FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH ENDOCRINOLOGIC & METABOLIC DRUGS ADVISORY COMMITTEE MEETING

Transcription

1 FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH ENDOCRINOLOGIC & METABOLIC DRUGS ADVISORY COMMITTEE MEETING WEDNESDAY, FEBRUARY, :00 a.m. to :00 p.m. FDA White Oak Campus White Oak Conference Center Building, The Great Room Silver Spring, Maryland (0) 0-

2 Meeting Roster DESIGNATED FEDERAL OFFICER (Non-Voting) Paul T. Tran, R.Ph. Division of Advisory Committee and Consultant Management Office of Executive Programs, CDER, FDA ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE MEMBERS (Voting) Erica H. Brittain, Ph.D. Mathematical Statistician Biostatistics Research Branch National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) Bethesda, Maryland David M. Capuzzi, M.D., Ph.D. Professor of Medicine and Biochemistry Thomas Jefferson University & Lankenau Institute for Medical Research Philadelphia, Pennsylvania (0) 0-

3 Eric I. Felner, M.D., MSCR Associate Professor of Pediatrics Division of Pediatric Endocrinology Director, Pediatric Endocrinology Fellowship Program Emory University School of Medicine Atlanta, Georgia Edward W. Gregg, Ph.D. Chief, Epidemiology and Statistics Branch Division of Diabetes Translation Centers for Disease Control and Prevention (CDC) Atlanta, Georgia Abraham Thomas, M.D., M.P.H., FACP (Chair) Division Head, Endocrinology, Diabetes, Bone, and Mineral Disorders Henry Ford Hospital Whitehouse Chair of Endocrinology Detroit, Michigan (0) 0-

4 Lamont G. Weide, M.D., Ph.D., FACE Chief, Diabetes & Endocrinology Professor, Internal Medicine University of Missouri - Kansas City Truman Medical Centers, Diabetes Center Kansas City, Missouri ACTING INDUSTRY REPRESENTATIVE TO THE COMMITTEE (Non-Voting) Mads F. Rasmussen, M.D., Ph.D. (Acting Industry Representative) Executive Director Diabetes - Clinical Development and Research Clinical Development, Medical and Regulatory Affairs Novo Nordisk Inc. Princeton, New Jersey TEMPORARY MEMBERS (Voting) Kenneth D. Burman, M.D. Chief, Endocrine Section Washington Hospital Center Washington, District of Columbia (0) 0-

5 Robert R. Clancy, M.D. Professor of Neurology and Pediatrics The University of Pennsylvania School of Medicine The Children's Hospital of Philadelphia Philadelphia, Pennsylvania Melanie Coffin (Patient Representative) Washington, District of Columbia Janet D. Cragan, M.D., M.P.H. National Center on Birth Defects and Developmental Disabilities Division of Birth Defects and Developmental Disabilities, CDC Atlanta, Georgia Katherine M. Flegal, Ph.D. Senior Research Scientist Distinguished Consultant National Center for Health Statistics, CDC Hyattsville, Maryland (0) 0-

6 Allison B. Goldfine, M.D. Assistant Director of Clinical Research Joslin Diabetes Center, Research Division Boston, Massachusetts Jessica W. Henderson, Ph.D. (Acting Consumer Representative) Professor of Community Health Education Division of Health and Physical Education Western Oregon University Monmouth, Oregon Sanjay Kaul, M.D. Director, Fellowship Training Program in Cardiovascular Diseases Cedars-Sinai Heart Institute Professor, David Geffen School of Medicine at UCLA Division of Cardiology Cedar Sinai Medical Center Los Angeles, California (0) 0-

7 Michael S. Lauer, M.D., FACC, FAHA Director Division of Cardiovascular Sciences National Heart, Lung, and Blood Institute (NHLBI), NIH Bethesda, Maryland Elaine H. Morrato, Dr.PH., M.P.H., C.P.H. Assistant Professor Departments of Health Systems, Management & Policy Clinical Pharmacy and Pediatrics Assistant Director Children s Outcomes Research Program Anschutz Medical Campus University of Colorado-Denver Aurora, Colorado TEMPORARY MEMBERS (Voting) Sonja A., Rasmussen, M.D., M.S. Deputy Director Influenza Coordination Unit, CDC Atlanta, Georgia (0) 0-

8 Michael A. Rogawski, M.D., Ph.D. Professor and Chair, Department of Neurology University of California, Davis Sacramento, California Robert J. Smith, M.D. Professor of Medicine (Endocrinology) Alpert Medical School of Brown University East Providence, Rhode Island Myrlene A. Staten, M.D. Senior Advisor, Diabetes Translational Research Division of Diabetes, Endocrinology and Metabolism National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH Bethesda, Maryland (0) 0-

9 Almut G. Winterstein, Ph.D. Associate Professor Pharmaceutical Outcomes & Policy (POP) College of Pharmacy Epidemiology & Biostatistics College of Public Health and Health Professions Gainesville, Florida Susan Z. Yanovski, M.D. Co-Director, Office of Obesity Research Director, Obesity and Eating Disorders Program NIDDK, NIH Bethesda, Maryland SPEAKER (Non-Voting) Suzanne M. Gilboa, Ph.D. National Center on Birth Defects and Developmental Disabilities, CDC Atlanta, Georgia (0) 0-

