OBESITY DRUGS: CURRENT STATUS AND FUTURE POTENTIAL

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OBESITY DRUGS CURRENT STATUS AND FUTURE POTENTIAL

• Richard L. Atkinson, M.D.
• Director, Obetech Obesity
• Research Center
• Virginia Biotechnology Research Park
• Richmond, Virginia
• obesityvirus.com

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DEFINITION OF OBESITY

• Obesity is a chronic disease of multiple
  etiologies characterized by the presence of
  excess adipose tissue
• RL Atkinson, 1980

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RATIONALE FOR DRUG TREATMENT OF OBESITY

• 1. Obesity is a chronic disease
• 2. Most chronic diseases are treated with drugs
• 3. The biochemistry of obese individuals is
  different from that of lean people
• 4. When obese people lose weight, their
  biochemistry does not become the same as in lean
  people
• 5. Biochemistry is changed with drugs

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BARRIERS TO USE OFOBESITY DRUGS

• 1. Discrimination against obesity
• 2. Physician/clinician ignorance
• 3. Economic factors
• 4. Policy/political barriers
• 5. Lack of advocacy by obese people
• 6. Modest effectiveness of obesity drugs

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OBESITY IS THE LAST BASTION OF SOCIALLY
ACCEPTABLE BIOGTRY
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AREAS OF DISCRIMINATIONDEFINITION

• Labeling obesity a disease may be expedient but
  it is not a necessary step in a campaign to
  combat obesity and it may be interpreted as
  self-serving advocacy without a sound scientific
  basis.
• Heshka and Allison, IJO, 2001

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AREAS OF DISCRIMINATIONLACK OF MEDICALIZATION

• Comparison with other chronic diseases
• 1. Newly diagnosed Type 2 diabetes and
  hypertension respond very well to diet and
  exercise - but the primary treatments are drugs
• 2. The primary treatment for obesity is diet and
  exercise, drugs are an adjunct. Many patients
  must demonstrate that they have failed DE before
  getting drugs or surgery

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BARRIERS TO OBESITY DRUGSPHYSICIAN/CLINICIAN
IGNORANCE

• 1. Obesity thought not to be a real disease
• 2. Uncomfortable about counseling overweight or
  obese patients
• 3. Physicians/clinicians not knowledgeable about
  nutrition, physical activity, obesity drugs
• 4. Unaware of referral information
• 5. Bias that drug treatments are dangerous,
  ineffective, and somehow not worthy

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BARRIERS TO OBESITY DRUGSECONOMIC FACTORS

• 1. Third party payers, government dont cover
• 2. Treatment expensive, break the bank
• a. Large number of overweight/obese people
• b. A high of patients would use obesity drugs
• 3. Savings in future costs too remote compared to
  current expenses

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BARRIERS TO OBESITY DRUGS GOVERNMENT FDA

• 1. Past bias of FDA personnel against obesity/
  obesity drugs (quote Gaining weight doesnt
  hurt you and losing weight doesnt help you)
• 2. Obesity drugs have been held to a different
  standard than drugs for other diseases (eg
  phen-fen debacle vs troglitazone)
• 3. Experience of recent obesity drugs
  dexfenfluramine, sibutramine, orlistat
• 4. Intense political pressure on FDA

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BARRIERS TO OBESITY DRUGS GOVERNMENT CMS

• 1. Recent language in Medicare/Medicaid
  regulations
• Obesity is not a disease
• 2. Efficacy standards for treatment apparently
  will be applied, in contrast to most other
  chronic diseases

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BARRIERS TO OBESITY DRUGS

• The expectations and behavior of obese people
  themselves
• 1. Do not believe they are worthy of respect
• 2. Discriminate against the obese as much or more
  than do thin people
• 3. Do not bind together for action
• 4. Do not act as advocates for obesity

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BARRIERS TO OBESITY DRUGSLIMITED CHOICES, POOR
EFFICACY

• 1. Only two drugs still on patent
• 2. Only three categories of drugs
• 3. Poor understanding of etiology of obesity,
  mechanisms of action of drugs
• 4. Typical weight loss with single agents only
  about 10 of initial body weight
• 5. Very limited use of combinations of drugs

