FOOD AND DRUG ADMINISTRATION
1
CENTER FOR DRUG EVALUATION AND RESEARCH
2 3 4
ENDOCRINOLOGIC & METABOLIC DRUGS
5
ADVISORY COMMITTEE MEETING
6 7 8 9 WEDNESDAY, FEBRUARY 22, 2011 10 8:00 a.m. to 5:00 p.m. 11 12 13 14
FDA White Oak Campus
15
White Oak Conference Center
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Building 31, The Great Room
17
Silver Spring, Maryland
18 19 20 21 22
Meeting Roster
1
DESIGNATED FEDERAL OFFICER (Non-Voting)
2
Paul T. Tran, R.Ph.
3
Division of Advisory Committee and 4
Consultant Management 5
Office of Executive Programs, CDER, FDA 6
7
ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE MEMBERS
8 (Voting) 9 Erica H. Brittain, Ph.D. 10 Mathematical Statistician 11
Biostatistics Research Branch 12
National Institute of Allergy and Infectious Diseases 13
(NIAID), National Institutes of Health (NIH) 14 Bethesda, Maryland 15 16 David M. Capuzzi, M.D., Ph.D. 17
Professor of Medicine and Biochemistry 18
Thomas Jefferson University & 19
Lankenau Institute for Medical Research 20
Philadelphia, Pennsylvania 21
Eric I. Felner, M.D., MSCR
1
Associate Professor of Pediatrics 2
Division of Pediatric Endocrinology 3
Director, Pediatric Endocrinology Fellowship Program 4
Emory University School of Medicine 5 Atlanta, Georgia 6 7 Edward W. Gregg, Ph.D. 8
Chief, Epidemiology and Statistics Branch 9
Division of Diabetes Translation 10
Centers for Disease Control and Prevention (CDC) 11
Atlanta, Georgia 12
13
Abraham Thomas, M.D., M.P.H., FACP (Chair)
14
Division Head, Endocrinology, Diabetes, Bone, and Mineral 15
Disorders 16
Henry Ford Hospital 17
Whitehouse Chair of Endocrinology 18 Detroit, Michigan 19 20 21 22
Lamont G. Weide, M.D., Ph.D., FACE
1
Chief, Diabetes & Endocrinology 2
Professor, Internal Medicine 3
University of Missouri - Kansas City 4
Truman Medical Centers, Diabetes Center 5
Kansas City, Missouri 6
7
ACTING INDUSTRY REPRESENTATIVE TO THE COMMITTEE
8
(Non-Voting)
9
Mads F. Rasmussen, M.D., Ph.D.
10
(Acting Industry Representative)
11
Executive Director 12
Diabetes - Clinical Development and Research 13
Clinical Development, Medical and Regulatory Affairs 14
Novo Nordisk Inc. 15
Princeton, New Jersey 16
17
TEMPORARY MEMBERS (Voting)
18
Kenneth D. Burman, M.D.
19
Chief, Endocrine Section 20
Washington Hospital Center 21
Washington, District of Columbia 22
Robert R. Clancy, M.D.
1
Professor of Neurology and Pediatrics
2
The University of Pennsylvania School of Medicine
3
The Children's Hospital of Philadelphia
4
Philadelphia, Pennsylvania 5
6
Melanie Coffin (Patient Representative)
7
Washington, District of Columbia
8 9
Janet D. Cragan, M.D., M.P.H.
10
National Center on Birth Defects and Developmental
11
Disabilities
12
Division of Birth Defects and Developmental Disabilities, CDC 13 Atlanta, Georgia 14 15 Katherine M. Flegal, Ph.D. 16
Senior Research Scientist
17
Distinguished Consultant
18
National Center for Health Statistics, CDC
19
Hyattsville, Maryland 20
21 22
Allison B. Goldfine, M.D.
1
Assistant Director of Clinical Research
2
Joslin Diabetes Center, Research Division
3 Boston, Massachusetts 4 5 Jessica W. Henderson, Ph.D. 6
(Acting Consumer Representative) 7
Professor of Community Health Education
8
Division of Health and Physical Education
9
Western Oregon University
10 Monmouth, Oregon 11 12 Sanjay Kaul, M.D. 13
Director, Fellowship Training Program in
14
Cardiovascular Diseases
15
Cedars-Sinai Heart Institute
16
Professor, David Geffen School of Medicine at UCLA
17
Division of Cardiology
18
Cedar Sinai Medical Center
19
Los Angeles, California 20
21 22
Michael S. Lauer, M.D., FACC, FAHA
1
Director
2
Division of Cardiovascular Sciences
3
National Heart, Lung, and Blood Institute
4 (NHLBI), NIH 5 Bethesda, Maryland 6 7 Elaine H. Morrato, Dr.PH., M.P.H., C.P.H. 8 Assistant Professor 9
Departments of Health Systems, Management & Policy
10
Clinical Pharmacy and Pediatrics
11
Assistant Director
12
Children’s Outcomes Research Program
13
Anschutz Medical Campus
14 University of Colorado-Denver 15 Aurora, Colorado 16 17
TEMPORARY MEMBERS (Voting)
18
Sonja A., Rasmussen, M.D., M.S.
19
Deputy Director 20
Influenza Coordination Unit, CDC 21
Atlanta, Georgia 22
Michael A. Rogawski, M.D., Ph.D.
1
Professor and Chair, Department of Neurology
2
University of California, Davis
3 Sacramento, California 4 5 Robert J. Smith, M.D. 6
Professor of Medicine (Endocrinology)
7
Alpert Medical School of Brown University
8
East Providence, Rhode Island 9
10
Myrlene A. Staten, M.D.
11
Senior Advisor, Diabetes Translational Research
12
Division of Diabetes, Endocrinology and Metabolism
13
National Institute of Diabetes and Digestive and
14
Kidney Diseases (NIDDK), NIH
15 Bethesda, Maryland 16 17 18 19 20 21 22
Almut G. Winterstein, Ph.D.