10 FDA PARTICIPANTS (Non-Voting) John K. Jenkins, M.D. Director Office of New Drugs, CDER, FDA Mary H. Parks, M.D. Director Division of Metabolism and Endocrinology Products (DMEP) Office of Drug Evaluation II (ODE II) OND, CDER, FDA Eric C. Colman, M.D. Deputy Director DMEP, ODE II, OND, CDER, FDA Mary D. Roberts, M.D. Clinical Reviewer DMEP, ODE II, OND, CDER, FDA (0) 0-

11 Joyce Weaver, Pharm.D. Senior Drug Risk Management Analyst Division of Risk Management Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) CDER, FDA Claudia B. Karwoski, Pharm.D. Director, Division of Risk Management OMEPRM, OSE, CDER, FDA (0) 0-

12 C O N T E N T S AGENDA ITEM Call to Order and Introduction of Committee PAGE Abraham Thomas, M.D., M.P.H., FACP Conflict of Interest Statement Paul Tran, R.Ph. Introduction/Background Eric Colman, M.D. Sponsor Presentation Vivus, Inc. Introduction Peter Tam Review and Efficacy Wesley Day, Ph.D. 0 Review of Safety Neil Gesundheit, M.D., M.P.H. Review of Cardiovascular Safety Peter Kowey, M.D. Review of Teratogenicity Gary Shaw, Ph.D. Clinical Perspective on Teratogenicity Anthony Scialli, M.D. (0) 0-

13 C O N T E N T S (continued) AGENDA ITEM Cardiovascular Perspective PAGE A. Michael Lincoff, M.D. Medical Need and Risk Benefit Arya Sharma, M.D., Ph.D., D.Sc. Clarifying Questions from the Committee FDA Presentation Review of Phentermine/Topiramate (PHEN/TPM) Efficacy and Cardiovascular Safety Mary Roberts, M.D. Speaker Presentation Use of Monotherapy Topiramate in Pregnancy and Risk of Oral Clefts Suzanne Gilboa, Ph.D. FDA Presentation Review of Studies on Topiramate Use in Pregnancy and Risk of Oral Clefts and Major Congenital Malformations Julia Ju, Pharm.D., Ph.D. (0) 0-

14 C O N T E N T S (continued) AGENDA ITEM Risk Management Options for Phentermine/Topiramate PAGE Joyce Weaver, Pharm.D. Sponsor Presentation Vivus, Inc. Qnexa REMS Barbara Troupin, M.D. Clarifying Questions from the Committee Opening Public Hearing Session Clarifying Questions from the Committee (continued) Questions to the Committee and Committee Discussion Adjournment (0) 0-

15 P R O C E E D I N G S Call to Order DR. THOMAS: Good morning. I would first like to remind everyone present to please silence your cell phones, Blackberrys, and other devices if you've not already done so. I'd also like to identify the FDA press contact, Morgan Liscinsky. If you're present, please stand. Good morning. My name is Abraham Thomas. I'm the chair of the Endocrinologic and Metabolic Drugs Advisory Committee. I will now call the meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to order. We will go around the room and please introduce yourself. We will start with the FDA and Dr. Mary Parks to my left and go around the table. DR. PARKS: Good morning. I'm Mary Parks, director of the Division of Metabolism and Endocrinology Products. DR. COLMAN: I am Eric Colman, the deputy from that division. DR. ROBERTS: Mary Roberts, clinical (0) 0-

16 reviewer, Division of Metabolism and Endocrine Products. DR. WEAVER: Joyce Weaver, risk management analyst, Division of Risk Management. DR. MORRATO: Good morning. I'm Elaine Morrato from the Colorado School of Public Health. I'm an epidemiologist in the Department of Health Systems Management and Policy. DR. KAUL: Good morning. I'm Sanjay Kaul. I'm a cardiologist at Cedars-Sinai Medical Center in Los Angeles. DR. CRAGAN: Hi. I'm Janet Cragan from the Birth Defects branch at CDC. DR. CAPUZZI: Hi. I'm David Capuzzi at Thomas Jefferson University in Philadelphia. DR. WEIDE: Lamont Weide, chief of endocrinology, University of Missouri Kansas City and Truman Medical Centers. DR. YANOVSKI: I'm Susan Yanovski. I'm from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. DR. ROGAWSKI: Good morning. I'm Michael (0) 0-

17 Ragowski. I'm professor of neurology at the University of California Davis Medical Center in Sacramento, California. DR. BRITTAIN: I'm Erica Brittain. I'm a statistician at the National Institute of Allergy and Infectious Diseases. DR. THOMAS: I'm Abraham Thomas, division head of endocrinology at Henry Ford Hospital in Detroit, Michigan. MR. TRAN: Paul Tram, the designated federal officer for the EMDAC committee. DR. BURMAN: Ken Burman, head of endocrinology at the Washington Hospital Center and professor of medicine at Georgetown University. DR. HENDERSON: Jessica Henderson, consumer representative from Oregon. DR. FELNER: Eric Felner, associate professor of pediatrics, division of pediatric endocrinology at Emory University in Atlanta. DR. GREGG: Ed Gregg. I'm an epidemiologist from the diabetes division at CDC in Atlanta. DR. RASMUSSEN: Sonja Rasmussen. I'm a (0) 0-