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WEIGHT LOSS WITH PHENTERMINE

• 36 week trials
• Wt loss Wt loss
• Munro, et al -12.3 kg -13.0
• BMJ, 68
• Steel, et al -12.0 kg -12.8
• (Practitioner, 73)

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DRUGS FOR OBESITYTHE FUTURE
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POTENTIAL FUTURE AGENTS

• 1. Gut peptides
• 2. Opioid antagonists
• 3. Neurotransmitter agonists antagonists
• 4. Thermogenic agents
• 5. Growth hormone, growth factors
• 6. Lipid oxidizing agents
• 7. Nutrient partitioning agents

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POTENTIAL OBESITY AGENTS

• Bupropion Axokine
• Topiramate Melanocortin
• Zonisamide Serotonin agonists
• Rimonabant Exendin-4
• Glucagon-like peptide Leptin analogues
• PYY 3-36 GH analogues
• CCK agonists NPY antagonists
• Enterostatin Beta-3 agonists
• Lipid oxidizing agents Oleoyl-estrone

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Topiramate Body Weight Loss in Adults vs
Treatment Duration (Months)
6
4
Average Weight Loss (kg)
2
0
3
6
12
18
24
30
36
42
48
54
60
TPM Treatment Duration (mos)
N126-833
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ZONISAMIDE FOR WEIGHT LOSS

• 16 wk, randomized trial in 60 subjects
• 400-600 mg/d for 16 wk, 16 wk extension
• Placebo Zonisamide
• 16 wk wt loss (kg) 0.9 0.4 5.9 0.8
• 32 wk wt loss (kg) 1.5 0.7 9.2 1.7
• 32 wk loss of IBW 1.8 9.4
• losing 5 of IBW 10 57
• (16 wk) Gadde, et al JAMA 2891820, 03

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RATIONALE FOR OBESITYDRUG COMBINATIONS

• 1. Obesity is a chronic disease
• 2. Most chronic diseases are treated with drugs
• 3. Most chronic diseases require more than one
  drug
• 4. Combinations of drugs may have additive or
  synergistic effects
• 5. Side effects may be offset

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Body Mass Index of subjects who completed 6
months of treatment. Closed circle Phen-fen
Open circle Phen-flu.
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THOUGHTS ON FDA GUIDANCES FOR OBESITY DRUGS

• 1. Obesity is a major public health problem -
  should obesity drugs be fast-tracked?
• a. Efficacy shown by virtually all at 6 mo
• b. Virtually all safety issues seen by then
• 2. Extended run in periods serve little use
• 3. If safe, modest weight loss holds promise,
  particularly in combination with other drugs
• 4. Varied indications for use are justified

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RATIONAL EXPECTATIONS FOR OBESITY DRUGS

• 1. Current drugs are modestly effective
• 2. Drugs in pipeline appear to be similar in
• terms of efficacy - maximum wt loss about 17
• 3. Overhype by companies detrimental
• 4. Overcaution by FDA, others, detrimental
• 5. Media hasnt always been responsible
• 6. General public desperate, need perspective and
  understanding of obesity as a disease
• 7. For now, long term lifestyle changes needed

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OBESITY DRUGSPROMISE FOR THE FUTURE

• 1. Drugs are the future of obesity treatment
• 2. Obesity is due to biochemical differences
• 3. Drugs change biochemistry
• 4. Surgery produces wt losses of 25-40 of
  initial body weight
• 5. Surgery changes biochemistry
• 6. At least 350 drugs are in the pipeline
• 7. Combination treatment will be necessary
• 8. The future is extremely bright

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AMERICAN OBESITY ASSOCIATION

• A lay advocacy association dedicated to obesity
• Mission
• To improve the quality of life of obese people
• Contact information
• Website obesity.org
• Phone [phone]

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FOR COPIES OF SLIDES OR FURTHER INFORMATION

• Richard L. Atkinson, M.D.
• Obetech Obesity Research Center
• Virginia Biotechnology Research Park
• Richmond, Virginia
• 804-344-5360
• obesityvirus.com