Orexigen Therapeutics (NASDAQ: OREX) shares have dropped 27% to $5.01 since Tuesday, when the company announced termination of the cardiovascular outcomes trial (CVOT) of the obesity drug Contrave. To make matters worse, new data showed the drug doesn’t reduce cardiovascular risks.
Contrave is a sustained release formulation of two old drugs: bupropion and naltrexone. In September 2014, the FDA approved Contrave as a weight-loss drug but required a post-marketing CVOT because bupropion can raise blood pressure and heart rate.
Before the FDA approval, Orexigen had initiated a 9,000-patient CVOT, called LIGHT, to prove that Contrave caused no more than a 40% increase in cardiovascular risks. If all had gone well, the LIGHT trial would be completed in 2017.
However, during the review of Contrave, the FDA learned that more than 100 people saw the interim, unblinded results from the Light trial. (Orexigen only has 47 employees, which means people outside of the company got the data.) Leaking interim results to more unnecessary people could negatively impact the conduct of the remaining portion of the trial. Patients may opt to drop out of the trial and take Contrave rather than have a 50% chance of taking placebo. The FDA required Orexigen to do a second CVOT.
In March 2015, Orexigen disclosed the first 25% interim results from the LIGHT trial. Going against the longtime concerns that Contrave can increase major adverse cardiac events (MACE), the first 25% interim analysis suggested the drug not only helped patients lose weight but also prevented MACE. At the first 25% interim analysis, 59 patients in the placebo group recorded MACE compared to 35 in the Contrave group.
However, the next 25% of data showed that 43 patients in the placebo group had MACE compared to 55 on Contrave. Combining all the data, Contrave showed only a 12% decreased risk from placebo (90 vs. 102), which is not statistically significant. Moreover, 26 patients died of non-cardiovascular causes in the Contrave group, compared to 17 in the placebo group.
Orexigen has made two mistakes: (1) leaking interim results to more unnecessary people; (2) publicly releasing the first 25% interim analysis which might mislead patients and investors. Interim data are interim. The second 25% of data even suggested the drug could increase cardiovascular risks. Who knows what would have happened if the study went to completion.
Orexigen says that a new CVOT will begin later this year. The target completion date is 2022. Contrave’s approval was based on the FDA getting the LIGHT results by 2017, now it will be 2022 at the earliest. George Budwell at The Motley Fool concerns whether the FDA should pull Contrave from the market. Orexigen’s partner, Takeda, is seeking Orexigen to pay for the entire $200 million estimated cost of the new clinical trial.