1
Associate Professor
2
Pharmaceutical Outcomes & Policy (POP)
3
College of Pharmacy
4
Epidemiology & Biostatistics
5
College of Public Health and Health Professions
6 Gainesville, Florida 7 8 Susan Z. Yanovski, M.D. 9
Co-Director, Office of Obesity Research 10
Director, Obesity and Eating Disorders Program 11
NIDDK, NIH Bethesda, Maryland 12 13 SPEAKER (Non-Voting) 14 Suzanne M. Gilboa, Ph.D. 15
National Center on Birth Defects and Developmental 16 Disabilities, CDC 17 Atlanta, Georgia 18 19 20 21 22
FDA PARTICIPANTS (Non-Voting) 1 John K. Jenkins, M.D. 2 Director 3
Office of New Drugs, CDER, FDA 4 5 Mary H. Parks, M.D. 6 Director 7
Division of Metabolism and Endocrinology Products
8
(DMEP)
9
Office of Drug Evaluation II (ODE II)
10
OND, CDER, FDA 11 12 Eric C. Colman, M.D. 13 Deputy Director 14
DMEP, ODE II, OND, CDER, FDA 15 16 Mary D. Roberts, M.D. 17 Clinical Reviewer 18
DMEP, ODE II, OND, CDER, FDA 19
20 21 22
Joyce Weaver, Pharm.D.
1
Senior Drug Risk Management Analyst
2
Division of Risk Management
3
Office of Medication Error Prevention and Risk
4
Management (OMEPRM)
5
Office of Surveillance and Epidemiology (OSE)
6
CDER, FDA 7
8
Claudia B. Karwoski, Pharm.D.
9
Director, Division of Risk Management
10
OMEPRM, OSE, CDER, FDA 11 12 13 14 15 16 17 18 19 20 21 22
C O N T E N T S
1
AGENDA ITEM PAGE
2
Call to Order and Introduction of Committee
3
Abraham Thomas, M.D., M.P.H., FACP 15
4
Conflict of Interest Statement
5 Paul Tran, R.Ph. 20 6 Introduction/Background 7 Eric Colman, M.D. 25 8
Sponsor Presentation – Vivus, Inc.
9
Introduction
10
Peter Tam 31
11
Review and Efficacy
12 Wesley Day, Ph.D. 40 13 Review of Safety 14 Neil Gesundheit, M.D., M.P.H. 51 15
Review of Cardiovascular Safety
16 Peter Kowey, M.D. 59 17 Review of Teratogenicity 18 Gary Shaw, Ph.D. 71 19
Clinical Perspective on Teratogenicity
20
Anthony Scialli, M.D. 82
21 22
C O N T E N T S (continued)
1
AGENDA ITEM PAGE
2
Cardiovascular Perspective
3
A. Michael Lincoff, M.D. 85
4
Medical Need and Risk Benefit
5
Arya Sharma, M.D., Ph.D., D.Sc. 93
6
Clarifying Questions from the Committee 99
7
FDA Presentation
8
Review of Phentermine/Topiramate
9
(PHEN/TPM) Efficacy and Cardiovascular Safety
10
Mary Roberts, M.D. 125
11
Speaker Presentation
12
Use of Monotherapy Topiramate in Pregnancy
13
and Risk of Oral Clefts
14
Suzanne Gilboa, Ph.D. 145
15
FDA Presentation
16
Review of Studies on Topiramate Use in
17
Pregnancy and Risk of Oral Clefts and Major
18
Congenital Malformations
19
Julia Ju, Pharm.D., Ph.D. 162
20 21 22
C O N T E N T S (continued)
1
AGENDA ITEM PAGE
2
Risk Management Options for
3
Phentermine/Topiramate
4
Joyce Weaver, Pharm.D. 172
5
Sponsor Presentation – Vivus, Inc.
6
Qnexa REMS
7
Barbara Troupin, M.D. 182
8
Clarifying Questions from the Committee 198
9
Opening Public Hearing Session 238
10
Clarifying Questions from the
11
Committee (continued) 282
12
Questions to the Committee and
13 Committee Discussion 312 14 Adjournment 427 15 16 17 18 19 20 21 22
P R O C E E D I N G S
1
Call to Order
2
DR. THOMAS: Good morning. I would first
3
like to remind everyone present to please silence
4
your cell phones, Blackberrys, and other devices if
5
you've not already done so. I'd also like to
6
identify the FDA press contact, Morgan Liscinsky.
7
If you're present, please stand.
8
Good morning. My name is Abraham Thomas.
9
I'm the chair of the Endocrinologic and Metabolic
10
Drugs Advisory Committee. I will now call the
11
meeting of the Endocrinologic and Metabolic Drugs
12
Advisory Committee to order. We will go around the
13
room and please introduce yourself. We will start
14
with the FDA and Dr. Mary Parks to my left and go
15
around the table.
16
DR. PARKS: Good morning. I'm Mary Parks,
17
director of the Division of Metabolism and
18
Endocrinology Products.
19
DR. COLMAN: I am Eric Colman, the deputy
20
from that division.
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DR. ROBERTS: Mary Roberts, clinical
reviewer, Division of Metabolism and Endocrine
1
Products.
2
DR. WEAVER: Joyce Weaver, risk management
3
analyst, Division of Risk Management.
4
DR. MORRATO: Good morning. I'm Elaine
5
Morrato from the Colorado School of Public Health.
6
I'm an epidemiologist in the Department of Health
7
Systems Management and Policy.
8
DR. KAUL: Good morning. I'm Sanjay Kaul.
9
I'm a cardiologist at Cedars-Sinai Medical Center
10
in Los Angeles.
11
DR. CRAGAN: Hi. I'm Janet Cragan from the
12
Birth Defects branch at CDC.
13
DR. CAPUZZI: Hi. I'm David Capuzzi at
14
Thomas Jefferson University in Philadelphia.
15
DR. WEIDE: Lamont Weide, chief of
16
endocrinology, University of Missouri Kansas City
17
and Truman Medical Centers.
18
DR. YANOVSKI: I'm Susan Yanovski. I'm from
19
the National Institute of Diabetes and Digestive
20
and Kidney Diseases, NIH.
21
DR. ROGAWSKI: Good morning. I'm Michael
Ragowski. I'm professor of neurology at the
1
University of California Davis Medical Center in
2
Sacramento, California.
3
DR. BRITTAIN: I'm Erica Brittain. I'm a
4
statistician at the National Institute of Allergy
5
and Infectious Diseases.
6
DR. THOMAS: I'm Abraham Thomas, division
7
head of endocrinology at Henry Ford Hospital in
8
Detroit, Michigan.
9
MR. TRAN: Paul Tram, the designated federal
10
officer for the EMDAC committee.
11
DR. BURMAN: Ken Burman, head of
12
endocrinology at the Washington Hospital Center and
13
professor of medicine at Georgetown University.
14
DR. HENDERSON: Jessica Henderson, consumer
15
representative from Oregon.
16
DR. FELNER: Eric Felner, associate
17
professor of pediatrics, division of pediatric
18
endocrinology at Emory University in Atlanta.
