Amylin Pharmaceuticals and Takeda Pharmaceutical have suspended an ongoing Phase II trial examining pramlintide/metreleptin for the treatment of obesity. The companies are investigating a new antibody-related laboratory finding with metreleptin treatment in two patients who participated in a previously completed obesity clinical study.
Amylin says that this decision does not affect its lipodystrophy development program investigating the use of metreleptin to treat diabetes and/or hypertriglyceridemia in patients with rare forms of lipodystrophy. Initial sections of a rolling BLA for this indication were submitted in December 2010.
Pramlintide acetate is a synthetic analog of the natural hormone amylin. This neurohormone secreted by the pancreas is known to play a role in the regulation of appetite, food intake, and postprandial glucose concentrations. To date, approximately 8,000 individuals have received pramlintide in clinical trials, including more than 950 in obesity studies, according to Amylin and Takeda. It is the active ingredient in the antidiabetic medication Symlin.
Metreleptin (methionyl recombinant leptin) is an analog of human leptin. It is secreted by fat cells that play a fundamental role in the regulation of energy metabolism and body weight. The companies report that to date more than 1,200 overweight or obese individuals have received metreleptin in clinical trials, several of which were 16 weeks or longer in duration.
“One might postulate that if obese patients (who have elevated leptin levels due to their increased fat mass) develop neutralizing antibodies to leptin, they would lose the off signal for appetite and actually wind up eating more,” note Joshua Schimmer, M.D., and Steve Y. Yoo, biotechnology analysts at Leerink Swann. “This is arguably a predictable side effect of leptin given the existing data.
“Since lipodystrophy patients have extremely depressed levels of leptin to begin with, neutralizing antibodies should not be as problematic in this indication. One center in France has noted that neutralizing antibodies appear to correspond to waning efficacy in lipodystrophy patients treated with leptin, but there have been no reports of rebounding to worse metabolic states—although that may be hard to demonstrate in small clinical studies.
“We already assumed that leptin therapy would be reserved for patients with the most severely depressed leptin levels; since one cannot have negative levels of leptin, these antibodies should not worsen their condition. Furthermore, these patients have severe metabolic derangement to begin with, so the benefits in patients who do not develop antibodies should outweigh the risks,” Dr. Schimmer and Yoo conclude.
Bad news cannot seem to come fast enough for antiobesity drug development. While three drugs made it all the way to NDA submissions, between October 2010 and February 2011, all three got shot down. Arena Pharmaceuticals and Eisai were asked to provide additional clinical and nonclinical data as well as conduct another clinical trial with their candidate lorcaserin, a serotonin 2C receptor agonist. Arena was forced to nix about 25% of its staff, or 66 employees.
Vivus Pharmaceuticals was asked for clinical, labeling, REMS, safety-update, and drug-scheduling data, but no request was made for further clinical studies. The last one on the chopping block was Orexigen, but the agency also raised issues with its candidate Qnexa, asking for an additional clinical trial. Orexigen subsequently cut 40% of staff, or 23 employees.
Takeda also has a stake in Orexigen’s development of Contrave. In September 2010, it paid an initial $50 million fee for exclusive rights to develop the drug in North America. Successful development and commercialization would mean $1 billion in payments to Orexigen. Contrave is a combination therapy comprising sustained-release naltrexone and sustained-release bupropion.
Takeda signed on as Amylin’s partner for pramlintide/metreleptin in November 2009, paying Amylin $75 million up front. The deal covered development and commercialization of drugs for obesity and related indications, with $1 billion in potential milestones.
Amylin is responsible for developing each potential molecule through Phase II in the U.S., with Takeda taking over U.S. Phase III trials and all development activities outside the U.S. Takeda will lead product commercialization across the globe, with Amylin receiving tiered, double-digit royalties.
The pramlintide/metreleptin combination therapy has undergone a 28-week Phase IIb study and a 52-week extension study. Patients who continued treatment for a total of 52 weeks demonstrated sustained weight loss, whereas those continuing on placebo regained almost all of their weight. Consistent with results at 28 weeks, the most robust efficacy was seen in patients with a body mass index less than 35 kg/m2.
The combination therapy appeared to be generally well tolerated through 52 weeks, with nausea and injection site adverse events observed as the most common side effects on initiation of pramlintide or metreleptin in combination treatment. Following initiation of therapy, these adverse events reportedly occurred at a reduced rate over time in patients continuing combination therapy.