that.
16
So they're highest with the first
Just one bit of follow-up on the issue of
17
the nerve injury.
We did look at this in
18
preclinical models.
19
we found -- I'd like to have Dr. Robyn Phelps
20
discuss what's been seen in the preclinical models.
21
I didn't want to leave the panel with the
22
impression that this has not been looked into the
We have evaluated it, and what
A Matter of Record (301) 890-4188
200
1
animal setting.
2
I'll defer Dr. Phelps.
3
I'm not an expert in that area, so
DR. PHELPS:
Dr. Robyn Phelps.
4
clinical consultant.
5
I'm fighting laryngitis.
6
I'm a
My apologies for my voice;
We conducted volume concentration, injection
7
frequency, induration studies to see what the
8
relative correlation was between those.
9
duration -- sorry -- volume of injection did not
The
10
increase the locally mediated effects.
The effects
11
are related to concentration and frequency of
12
injection.
13
the animal studies until approached concentrations
14
greater than 12 percent.
So we did not see any nerve damage in
15
DR. DRAKE:
Thank you.
16
All right.
We're getting closer to the end.
17 18
Dr. Maloney, then Matarasso, and then Dr. Alam. DR. MALONEY:
I'm going to try and be very
19
brief with the comment, but I do have to quote my
20
mother who is an accountant.
21
"figures don't lie but liars do figure."
22
feel very much sort of that way about this product
She used to say that
A Matter of Record (301) 890-4188
And I
201
1
and many other products that have good indications
2
and a good safety profile when they're used
3
correctly.
4
I have to disagree with Dr. Glaser.
5
that people who don't do liposuction and they don't
6
have a lot of tools in their box do in fact use
7
things that they shouldn't use because they can.
8
But I'm not sure that we, sitting here, can keep
9
them from doing that any more than my mother could
10
I think
keep liars from figuring. I think we have to be mindful of toxicities
11 12
and be very aware of that kind of thing.
13
think there are some things that are out of our
14
control, and I think we have to sort of let go of
15
that at some point. DR. DRAKE:
16
But I
Thank you. Thank you, Mary.
By the way,
17
that was an appropriate comment.
18
things in proper perspective, so thank you very
19
much.
20
It helps keep
Dr. Matarasso? DR. MATARASSO:
Dr. Alan Matarasso.
I have
21
one comment and a question for the FDA.
22
comment is a point of clarification on Dr. Glaser's
A Matter of Record (301) 890-4188
The
202
1
quote.
2
mandibular injury.
3
could be correlated with swelling; it could be
4
directly neurotoxic such as demyelinization, or a
5
needle injection injury.
6
resolve spontaneously.
7
it, but I would comment that the 5 to 6 percent
8
marginal mandibular rate, even on open surgery, is
9
unacceptably high.
10
I'm less concerned about the marginal I think it's either -- probably
But I think they all I'm not that concerned with
That's an inaccurate number.
My question is for the FDA.
I'm not sure
11
which representative should answer this, but the
12
original published studies on DCA, there's been an
13
appropriate concern about large volumes of the use
14
of this drug elsewhere in the body.
15
However, the original published studies on
16
DCA were done on aging eyelids.
17
fat that gives people that tired appearance.
18
that FDA aware of these studies?
19
application is for submental fat, undoubtedly, it
20
will be used off-label elsewhere as has been
21
reflected by the questions.
22
That's herniated Is
And although this
What is the FDA's position on its use around
A Matter of Record (301) 890-4188
203
1
the eye in similar small volumes as we would expect
2
in the submental area? DR. DRAKE:
3 4
Anybody?
Who's going to take
that question? DR. MARCUS:
5
I'm just asking my colleagues
6
for a little clarification prior to responding so
7
bear with me, please. DR. DRAKE:
8 9
time.
That's fine.
Please take your
In the meantime, while they're having a
10
little offside discussion, in just a moment, the
11
question will be put before you.
12
some of my reminders now while they're talking.
13
The question will be before, and you'll push your
14
little buttons.
15
vote.
16
And I can just do
You'll say yes, no.
You'll just
The vote will be private until it's closed.
17
And then at that point in time, it'll be open and
18
Lieutenant Commander Shepherd here will talk about
19
how we voted.
20
around the room right quick and ask for any
21
additional comments or suggestions that you might
22
have to help the FDA and the sponsor move forward
And then you'll be asked -- we'll go
A Matter of Record (301) 890-4188
204
1
or backwards, or whatever you guys decide.
2
then we'll do the same with the second question.
3
Okay.