19
DR. GREGG: Ed Gregg. I'm an epidemiologist
20
from the diabetes division at CDC in Atlanta.
21
DR. RASMUSSEN: Sonja Rasmussen. I'm a
pediatrician and clinical geneticist from CDC.
1
DR. WINTERSTEIN: Good morning. I'm Almut
2
Winterstein. I'm a pharmacoepidemiologist at the
3
University of Florida.
4
DR. STATEN: Hello, Myrlene Staten, NIDDK,
5
NIH.
6
MS. COFFIN: Hi, Melanie Coffin, patient
7
representative.
8
DR. LAUER: Mike Lauer. I'm a cardiologist
9
and a clinical epidemiologist, and I direct the
10
division of cardiovascular sciences at the National
11
Heart, Lung, and Blood Institute of the NIH.
12
DR. SMITH: I'm Robert Smith. I'm professor
13
of medicine at the medical school at Brown
14
University, former director of endocrinology there.
15
DR. FLEGAL: I'm Katherine Flegal,
16
epidemiologist from the National Center for Health
17
Statistics, CDC.
18
DR. CLANCY: I'm Robert Clancy, professor of
19
neurology and pediatrics at the Children's Hospital
20
of Philadelphia at the University of Pennsylvania.
21
DR. GOLDFINE: Allison Goldfine. I'm an
associate professor at Harvard Medical School and
1
head of clinical research at the Joslin Diabetes
2
Center, Boston.
3
DR. RASMUSSEN: Good morning. I am Mads
4
Rasmussen from Novo Nordisk, and I'm the industry
5
representative.
6
DR. THOMAS: And Dr. Jenkins, if you could
7
introduce yourself.
8
DR. JENKINS: Good morning. I'm John
9
Jenkins. I'm the director of the Office of New
10
Drugs at FDA.
11
DR. THOMAS: For topics such as those being
12
discussed at today's meeting, there are often a
13
variety of opinions, some of which are quite
14
strongly held. Our goal is that today's meeting
15
will be a fair and open forum for discussion of
16
these issues and that individuals can express their
17
views without interruption. Thus, as a general
18
reminder, individuals will be allowed to speak into
19
the record only if recognized by the chair. We
20
look forward to a productive meeting.
21
In the spirit of the Federal Advisory
Committee Act and the Government in the Sunshine
1
Act, we ask that the advisory committee members
2
take care that their conversations about the topics
3
at hand take place in the open forum of the
4
meeting. We are aware that members of the media
5
are anxious to speak with the FDA about these
6
proceedings. However, FDA will refrain from
7
discussing the details of this meeting with the
8
media until its conclusion. Also, the committee is
9
reminded to please refrain from discussing the
10
meeting topics during breaks or lunch. Thank you.
11
Conflict of Interest Statement
12
MR. TRAN: Good morning. The Food and Drug
13
Administration is convening today's meeting of the
14
Endocrinologic and Metabolic Drugs Advisory
15
Committee under the authority of the Federal
16
Advisory Committee Act of 1972. With the exception
17
of the industry representative, all members and
18
temporary voting members of the committee are
19
special government employees or regular federal
20
employees from other agencies and are subject to
21
federal conflict of interest laws and regulations.
The following information on the status of
1
this committee's compliance with the federal ethics
2
and conflict of interest laws, covered by but not
3
limited to those found at 18 U.S.C. Section 208 and
4
Section 712 of the Federal Food, Drug, and Cosmetic
5
Act, is being provided to participants in today's
6
meeting and to the public. FDA has determined that
7
members and temporary voting members of this
8
committee are in compliance with the federal ethics
9
and conflict of interest laws.
10
Under 18 U.S.C., Section 208, Congress has
11
authorized FDA to grant waivers to special
12
government employees and regular federal employees
13
who have potential financial conflicts, when it is
14
determined that the agency's need for a particular
15
individual's services outweighs his or her
16
potential financial conflict of interest.
17
Under Section 712 of the Federal Food, Drug
18
and Cosmetic Act, Congress has authorized FDA to
19
grant waivers to special government employees and
20
regular federal employees with potential financial
21
conflicts when necessary to afford the committee
essential expertise.
1
Related to the discussion of today's
2
meeting, members and temporary voting members of
3
this committee have been screened for potential
4
financial conflicts of interest of their own, as
5
well as those imputed to them, including those of
6
their spouses or minor children, and for purposes
7
of 18 U.S.C. Section 208, their employers. These
8
interests may include investments, consulting,
9
expert witness testimony, contracts, grants,
10
CRADAs, teaching, speaking, writing, patents and
11
royalties, and primary employment.
12
Today's agenda involves discussion of the
13
safety and efficacy of new drug application
14
NDA 22-580, proposed trade name Qnexa, a
15
combination of phentermine and topiramate, a
16
controlled-release capsule by Vivus, Incorporated,
17
as an adjunct to diet and exercise for weight
18
management in a patient with a body mass index
19
equal to or greater than 30 kilograms per square
20
meter or a body mass index equal to or greater than
21
27 kilograms per square meter if accompanied by
weight-related comorbidity.
1
This is a particular matters meeting, during
2
which specific matters related to the Vivus'
3
product Qnexa will be discussed. Based on the
4
agenda for today's meeting and all financial
5
interests reported by the committee members and
6
temporary voting members, no conflict of interest
7
waivers have been issued in connection with this
8
meeting.
9
To ensure transparency, we encourage all
10
standing committee members and temporary voting
11
members to disclose any public statements that they
12
have made concerning the topic at issue.
13
With respect to FDA's invited industry
14
representative, we would like to disclose that
15
Dr. Mads Rasmussen is participating in this meeting
16
as a non-voting industry representative, acting on
17
behalf of regulated industry. Dr. Rasmussen's role
18
at this meeting is to represent industry in general
19
and not any particular company. Dr. Rasmussen is
20
employed by Novo Nordisk.
21
We would like to remind members and
temporary voting members that if the discussion
1
involves any other product or firm not already on
2
the agenda for which the FDA participant has a
3
personal or imputed financial interest, the
4
participants need to exclude themselves from such
5
involvement and their exclusion will be noted for
6
the record.
7
FDA encourages all other participants to
8
advise the committee of any financial relationships
9
that they may have with any firms at issue. Thank
10
you.
11
DR. THOMAS: Could Dr. Karwoski introduce
12
himself?
13
DR. KARWOSKI: Yes. My name is Claudia
14
Karwoski. I'm the director of the Division of Risk
15
Management in the Office of Surveillance and
16
Epidemiology.
