In the first round of a three-way horse race for an anti-obesity drug, there were no winners as all the three prescription diet drug candidates were shot down by the FDA on safety concerns over the past one year. But it's not the end of the story as the drug makers are planning to re-file their applications seeking approval of their respective obesity drugs.
Read on to find out who are still in the race to find a cure for obesity and who has limped out...
Arena Pharmaceuticals Inc. (ARNA), Orexigen Therapeutics Inc. (OREX) and Vivus Inc. (VVUS), were the three contenders in the first round of the race for prescription diet drugs.
Arena Pharma was the first to be handed down a complete response letter for its obesity drug candidate Lorcaserin. The FDA panel members who reviewed the Lorcaserin New Drug Application had also voted 9-5 against the drug last September.
In the complete response letter issued on October 23, 2010, the regulatory agency had questioned the marginal efficacy of Lorcaserin in overweight and obese individuals without type 2 diabetes and had also sought additional information from a preclinical study regarding breast tumors in rats.
The next to be issued a complete response letter was Vivus Inc. ( VVUS) for its obesity drug candidate Qnexa, a controlled-release combo of phentermine and topiramate. Last July, the FDA panel voted 10-6 against Qnexa.
In line with the panel members' recommendation, the FDA, which issued a complete response letter on October 28, 2010, requested the company to submit a detailed plan and strategy to evaluate and mitigate the possible *teratogenic risks of phentermine/topiramate in women of childbearing potential taking the drug for the treatment of obesity. (*fetal malformations). In addition, the company had also been asked to provide evidence that the elevation in heart rate associated with phentermine/topiramate did not increase the risk for major adverse cardiovascular events.
Orexigen was issued a complete response letter for its investigational weight-loss pill Contrave on February 1, 2011. Like Qnexa, Contrave is a combo drug and it consists of anti-addiction drug naltrexone HCl and antidepressant bupropion HCl.
In its complete response letter issued for Contrave, the regulatory agency raised concerns about the cardiovascular safety profile of naltrexone/bupropion when used long-term in a population of overweight and obese subjects. The company is required to conduct an additional study to prove that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug's benefit-risk profile.
Unlike Lorcaserin and Qnexa, Contrave got a recommendation for approval by an FDA panel last December, even though safety concerns were raised.
The process of drug development is challenging. Some drugs pass the FDA muster easily, while some struggle through the arcane process of regulatory approval.
Only few companies, in spite of various setbacks, exude a steely determination and press on without quitting.
Here's what the trio in the race for fat-busting drugs, which have once failed, are up to now...
Vivus is planning to resubmit the Qnexa New Drug Application by the end of October 2011. Since the NDA will be resubmitted prior to completion of the FORTRESS study, Vivus will be seeking approval of Qnexa for an initial indication that includes obese men and women of non-child bearing potential. Qnexa NDA is slated to be reviewed by the FDA panel in the first quarter of 2012.
Note that the FORTRESS study is an observational study to assess fetal outcomes, in the offspring of women who were exposed to topiramate during the first trimester of pregnancy. Top-line results from FORTRESS are expected in December 2011, with validation of study results expected in the third quarter of 2012. If the FORTRESS results are favorable, the company expects to seek approval for Qnexa for the full indication, including treatment of obese women of child-bearing potential in late 2012.
Arena expects to resubmit the Lorcaserin NDA by the end of 2011. The company met with the FDA last December and received some guidance on the path forward for approval of its obesity drug. In what would address the concerns regarding mammary tumors in female rats in a preclinical study of Lorcaserin, re-adjudication of the two-year rat carcinogenicity study by Pathology Working Group has demonstrated that the malignant tumors were no longer numerically higher than the control group in the Lorcaserin low- and mid-dose groups. The Pathology Working Group, or PWG for short, consisted of five pathologists contracted by Arena. The pathologists were selected in consultation with FDA. However, it is to be noted that the FDA may or may not have the same interpretation of the re-adjudication and conclusions of the PWG.
Orexigen, which was required to conduct an additional study for Contrave, has planned to put on hold any further clinical development for its obesity programs in the United States until a clear and feasible path to regulatory approval is identified.
The drug therapy for treatment of obesity has a checkered past. A couple of approved diet drugs have been recalled, following reports of adverse side reactions like heart damage, and some of the investigational obesity drugs have also gone belly-up.
Headstones In Graveyard Of Obesity Drugs
Fen-phen, a combination drug of Phentermine and Fenfluramine, and a related drug Redux marketed by Wyeth were withdrawn from the U.S. market in September 1997 after the drugs were found to be associated with a serious heart condition known as valvular regurgitation, or leaky heart valves.
In November 2008, Solvay Pharmaceuticals pulled the plug on its obesity compound SLV319, which was under phase II development, citing the stringent regulatory environment. According to the company, the discontinuation was not related to any adverse events or the efficacy of the compound.
Considering the changing regulatory perspectives on the risk/benefit profile of the cannabinoid type 1 class of drugs, Pfizer Inc. (PFE) abandoned the development of CP-945598 (Otenabant) for weight management in November 2008. CP-945598, a selective antagonist of the cannabinoid type 1 receptor was in late-stage development when the company pulled the plug on the trial.
Yet another investigational obesity drug, which was under phase III development, to bite the dust in 2008 was Merck's Taranabant. Merck halted development of the drug as it had too many side effects. Though Taranabant was considered a potential blockbuster, some analysts were wary of the drug's approval as it belonged to the same class as Sanofi-Aventis' (SNY) weight-loss drug Acomplia. In June 2007, the FDA rejected Acomplia saying that the drug's benefits did not outweigh its risks.
The much-touted Acomplia, which was approved in the European Union in 2006, also had an abrupt end. The drug was withdrawn from the European markets in October of 2008 as it was linked to serious psychiatric disorders.
In October 2010, Abbott Laboratories (ABT) withdrew its diet pill Meridia in the U.S. and Canada at the request of health regulators as the drug was found to increase the risk for heart attacks and strokes in a post-marketing study.
Market Opportunity
The market for anti-obesity drugs is virtually untapped and till date, there has been no 'silver bullet' remedy for obesity. Industry forecaster GlobalData estimates that the potential market for obesity drugs could reach $2 billion by 2017 if new, safe and effective drugs are approved.
Roche's Xenical, a prescription anti-obesity drug and GlaxoSmithKline plc's (GSK) Alli, an over-the-counter weight-loss product are the two FDA-approved drugs for obesity on the market.
Closing Thoughts
Obesity, a public health epidemic is growing at an alarming rate. In the U.S., about 33 percent of adults and roughly 17 percent of children and adolescents aged 2-19 years are obese, according to the National Health and Nutrition Examination Survey. Given the growing unmet demand and patients clamoring for a quick remedy, a really effective and safe weight-loss therapy is long overdue. Could 2012 see an obesity drug reach the regulatory finish line?
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