18 pediatrician and clinical geneticist from CDC. DR. WINTERSTEIN: Good morning. I'm Almut Winterstein. I'm a pharmacoepidemiologist at the University of Florida. DR. STATEN: Hello, Myrlene Staten, NIDDK, NIH. MS. COFFIN: Hi, Melanie Coffin, patient representative. DR. LAUER: Mike Lauer. I'm a cardiologist and a clinical epidemiologist, and I direct the division of cardiovascular sciences at the National Heart, Lung, and Blood Institute of the NIH. DR. SMITH: I'm Robert Smith. I'm professor of medicine at the medical school at Brown University, former director of endocrinology there. DR. FLEGAL: I'm Katherine Flegal, epidemiologist from the National Center for Health Statistics, CDC. DR. CLANCY: I'm Robert Clancy, professor of neurology and pediatrics at the Children's Hospital of Philadelphia at the University of Pennsylvania. DR. GOLDFINE: Allison Goldfine. I'm an (0) 0-

19 associate professor at Harvard Medical School and head of clinical research at the Joslin Diabetes Center, Boston. DR. RASMUSSEN: Good morning. I am Mads Rasmussen from Novo Nordisk, and I'm the industry representative. DR. THOMAS: And Dr. Jenkins, if you could introduce yourself. DR. JENKINS: Good morning. I'm John Jenkins. I'm the director of the Office of New Drugs at FDA. DR. THOMAS: For topics such as those being discussed at today's meeting, there are often a variety of opinions, some of which are quite strongly held. Our goal is that today's meeting will be a fair and open forum for discussion of these issues and that individuals can express their views without interruption. Thus, as a general reminder, individuals will be allowed to speak into the record only if recognized by the chair. We look forward to a productive meeting. In the spirit of the Federal Advisory (0) 0-

20 Committee Act and the Government in the Sunshine Act, we ask that the advisory committee members take care that their conversations about the topics at hand take place in the open forum of the meeting. We are aware that members of the media are anxious to speak with the FDA about these proceedings. However, FDA will refrain from discussing the details of this meeting with the media until its conclusion. Also, the committee is reminded to please refrain from discussing the meeting topics during breaks or lunch. Thank you. Conflict of Interest Statement MR. TRAN: Good morning. The Food and Drug Administration is convening today's meeting of the Endocrinologic and Metabolic Drugs Advisory Committee under the authority of the Federal Advisory Committee Act of. With the exception of the industry representative, all members and temporary voting members of the committee are special government employees or regular federal employees from other agencies and are subject to federal conflict of interest laws and regulations. (0) 0-

21 The following information on the status of this committee's compliance with the federal ethics and conflict of interest laws, covered by but not limited to those found at U.S.C. Section and Section of the Federal Food, Drug, and Cosmetic Act, is being provided to participants in today's meeting and to the public. FDA has determined that members and temporary voting members of this committee are in compliance with the federal ethics and conflict of interest laws. Under U.S.C., Section, Congress has authorized FDA to grant waivers to special government employees and regular federal employees who have potential financial conflicts, when it is determined that the agency's need for a particular individual's services outweighs his or her potential financial conflict of interest. Under Section of the Federal Food, Drug and Cosmetic Act, Congress has authorized FDA to grant waivers to special government employees and regular federal employees with potential financial conflicts when necessary to afford the committee (0) 0-

22 essential expertise. Related to the discussion of today's meeting, members and temporary voting members of this committee have been screened for potential financial conflicts of interest of their own, as well as those imputed to them, including those of their spouses or minor children, and for purposes of U.S.C. Section, their employers. These interests may include investments, consulting, expert witness testimony, contracts, grants, CRADAs, teaching, speaking, writing, patents and royalties, and primary employment. Today's agenda involves discussion of the safety and efficacy of new drug application NDA -0, proposed trade name Qnexa, a combination of phentermine and topiramate, a controlled-release capsule by Vivus, Incorporated, as an adjunct to diet and exercise for weight management in a patient with a body mass index equal to or greater than 0 kilograms per square meter or a body mass index equal to or greater than kilograms per square meter if accompanied by (0) 0-

23 weight-related comorbidity. This is a particular matters meeting, during which specific matters related to the Vivus' product Qnexa will be discussed. Based on the agenda for today's meeting and all financial interests reported by the committee members and temporary voting members, no conflict of interest waivers have been issued in connection with this meeting. To ensure transparency, we encourage all standing committee members and temporary voting members to disclose any public statements that they have made concerning the topic at issue. With respect to FDA's invited industry representative, we would like to disclose that Dr. Mads Rasmussen is participating in this meeting as a non-voting industry representative, acting on behalf of regulated industry. Dr. Rasmussen's role at this meeting is to represent industry in general and not any particular company. Dr. Rasmussen is employed by Novo Nordisk. We would like to remind members and (0) 0-

24 temporary voting members that if the discussion involves any other product or firm not already on the agenda for which the FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from such involvement and their exclusion will be noted for the record. FDA encourages all other participants to advise the committee of any financial relationships that they may have with any firms at issue. Thank you. DR. THOMAS: Could Dr. Karwoski introduce himself? DR. KARWOSKI: Yes. My name is Claudia Karwoski. I'm the director of the Division of Risk Management in the Office of Surveillance and Epidemiology. DR. THOMAS: Thank you. We will now proceed with the FDA opening remarks from Dr. Eric Colman. I'd like to remind public observers at this meeting that while this meeting is open for public observation, public attendees may not participate (0) 0-

25 except at the specific request of the panel. Introduction and Background Eric Colman DR. COLMAN: Thank you, Abe. Good morning and welcome to the second advisory committee meeting for Vivus' fixed-dose combination of phentermine and topiramate, a drug with a proposed trade name of Qnexa. This committee met in July of to discuss the then available efficacy and safety data for phentermine/topiramate. At that time, there was general agreement that the phentermine/topiramate satisfied the agency's weight-loss criteria for an effective obesity drug. The discussion of phentermine/topiramate safety profile focused on psychiatric and cognitive adverse events, metabolic acidosis, elevations in heart rate, and potential or possible teratogenicity. While today's meeting will include presentations on weight-loss efficacy and changes in weight-related comorbidity, in particular, new data that's spanned two years of drug treatment, we (0) 0-

