A Weighty Problem
by Sarah Stone Wunder
June 2008
As pharmaceutical companies search for a blockbuster fat-fighting drug, the biggest battle is against side effects.
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According to the World Health Organization, as of 2005, 1.6 billion adults worldwide were overweight (BMI equal to or more than 25), with 400 million classified as obese (BMI equal to or more than 30). The number of overweight and obese adults is projected to grow to 2.3 billion and 700 million, respectively, by 2015.
As these figures continue tipping the scales, biopharmaceutical companies have an ever-expanding incentive to develop a drug to combat obesity. Ultimately, such a therapy could prove to be a tremendous blockbuster drug—assuming it produces minimal side effects.
Overall, side effects associated with obesity medications—from mild issues such as oily stools and insomnia to severe complications such as fatal pulmonary hypertension and heart valve damage—have derailed potential blockbusters, such as the case with Orlistat, Redux and Fen-phen.
A New Frontier
In March, Merck released preliminary Phase III data for its obesity drug taranabant. According to the 52-week results of the two-year study, patients taking taranabant 2 mg—an investigational cannabinoid-1 receptor (CB1R) blocking pill—demonstrated a mean weight loss reduction from baseline of 6.6 kg (or 14.5 lbs), compared to 2.6 kg (or 5.7 lbs) for patients on placebo, which was statistically significant (p<0.001 vs. placebo). Patients in all treatment groups were placed on a diet and exercise regimen in addition to therapy or placebo.
Despite these results, however, patients in the study reported side effects ranging from gastrointestinal issues to psychiatric adverse events. According to the results, 42 percent of patients taking 2 mg taranabant (n=414) reported gastrointestinal side effects, which rose to 47 percent among patients taking 4 mg (n=415), 46 percent in 6 mg (n=1256) and only 29 percent on placebo (n=417). The incidences of psychiatric adverse events also were greater at higher doses of taranabant, with 28 percent of patients on taranabant 2 mg reporting their occurrence, 40 percent on taranabant 4 mg, 38 percent on taranabant 6 mg and 20 percent on placebo. In addition, 13 percent of patients on taranabant 2 mg discontinued the study due to clinical adverse events, compared to 10 percent of patients on placebo.
These side effects may hinder the drug during U.S. Food and Drug Administration (FDA) approval considerations down the line. In June 2007, the FDA rejected approval of Zimulti/Acomplia, another cannabinoid receptor blocker from sanofi-aventis that showed psychiatric side effects such as depression and thoughts of suicide.
Measured Success
Meanwhile, San Diego, Calif., USA-based Amylin Pharmaceuticals, Inc. has seen positive results from a Phase IIA, 24-week proof-of-concept study with pramlintide, an analog of human amylin, and recombinant human leptin combination treatment in overweight or obese subjects. At study end, pramlintide/metreleptin treatment reduced body weight on average by 12.7 percent, significantly more than treatment with pramlintide alone (8.4 percent; p<0.001). Subjects treated with pramlintide/metreleptin lost an average of 25 pounds from study start compared with an average of 17 pounds for subjects treated with pramlintide alone. Subjects receiving pramlintide/metreleptin had continuous weight loss through the end of the study compared to those treated with pramlintide alone, whose weight loss had stabilized toward the end of the study.
Pramlintide is a synthetic analog of amylin, a neurohormone secreted by the pancreas that is known to play a role in the regulation of appetite, food intake and postprandial glucose concentrations. Pramlintide is the active ingredient in SYMLIN, which is indicated for use by patients with type 1 and type 2 diabetes who use mealtime insulin. Metreleptin (methionyl recombinant leptin; r-metHuLeptin) is an analog of human leptin, a neurohormone secreted by fat cells that plays a fundamental role in the regulation of energy metabolism and body weight.
Consistent with previous clinical experience with pramlintide and metreleptin as single agents, the most common side effects seen with the combination treatment were injection-site adverse events and nausea, which were mostly mild to moderate and transient in nature.
The company initiated its Phase IIB study in April, says Alice Bahner Izzo, executive director of corporate affairs for Amylin. The six-month randomized, double-blind, placebo-controlled multi-center study includes 600 overweight and obese patients and will test different dosing combinations.
“We’re very excited about that,” Izzo says. “We hope to be able to determine optimal dosing and move into Phase III after that.”
The majority of Amylin’s therapies and research focus on diabetes treatment, including injectable drugs such as SYMLIN (pramlintide acetate injection) and BYETTA (exenatide injection). Amylin has moved into obesity treatments through its Integrated Neurohormonal Therapy for Obesity (INTO) program.
“It’s a vast market, that’s for certain,” Izzo says. “It’s very underserved. We see that this is a patient need, and we think we have a tremendous opportunity to develop a safe and effective therapy.”
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