1. FDA 2004: Toward new therapeutics for obesity David G. Orloff, M.D. Division of Metabolic and Endocrine Drug Products, CDER

2. 2 Health consequences of excess weight: we’ve known about it all along… “sudden death is more common in those who are naturally fat than in the lean” “corpulency, when in an extraordinary degree, may be reckoned a disease, as it in some measure obstructs the free exercise of the animal functions; and hath a tendency to shorten life, by paving the way to dangerous distempers” - cited in Bray, G.A. Endocrinol Metab Clin N. Amer 32 (2003) 787-804

3. 3 Health consequences of excess weight: we’ve known about it all along… “sudden death is more common in those who are naturally fat than in the lean” Hippocrates “corpulency, when in an extraordinary degree, may be reckoned a disease, as it in some measure obstructs the free exercise of the animal functions; and hath a tendency to shorten life, by paving the way to dangerous distempers” - cited in Bray, G.A. Endocrinol Metab Clin N. Amer 32 (2003) 787-804

4. 4 Health consequences of excess weight: we’ve known about it all along… “sudden death is more common in those who are naturally fat than in the lean” Hippocrates “corpulency, when in an extraordinary degree, may be reckoned a disease, as it in some measure obstructs the free exercise of the animal functions; and hath a tendency to shorten life, by paving the way to dangerous distempers” Flemyng 1760 - cited in Bray, G.A. Endocrinol Metab Clin N. Amer 32 (2003) 787-804

5. 5 Obesity comorbidities Cardiovascular: hypertension, coronary artery disease, angina pectoris, congestive heart failure Cardiovascular: hypertension, coronary artery disease, angina pectoris, congestive heart failure Cerebrovascular: stroke Cerebrovascular: stroke Hyperlipidemia Hyperlipidemia Metabolic syndrome/type 2 DM Metabolic syndrome/type 2 DM Cholelithiasis Cholelithiasis Gout, uric acid nephrolithiasis Gout, uric acid nephrolithiasis Osteoarthritis Osteoarthritis Obstructive sleep apnea, hypoventilation Obstructive sleep apnea, hypoventilation Hyperandrogenism, hirsutism, irregular menses, complications of pregnancy, stress incontinence Hyperandrogenism, hirsutism, irregular menses, complications of pregnancy, stress incontinence Malignancies: breast, endometrium, colon, prostate Malignancies: breast, endometrium, colon, prostate Increased surgical risk Increased surgical risk Psychological disorders Psychological disorders

6. 6 FDA: Facilitating the development and marketing of safe and effective new therapies for obesity Charge from Dr. McClellan to OWG/Therapeutics  “…[assess] real or perceived barriers to development of new or enhanced therapeutics”  “Make recommendations… on…ways to encourage development of new or enhanced therapeutics” Revisiting FDA guidance to industry on development of drugs for obesity  Open comment period to 4-26-04 on 1996 document  Dialogue with AOA/PhRMA 3-16-04  Likely Advisory Committee meeting in late 2004

7. 7 The harsh reality: current state of medical therapeutics in obesity Weight loss: Weight loss:  Current therapies generally induce only modest degrees of weight loss (mean 1-5 kg relative to pbo, diet, exercise). Maintenance: Maintenance:  Weight loss is maintained only when on therapy and only in a subset of individuals treated. “Natural history “: about 90% regain lost weight within 6 months; 95% within 2-3 years. N.B. Limited data available on impact of drug-associated weight loss on morbid outcomes; no mortality data

8. 8 Opportunities: multiple potential targets in obesity therapeutics Serotonin, NE, DA Leptin/CNTF Neuropeptide Y Peptide YY Ghrelin MC 3, MC 4 MSH MCH CRH Urocortin Galanin H3 CART Amylin Orexin CCK-A GLP-1 Bombesin Beta 3 adrenergic system GH Cannabinoid receptor Topiramate Selective thyroid modulators

9. 9 Path forward to safe and effective obesity drugs Modern history Standards of evidence for approval: pre-1996 Transformation in medical perception of obesity Clinical development standards and rationale: post-1996 Areas for discussion  Trial duration, efficacy criteria  Trial duration, safety exposures  Promotion/selection of therapies based on effects on comorbidities Unanswered questions  Combination therapy (after fen-phen)  Head-to-head comparisons of approved agents  Long-term safety and efficacy of older drugs (e.g., phentermine)  Do drugs (today’s and tomorrow’s) confer long-term, individual and population, reductions in morbid and mortal sequelae of obesity

10. 10 Modern History of Weight Loss Drugs  1880’s Thyroid extract (hyperthyroidism)  1930’s Dinitrophenol (cataracts, neuropathy)  1940’s Amphetamines (addiction, CNS/cardiac toxic)  1960’s Rainbow pills -digitalis/diuretics (sudden death)  1970’s Aminorex (pulmonary hypertension)  1990’s Redux (cardiac valvulopathy)

11. 11 Centrally-Acting Anorexigens Approved Post-1938 1  1947 – Desoxyephedrine/methamphetamine (available pre-’38)  1956 – Phenmetrizine (Preludin)  1959 - Phendimetrazine (Bontril)  1959 - Phentermine (Fastin, Ionamin) – W/D CPMP 2000  1959 - Diethylpropion (Tenuate)  1960 - Benzphetamine (Didrex)  1972 - Fenfluramine (Pondimin) – W/D 1997  1973 - Mazindol (Sanorex) 2  1995 – Dexfenfluramine (Redux) – W/D 1997  1997 – Sibutramine (Meridia)  1. All save Redux and Meridia for short-term use  2. All save Mazindol amphetamine related