17
DR. THOMAS: Thank you. We will now proceed
18
with the FDA opening remarks from Dr. Eric Colman.
19
I'd like to remind public observers at this meeting
20
that while this meeting is open for public
21
observation, public attendees may not participate
except at the specific request of the panel.
1
Introduction and Background – Eric Colman
2
DR. COLMAN: Thank you, Abe.
3
Good morning and welcome to the second
4
advisory committee meeting for Vivus' fixed-dose
5
combination of phentermine and topiramate, a drug
6
with a proposed trade name of Qnexa.
7
This committee met in July of 2010 to
8
discuss the then available efficacy and safety data
9
for phentermine/topiramate. At that time, there
10
was general agreement that the
11
phentermine/topiramate satisfied the agency's
12
weight-loss criteria for an effective obesity drug.
13
The discussion of phentermine/topiramate safety
14
profile focused on psychiatric and cognitive
15
adverse events, metabolic acidosis, elevations in
16
heart rate, and potential or possible
17
teratogenicity.
18
While today's meeting will include
19
presentations on weight-loss efficacy and changes
20
in weight-related comorbidity, in particular, new
21
data that's spanned two years of drug treatment, we
will also touch upon all of the aforementioned
1
safety issues.
2
I want to remind the committee that the
3
focus of today's meeting will be
4
phentermine/topiramate's effects on heart rate and
5
blood pressure, and its cardiovascular safety
6
profile. We will also be focusing on data from
7
observational studies that have examined the
8
teratogenic potential of topiramate.
9
Regarding this latter point, we will also be
10
spending considerable time discussing risk
11
evaluation and mitigation strategies, or REMS, as
12
they pertain to the topiramate component of
13
phentermine/topiramate.
14
These topics of focus for today's meeting
15
are reflected in the agenda, and in the discussion
16
points, and voting question that you will be asked
17
to respond to this afternoon. This is a very short
18
list. There are no details on this agenda. But
19
the sponsor will present a series of talks covering
20
safety, efficacy, cardiovascular safety, and
21
teratogenicity.
FDA will then follow with several talks.
1
One will cover general safety, efficacy,
2
cardiovascular safety; two talks, one from a guest
3
speaker from CDC, will deal with observational
4
data, looking at major congenital malformations,
5
and, in particular, oral clefts. Then finally, the
6
FDA personnel will deal with the risk mitigation
7
proposals that we think are reasonable to discuss
8
this afternoon.
9
The morning session will be completed by the
10
sponsor's discussion of their risk mitigation
11
proposals as they related to the topiramate
12
component of their drug. When we get back from
13
lunch, we'll have the open public hearing. I think
14
that's probably an hour, and then we will have some
15
discussion.
16
If I could see the discussion points.
17
So the first discussion point that we will
18
be asking you to discuss is the interpretation of
19
whether the data you see and the data you have read
20
in your background packages, if you believe those
21
data indicate that topiramate poses a risk, in this
case, for oral clefts.
1
This relates to the risk mitigation
2
strategies that you will hear about this morning.
3
We'd like to hear your thoughts on the potential
4
strengths and weaknesses of the proposed risk
5
management strategies.
6
The third discussion point relates to heart
7
rate and blood pressure. And in specific, it says,
8
"Taking into account the reported changes in
anti-9
hypertensive therapy, discuss the clinical
10
significance of the changes in blood pressure and
11
heart rate in overweight and obese patients treated
12
with phentermine/topiramate versus placebo." And
13
this ties into the next question.
14
I point out this is not a voting question.
15
We're not asking for a yes or no, but we really
16
just want you to provide your deepest thoughts as
17
to whether you believe the available data warrant
18
that a cardiovascular outcomes trial be conducted
19
prior to this drug's approval.
20
Finally, we will ask you to respond to this
21
voting question. "Considering all of the available
data in the application and in today's discussions,
1
does the overall benefit-risk assessment of
2
phentermine/topiramate support its approval for the
3
treatment of obesity in individuals with a BMI of
4
greater than 30 or greater than 20 in the presence
5
of a comorbid condition?"
6
If you vote yes, we'd like to hear your
7
rationale and perhaps any kind of risk management
8
post-approval. If you vote no, we'd like to know
9
why you voted no, and if you believe there are
10
additional clinical studies or data that you
11
believe might support future approval.
12
So with that, I'll turn it back to
13
Dr. Thomas.
14
DR. THOMAS: Thank you.
15
We'll now proceed to the sponsor's
16
presentations. I'd like to remind public observers
17
at this meeting that while this meeting is open for
18
public observation, public attendees may not
19
participate except at the specific request of the
20
panel.
21
Both the Food and Drug Administration and
the public believe in a transparent process for
1
information gathering and decision making. To
2
ensure such transparency of the advisory committee
3
meeting, FDA believes it is important to understand
4
the context of an individual's presentation.
5
For this reason, FDA encourages all
6
participants, including the sponsor's non-employee
7
presenters, to advise the committee of any
8
financial relationships that they may have with the
9
firm at issue, such as consulting fees, travel
10
expenses, honoraria, and interest in the sponsor,
11
including equity interests, and those based upon
12
the outcome of the meeting.
13
Likewise, FDA encourages you, at the
14
beginning of your presentation, to advise the
15
committee if you do not have any such financial
16
relationships.
17
If you choose not to address this issue of
18
financial relationships at the beginning of your
19
presentation, it will not preclude you from
20
speaking.
21
Dr. Tam?
Sponsor Presentation – Peter Tam
1
MR. TAM: Good morning, Mr. Chairman,
2
members of the advisory committee, FDA, and
3
colleagues. My name is Peter Tam. I'm president
4
of Vivus and have been with the company for more
5
than 18 years. My primary role at Vivus is to
6
oversee all aspects of drug development and
7
regulatory affairs. We are here today to reexamine
8
a fixed-dose combination treatment for obesity
9
called Qnexa.
10
This novel combination is comprised of low
11
doses of phentermine and topiramate in a
12
controlled-release formulation. In context of
13
several treatments that have been reviewed by this
14
committee, Qnexa, when used in conjunction with
15
lifestyle modification, is the only oral medication
16
that produces weight loss that consistently
17
achieves 10 percent.
18
Importantly, unlike other obesity treatments
19
which have been found to increase blood pressure,
20
Qnexa produces a clinically meaningful reduction in
21
blood pressure. We are pleased to present to you
data that support these unique characteristics of
1
Qnexa this morning.
