12:00 AM
 | 
Feb 07, 2011
 |  BioCentury  |  Product Development

Obesity Reset

Next generation of obesity drugs unlikely to reach regulators before 2014

Even after FDA rejected the advice of its advisory committee and requested a cardiovascular outcomes trial of Orexigen Inc.'s Contrave bupropion/naltrexone to treat obesity, companies with earlier stage programs remain hopeful they will be able to avoid the issues that have now prevented three late stage compounds from reaching the market.

There are no other obesity compounds under review or in Phase III testing in the U.S. or Europe. But there are more than 50 obesity candidates against at least a dozen targets in preclinical through Phase II development (see "Obesity Opportunities," A3).

Early stage obesity companies contacted by BioCentury believe their focus on novel targets, combined with the availability of more sensitive preclinical assays capable of identifying safety concerns earlier in development, will allow them to win approval.

Based on the length of time it took Orexigen, Vivus Inc. and Arena Pharmaceuticals Inc. to run their Phase III obesity programs - three, three and four years, respectively - it is unlikely anyone new could file before 2014.

If randomized, controlled CV outcomes studies become a requirement before a drug can be approved for the indication, that timeline will extend even further. In briefing documents prepared for a December 2010 meeting of FDA's Endocrinologic and Metabolic Drugs Advisory Committee, Orexigen outlined a potential postmarket cardiovascular outcomes study that would take a minimum of four years to run.

The biotech did not specify if the timeline applied to an observational or a randomized trial.

SCOUT, a postmarket CV outcomes trial of Meridia sibutramine from Abbott Laboratories that led to the drug's withdrawal late last year, took seven years to complete.

Au Contrave

FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 13-7 in December that Contrave's benefit-risk profile supported approval as a long-term treatment for obesity. The panel also voted 11-8 that a cardiovascular outcomes trial to assess Contrave's risks could be conducted after approval rather than before (see BioCentury, Dec. 13, 2010).

Of the three obesity therapeutics the panel reviewed in 2010, only Contrave received a positive vote.

But last week, the agency issued a complete response letter asking Orexigen to complete a randomized, placebo-controlled CV outcomes study of "sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with Contrave does not adversely affect the drug's benefit-risk profile."

The SCOUT results no doubt influenced FDA's request.

That trial showed patients taking the norepinephrine and serotonin reuptake inhibitor Meridia had a 16% greater risk of experiencing a major cardiovascular event than patients following diet and exercise regimens (see BioCentury, Sept. 20, 2010).

According to FDA's medical review of Meridia, there were signals of an effect on blood pressure and heart rate in preclinical animal toxicology tests, but the results were not consistent. Increased heart rate, blood pressure and increased QT intervals also were reported in a Phase I dose-escalation study of Meridia.

Contrave also was associated with an increase in blood pressure and pulse. Orexigen knew of the blood pressure signal prior to starting the Contrave development program based on data for bupropion, which has been on the market for more than 25 years.

Since bupropion launched in 1985, there have been 18 reports of death due to cardiac arrhythmia reported via the FDA's adverse events reporting system (AERS).

Bupropion inhibits neuronal uptake of norepinephrine and dopamine. This inhibition mimics the effects of the sympathetic nervous system and can lead to an increase in blood pressure and heart rate. Meridia exerts a similar effect.

On a conference call last week, Orexigen President and CEO Michael Narachi said it is too early to say what the outcomes trial might look like and how long it could take.

The company expects to meet with FDA to clarify the type of population that should be the tested, such as a group of obese patients at greater risk for experiencing a CV event, as well as the level of risk that needs to be ruled out.

In briefing materials Orexigen prepared for the December panel, the company modeled the different samples sizes that might be needed for a postmarket CV outcomes trial. The estimation assumed a two-year recruitment period, two years of follow-up and a lost to follow-up rate of 2%. The variables were the non-inferiority margin, the relative risk of the population and the annualized event rate, which ranged from 0.15% to 0.25%.

Using this model, the biotech estimated population sizes of 14,000, with an event rate of 0.25%, and up to 59,000 with an event rate of only 0.15%.

The company did not specify if the model was for a randomized, placebo-controlled trial or an observational study. However, Orexigen did note that an observational study could allow for rapid enrollment.

In October, FDA issued complete response letters to Arena for lorcaserin and Vivus for Qnexa phentermine/topiramate.

For lorcaserin, a small molecule serotonin (5-HT2C) receptor agonist, the agency asked for additional preclinical studies to assess a cancer signal in rodents. Last month, the agency also asked Arena to repeat two nonclinical studies to assess lorcaserin's abuse potential and asked the biotech to consider 12-month rodent toxicity tests in addition to the planned three-month studies.

For Qnexa, FDA asked Vivus to further characterize the cardiovascular profile by providing two-year follow-up data as well as additional information from the clinical program. The combination treatment was associated with an...

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