FDA 2004: Toward new therapeutics for obesity

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FDA 2004 Toward new therapeutics for obesity

• David G. Orloff, M.D.
• Division of Metabolic and Endocrine Drug
  Products, CDER

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Health consequences of excess weight weve 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

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Health consequences of excess weight weve 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
Health consequences of excess weight weve 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

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Obesity comorbidities

• Cardiovascular hypertension, coronary artery
  disease, angina pectoris, congestive heart
  failure
• Cerebrovascular stroke
• Hyperlipidemia
• Metabolic syndrome/type 2 DM
• Cholelithiasis
• Gout, uric acid nephrolithiasis

• Osteoarthritis
• Obstructive sleep apnea, hypoventilation
• Hyperandrogenism, hirsutism, irregular menses,
  complications of pregnancy, stress incontinence
• Malignancies breast, endometrium, colon,
  prostate
• Increased surgical risk
• Psychological disorders

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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 onways 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

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The harsh reality current state of medical
therapeutics in obesity

• Weight loss
• Current therapies generally induce only modest
  degrees of weight loss (mean 1-5 kg relative to
  pbo, diet, exercise).
• 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

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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

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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 (todays and tomorrows) confer
  long-term, individual and population, reductions
  in morbid and mortal sequelae of obesity

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Modern History of Weight Loss Drugs

• 1880s Thyroid extract (hyperthyroidism)
• 1930s Dinitrophenol (cataracts, neuropathy)
• 1940s Amphetamines (addiction, CNS/cardiac
  toxic)
• 1960s Rainbow pills -digitalis/diuretics (sudden
  death)
• 1970s Aminorex (pulmonary hypertension)
• 1990s Redux (cardiac valvulopathy)

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Centrally-Acting Anorexigens Approved Post-19381

• 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

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Standards of evidence pre-1996Short-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

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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

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FDAs Obesity Guidance

• 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

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Clinical development standards and rationale
1996 Obesity Guidance

• Patient Population patients with high risk for
  sequelae
• Body mass index (morbid obesity)
• 27 kg/m2 with comorbidities
• 30 kg/m2 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

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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

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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

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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

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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

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Therapeutic gaps and unanswered questions

• Head-to-head comparisons of approved agents

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Therapeutic gaps and unanswered questions

• Head-to-head comparisons of approved agents
• Long-term safety and efficacy of older drugs
  (e.g., phentermine)

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Drug use data 1991-2002
Annual volume of antiobesity medications reported
in the United States, 19912002, 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, 2003.10461050
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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

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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 (todays and tomorrows) confer
  long-term, individual and population, reductions
  in morbid and mortal sequelae of obesity

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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

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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