4
DR. MARCUS:
And
Are you ready? Yes.
I was getting some
5
information as to whether we were aware of the
6
studies that were conducted around the eye.
7
I understand, we have not received or reviewed that
8
data.
9
this with reviewing data that is restricted to the
And as
We do approach limited indications such as
10
indication and taking action on that available data
11
without requiring evaluation of the product for a
12
potential off-label use.
13
If the product receives marketing approval
14
and it is marketed, and we receive substantial
15
post-marketing data indicating significant safety
16
issue with an off-label use, we would consider
17
restricting use of the product in some way with
18
measures that might include labeling, might include
19
additional labeling and communication to healthcare
20
providers, or might include actually restricting,
21
in some form or way, the distribution of the
22
product.
A Matter of Record (301) 890-4188
205
1
At this time, we can certainly consider
2
prominently labeling the product prior to
3
marketing, as one approach to minimizing any risk
4
that the product be used off-label.
5
time, I guess I would venture to say in the context
6
of all of the discussion about risk of injury to
7
the mandibular nerve, that at this point, we don't
8
have any cases reported of permanent injury or
9
disability that have resulted from use of the
10 11
At the current
product. I do acknowledge that education on proper
12
use of the product appears to be very important to
13
minimizing such risks, and I think we've heard from
14
the product sponsor, their commitment to education
15
of people that will be interested in using the
16
product for their patient populations.
17
certainly take all of this into consideration when
18
we review marketing applications.
19 20 21 22
DR. DRAKE:
Thank you very much.
And we
Last
question, Dr. Alam? DR. ALAM:
It's more of a comment, but I
will try to be brief.
I just wanted commend both
A Matter of Record (301) 890-4188
206
1
the FDA and the sponsor for really a very thorough
2
evaluation.
3
seem to be very aware of all of the adverse events.
I think the sponsor in particular does
I also wanted to just place this in context,
4 5
which I think has been alluded to already, that
6
this drug, not as a drug but as a compounded
7
formulation, has been in wide usage in the U.S. and
8
elsewhere for many years. So we do have some data, albeit not very
9 10
well codified on its effectiveness.
11
reason why we are going through this process is to
12
get a better sense of safety.
13
things that happen with the compounded formulation,
14
like terrible infections, clearly don't happen
15
here.
16
mandibular nerve palsy that is completely remitting
17
within a reasonable interval, which is something
18
that is seen at whatever rate with other procedures
19
similarly.
20
And the real
Some of the very bad
And the worst thing we're talking about is
So I think, in my opinion, the safety
21
profile has been shown to be very good.
22
certainly agree that we can't necessarily say much
A Matter of Record (301) 890-4188
I would
207
1
about off-label use.
2
major abuse, FDA might step in, but realistically
3
we have a drug potentially for a specific
4
indication for which it seems to be very safe and
5
well-tolerated, and the SAEs are really negligible.
6
Obviously, if there's some
So I feel very satisfied, and I think the
7
fact that we're talking about relatively minor
8
problems is indicative of the fact that there are
9
not really any major problems.
10
DR. DRAKE:
Very nice.
11
a summary statement there.
You just sort of did
Cool.
12
With that, I think -- unless there's
13
something really urgent, is that all right with the
14
committee?
15
move forward to a vote?
16
Do I have the committee's permission to Cool.
May I have the question back up, please?
I
17
want to draw your attention to the background for
18
consideration, and this relates to what some of the
19
things that have been said around the table most
20
recently.
21
Please note that a vote for approval, in
22
general terms, does not mean that you must agree
A Matter of Record (301) 890-4188
208
1
with the proposed dosing, recommendation, or
2
proposed labeling.
3
I've said, by the FDA and the sponsor.
4
our responsibility.
5
That will all be worked out, as That's not
With that, I'm going to call for the
6
question.
7
read the question so that everybody totally
8
understands it.
9
I want to ask Lieutenant Commander to
LCDR SHEPHERD:
The question is, do the
10
efficacy and safety data provided to you today
11
support the approval of deoxycholic acid injection
12
for the improvement in the appearance of moderate
13
to severe convexity or fullness associated with
14
submental fat?
15
DR. DRAKE:
16
yes or no.
17
vote closed now?
So you've got buttons that say
Would you please push one?
Has the
18
(Vote taken.)
19
So we have 17 yes, zero noes, zero abstains,
20
and zero no voting.
That's pretty clear cut.
21
think now we go around the room and record the
22
vote -- is that correct-- verbally.
A Matter of Record (301) 890-4188
I
Just to make
209
1
sure it's clear, please state your name for the
2
record and your vote.
