As we reported in several earlier blog posts, 2010 has been a very busy year for FDA review of antiobesity drugs. At the same time, as we also reported, sibutramine (Abbott’s Meridia/ Reductil), one of the only two antiobesity agents on the market, had been under review by regulatory agencies because of cardiovascular safety concerns. In January 2010, sibutramine was suspended from the market in Europe. Early in 2010, the FDA also issued a warning that sibutramine posed an increased risk of heart attack and stroke in patients with a history of cardiovascular disease. This resulted in an additional contraindication on the drug’s label.
On October 8, 2010, at the FDA’s request, Abbott voluntarily withdrew Meridia from the U.S. market. This leaves only one approved antiobesity drug–orlistat (Roche’s Xenical–also marketed as a low-dose over the counter formulation, GlaxoSmithKline’s alli)–on the market. Orlistat’s adverse effects are unacceptable to many patients, and its efficacy is minimal.
The FDA’s request to withdraw Meridia from the market was based mainly on the results of the SCOUT (Sibutramine Cardiovascular OUTcome Trial) study. This was a 10,744 patient, 6-year study designed to evaluate cardiovascular safety of sibutramine in obese patients over age 55 with preexisting cardiovascular disease, diabetes, or both. Most of these patients had underlying cardiovascular disease, which made them ineligible to receive sibutramine under its then current labeling. The study had been requested of Abbott by European regulatory authorities as a post-marketing commitment. The SCOUT study showed that patients with a preexisting cardiovascular condition receiving long-term treatment with sibutramine had an increased risk of nonfatal myocardial infarction and nonfatal stroke, but not of cardiovascular death or death from any cause.
According to Abbott, the great majority of studies of sibutramine (46 controlled clinical trials and over 6 million patient years of use in the 13 years since the drug’s entry onto the market) in patents in the on-label population showed no such excess cardiovascular risk as in the SCOUT study. Abbott therefore believes that Meridia has a positive risk/benefit profile in the approved patient population. However, the FDA was concerned that patients with undiagnosed cardiovascular disease might be harmed by the drug, and that since the efficacy of the drug was minimal, the risk/benefit ratio was unfavorable. Therefore, the FDA requested that Meridia be withdrawn, and Abbott, despite its objections, complied.
Also in October 2010, in accord with the recommendation of its Endocrinologic and Metabolic Drugs Advisory Committee, the FDA issued a Complete Response Letter to Arena Pharmaceuticals regarding its New Drug Application for lorcaserin (Lorqess). (See our discussion of the advisory committee’s recommendations. The FDA requested additional data from Arena regarding studies of tumor formation in rats receiving lorcaserin, and regarding final study data from a clinical study of lorcaserin in patients with type 2 diabetes.
In the same month, and also in accord with the recommendation of its Endocrinologic and Metabolic Drugs Advisory Committee, the FDA issued a Complete Response Letter to Vivus Pharmaceuticals regarding its New Drug Application for Qnexa (phentermine/topiramate). (See our discussion of the advisory committee’s recommendations. The FDA requested additional data from Vivus regarding the results of an extension study of Qnexa in patients who had already completed a previously-reported trial, as well as an assessment of topiramate and phentermine/topiramate’s teratogenic potential. The agency also requested evidence that the elevation in heart rate associated with Qnexa does not increase the risk of major cardiovascular events.
A third preregistration-stage antiobesity drug, Contrave, (bupropion/naltrexone) is up for review by the Endocrinologic and Metabolic Drugs Advisory Committee in December 2010.
The withdrawal of Meridia from the market, coupled with the FDA rejections of lorcaserin and Qnexa, has cast a pall of gloom on the obesity drug market. Some commentators have declared the field to be dead, and have stated that the FDA’s safety standards require antiobesity drugs to have safety profiles comparable to diet and exercise. However, John Jenkins, M.D., director of the FDA’s Office of New Drugs, Center for Drug Evaluation and Research (CDER), said in an interview that the FDA was “committed to working toward approval” of new obesity drugs, “so long as they are safe and effective for the population for which they are intended.”
Meanwhile, on September 21, 2010, the Lasker Foundation announced that its 2010 Lasker Award for Basic Medical Research was given to Drs. Douglas Coleman (Jackson Laboratory) and Jeffrey M. Friedman (Rockefeller University) for “the discovery of leptin, a hormone that regulates appetite and body weight—a breakthrough that opened obesity research to molecular exploration.”
