Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

With Vivus receiving a positive recommendation, analysts see CV risk as one that can be evaluated post-approval.

On February 22, an FDA advisory committee voted 20 to 2 in favor of Vivus’ anti-obesity drug Qnexa, concluding that its weight loss benefits outweighed its potential risks. While not bound by committee recommendations, the FDA will consider the guidance during its review, scheduled for April 2.

The committee decision marked the end of a long road for Qnexa, which had been rejected by the agency in September 2010 in a 10–6 vote. The reason was not a lack of efficacy but its side effects including serious birth defects and heart problems.

Should the drug be approved, some analysts predict that Vivus’ stock could climb into the $30s. The company’s shares had fallen as much as 60% to $4.90 last year after a previous FDA panel voted against the drug in July 2011. The stock surged 78% on the latest positive recommendation and went as high as $21.50.

In clear evidence that a rising tide floats all boats, the news about Qnexa boosted shares of the other two late-stage obesity drug development firms—Orexigen Therapeutics and Arena Pharmaceuticals. Orexigen’s stock jumped nearly 18% to $3.78, while shares of Arena Pharmaceuticals rose 17% to $2.12.

The seemingly more hospitable regulatory environment could indeed ease the approval path for Arena’s lorcaserin and Orexigen’s Contrave. Both remain in development after earlier setbacks.

Concerns about Obesity Drug Candidates

One of the questions raised during the February Qnexa panel was whether Vivus should conduct a pre- or post-approval cardiovascular (CV) outcomes study. In commenting on the panel outcome, Leerink Swann biotechnology analysts Steven Yoo and Joshua Schimmer, M.D., said that while several members of the panel expressed some concern about the ability to initiate and complete a post-approval CV outcomes study, “we believe that a CV outcomes trial will likely be a requirement for obesity drugs but only as a post-approval commitment.”

Vivus says it designed and developed the drug to decrease appetite and increase satiety. Phase II and III data to date has shown that patients taking Qnexa experienced statistically significant weight loss, glycemic control, and improvement in cardiovascular risk factors when used in combination with a diet and lifestyle modification program.

Qnexa combines two existing drugs, the stimulant phentermine approved for short-term use as a weight loss drug and on the market for about 50 years with topiramate, marketed by Johnson & Johnson for about 16 years as Topamax to treat epilepsy and migraine headache.

Arena’s lorcaserin unlike Qnexa does not combine existing drugs, a company spokesperson pointed out to GEN. It is an NCE thought to act as a selective serotonin 2C receptor agonist. The serotonin 2C receptor is expressed in the brain including the hypothalamus, an area believed to be involved in the control of appetite and metabolism.

Clinical trial results have shown that individuals taking the drug lost 5.8% of their weight after a year compared to 2.5% for those taking a placebo. The difference failed to meet the 5 percentage point criterion set by the FDA. But 47% of those taking lorcaserin lost at least 5% of their weight compared to 22% of those getting a placebo, a result that just exceeded the FDA standard that twice as many people on the drug as on the placebo lose 5% of their weight.

In 2010, the FDA issued a complete response letter (CRL) to Arena for lorcaserin. Nonclinical issues identified by the agency included diagnostic uncertainty in the classification of mammary masses in female rats, unresolved exposure-response relationship for lorcaserin-emergent mammary adenocarcinoma, and unidentified mode of action and unclear safety margin for lorcaserin-emergent brain astrocytoma, the company reported.

With regard to clinical issues, the agency stated that the weight loss efficacy of lorcaserin in overweight and obese individuals without type 2 diabetes was marginal. It recommended that Arena submit the final study report of the trial called BLOOM-DM (behavioral modification and lorcaserin for overweight and obesity management in diabetes mellitus).

Arena resubmitted the NDA last December, and the agency assigned a PDUFA date of June 27. And on March 2 the company announced that it had filed an MAA with the EMA.

Orexigen was the third company to receive a CRL for its anti-obesity candidate, Contrave. The CRL, issued January 31, 2011, noted a single approval deficiency related to cardiovascular safety. The agency asked Orexigen to conduct a randomized, double-blind, placebo-controlled cardiovascular outcomes trial prior to approval.

On February 6, the company said that it reached an agreement with the FDA on an SPA for the outcomes trial. The objective of the study will be to demonstrate that Contrave does not unacceptably increase the risk of major adverse cardiovascular events. The company plans to initiate the Contrave outcomes trial, which will enroll approximately 10,000 patients, late in the second quarter of 2012.

Orexigen’s Contrave is comprised of two existing drugs, the antidepressant Wellbutrin and the addiction drug naltrexone. Naltrexone acts as an opiate antagonist by blocking opioid brain receptors. Bupropion is a norepinephrine-dopamine reuptake inhibitor.

Potential for New Treatments

If the FDA follows the committee’s February 22 recommendation on Qnexa, the approval would make it the first new prescription drug for weight loss to reach the market in 13 years. Obesity drugs have proven risky business for pharmaceutical companies. Following previous setbacks, the industry has been reluctant to invest in their development.

In 2010, FDA announced that Abbott Laboratories’ had voluntarily withdrawn its Meridia from the market. The agency said that the advantage of a relatively small weight loss did not outweigh the heightened risk of heart attack and stroke associated with the drug, which had been withdrawn from European markets in January 2010.

The previous withdrawal of the two key ingredients used in the fen-phen obesity drug caused Wyeth (now part of Pfizer) to set aside about $21.1 billion to pay claims of individuals who had used the anti-obesity drug and suffered heart damage. The company recorded a $4.5 billion charge in 2004, resulting in a $1.32 per share loss for the company in the fourth quarter of that year.

Three years ago the FDA, citing the risk of suicidal thoughts and depression, declined to approve rimonabant (Accompli or Zimulti) from sanofi. Merck & Co. and Pfizer then abandoned their development plans for drugs with a similar mechanism of action. Rimonibant works by selectively blocking the cannabinoid-1 receptors resulting in central and metabolic peripheral effects that decrease food intake.

A September 2011 report from Decision Resources found that physicians and patients alike consider the weight-loss efficacy of the current market leaders—Roche’s Xenical (orlistat), GlaxoSmithKline’s over-the-counter version of orlistat Alli, and the generic agent phentermine—to be unsatisfactory.

The study concluded that the obesity drug market will increase more than six-fold over the next decade, increasing from $420 million in 2010 to $2.6 billion in 2020 in the U.S., France, Germany, Italy, Spain, the U.K., and Japan. The report expects the market growth to be driven by the rapid uptake of novel emerging agents and the high prevalence of obesity.

Vivus could be the first to deliver on the promise of new medications to treat obesity. On February 29, the company said that it expected to raise more than $200 million through a share offering ahead of the April PDUFA date and use the money to develop and market the obesity pill.

“We view this move as a smart one by Vivus,” Cowen analyst Simon Simeonidis commented. “Despite what we view as a high probability that Qnexa gets approved by the April 17th PDUFA, we believe it’s the prudent and conservative move for the company to take advantage of the substantial move in the stock to significantly strengthen the balance sheet, especially given the potential launch of Qnexa in the U.S.”

Even if Qnexa does win over the FDA next month, it will have to win over the marketplace and likely have to satisfy a post-approval evaluation of its impact on CV risks. Its clinical performance and potential for profits coupled with the path that lorcaserin and Contrave take will shape whether or not drug developers and investors renew their interest in the obesity space.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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