Neumora Therapeutics’ phase 3 fail was worse than analysts feared. The biotech provided a closer look at the data Tuesday, shutting down one source of hope analysts had clung to after the initial blow.
The biotech reported the failure of its oral kappa opioid receptor antagonist to beat placebo in a phase 3 trial at the start of the year. At the time, Neumora said changes on a depression rating scale were exactly the same in the navacaprant and placebo groups after six weeks of daily dosing. The readout left scope for William Blair analysts to hope “a meaningful curve separation” was seen at earlier time points.
Neumora snuffed out that hope in its presentation at the J.P. Morgan Healthcare Conference. Executives presented a chart showing scores on the MADRS depression scale were nearly identical in the drug and placebo groups at weeks 1, 4 and 6. Navacaprant had a slight numerical advantage over placebo at Week 2—and throughout the trial on the SHAPS pleasure scale—but analysts were distinctly underwhelmed.
“We are obviously disappointed in the KOASTAL-1 study top line,” the William Blair analysts said, pointing to the “0-point placebo adjusted delta on the primary Week 6 MADRS endpoint, lack of placebo-adjusted anhedonia improvement on SHAPS and total population efficacy curves over time that largely overlap” to explain their frustration.
Neumora highlighted a disconnect between how navacaprant performed in men and women as a cause for optimism when it shared the initial results earlier this month. Management built on the theme and its implications for further development of the drug candidate at JPM, explaining how the team is now assessing the factors that may explain the high placebo response in men to improve other trials.
“The goal would be to incorporate those [insights] from a much richer data set than we had when we initiated the KOASTAL-1 study and make modifications to KOASTAL-2 and KOASTAL-3 to optimize the sites that we're utilizing in those ongoing studies, as well as to potentially optimize the patient to ensure that the most appropriate patients are entering the study,” Robert Lenz, M.D., Ph.D., head of R&D at Neumora, said.
William Blair analysts pushed back against the idea that a high placebo response in men drove the result. The counterargument, according to the analysts, is that men on navacaprant “would have trended in line with the placebo response, rather than improve less compared to placebo.” Neumora management told the analysts they are unaware of another example of the drug’s mechanism working better in women.
“The questions now become what can be done to reduce the risk of professional patient impact on placebo responses in KOASTAL-2 and -3 trials and if the potential sex difference signal is not a false positive, how can this be controlled for in these studies?,” the analysts said.
Finding an answer may take time. Neumora has dropped its forecast that data from KOASTAL-2 and -3 will be available in the first half of the year. Instead, the biotech is now planning to update its program guidance when it files its annual financial report. With a cash runway that lasts into mid-2026, Neumora is content to take time to maximize the chance of achieving a better result in the next two trials.
“Our financial flexibility gives us the firepower to really study these trends in great detail to identify the learnings and to incorporate those learnings into the ongoing development of navacaprant,” Neumora CEO Henry Gosebruch said. “The KOASTAL-1 study does not impact our confidence that navacaprant can be an important therapy for patients.”