2
After my brief introductory remarks,
3
Dr. Wesley Day, vice-president of clinical
4
development, will summarize the efficacy data.
5
Dr. Neil Gesundheit, clinical advisor and former
6
chief medical officers at Vivus, will present the
7
general safety data.
8
We will then focus on two main issues in our
9
complete response letter: increased heart rate and
10
teratogenicity. Dr. Peter Kowey, professor of
11
medicine at Jefferson Medical College, will present
12
data on heart rate and cardiovascular safety. And
13
Dr. Gary Shaw, professor of pediatrics, neonatal,
14
and developmental medicine of Stanford University,
15
will summarize the results from several
nearly-16
completed studies, characterizing the teratogenic
17
potential of topiramate.
18
Dr. Anthony Scialli, clinical professor of
19
obstetrics and gynecology of George Washington
20
University School of Medicine and former president
21
of the Teratology Society, will provide a clinical
perspective on the teratogenic potential of
1
topiramate.
2
After that, Dr. Michael Lincoff, vice
3
chairman, department of cardiovascular medicine at
4
the Cleveland Clinic, will provide a cardiologist's
5
perspective on Qnexa.
6
Finally, Dr. Arya Sharma, professor of
7
medicine, chair of obesity research and management
8
at University of Albert, will provide his medical
9
perspective on obesity and assessment of the
10
risk-benefit profile of Qnexa.
11
After this portion of the sponsor's
12
presentation, FDA will make a presentation on REMS.
13
Dr. Barbara Troupin, senior director of Global
14
Medical Affairs, will then present Vivus' REMS,
15
based on the current discussions with FDA.
16
Qnexa is comprised of phentermine and
17
topiramate, two drugs that are now generic and have
18
been approved by FDA multiple times. Phentermine
19
is the most widely-prescribed obesity treatment
20
today. It was approved over 50 years ago as
21
short-term treatment for weight loss. Last year,
FDA approved two novel formulations of phentermine
1
at doses two to four times higher than Qnexa.
2
Topiramate was first approved for the
3
treatment of epilepsy 15 years ago. In 2004, it
4
was approved for migraine prophylaxis. The most
5
recent approval for topiramate occurred last year
6
for use as monotherapy for epilepsy in pediatric
7
patients between the ages of 2 and 10. Today,
8
topiramate is used primarily by women of
child-9
bearing potential for migraine prophylaxis.
10
What is the rationale for a fixed-dose
11
combination treatment for obesity? It is worth
12
noting that body weight regulation involves many
13
redundant pathways. Therefore, a treatment that
14
targets multiple mechanisms may have a greater
15
effect on reducing hunger and improving satiety.
16
With greater weight loss, one may lower the dose of
17
each drug so that dose-limited side effects would
18
be reduced and the overall risk-benefit profile is
19
improved.
20
This is what we found when we combined
21
topiramate and phentermine. Since both drugs
address different and unique mechanisms, lower
1
doses of these two agents, in combination, were
2
shown to achieve clinically meaningful weight loss
3
in early clinical trials.
4
To understand the doses of Qnexa, let's
5
first examine the approved doses of these two
6
agents. Phentermine's maximum approved dose is
7
30 milligrams; for topiramate, it's 400 milligrams.
8
The starting dose of Qnexa contains one-eighth of
9
the approved dose of phentermine and one-sixteenth
10
of the approved dose of topiramate. The mid-dose
11
is the recommended dose of Qnexa. It contains
one-12
quarter of phentermine and one-eighth of
13
topiramate, respectively. The top dose contains
14
one-half of phentermine and less than one-quarter
15
of the approved dose of topiramate.
16
It is important to note that in our proposed
17
label, the top dose is reserved for patients who
18
need a higher dose to achieve treatment goals after
19
having been on mid-dose for six months. Vivus
20
recommends that for patients who do not lose
21
3 percent or more of their body weight after three
months on the mid-dose, they should discontinue
1
treatment.
2
Let me review recent regulatory history of
3
Qnexa. The first advisory committee meeting for
4
Qnexa was held in July 2010, where these safety
5
topics were discussed. These are the known and
6
expected effects of topiramate and phentermine.
7
These safety topics were discussed
8
extensively during that meeting. The remaining
9
issues at the end of the meeting were increased
10
heart rate and teratogenic potential of topiramate.
11
The panel also asked for data from a two-year
12
study, OB-305, which had not been completed at the
13
time of the first meeting, as it was not a
14
requirement for the original NDA submission.
15
Following the panel's non-approval
16
recommendation in October 2010, Vivus received a
17
complete response letter detailing the remaining
18
two reasons for non-approval and the FDA's
19
recommended actions to address them. The agency
20
asked us to provide evidence that elevations in
21
heart rate associated with Qnexa do not increase
the risk of major adverse cardiovascular events.
1
In addition, the agency asked for the results from
2
the two-year study.
3
The FDA also asked Vivus to provide a
4
comprehensive assessment of topiramate's and
5
Qnexa's teratogenic potential and to provide a
6
detailed strategy to evaluate and mitigate the
7
potential risk for teratogenicity in women of
8
child-bearing potential.
9
With the FDA's agreement, Vivus resubmitted
10
the Qnexa NDA in October 2011 with a
11
contraindication for use in women of child-bearing
12
potential. The unique controlled distribution
13
system we included in the REMS would ensure a
near-14
100 percent exclusion of women of child-bearing
15
potential from accessing Qnexa.
16
In a subsequent discussion with the agency
17
in December 2011, the FDA asked that we remove this
18
contraindication because they believed it was too
19
broad, and that in some women, the benefits of
20
treatment may outweigh the risks. The FDA also
21
informed us that a more restrictive
contraindication and REMS would potentially drive
1
these patients to use generic topiramate and
2
phentermine off label.
3
In response, we developed a rigorous REMS
4
that we believe will be effective in managing the
5
risk while not being overly restrictive or too
6
burdensome for patients or providers.
7
As such, we are here today seeking a
8
recommendation from the panel for the approval of
9
Qnexa for the indication of treatment of obesity,
10
including weight loss and maintenance of weight
11
loss. It is recommended for obese patients or
12
overweight patients with a weight-related
13
comorbidity such as hypertension, type 2 diabetes,
14
dyslipidemia, or central adiposity.
15
Further, with FDA's guidance, we've modified
16
the contraindication. Women who are pregnant may
17
not take Qnexa. Women who become pregnant while
18
taking Qnexa must stop treatment immediately. In
19
addition, we agree with FDA that Qnexa, as well as
20
all weight-loss products, be classified as
21
Category X, since there is no benefit for use
during pregnancy. This is consistent with clinical
1
guidelines for weight gain during pregnancy and
2
recommendations against weight loss during
3
pregnancies, even in obese, pregnant women.