12. 12 Standards of evidence pre-1996: Short-Term Use  Prior to 1996, all obesity drugs were approved for short-term treatment of obesity  Pre-approval trials up to 12 weeks’ duration  Limited safety exposures: 200-400 patients  Concerns about abuse/addiction  Labeled for short term use, i.e., “a few weeks”  Efficacy: Short-term indication drugs  Mean loss of 5.0 kg vs. placebo  range of placebo-subtracted means across studies 1.0 to 10.0 kg

13. 13 Transformation in medical perception of obesity: chronic disease model  Obesity as a chronic condition associated with “metabolic” derangements and conferring risk for long-term morbid and mortal sequelae (i.e., risk factor/etiologic in DM, CHD, etc.)  High rate of weight regain following discontinuation of drug treatment  Recognition that maintenance of “healthy” weight is critical to reduction in risk for obesity-associated adverse outcomes

14. 14  1992 - obesity drugs transferred from Division of Neuropharmacologic to Metabolic and Endocrine Drugs  1995 - Advisory Committee meeting  Evolution in disease model: lifelong treatment  Discussions of clinical trial design and evidentiary standards for approval for long-term use  1996 - Draft Guidance issued: development of chronic use anti-obesity drugs

15. 15 Clinical development standards and rationale: 1996 Obesity Guidance  Patient Population: patients with high risk for sequelae  Body mass index (“morbid obesity”)  > 27 kg/m 2 with comorbidities  > 30 kg/m 2 without comorbidities  Duration of Phase 3 Trials: historical “bad luck” with antiobesity drugs; absence of outcomes data  First year placebo-controlled - proof of principle of efficacy  Second year open-label – durable efficacy and safety in long-term use

16. 16 Obesity Guidance: Efficacy Criteria  Efficacy criteria at end of year 1: presumed reduction in risk for sequelae with modest (sustained) weight loss in serious obesity  Mean placebo-subtracted weight loss > 5%  Proportion of subjects who lose > 5% of baseline body weight is greater in drug- vs. placebo-treated group  EMEA criteria at end of year 1:  mean placebo-subtracted weight loss > 10%  Proportion of patients who lose > 10% of baseline body weight is greater in drug- vs. placebo-treated group

17. 17 Drugs Approved for Long-Term Treatment of Obesity  1996 - Dexfenfluramine (Redux): w/d ‘97  1997 - Sibutramine (Meridia)  1999 - Orlistat (Xenical)  Efficacy: Long-term indication drugs  Mean loss of 5.0 kg vs. placebo  range of placebo-subtracted means across studies 1.5 to 6.0 kg

18. 18 “Barriers”: Safety exposures must be substantial Safety exposures  1500 patients for 1 year  200-500 patients completing a second year ICH E1A: Drugs for long-term treatment of non-life-threatening conditions  300-600 for 6 months  100 for one year

19. 19 Rationale: Expectations of efficacy of new agents Larger/longer exposures if benefit of drug is:  Small (e.g., symptomatic improvement, less serious disease)  Experienced by only a fraction of treated patients (prevention)  Of uncertain magnitude (reliance on a surrogate) Average placebo-subtracted weight loss of drugs evaluated to date 3-5% of baseline at year 1 Not all treated patients lose weight; some gain No data to date from controlled trials of benefits in terms of irreversible morbidity or mortality

20. 20 Therapeutic “gaps” and unanswered questions Head-to-head comparisons of approved agents

21. 21 Therapeutic “gaps” and unanswered questions Head-to-head comparisons of approved agents Long-term safety and efficacy of older drugs (e.g., phentermine)

22. 22 Drug use data: 1991-2002 Annual volume of antiobesity medications reported in the United States, 1991–2002, IMS HEALTH National Disease and Therapeutic Index. Data for 2002 are an estimate (E) based on January to March 2002 figures. HCl indicates hydrochloride. From: Stafford: Arch Intern Med, Volume 163(9).May 12, 2003.1046–1050

23. 23 Therapeutic “gaps” and unanswered questions Head-to-head comparisons of approved agents Long-term safety and efficacy of older drugs (e.g., phentermine) Combination therapy

24. 24 Therapeutic “gaps” and unanswered questions Head-to-head comparisons of approved agents Long-term safety and efficacy of older drugs (e.g., phentermine) Combination therapy Do drugs (today’s and tomorrow’s) confer long-term, individual and population, reductions in morbid and mortal sequelae of obesity

25. 25 Obesity and Type 2 Diabetes: an epidemic of genetic disease “an epidemic of a genetic disease waxes because of a rise in environmental risk factors, and then wanes when the number of susceptible potential victims falls (but only because of the preferential deaths of those who are genetically more susceptible)”  Diamond, J. Nature 2003; 423: 599-602

26. 26 Conclusions The magnitude of the obesity epidemic, its contribution to chronic disease, its costs to individuals and society, and the absence of broadly effective therapeutics constitute a “call to action” by the collective medical community, including FDA Resolution of issues around real or perceived barriers to development is paramount to advancing the field of obesity therapeutics, though without sacrificing the “quality” of the obesity armamentarium Diet and exercise remain the mainstays of prevention and treatment of obesity; drugs are adjunctive to hygienic measures Precedent with older as well newer drugs, reliance on weight loss alone as measure of health effects, directs a cautious, measured approach in obesity therapeutics Questions of, among others, comparative efficacy and safety, long- term clinical outcomes of treatment, and effects of combination therapy regimens must be addressed sooner rather than later