Orexigen Therapeutics along with its partner Takeda announced termination of the Light Study a cardiovascular (CV) outcomes trial of their obesity drug Contrave (naltrexone HCI and bupropion HCl extended-release tablets) after a third-party disclosed 50 per cent data related to the study.
The obesity drug trial involved 8,909 overweight and obese patients with certain CV risk factors. The two companies came to an understand with the US Food and Drug Administration (FDA) that it was best to conclude the study in an orderly fashion, search for and gather all CV events and other safety data, have the CV events properly adjudicated, carefully analyze the final data and have these data presented and published in a scientific forum.
“Today some of the 50% interim analysis of the Light Study was disclosed by a third party. Because most of our management team remains blinded to the 50% data, we are unable to comment”, announced Orexigen.
According to Cleveland Clinic, the primary endpoint in the Light Study is the composite of major adverse cardiovascular events (MACE) that included death, non-fatal stroke and non-fatal myocardial infarction (MI). Orexigen was permitted to file for approval of Contrave with a pre-specified interim analysis after approximately 25 per cent of MACE had occurred in the Light Study, if the results ruled out a doubling of cardiovascular risk for patients taking Contrave. The results of this interim analysis, which were intended to remain confidential, demonstrated that Contrave met this criterion, and the FDA approved Contrave on September 10, 2014.
At the time of approval of Contrave, the FDA determined that Orexigen had violated the terms of a data access agreement by revealing the 25 per cent interim results to both a wide group of individuals within the company and external business partners. The FDA also stated that this breach of confidentiality had sufficiently undermined its confidence in the ongoing trial; a new trial would be required to determine whether a 40 per cent increase in cardiovascular risk could be ruled out.
Subsequently, in March 2015, Orexigen publicly disclosed the confidential 25 percent interim analysis of the Light Study as part of a patent and securities filing, without the authorization of the study’s academic leadership. At the time of this disclosure, the study’s executive steering committee strongly cautioned against any potential misinterpretation of the preliminary 25 percent interim data inappropriately released in this disclosure by Orexigen. As a large number of MACE events are necessary to determine effect in a cardiovascular outcome trial, the 25 percent interim data are not conclusive in establishing either benefit or risk of Contrave on cardiovascular risk.
The data obtained after 50 percent completion of the trial with a total of 192 events, demonstrate that 102 primary endpoints (cardiovascular death, stroke, myocardial infarction) occurred in the placebo group compared with 90 in the Contrave group (HR=0.88, 95 percent CI 0.66 – 1.17). As previously reported, during the first 25 percent of the Light Study, 59 cardiovascular events occurred in the placebo treatment group and 35 events in the Contrave group, an estimated hazard ratio (HR) of 0.59. During the second 25 percent of the Light Study, 43 events occurred in the placebo group and 55 events occurred in the Contrave group. When non-cardiovascular deaths (Contrave 26, placebo 17) are included in the primary composite endpoint with stroke and MI, the results at the 50 percent time point include 114 events in the placebo group vs. 119 in the Contrave group (HR=0.95, 95 percent CI 0.74 – 1.23).
“These results do not confirm cardiovascular benefits of Contrave claimed by Orexigen in the patent application based on the data obtained at the 25 percent time point in the trial,” said Steven Nissen, MD, chair of the study’s executive steering committee and chair of cardiovascular medicine at Cleveland Clinic.
“These results show neither benefit nor harm for patients taking the drug, but are consistent with the requirement by the FDA that the Light Trial demonstrate an absence of a doubling of cardiovascular risk for patients taking the drug,” Dr. Nissen added. “The inconsistency of effects on cardiovascular outcomes between the first 25 percent and the second 25 percent of the Light Study clearly illustrates the risks inherent in pre-judgment of clinical trial results based upon an interim analysis and demonstrate why interim results should remain confidential during any ongoing trial.”
The executive steering committee expects to report the final Light Study data in a scientific forum after all of the cardiovascular events in the Light Study have been collected and properly adjudicated.