4
Vivus also believes it would be important to
5
warn, through labeling and patient and provider
6
education, that for women at risk of becoming
7
pregnant, they must use effective contraception.
8
Vivus is committed to continuing to work
9
with the FDA to ensure that maximum safety is
10
obtained with the use of Qnexa, without creating
11
undue burden to patients or to healthcare
12
providers.
13
Before I conclude, permit me to make an
14
important observation that we hope you will keep in
15
mind during your deliberations today. Vivus has
16
responded to FDA's challenge and worked
17
collaboratively with the agency to create a risk
18
management plan with a specific REMS for women of
19
child-bearing potential, in particular women at
20
risk of becoming pregnant, not using effective
21
contraception. It will be the focus of some of
your discussions today.
1
But as you deliberate, please remember that
2
Qnexa was developed for the entire obese population
3
and offers real and tangible benefits to men, women
4
of non-child-bearing potential, as well as women of
5
child-bearing potential suffering from this
6
epidemic for which there are no effective medical
7
therapies.
8
Thank you. I will now turn the podium over
9
to Dr. Wesley Day, who will discuss the efficacy
10
results of our trials.
11
Sponsor Presentation – Wesley Day
12
DR. DAY: Thank you, Mr. Tam.
13
Mr. Chairman, members of the panel, FDA, and
14
audience, good morning. My name is Wesley Day, and
15
I'm the vice president responsible for clinical
16
development at Vivus. I am also an adjunct
17
associate professor for the school of pharmacy at
18
the University of Maryland at Baltimore.
19
I will provide an overview of the Qnexa
20
clinical development program and review the
21
efficacy data supporting the NDA. This will
include a discussion of the one- and two-year
1
weight-loss data, including weight-related
2
comorbidities and effects on quality of life.
3
Dr. Gesundheit will follow my presentation with an
4
overview of the general safety of Qnexa for the
5
pivotal and second year of treatment.
6
Let's start with the discussion of the
7
phase 3 program. The Qnexa program was comprised
8
of four studies. OB-301, a factorial study, tested
9
the combination compared to the individual
10
components and placebo. The pivotal studies were
11
designed to include important medical-need
12
populations.
13
OB-302 assessed the effects of Qnexa in a
14
severely obese population that would qualify for
15
gastric surgery. OB-303 examined a population with
16
confirmed weight-related comorbidities at baseline,
17
providing insight regarding the effects of weight
18
loss on recognized cardiovascular risk factors.
19
OB-305 was a double-blind, placebo-controlled
20
extension of OB-303 that provided second-year
21
safety and efficacy experience in a population
completing one year of treatment.
1
Now, let's look at the elements of each
2
study. OB-301 confirmed that the combination could
3
provide significantly better weight loss than
4
either phentermine or topiramate. OB-302 was
5
conducted in severely obese patients with a minimum
6
BMI of 35, with no upper limit. Patients with a
7
BMI greater than 50 were studied.
8
OB-303 was the largest pivotal study with
9
confirmed presence of hypertension, dyslipidemia,
10
or diabetes at baseline. Finally, OB-305 included
11
675 patients with blinding and randomization
12
maintained.
13
All phase 3 studies used the Learn program,
14
which included counseling in diet and exercise and
15
was intended to provide relevant background weight
16
loss for the entire study population.
17
Looking at the baseline demographics for
18
each study, you can see a similarity in most
19
criteria, such as gender, race, and ethnicity. I
20
draw your attention to the top of the slide. The
21
differences in BMI are a result of the study
inclusion criteria. By requirement of the severely
1
obese population, OB-305 would be expected to have
2
a higher baseline BMI. At the bottom of the slide,
3
note the greater presence of weight-related
4
comorbidities in OB-303 patients.
5
Now, let's look at disposition for these
6
studies. The rate of study completion was
7
significantly greater for Qnexa-treated patients as
8
compared to placebo. Seventy-one percent retention
9
is among the highest completion rates for phase 3
10
obesity studies. The pivotal program also sought
11
to retain patients within the study on or off drug.
12
Approximately 4 to 9 percent of patients remained
13
in the study off drug.
14
Now, looking at the co-primary endpoints,
15
here you see the results for percent weight loss,
16
the first co-primary endpoint. All doses were
17
significant compared to placebo. Top dose, shown
18
in purple on the far right side of each set of
19
bars, was significant compared to mid-dose in green
20
and low dose in blue. Importantly, there was
21
greater than 10 percent mean weight loss for top
dose in both studies.
1
The second co-primary endpoint was
2
categorical weight loss defined as percent of
3
patients achieving at least 5 percent reduction in
4
body weight. There was a significant effect with
5
all doses of Qnexa compared to placebo in both
6
studies.
7
Please also note not only did the
8
categorical weight loss of 5 percent exceed the FDA
9
threshold of 35 percent, this was also the case for
10
10 percent categorical weight loss for the top and
11
mid-dose. Another way to look at this data is by
12
examining weight loss over time in patients on
13
drug.
14
For comparison, on the right side of each
15
graph are the results of the ITT-LOCF analysis that
16
I just described. In OB-302, the low dose produced
17
6.1 percent weight loss following 56 weeks of
18
treatment, compared to 2 and a half percent for
19
placebo. In OB-303, the mid-dose produced
20
10.1 percent weight loss compared to a placebo
21
effect of 2 and a half percent. Finally, the top
dose achieved weight loss of 14.1 percent in OB-302
1
and 12.4 percent in OB-303.
2
In summary, both studies demonstrated
dose-3
related, rapid, and sustained weight loss over
4
56 weeks of treatment. All Qnexa doses were
5
significant compared to placebo.
6
Moving on to the second year of treatment,
7
as discussed in the phase 3 program outline, OB-305
8
was a one-year extension to OB-303 that was
9
conducted at 36 high-retention sites. There were a
10
total of 866 OB-303 patients that were eligible to
11
continue into OB-305. Of the eligible patients,
12
78 percent elected to continue.
13
A greater proportion of Qnexa-treated
14
patients elected to continue treatment, 86 percent,
15
as compared to 69 percent on placebo. Retention in
16
OB-305 was high and comparable between treatment
17
arms.