26 will also touch upon all of the aforementioned safety issues. I want to remind the committee that the focus of today's meeting will be phentermine/topiramate's effects on heart rate and blood pressure, and its cardiovascular safety profile. We will also be focusing on data from observational studies that have examined the teratogenic potential of topiramate. Regarding this latter point, we will also be spending considerable time discussing risk evaluation and mitigation strategies, or REMS, as they pertain to the topiramate component of phentermine/topiramate. These topics of focus for today's meeting are reflected in the agenda, and in the discussion points, and voting question that you will be asked to respond to this afternoon. This is a very short list. There are no details on this agenda. But the sponsor will present a series of talks covering safety, efficacy, cardiovascular safety, and teratogenicity. (0) 0-

27 FDA will then follow with several talks. One will cover general safety, efficacy, cardiovascular safety; two talks, one from a guest speaker from CDC, will deal with observational data, looking at major congenital malformations, and, in particular, oral clefts. Then finally, the FDA personnel will deal with the risk mitigation proposals that we think are reasonable to discuss this afternoon. The morning session will be completed by the sponsor's discussion of their risk mitigation proposals as they related to the topiramate component of their drug. When we get back from lunch, we'll have the open public hearing. I think that's probably an hour, and then we will have some discussion. If I could see the discussion points. So the first discussion point that we will be asking you to discuss is the interpretation of whether the data you see and the data you have read in your background packages, if you believe those data indicate that topiramate poses a risk, in this (0) 0-

28 case, for oral clefts. This relates to the risk mitigation strategies that you will hear about this morning. We'd like to hear your thoughts on the potential strengths and weaknesses of the proposed risk management strategies. The third discussion point relates to heart rate and blood pressure. And in specific, it says, "Taking into account the reported changes in antihypertensive therapy, discuss the clinical significance of the changes in blood pressure and heart rate in overweight and obese patients treated with phentermine/topiramate versus placebo." And this ties into the next question. I point out this is not a voting question. We're not asking for a yes or no, but we really just want you to provide your deepest thoughts as to whether you believe the available data warrant that a cardiovascular outcomes trial be conducted prior to this drug's approval. Finally, we will ask you to respond to this voting question. "Considering all of the available (0) 0-

29 data in the application and in today's discussions, does the overall benefit-risk assessment of phentermine/topiramate support its approval for the treatment of obesity in individuals with a BMI of greater than 0 or greater than in the presence of a comorbid condition?" If you vote yes, we'd like to hear your rationale and perhaps any kind of risk management post-approval. If you vote no, we'd like to know why you voted no, and if you believe there are additional clinical studies or data that you believe might support future approval. So with that, I'll turn it back to Dr. Thomas. DR. THOMAS: Thank you. We'll now proceed to the sponsor's presentations. I'd like to remind public observers at this meeting that while this meeting is open for public observation, public attendees may not participate except at the specific request of the panel. Both the Food and Drug Administration and (0) 0-

30 0 the public believe in a transparent process for information gathering and decision making. To ensure such transparency of the advisory committee meeting, FDA believes it is important to understand the context of an individual's presentation. For this reason, FDA encourages all participants, including the sponsor's non-employee presenters, to advise the committee of any financial relationships that they may have with the firm at issue, such as consulting fees, travel expenses, honoraria, and interest in the sponsor, including equity interests, and those based upon the outcome of the meeting. Likewise, FDA encourages you, at the beginning of your presentation, to advise the committee if you do not have any such financial relationships. If you choose not to address this issue of financial relationships at the beginning of your presentation, it will not preclude you from speaking. Dr. Tam? (0) 0-

31 Sponsor Presentation Peter Tam MR. TAM: Good morning, Mr. Chairman, members of the advisory committee, FDA, and colleagues. My name is Peter Tam. I'm president of Vivus and have been with the company for more than years. My primary role at Vivus is to oversee all aspects of drug development and regulatory affairs. We are here today to reexamine a fixed-dose combination treatment for obesity called Qnexa. This novel combination is comprised of low doses of phentermine and topiramate in a controlled-release formulation. In context of several treatments that have been reviewed by this committee, Qnexa, when used in conjunction with lifestyle modification, is the only oral medication that produces weight loss that consistently achieves percent. Importantly, unlike other obesity treatments which have been found to increase blood pressure, Qnexa produces a clinically meaningful reduction in blood pressure. We are pleased to present to you (0) 0-

32 data that support these unique characteristics of Qnexa this morning. After my brief introductory remarks, Dr. Wesley Day, vice-president of clinical development, will summarize the efficacy data. Dr. Neil Gesundheit, clinical advisor and former chief medical officers at Vivus, will present the general safety data. We will then focus on two main issues in our complete response letter: increased heart rate and teratogenicity. Dr. Peter Kowey, professor of medicine at Jefferson Medical College, will present data on heart rate and cardiovascular safety. And Dr. Gary Shaw, professor of pediatrics, neonatal, and developmental medicine of Stanford University, will summarize the results from several nearlycompleted studies, characterizing the teratogenic potential of topiramate. Dr. Anthony Scialli, clinical professor of obstetrics and gynecology of George Washington University School of Medicine and former president of the Teratology Society, will provide a clinical (0) 0-