Mouse researcher Coleman, working with obese diabetic mouse strains in the 1960s, showed that an appetite-suppressing substance (encoded by the ob gene) circulates in the bloodstream and signals a second molecule (encoded by the db gene) to curb hunger. Molecular geneticist Friedman, in the 1990s, showed that the ob gene encoded a hormone called leptin. The db gene encodes the leptin receptor. Leptin is produced by fat cells and is released into the circulation, and signals via leptin receptors in the hypothalamus of the brain to curb appetite and control fat mass. Although obese humans have elevated levels of leptin, these high levels of leptin fail to control fat mass. Obese humans are therefore said to be leptin resistant.
Leptin resistance caused the clinical failure of Amgen’s recombinant leptin product metreleptin, although this product does help humans with a rare familial type of morbid obesity that is caused by a loss-of-function mutation in the human homologue of the mouse ob gene. So far, researchers have not been able to unravel the mechanisms of leptin resistance in humans.
The Lasker Award-winning research on leptin showed once and for all that obesity is a complex disease which results from both genetic and environmental factors. Subsequent research has abundantly confirmed this picture. Most recently, a large genome-wide association study (GWAS) of body-mass index confirmed 14 known obesity susceptibility loci, and identified 18 new loci, including one copy number variant. These results add to the picture of obesity as a complex disease, and genes in some of the new loci may provide new insights into body weight regulation in humans. This research may also provide new leads for drug discovery and development.
The development of the three preregistration drugs that have been up for review by the FDA–lorcaserin, Qnexa, and Contrave–owe very little to the basic research on the genetics of obesity begun by Drs. Coleman and Friedman. The discovery and development of these drugs has been based on the same strategy as the development of such antiobesity drugs as phentermine, dexfenfluramine, and sibutramine–target common receptors in the CNS that are involved in (or deemed to be involved In) appetite control.
The only way that this strategy benefits from the study of the genetics of obesity is that that work demonstrated that obesity is indeed a disease, not just due to a failure of willpower. Therefore, there is a rationale to develop drugs to treat obesity. Nevertheless, so far the appetite-suppressant strategy has been a failure, leading to clinical attrition or expensive postmarketing safety failures, with the resulting product withdrawals and lawsuits.
As we discussed in previous blog posts, appetite suppressant drugs that address common neurotransmitter receptors might be expected to have significant adverse effects, since their targets are involved in multiple CNS and/or peripheral tissue pathways. They also tend to have low efficacy, as is true for all of these drugs so far except for Qnexa.
The drug candidate that is specifically based on the Lasker Award-winning discovery of leptin by Drs. Coleman and Friedman is Amylin/Takeda’s combination product pramlintide/metreleptin. We discussed this drug in an earlier blog post. A proof-of-concept study of pramalintide/metreleptin showed that this product was well tolerated, and gave a 12.7% mean weight loss in patients treated for 24 weeks. This appears to be superior to the efficacy of any antiobesity drug that is or ever has been on the market, as well as to lorcaserin and Contrave. Amylin and Takeda are moving to enter pramlintide/metreleptin into Phase III clinical trials.
We also discussed other drug discovery and development programs that are based on alternative strategies to CNS-targeting appetite suppressants in an earlier blog post.
The recent Advisory Panel and FDA reviews of antiobesity drugs in 2010 not only highlight the inadequacy of the CNS-targeting appetite suppressant strategy, but also the importance of regulatory policy in fostering development of innovative drugs that address unmet medical needs. In a Nov. 3, 2010 speech at the Cleveland Clinic Medical Innovation Summit, John C. Lechleiter, Ph.D., the chairman, president and CEO Lilly outlined the need for new, innovative drugs to address the epidemic of type 2 diabetes, in the United States and in the world. Dr. Lechleiter considers diabetes to be part of a network of complex conditions, including not only diabetes, but also obesity and metabolic syndrome.
In addition to the development of novel research and clinical trial strategies in academia, biotech companies, and pharmaceutical companies, Dr. Lechleiter sees the need for “public policies that enable and reward medical innovation.” Dr. Lechleiter said, “To sustain progress against diabetes, public policies – including benefit/risk assessments, reimbursement decisions, and prescribing guidelines – must enable and foster true medical innovation.”
This includes “creation of a systematic and transparent regulatory approach to assessing the benefits and risks of new medicines.” Dr. Lechleiter noted the ongoing discussions with the FDA on the Prescription Drug User Fee Act, which is up for reauthorization in 2012. He sees these discussions as offering an opportunity for a “real victory for innovation and for patients.”
In the area of obesity–which is a major risk factor for type 2 diabetes and cardiovascular disease (CVD)–there is a need for both innovative strategies to develop a new generation of safe and efficacious drugs (especially for obese patients who have–or are at high risk of developing–diabetes and/or CVD), and a regulatory environment that fosters successful development and marketing of such innovative drugs. This will require negotiation between industry and the FDA, as well as other stakeholders involved in policy decisions that affect the development, approval, reimbursement, and market acceptance of innovative drugs for obesity and its complications.
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