18
Let's look at the weight loss in these
19
patients. A plot of percent weight loss over time
20
based on all observed data for the two-year
21
population is shown. Both Qnexa treatment arms
demonstrated greater than 10 percent weight loss
1
that was achieved in six to nine months and
2
sustained over the two-year treatment period,
3
compared with 2 and a half percent weight loss for
4
placebo. As shown in the right-hand bar, ITT-LOCF
5
results at week 108 are similar to patients
6
completing the full two years of treatment.
7
Now, let's examine the effects of Qnexa on a
8
spectrum of cardiovascular risk factors across the
9
entire population and the effects on a
10
subpopulation of hypertensives and diabetics. We
11
will also examine the weight-loss effect on
12
development of new, onset diabetes.
13
On the left, you see a range of endpoints,
14
including blood pressure, CRP, lipid, liver
15
function, glycemic, sleep apnea, and quality of
16
life. On the graphs, any confidence interval to
17
the left of the center line represents a
18
statistically significant improvement associated
19
with Qnexa.
20
For the mid-dose, significant improvements
21
were observed for all endpoints except diastolic
blood pressure. For the top dose, we observed
1
meaningful and significant improvements compared to
2
placebo for all endpoints, including diastolic
3
blood pressure. Overall, based on the full ITT
4
population, regardless of baseline values, the mid-
5
and top dose Qnexa treatment produced improvements
6
across a broad spectrum of weight-related
7
comorbidities and cardiovascular risk factors.
8
Several of these comorbidities were required
9
by study inclusion criteria in patients at
10
baseline. Two examples we can look at are patients
11
with hypertension or diabetes, as shown in the next
12
two slides.
13
In patients with hypertension at baseline,
14
defined as those with a blood pressure greater than
15
140 over 90 or using two or more medications, we
16
observed that the effects of Qnexa on blood
17
pressure are dose related and of greater magnitude
18
compared to placebo.
19
For systolic blood pressure, the top dose
20
produced a significant reduction of
21
9.1 millimeters, compared to 6.9 and 4.9 on mid-
and placebo, respectively. The study allowed
1
active management of anti-hypertensive medications.
2
Here, we see more Qnexa-treated patients
3
experience a reduction in the starting of new
4
medications and a greater discontinuation of
5
existing meds, as compared to placebo. Overall,
6
the data suggests a clinically meaningful
7
improvement in blood pressure occurred with Qnexa
8
treatment in the presence of fewer
anti-9
hypertensive medications.
10
Now, let's look at patients with diabetes.
11
Diabetes at baseline was defined as a fast in
12
glucose greater than or equal to 126 mgs per
13
deciliter or use of medication to control blood
14
glucose. This population was well-controlled,
15
primarily on metformin, with a baseline HbA1c of
16
6.8 percent. We observed that the effects of Qnexa
17
on HbA1c are significant in both the mid- and
top-18
dose Qnexa compared to placebo. As with the
19
previous example, investigators were allowed to
20
actively manage the diabetic patients with
21
medications.
Here, we see a significant reduction in the
1
starting of new medications and a greater
2
discontinuation of existing medications for
3
Qnexa-treated patients compared to placebo.
4
Consistent with blood pressure effects, clinically
5
meaningful improvement in HbA1c occurred in the
6
presence of less use of anti-diabetic medication.
7
Now, for non-diabetic obese patients who are
8
at risk to develop the disease, following one year
9
of treatment, the annualized incidence rate of
10
progression to diabetes was significantly reduced
11
with both doses of Qnexa.
12
Diabetes was defined as two consecutive
13
visits with fasts in glucose greater than or equal
14
to 126 mgs per deciliter or a two-hour post-oral
15
glucose test greater than 200. Following two years
16
of treatment, the improvements in progression were
17
observed for both doses. Importantly, top-dose
18
Qnexa resulted in a 76 percent reduction in new
19
cases of diabetes in two years of treatment. Thus,
20
the Qnexa-related improvements in weight, as well
21
as a broad spectrum of glycemic endpoints, supports
an overall reduction in new cases of diabetes.
1
Finally, changes in weight and other
2
comorbidities appear to equate with improvements in
3
quality of life. The impact of weight on quality
4
of life, IWQOL, instrument was used throughout the
5
phase 3 program. The results suggest that both
6
doses of Qnexa produced significant improvements in
7
the composite score as well as all domains,
8
including physical function, self-esteem, sexual
9
life, public distress, and work.
10
In addition to the IWQOL instrument, we used
11
the SF-36, a general health instrument, throughout
12
OB-303. The results suggest that both doses of
13
Qnexa produced significant improvements in physical
14
function and role, bodily pain, general health, and
15
vitality. There were no significant changes in
16
emotional role or mental health.
17
In summary, the pivotal and two-year study
18
has confirmed that treatment with Qnexa is
19
associated with significant weight loss and
20
improvement of cardiovascular risk factors, as well
21
as meaningful quality of life improvements.
The dose-related weight-loss effects of
1
Qnexa exceeded FDA benchmarks with mean reductions
2
in body weight that exceeded 10 percent and were
3
sustained over two years. As would be expected
4
with clinically meaningful weight loss, we see a
5
significant and sustained improvement in quality of
6
life and a broad spectrum of cardiovascular risk
7
factors, including blood pressure, glycemic, liver,
8
and lipid endpoints. Finally, we observed a
9
significant reduction in new cases of new onset
10
diabetes compared to placebo.
11
I will now turn the presentation over to
12
Dr. Gesundheit, who will discuss the safety data.
13
Sponsor Presentation – Neil Gesundheit
14
DR. GESUNDHEIT: Good morning. My name is
15
Neil Gesundheit. I am an endocrinologist and a
16
paid clinical advisor to the sponsor. I previously
17
served as vice president and chief medical officer
18
of Vivus and have remained a company shareholder.
19
I am currently an associate professor of medicine
20
at Stanford University. The views expressed today
21
are my own and not those of Stanford.
In this section, I will discuss the safety
1
of Qnexa by reviewing common side effects observed
2
with phentermine and topiramate. Next, I will show
3
data from the one-year cohort and the second year
4
of study, OB-305. Finally, I would like to review
5
three safety concerns raised at the advisory
6
committee meeting in 2010, psychiatric- and
7
cognition-related adverse events and the lowering
8
of serum bicarbonate. Dr. Peter Kowey will discuss
9
the effects of Qnexa on heart rate and Dr. Gary
10
Shaw will discuss potential teratogenicity.
11
The common adverse events observed with
12
Qnexa are those expected from the prior clinical
13
experience with the two component drugs. Common
14
side effects of phentermine are shown on the left
15
and for topiramate on the right.