33 perspective on the teratogenic potential of topiramate. After that, Dr. Michael Lincoff, vice chairman, department of cardiovascular medicine at the Cleveland Clinic, will provide a cardiologist's perspective on Qnexa. Finally, Dr. Arya Sharma, professor of medicine, chair of obesity research and management at University of Albert, will provide his medical perspective on obesity and assessment of the risk-benefit profile of Qnexa. After this portion of the sponsor's presentation, FDA will make a presentation on REMS. Dr. Barbara Troupin, senior director of Global Medical Affairs, will then present Vivus' REMS, based on the current discussions with FDA. Qnexa is comprised of phentermine and topiramate, two drugs that are now generic and have been approved by FDA multiple times. Phentermine is the most widely-prescribed obesity treatment today. It was approved over 0 years ago as short-term treatment for weight loss. Last year, (0) 0-

34 FDA approved two novel formulations of phentermine at doses two to four times higher than Qnexa. Topiramate was first approved for the treatment of epilepsy years ago. In 0, it was approved for migraine prophylaxis. The most recent approval for topiramate occurred last year for use as monotherapy for epilepsy in pediatric patients between the ages of and. Today, topiramate is used primarily by women of childbearing potential for migraine prophylaxis. What is the rationale for a fixed-dose combination treatment for obesity? It is worth noting that body weight regulation involves many redundant pathways. Therefore, a treatment that targets multiple mechanisms may have a greater effect on reducing hunger and improving satiety. With greater weight loss, one may lower the dose of each drug so that dose-limited side effects would be reduced and the overall risk-benefit profile is improved. This is what we found when we combined topiramate and phentermine. Since both drugs (0) 0-

35 address different and unique mechanisms, lower doses of these two agents, in combination, were shown to achieve clinically meaningful weight loss in early clinical trials. To understand the doses of Qnexa, let's first examine the approved doses of these two agents. Phentermine's maximum approved dose is 0 milligrams; for topiramate, it's 00 milligrams. The starting dose of Qnexa contains one-eighth of the approved dose of phentermine and one-sixteenth of the approved dose of topiramate. The mid-dose is the recommended dose of Qnexa. It contains onequarter of phentermine and one-eighth of topiramate, respectively. The top dose contains one-half of phentermine and less than one-quarter of the approved dose of topiramate. It is important to note that in our proposed label, the top dose is reserved for patients who need a higher dose to achieve treatment goals after having been on mid-dose for six months. Vivus recommends that for patients who do not lose percent or more of their body weight after three (0) 0-

36 months on the mid-dose, they should discontinue treatment. Let me review recent regulatory history of Qnexa. The first advisory committee meeting for Qnexa was held in July, where these safety topics were discussed. These are the known and expected effects of topiramate and phentermine. These safety topics were discussed extensively during that meeting. The remaining issues at the end of the meeting were increased heart rate and teratogenic potential of topiramate. The panel also asked for data from a two-year study, OB-0, which had not been completed at the time of the first meeting, as it was not a requirement for the original NDA submission. Following the panel's non-approval recommendation in October, Vivus received a complete response letter detailing the remaining two reasons for non-approval and the FDA's recommended actions to address them. The agency asked us to provide evidence that elevations in heart rate associated with Qnexa do not increase (0) 0-

37 the risk of major adverse cardiovascular events. In addition, the agency asked for the results from the two-year study. The FDA also asked Vivus to provide a comprehensive assessment of topiramate's and Qnexa's teratogenic potential and to provide a detailed strategy to evaluate and mitigate the potential risk for teratogenicity in women of child-bearing potential. With the FDA's agreement, Vivus resubmitted the Qnexa NDA in October with a contraindication for use in women of child-bearing potential. The unique controlled distribution system we included in the REMS would ensure a near- 0 percent exclusion of women of child-bearing potential from accessing Qnexa. In a subsequent discussion with the agency in December, the FDA asked that we remove this contraindication because they believed it was too broad, and that in some women, the benefits of treatment may outweigh the risks. The FDA also informed us that a more restrictive (0) 0-

38 contraindication and REMS would potentially drive these patients to use generic topiramate and phentermine off label. In response, we developed a rigorous REMS that we believe will be effective in managing the risk while not being overly restrictive or too burdensome for patients or providers. As such, we are here today seeking a recommendation from the panel for the approval of Qnexa for the indication of treatment of obesity, including weight loss and maintenance of weight loss. It is recommended for obese patients or overweight patients with a weight-related comorbidity such as hypertension, type diabetes, dyslipidemia, or central adiposity. Further, with FDA's guidance, we've modified the contraindication. Women who are pregnant may not take Qnexa. Women who become pregnant while taking Qnexa must stop treatment immediately. In addition, we agree with FDA that Qnexa, as well as all weight-loss products, be classified as Category X, since there is no benefit for use (0) 0-

39 during pregnancy. This is consistent with clinical guidelines for weight gain during pregnancy and recommendations against weight loss during pregnancies, even in obese, pregnant women. Vivus also believes it would be important to warn, through labeling and patient and provider education, that for women at risk of becoming pregnant, they must use effective contraception. Vivus is committed to continuing to work with the FDA to ensure that maximum safety is obtained with the use of Qnexa, without creating undue burden to patients or to healthcare providers. Before I conclude, permit me to make an important observation that we hope you will keep in mind during your deliberations today. Vivus has responded to FDA's challenge and worked collaboratively with the agency to create a risk management plan with a specific REMS for women of child-bearing potential, in particular women at risk of becoming pregnant, not using effective contraception. It will be the focus of some of (0) 0-