3
down there?
4
DR. CORCORAN:
5
DR. DRAKE:
6 7
Of course.
Dr. Gavin, would you start
I don't vote.
Oh, you don't vote.
Excuse me.
Dr. Murphy, would you please start?
DR. MURPHY:
I obviously voted in the
8
affirmative.
I've thought this was a nicely
9
presented and controlled exercise.
Going forward,
10
my concerns would only be the use of it in the
11
periorbitum.
12
we don't have any indication of how the timing of
13
that or whatever.
And if there is a second treatment,
14
Congratulations to both the FDA and the
15
company for a nice study, but I think there are
16
some open-ended questions that need to be
17
considered going forward.
18
DR. DRAKE:
19
DR. MATARASSO:
20
DR. DRAKE:
21
DR. MATARASSO:
22
DR. MRZLJAK:
Thank you. I voted yes.
Name?
Name please?
Alan Matarasso. I'm Vesna Mrzljak.
A Matter of Record (301) 890-4188
I voted
210
1
yes.
2
DR. DRAKE:
3
DR. ALAM:
4
Thank you. I'm Mural Alam.
I voted yes.
thought it was shown to be both safe and effective.
5
DR. SKELSEY:
6
DR. BERGFELD:
Maral Skelsey.
I voted yes.
Wilma Bergfeld.
I voted yes.
7
I had only one additional question.
8
acid, I don't believe it isn't reversible.
9
like to have reversible looked into by the FDA. Sharon Raimer.
Since it is an
10
DR. RAIMER:
11
MS. CHAUHAN:
Cynthia Chauhan.
12
DR. MALONEY:
Mary Maloney.
13
DR. DRAKE:
14
DR. WILLIAMS:
15
Lynn Drake.
I would
I voted yes. I voted yes.
I voted yes.
I voted yes.
Carmen Williams.
I voted
yes.
16
DR. BILKER:
17
DR. BRITTAIN:
18
DR. GASPARI:
19
DR. DiGIOVANNA:
20
I
Warren Bilker.
I voted yes.
Erica Brittain, voted yes. Tony Gaspari.
I voted yes.
John DiGiovanna.
I voted
yes.
21
DR. MOUNT:
22
DR. ORLOFF:
Delora Mount.
I voted yes.
Lisa Orloff.
I voted yes.
A Matter of Record (301) 890-4188
211
DR. DRAKE:
1
Thank you.
We've moved so
2
quickly through that voting thing.
Is there
3
anybody that has a -- the second part of that
4
question -- well, there's no no-vote, so I don't
5
have to worry about that. I would also like to ask, do you have any
6 7
specific comment -- let me just move on to
8
question 2, and then I'll do the last thing.
9
move to question 2.
I'm going to ask our
10
Lieutenant Commander here to please read the
11
question. LCDR SHEPHERD:
12
Let's
Do the members of the
13
committee have any comments on the approach, which
14
was developed for evaluation of safety and efficacy
15
for this novel indication?
16
DR. DRAKE:
And so this is not actually a
17
vote.
18
quite a few suggestions, but you have some others
19
that haven't been spoken to?
20
This is a discussion.
DR. DiGIOVANNA:
I think we've heard
Yes, John?
John DiGiovanna.
I think
21
it's an interesting approach for development of a
22
grading system.
My concern is that the endpoints
A Matter of Record (301) 890-4188
212
1
are very subjective.
I think depending upon how
2
the patient and physician grading is executed, it
3
makes it a little bit difficult to be really sure
4
that it would be reproducible. I think, in this particular scenario, the
5 6
company and the FDA have done a very good job of
7
adding in an objective measurement of an MRI scan.
8
And I think that it would be wise to take an
9
additional look at what other objective
10
measurements might be useful going forward for
11
additional products that may have similar
12
indications, which are based on appearance, in
13
order to have better objective measurements. DR. DRAKE:
14
Other comments?
15
for you to make your comments.
16
sorry.
17
first, and then Dr. Alam.
18
I misspoke.
DR. BRITTAIN:
This is a time
Dr. Alam -- I'm
Dr. Brittain had her hand up
Yes.
Yes.
Sorry.
I guess I would second
19
the idea of it's important to have objective
20
measurements.
21
but anything more that can be done, I think would
22
be useful, and especially with the potential for
That was very good to have the MRI,
A Matter of Record (301) 890-4188
213
1 2
unblinding with the adverse events. This is probably pretty obvious, but I think
3
these trials show the importance of the placebo
4
control because you saw the event, what looked
5
like -- if you had only seen that one arm, you
6
might've thought, "Gee, those patients got better,"
7
and it's only in comparison to placebo that you can
8
interpret the results.