16
Two of the side effects of topiramate merit
17
clarification. Paresthesia refers to tingling in
18
the hands and feet. Dysgeusia refers to an
19
alteration in taste. These are both common side
20
effects of carbonic anhydrase inhibitors.
21
As you will see in the next slides, the
adverse events observed with Qnexa are consistent
1
with those observed with the individual components.
2
In this section, I will discuss the key safety
3
findings of the one-year studies that provide the
4
core safety experience in more than 3800 patients,
5
shown in blue. In addition, we examined data from
6
the two-year cohort, shown in light blue at the
7
bottom. Patients in the two-year continuation
8
study were drawn from 36 of the 92 sites in
9
protocol OB-303.
10
Study sites were chosen primarily by the
11
number of patients recruited and the site retention
12
rate. There was no a priori knowledge of patient
13
outcomes during year one. Nearly 80 percent of the
14
patients from these 36 sites, or 675 patients,
15
elected to continue into a second year of study.
16
Patients remained in their treatment group and the
17
placebo-controlled, double-blind design was
18
maintained for the second year.
19
In its briefing book, the FDA examined the
20
two-year cohort in its entirety. We agree with the
21
agency's findings regarding the two-year cohort.
Vivus also presented data to the agency for
1
the second year of study, OB-305. In the next
2
slides, we will show the results of the one-year
3
safety cohort, our comprehensive safety baseline,
4
shown on the left in deep blue, and in OB-305,
5
shown on the right in light blue. The baseline
6
demographics and first-year adverse event profiles
7
of the 675 patients who entered OB-305 were
8
representative overall of patients from the
one-9
year safety cohort.
10
Shown here are the 10 most common adverse
11
events from the one-year cohort on the left and
12
from the second year of study from OB-305 on the
13
right. Constipation, dry mouth, and paresthesia
14
were the most common side effects showing an
15
increased incidence in Qnexa-treated patients
16
compared with placebo. These side effects reported
17
less commonly in protocol OB-305, although the
18
rates continued to be higher on Qnexa. Most other
19
common side effects reported with similar
20
frequencies in the second year of Qnexa use
21
compared with the one-year cohort.
In the one-year cohort, study completion
1
rates ranged from 60 percent on placebo to 72 to
2
75 percent on Qnexa. Study completion rates on
3
drug ranged from 55 percent on placebo to 63 to
4
69 percent on Qnexa.
5
In the second year of study -- and remember
6
that all of these patients completed the first year
7
of study by definition -- the study completion
8
rates averaged 85 percent across groups.
9
Treatment-emergent adverse events were
10
higher on Qnexa than placebo in the one-year
11
cohort, but were similar across treatments in the
12
second-year group. Treatment-emergent adverse
13
events leading to discontinuation were higher on
14
Qnexa than placebo during year 1, but were more
15
similar across treatments from 2.6 to 4.1 percent
16
during the second year.
17
Importantly, we examined serious adverse
18
events, SAEs, in the two cohorts. SAEs are events
19
leading to hospitalization, death, or disability.
20
In the one-year cohort, the incidence of SAEs was
21
3.3 percent on placebo and ranged from 2.8 to
3.6 percent on Qnexa. In the second-year cohort,
1
the incidence was 4.0 percent on placebo and ranged
2
from 2.6 to 4.1 percent on Qnexa. There was one
3
death in the program, and that occurred in a
4
patient on placebo in the one-year cohort. There
5
were no SAEs for psychiatric of cognitive disorders
6
in Qnexa patients in either cohort.
7
In summary, the incidence of SAEs was
8
similar between placebo and active treatment groups
9
in the one-year and second-year cohorts. No new or
10
unexpected events appeared during the second year
11
of Qnexa treatment.
12
Now, let's turn our attention to the three
13
safety concerns raised at the 2010 meeting.
14
Psychiatric disorders were identified as TMEs, or
15
targeted medical events. The incidences in the
16
one-year cohort are again shown on the left and the
17
second-year cohort on the right.
18
For each of the top three categories, the
19
incidences in Qnexa-treated patients were generally
20
higher than a placebo. For suicide or self-injury,
21
the adverse event of greatest concern, there was
only one report in a patient on placebo at any
1
point in the two-year program.
2
Cognitive disorders were another TME. Shown
3
here are four specific cognitive disorders. In the
4
one-year cohort, the incidence of cognitive
5
disorders was low, but occurred with increased
6
frequency on Qnexa treatment. During the second
7
year of treatment, there were very few reports in
8
this TME in either treatment group.
9
Another adverse event discussed at the 2010
10
advisory committee meeting was the lowering of
11
serum bicarbonate. The lower limit of serum
12
bicarbonate in our reference lab was
13
21 milliequivalents per liter.
14
Shown here are patients who showed a
15
persistent lowering to below 21 or
16
17 milliequivalents per liter. As you can see from
17
the one-year cohort, there was an increased
18
incidence of persistent lowering of serum
19
bicarbonate with Qnexa treatment. In the
second-20
year cohort on the right, there were fewer reports
21
to below 21, although they occurred more on Qnexa.
There were no reports of persisting lowering of
1
serum bicarbonate to below 17 in the second year of
2
treatment in any group.
3
We examined the time course of serum
4
bicarbonate lowering in the two-year cohort in
5
subjects who had a level below 21 milliequivalents
6
per liter at any time. As you can see, the nadir
7
of mean serum bicarbonate occurred between 4 and
8
8 weeks. In all three groups, the mean serum
9
bicarbonate self-corrected over time. There were
10
no discontinuations due to a lowering of serum
11
bicarbonate.
12
In summary, the adverse event profiles in
13
the second year of treatment, study OB-305, were
14
consistent with those in the one-year cohort. The
15
safety profiles are consistent with the known side
16
effects of the two component drugs.
17
There is the important caveat that the
18
second-year cohort consisted of patients who had
19
successfully completed one year of treatment.
20
Nevertheless, the second-year cohort allowed us to
21
examine for new or unexpected safety concerns that
might arise during a second year of treatment.
1
Psychiatric adverse events, cognitive
2
adverse events, and persistently reduced serum
3
bicarbonate occurred less in year 2 than in year 1,
4
but occurred more with Qnexa than placebo in the
5
program.
6
Importantly, there was no difference in
7
serious adverse events when comparing Qnexa to
8
placebo in the one-year or in the second-year
9
cohort. There was no signal of suicidality in
10
Qnexa patients in the program. There was no signal
11
of delayed or cumulative toxicity.
12
Dr. Kowey will now discuss the
13
cardiovascular safety of Qnexa.
14