40 0 your discussions today. But as you deliberate, please remember that Qnexa was developed for the entire obese population and offers real and tangible benefits to men, women of non-child-bearing potential, as well as women of child-bearing potential suffering from this epidemic for which there are no effective medical therapies. Thank you. I will now turn the podium over to Dr. Wesley Day, who will discuss the efficacy results of our trials. Sponsor Presentation Wesley Day DR. DAY: Thank you, Mr. Tam. Mr. Chairman, members of the panel, FDA, and audience, good morning. My name is Wesley Day, and I'm the vice president responsible for clinical development at Vivus. I am also an adjunct associate professor for the school of pharmacy at the University of Maryland at Baltimore. I will provide an overview of the Qnexa clinical development program and review the efficacy data supporting the NDA. This will (0) 0-

41 include a discussion of the one- and two-year weight-loss data, including weight-related comorbidities and effects on quality of life. Dr. Gesundheit will follow my presentation with an overview of the general safety of Qnexa for the pivotal and second year of treatment. Let's start with the discussion of the phase program. The Qnexa program was comprised of four studies. OB-0, a factorial study, tested the combination compared to the individual components and placebo. The pivotal studies were designed to include important medical-need populations. OB-0 assessed the effects of Qnexa in a severely obese population that would qualify for gastric surgery. OB-0 examined a population with confirmed weight-related comorbidities at baseline, providing insight regarding the effects of weight loss on recognized cardiovascular risk factors. OB-0 was a double-blind, placebo-controlled extension of OB-0 that provided second-year safety and efficacy experience in a population (0) 0-

42 completing one year of treatment. Now, let's look at the elements of each study. OB-0 confirmed that the combination could provide significantly better weight loss than either phentermine or topiramate. OB-0 was conducted in severely obese patients with a minimum BMI of, with no upper limit. Patients with a BMI greater than 0 were studied. OB-0 was the largest pivotal study with confirmed presence of hypertension, dyslipidemia, or diabetes at baseline. Finally, OB-0 included patients with blinding and randomization maintained. All phase studies used the Learn program, which included counseling in diet and exercise and was intended to provide relevant background weight loss for the entire study population. Looking at the baseline demographics for each study, you can see a similarity in most criteria, such as gender, race, and ethnicity. I draw your attention to the top of the slide. The differences in BMI are a result of the study (0) 0-

43 inclusion criteria. By requirement of the severely obese population, OB-0 would be expected to have a higher baseline BMI. At the bottom of the slide, note the greater presence of weight-related comorbidities in OB-0 patients. Now, let's look at disposition for these studies. The rate of study completion was significantly greater for Qnexa-treated patients as compared to placebo. Seventy-one percent retention is among the highest completion rates for phase obesity studies. The pivotal program also sought to retain patients within the study on or off drug. Approximately to percent of patients remained in the study off drug. Now, looking at the co-primary endpoints, here you see the results for percent weight loss, the first co-primary endpoint. All doses were significant compared to placebo. Top dose, shown in purple on the far right side of each set of bars, was significant compared to mid-dose in green and low dose in blue. Importantly, there was greater than percent mean weight loss for top (0) 0-

44 dose in both studies. The second co-primary endpoint was categorical weight loss defined as percent of patients achieving at least percent reduction in body weight. There was a significant effect with all doses of Qnexa compared to placebo in both studies. Please also note not only did the categorical weight loss of percent exceed the FDA threshold of percent, this was also the case for percent categorical weight loss for the top and mid-dose. Another way to look at this data is by examining weight loss over time in patients on drug. For comparison, on the right side of each graph are the results of the ITT-LOCF analysis that I just described. In OB-0, the low dose produced. percent weight loss following weeks of treatment, compared to and a half percent for placebo. In OB-0, the mid-dose produced. percent weight loss compared to a placebo effect of and a half percent. Finally, the top (0) 0-

45 dose achieved weight loss of. percent in OB-0 and. percent in OB-0. In summary, both studies demonstrated doserelated, rapid, and sustained weight loss over weeks of treatment. All Qnexa doses were significant compared to placebo. Moving on to the second year of treatment, as discussed in the phase program outline, OB-0 was a one-year extension to OB-0 that was conducted at high-retention sites. There were a total of OB-0 patients that were eligible to continue into OB-0. Of the eligible patients, percent elected to continue. A greater proportion of Qnexa-treated patients elected to continue treatment, percent, as compared to percent on placebo. Retention in OB-0 was high and comparable between treatment arms. Let's look at the weight loss in these patients. A plot of percent weight loss over time based on all observed data for the two-year population is shown. Both Qnexa treatment arms (0) 0-

46 demonstrated greater than percent weight loss that was achieved in six to nine months and sustained over the two-year treatment period, compared with and a half percent weight loss for placebo. As shown in the right-hand bar, ITT-LOCF results at week are similar to patients completing the full two years of treatment. Now, let's examine the effects of Qnexa on a spectrum of cardiovascular risk factors across the entire population and the effects on a subpopulation of hypertensives and diabetics. We will also examine the weight-loss effect on development of new, onset diabetes. On the left, you see a range of endpoints, including blood pressure, CRP, lipid, liver function, glycemic, sleep apnea, and quality of life. On the graphs, any confidence interval to the left of the center line represents a statistically significant improvement associated with Qnexa. For the mid-dose, significant improvements were observed for all endpoints except diastolic (0) 0-