9 10
DR. DRAKE:
Other comments?
DR. CORCORAN:
One comment that I wanted to
11
make is I think it's very difficult to find decent
12
endpoints when you're trying to get a surgical
13
outcome with a medical procedure.
14
it makes it really difficult because these are very
15
subjective.
16
And so I think
But I do think -- again, I would like to
17
echo the comments about I think the FDA and the
18
company worked very well together to be able to try
19
to define something clearly focused on the product,
20
which was what the end game was here.
21
might be a larger scale or a different scale that
22
may need to be done.
A Matter of Record (301) 890-4188
And there
214
1
But I think it's always going to be
2
difficult when you get to a point where you're
3
trying to measure kind of a surgical outcome for a
4
medical procedure.
5
DR. DRAKE:
6
DR. ALAM:
And so it's somewhat difficult. Dr. Alam? I think we have to be careful
7
because it is a very subjective measure.
And so if
8
we have primary reliance on an objective measure,
9
we could have an objective measure that detects the
10
difference that patients don't perceive or that
11
fails to detect the differences that patients do
12
perceive.
13
standard really is what the patient sees.
14
And for aesthetic indications, the gold
I think it is very important, to your point
15
though, that it be very unbiased, that our
16
detection of that subjective measure be robust and
17
unbiased.
18
that the company consider publishing the full
19
validation of their scale so everyone can see how
20
it works.
And to that end, I would gently suggest
21
DR. DRAKE:
Dr. Orloff?
22
DR. ORLOFF:
Yes.
I just would like to echo
A Matter of Record (301) 890-4188
215
1
the comments of -- and applaud the collaborative
2
efforts between the sponsor and the FDA.
3
since the question is asking about evaluation of
4
safety -- the methods for evaluating safety and
5
efficacy, I sense the commitment of the sponsor to
6
the training that is offered for use of this
7
product if it's approved.
8 9
I think
I think about other injectables and the -- it's not accurate in all senses to compare
10
surgical procedures with injectable procedures when
11
the description -- similar to what Dr. Maloney said
12
about her mother's adage that you can load up a
13
syringe but you can't control where something goes
14
after you inject it.
15
your children, raise your children a certain way,
16
but you can't control where they go after they
17
leave your hands or your injection.
18
It's similar to you can train
The training, I'm hoping, will involve
19
emphasis because there was probably the majority of
20
the debate about adverse events related to the
21
nerve injury and the possibility that the mechanism
22
of injection and the manner in which the product is
A Matter of Record (301) 890-4188
216
1
actually delivered will be a part of that training
2
process.
3
commitment, so I would just encourage the ongoing
4
efforts and collaboration in that regard.
And I do sense that there's that
DR. DRAKE:
5
Nobody else has any comments?
6
Oh, my goodness.
I guess you're hungry.
All
7
right.
8
going to be hard because you -- I have to say --
So it's my job now to summarize -- it's
The first thing I'm going to say in my
9 10
summary is this committee has been a pleasure to
11
work with.
12
intelligence, and the questions, and the
13
thoughtfulness that went into it, it's just been
14
amazing.
15
presentations were very helpful.
I mean the diversity, and the
And I also think that audience's
But this committee, I've participated in
16 17
many of these and chaired many, and I have to tell
18
you, this is absolutely one of the best because it
19
was so thoughtfully done and so professionally
20
done.
21
together such a good committee.
22
you for your wonderful preparation and
I also want to thank the FDA for putting
A Matter of Record (301) 890-4188
I want to thank
217
1
presentation. I want to thank the sponsor.
2 3
right on.
4
concise.
5
think many, many things about this was very well
6
done, and I particularly echo the comment about the
7
collaboration between the FDA and the sponsor.
It was factual.
It was
It was scientific.
I think this was exceptional.
8 9
I mean you presented it.
You guys were
I
In my
experience, this was an exceptional collaboration
10
and well done.
11
that.
Well done.
I just have to tell you
12
Now, to go on to the -- I think the
13
committee has validated that it's our opinion, and
14
we're an advisor, but I think it's validated that
15
this is both safe and effective.
16
there aren't some questions that have to be
17
answered.
18
there's an unmet clinical need that this product
19
will specifically address and will help lots of
20
people.
21 22
That doesn't mean
I think it's been clearly identified
I mean we sometimes underestimate self-esteem and self-worth and how important these
A Matter of Record (301) 890-4188
218
1
little things are, and yet they're really important
2
to patients.
