Orexigen Therapeutics Inc.'s Contrave hit its endpoints in the first of four Phase III studies, but concerns that the data missed the FDA's benchmark for efficacy in obesity sent shares of the San Diego-based company falling 15.7 percent.
Data from the NB-302 study, which involved 793 obese patients participating in an intensive diet and exercise behavior modification program, showed that those treated with Contrave, a combination of sustained-release versions of naltrexone and bupropion, showed a significant reduction in body weight, meeting co-primary endpoints. Data from the intent-to-treat population demonstrated an average weight loss of 20.3 pounds, or 9.3 percent of patients' baseline body weight, vs. 11 pounds, or 5.1 percent, in the placebo arm. The completer analyses showed an even greater reduction, with Contrave-treated patients losing an average of 25 pounds, of 11.5 percent of their baseline body weight, compared to 16 pounds, or 7.3 percent, on placebo.
About 66 percent of patients receiving Contrave lost at least 5 percent of their total body weight vs. 42 percent of patients on placebo. Those results should have been good news for the Orexigen - the company and many analysts hailed the study's outcome as positive - but investors clearly worried that the FDA's 2007 guidelines for obesity drug development could hamper the drug's chances for approval.
Orexigen's stock (NASDAQ:OREX) lost 95 cents to close Friday at $5.10.
According to those guidelines, the difference in weight loss between drug and placebo should be at least 5 percent, and Contrave's difference to placebo was 4.1 percent.
Guidelines also look for twice the number of patients in the treatment group compared to placebo to achieve weight loss of greater than 5 percent of their baseline body weight. By that requirement, Contrave fell short again, though Orexigen pointed out that the percentage of patients on Contrave to lose at least 10 percent of their baseline body weight was double that of the placebo arm, 41.5 percent vs. 20.2 percent.
But the company maintained that those guidelines are not binding, and Chief Financial Officer Graham Cooper added that they do not take into account the intense diet and exercise regimen of patients.
"This trial is a little different from the standard [obesity] trial, which has minimum placebo intervention," he told investors during a conference call. In the NB-302 study, all patients underwent the behavior modification therapy.
In addition to the weight loss, results showed that Contrave resulted in improved markers associated with cardiovascular disease in obese patients. The most common adverse event associated with treatment was nausea, which accounted for much of the 25.9 percent discontinuation rate in the study. "Overall, we're pleased with the results of this trial on a number of fronts," said Eduardo Dunayevich, Orexigen's chief medical officer.
Analyst Phil Nadeau, of Cowen and Co., wrote in a research note that while "investors are likely to debate whether the weight loss data surpass the FDA's bar" for clinical significance, "we think Orexigen makes a good case that the data do," meaning that the FDA likely would accept the NB-302 study as one of the two positive Phase III studies needed for approval.
Three additional Phase III trials are ongoing, though none with the same rigorous diet and exercise regimen as the NB-302 trial. Patient enrollment in all three has concluded, and top-line results are expected in the middle of this year. Pending positive data, a new drug application is anticipated before year-end.
Though he declined to speculate too much on the ongoing trials, Cooper said Orexigen believes "we may have taken one big step" toward approval, with the results of the NB-302 study. "We're feeling very good about our chances at this point."
Following the recent discontinuations of cannabinoid type 1 (CB1) blockers in development by big pharma firms Pfizer Inc. and Merck & Co. Inc., as well as Sanofi-Aventis Group's withdrawal of a marketing application for another CB1 blocker, the obesity space has been narrowed to three late-stage competitors, all of which are expected to file for approval sometime this year, pending positive data.
Mountain View, Calif.-based Vivus Inc. already has reported data from the first of its three Phase III trials. Last month, the firm said Qnexa, a compound composed of epilepsy drug topiramate and generic diet drug phentermine, met its endpoints, demonstrating an average weight loss of 19.8 pounds, or 9.2 percent, for patients receiving the full dose, vs. 3.3 pounds, or 1.7 percent, in the placebo arm. Data from the two remaining Qnexa trials are expected around midyear. (See BioWorld Today, Dec. 12, 2008.)
Also expected this year are data from Phase III trials of lorcaserin, a 5-HT2c serotonin receptor agonist from San Diego-based Arena Pharmaceuticals Inc.
Orexigen, which raised eyebrows last month following the departure of three members of its management team, recently cut back on its pipeline work to conserve cash for work on Contrave and an earlier-stage drug, Empatic (zonisamide and buproprion), which is in Phase II development and aimed at promoting rapid weight loss in severely obese patients. (See BioWorld Today, Dec. 8, 2008.)
The company has halted exploratory Phase II studies of OREX-003 (zonisamide and olanzapine) in mitigating antipsychotic-associated weight gain, and OREX-004 (fluoxetine and naltrexone) in reducing symptoms of obsessive-compulsive disorder, though it intends to retain rights to those assets for potential future development.
The firm ended 2008 with about $85 million in cash, equivalents and investments. With a cash burn of between $60 million and $65 million expected for this year, Cooper said Orexigen's current resources should last until mid-2010.