47 blood pressure. For the top dose, we observed meaningful and significant improvements compared to placebo for all endpoints, including diastolic blood pressure. Overall, based on the full ITT population, regardless of baseline values, the midand top dose Qnexa treatment produced improvements across a broad spectrum of weight-related comorbidities and cardiovascular risk factors. Several of these comorbidities were required by study inclusion criteria in patients at baseline. Two examples we can look at are patients with hypertension or diabetes, as shown in the next two slides. In patients with hypertension at baseline, defined as those with a blood pressure greater than 0 over 0 or using two or more medications, we observed that the effects of Qnexa on blood pressure are dose related and of greater magnitude compared to placebo. For systolic blood pressure, the top dose produced a significant reduction of. millimeters, compared to. and. on mid- (0) 0-

48 and placebo, respectively. The study allowed active management of anti-hypertensive medications. Here, we see more Qnexa-treated patients experience a reduction in the starting of new medications and a greater discontinuation of existing meds, as compared to placebo. Overall, the data suggests a clinically meaningful improvement in blood pressure occurred with Qnexa treatment in the presence of fewer antihypertensive medications. Now, let's look at patients with diabetes. Diabetes at baseline was defined as a fast in glucose greater than or equal to mgs per deciliter or use of medication to control blood glucose. This population was well-controlled, primarily on metformin, with a baseline HbAc of. percent. We observed that the effects of Qnexa on HbAc are significant in both the mid- and topdose Qnexa compared to placebo. As with the previous example, investigators were allowed to actively manage the diabetic patients with medications. (0) 0-

49 Here, we see a significant reduction in the starting of new medications and a greater discontinuation of existing medications for Qnexa-treated patients compared to placebo. Consistent with blood pressure effects, clinically meaningful improvement in HbAc occurred in the presence of less use of anti-diabetic medication. Now, for non-diabetic obese patients who are at risk to develop the disease, following one year of treatment, the annualized incidence rate of progression to diabetes was significantly reduced with both doses of Qnexa. Diabetes was defined as two consecutive visits with fasts in glucose greater than or equal to mgs per deciliter or a two-hour post-oral glucose test greater than 0. Following two years of treatment, the improvements in progression were observed for both doses. Importantly, top-dose Qnexa resulted in a percent reduction in new cases of diabetes in two years of treatment. Thus, the Qnexa-related improvements in weight, as well as a broad spectrum of glycemic endpoints, supports (0) 0-

50 0 an overall reduction in new cases of diabetes. Finally, changes in weight and other comorbidities appear to equate with improvements in quality of life. The impact of weight on quality of life, IWQOL, instrument was used throughout the phase program. The results suggest that both doses of Qnexa produced significant improvements in the composite score as well as all domains, including physical function, self-esteem, sexual life, public distress, and work. In addition to the IWQOL instrument, we used the SF-, a general health instrument, throughout OB-0. The results suggest that both doses of Qnexa produced significant improvements in physical function and role, bodily pain, general health, and vitality. There were no significant changes in emotional role or mental health. In summary, the pivotal and two-year study has confirmed that treatment with Qnexa is associated with significant weight loss and improvement of cardiovascular risk factors, as well as meaningful quality of life improvements. (0) 0-

51 The dose-related weight-loss effects of Qnexa exceeded FDA benchmarks with mean reductions in body weight that exceeded percent and were sustained over two years. As would be expected with clinically meaningful weight loss, we see a significant and sustained improvement in quality of life and a broad spectrum of cardiovascular risk factors, including blood pressure, glycemic, liver, and lipid endpoints. Finally, we observed a significant reduction in new cases of new onset diabetes compared to placebo. I will now turn the presentation over to Dr. Gesundheit, who will discuss the safety data. Sponsor Presentation Neil Gesundheit DR. GESUNDHEIT: Good morning. My name is Neil Gesundheit. I am an endocrinologist and a paid clinical advisor to the sponsor. I previously served as vice president and chief medical officer of Vivus and have remained a company shareholder. I am currently an associate professor of medicine at Stanford University. The views expressed today are my own and not those of Stanford. (0) 0-

52 In this section, I will discuss the safety of Qnexa by reviewing common side effects observed with phentermine and topiramate. Next, I will show data from the one-year cohort and the second year of study, OB-0. Finally, I would like to review three safety concerns raised at the advisory committee meeting in, psychiatric- and cognition-related adverse events and the lowering of serum bicarbonate. Dr. Peter Kowey will discuss the effects of Qnexa on heart rate and Dr. Gary Shaw will discuss potential teratogenicity. The common adverse events observed with Qnexa are those expected from the prior clinical experience with the two component drugs. Common side effects of phentermine are shown on the left and for topiramate on the right. Two of the side effects of topiramate merit clarification. Paresthesia refers to tingling in the hands and feet. Dysgeusia refers to an alteration in taste. These are both common side effects of carbonic anhydrase inhibitors. As you will see in the next slides, the (0) 0-

53 adverse events observed with Qnexa are consistent with those observed with the individual components. In this section, I will discuss the key safety findings of the one-year studies that provide the core safety experience in more than 00 patients, shown in blue. In addition, we examined data from the two-year cohort, shown in light blue at the bottom. Patients in the two-year continuation study were drawn from of the sites in protocol OB-0. Study sites were chosen primarily by the number of patients recruited and the site retention rate. There was no a priori knowledge of patient outcomes during year one. Nearly 0 percent of the patients from these sites, or patients, elected to continue into a second year of study. Patients remained in their treatment group and the placebo-controlled, double-blind design was maintained for the second year. In its briefing book, the FDA examined the two-year cohort in its entirety. We agree with the agency's findings regarding the two-year cohort. (0) 0-