3
who all deal in aesthetics at some level clearly
4
understand that.
I think those of us around this table
Just because you're not having a heart
5 6
attack and dying, it doesn't mean it's not
7
important to you.
8
we've grappled with.
9
want to make sure the risk-benefit ratio is
I think this is exactly what
10
appropriate.
11
certainly clearly is.
We grapple with it because we
And I believe in this instance, it I'm very happy about that.
I love the -- can I tell you what I really
12 13
liked?
14
create new endpoints.
15
effort to create new endpoints on something that
16
didn't have predefined endpoints; really a good
17
job.
18
chart.
19
for wet macular degeneration, and it's so simple,
20
and yet it was so nice.
21 22
I liked the fact that you guys had to It was a collaborative
I particularly liked the little graphic The ophthalmologists use that sort of thing
I like the fact very much that you had some objective data with the MRIs.
A Matter of Record (301) 890-4188
And I would like to
219
1
add just one comment to the sponsor.
2
want to look at some of the new imaging
3
technologies that are out there today.
4
Mass General, we have some imaging technologies
5
that are just incredible that can give you the -- I
6
mean, some of them aren't even out yet, but they're
7
so incredible.
8 9
You guys may
I know at
Like there's OC, optical clearance tomography, is a good one, but we've got steps past
10
that, ODIF.
11
technologies that might really be useful in
12
answering some of the questions.
13
I mean, there's all kinds of imaging
The committee has expressed a concern about
14
off-label use, and that's important.
15
that's important because what we don't want people
16
doing is going off-label.
17
control it, but we can try to deal with it in the
18
label as much as possible.
19
I think
As Mary said, you can't
I also think that training has surfaced as a
20
major, major issue.
Without appropriate training,
21
this product could be misused, and mishandled, and
22
cause damage.
On the other hand, if used properly
A Matter of Record (301) 890-4188
220
1
with appropriate training and appropriate
2
precautions, I think it's helpful.
3
I do think some of the novel measurement
4
tools for people to administer it, the little
5
roadmap if you -- I call it a little roadmap that
6
you put on the chin -- I thought they're some very
7
novel things in the design of this that will help
8
all kinds of users out there to protect the
9
patients, and it'll help the users or the docs who
10 11
are using this. I'd love the suggestion about validating the
12
scale because I think the scale -- I think the
13
stuff that the sponsor and the FDA -- the fact that
14
you guys went through all this new method of
15
validating this particular indication and looking
16
at these endpoints, that should be published
17
because it could help in all kinds of arenas.
18
like that a lot.
19
I
I do think there's probably a need for
20
phase 4 data because everybody's brought up the
21
concern, is this going to cause some kind of
22
scarring that may impact future surgeries or future
A Matter of Record (301) 890-4188
221
1
interventions?
I agree that I doubt it, but on the
2
other hand, it's always smart to pay attention to
3
those kind of things so that if signals come
4
percolating up, it can be identified early and
5
addressed early. I think that kind of exhausts my summary.
6
I
7
would like to ask everybody at this table to please
8
add to it because the FDA will go by my summary a
9
lot, and so I want to make sure I've expressed your
10
opinions and your concerns in this summary that I
11
just gave. Did I miss something?
12
My ego is not in
13
this.
14
something, please speak up now.
15
If I missed something or you want to correct
(No response.) Adjournment
16 17
DR. DRAKE:
Well, that was cool.
18
(Laughter.)
19
Well, we did pretty good.
We finished
20
almost on time.
Once again, congratulations.
21
was just a superb, superb meeting, and it's been a
22
real pleasure working with all of you.
A Matter of Record (301) 890-4188
This
Thank you
222
1
so much. The committee will reconvene at 1:00 to
2 3
consider another issue, and thank you so much once
4
again.
5
Excuse me.
May I interrupt one moment, the
6
committee?.
7
your attention for one moment?
8
all something.
9
absolutely, hugely important.
10
May I have your attention?
May I have
I need to tell you
I forgot to do something that was I always end up
missing the biggest thing.
11
I'd like you to give Lieutenant Commander
12
Shepherd, Jennifer Shepherd, a round of applause.
13
She handled this with such great dignity.
14
mindboggling.
15
(Applause.)
16
DR. DRAKE:
17 18 19
She just got applauded.
It's
Thank
you, guys. (Whereupon, at 12:10 p.m., the morning session was adjourned.)
20 21 22
A Matter of Record (301) 890-4188
View more...
Comments