54 Vivus also presented data to the agency for the second year of study, OB-0. In the next slides, we will show the results of the one-year safety cohort, our comprehensive safety baseline, shown on the left in deep blue, and in OB-0, shown on the right in light blue. The baseline demographics and first-year adverse event profiles of the patients who entered OB-0 were representative overall of patients from the oneyear safety cohort. Shown here are the most common adverse events from the one-year cohort on the left and from the second year of study from OB-0 on the right. Constipation, dry mouth, and paresthesia were the most common side effects showing an increased incidence in Qnexa-treated patients compared with placebo. These side effects reported less commonly in protocol OB-0, although the rates continued to be higher on Qnexa. Most other common side effects reported with similar frequencies in the second year of Qnexa use compared with the one-year cohort. (0) 0-

55 In the one-year cohort, study completion rates ranged from 0 percent on placebo to to percent on Qnexa. Study completion rates on drug ranged from percent on placebo to to percent on Qnexa. In the second year of study -- and remember that all of these patients completed the first year of study by definition -- the study completion rates averaged percent across groups. Treatment-emergent adverse events were higher on Qnexa than placebo in the one-year cohort, but were similar across treatments in the second-year group. Treatment-emergent adverse events leading to discontinuation were higher on Qnexa than placebo during year, but were more similar across treatments from. to. percent during the second year. Importantly, we examined serious adverse events, SAEs, in the two cohorts. SAEs are events leading to hospitalization, death, or disability. In the one-year cohort, the incidence of SAEs was. percent on placebo and ranged from. to (0) 0-

56 . percent on Qnexa. In the second-year cohort, the incidence was.0 percent on placebo and ranged from. to. percent on Qnexa. There was one death in the program, and that occurred in a patient on placebo in the one-year cohort. There were no SAEs for psychiatric of cognitive disorders in Qnexa patients in either cohort. In summary, the incidence of SAEs was similar between placebo and active treatment groups in the one-year and second-year cohorts. No new or unexpected events appeared during the second year of Qnexa treatment. Now, let's turn our attention to the three safety concerns raised at the meeting. Psychiatric disorders were identified as TMEs, or targeted medical events. The incidences in the one-year cohort are again shown on the left and the second-year cohort on the right. For each of the top three categories, the incidences in Qnexa-treated patients were generally higher than a placebo. For suicide or self-injury, the adverse event of greatest concern, there was (0) 0-

57 only one report in a patient on placebo at any point in the two-year program. Cognitive disorders were another TME. Shown here are four specific cognitive disorders. In the one-year cohort, the incidence of cognitive disorders was low, but occurred with increased frequency on Qnexa treatment. During the second year of treatment, there were very few reports in this TME in either treatment group. Another adverse event discussed at the advisory committee meeting was the lowering of serum bicarbonate. The lower limit of serum bicarbonate in our reference lab was milliequivalents per liter. Shown here are patients who showed a persistent lowering to below or milliequivalents per liter. As you can see from the one-year cohort, there was an increased incidence of persistent lowering of serum bicarbonate with Qnexa treatment. In the secondyear cohort on the right, there were fewer reports to below, although they occurred more on Qnexa. (0) 0-

58 There were no reports of persisting lowering of serum bicarbonate to below in the second year of treatment in any group. We examined the time course of serum bicarbonate lowering in the two-year cohort in subjects who had a level below milliequivalents per liter at any time. As you can see, the nadir of mean serum bicarbonate occurred between and weeks. In all three groups, the mean serum bicarbonate self-corrected over time. There were no discontinuations due to a lowering of serum bicarbonate. In summary, the adverse event profiles in the second year of treatment, study OB-0, were consistent with those in the one-year cohort. The safety profiles are consistent with the known side effects of the two component drugs. There is the important caveat that the second-year cohort consisted of patients who had successfully completed one year of treatment. Nevertheless, the second-year cohort allowed us to examine for new or unexpected safety concerns that (0) 0-

59 might arise during a second year of treatment. Psychiatric adverse events, cognitive adverse events, and persistently reduced serum bicarbonate occurred less in year than in year, but occurred more with Qnexa than placebo in the program. Importantly, there was no difference in serious adverse events when comparing Qnexa to placebo in the one-year or in the second-year cohort. There was no signal of suicidality in Qnexa patients in the program. There was no signal of delayed or cumulative toxicity. Dr. Kowey will now discuss the cardiovascular safety of Qnexa. Sponsor Presentation Peter Kowey DR. KOWEY: Thank you, Neil. I've been tasked this morning to discuss heart rate and blood pressure clinical implications. My name is Peter Kowey. I'm a cardiologist and electrophysiologist in Philadelphia at Jefferson Medical College and at the Lankenau Medical Center in Wynnewood, (0) 0-

60 0 Pennsylvania. I am a paid consultant to the sponsor. I am paid on an hourly basis for my work, and I hold no equity interest in this company or any other pharmaceutical company. In order to get through this relatively expeditiously, I will refer you several times to the briefing document, where there is a tremendous amount of information on this topic. But for the purposes of my presentation, I'll present my information in this outline, beginning with heart rate and blood pressure, integrating those variables into a common clinical parameter called the rate pressure product, discussing briefly the outlier analysis that was carried out by the sponsor and also by the FDA, discuss briefly arrhythmia adverse events, discuss cardiac SAEs, and then wrap up with discussion of the major adverse cardiovascular events that you saw was an area of interest during the last advisory committee in. I'll start off with a relatively simple slide that breaks out the two components of this (0) 0-