In a highly anticipated readout for the kappa opioid receptor class in major depressive disorder, Neumora’s navacaprant failed to meet the primary and key secondary endpoint in the first of three identical Phase III studies.
The downward trend set in depression in 2024 continued into the New Year as Neumora Therapeutics reported that its highly anticipated major depressive disorder candidate navacaprant failed the first of three Phase III trials.
A kappa opioid receptor (KOR) antagonist, navacaprant is designed to modulate the dopamine and reward processing pathways, which play a central role in the regulation of mood, cognition, reward and behavior. In the clinic, it is going up against Janssen’s aticaprant, which is also being studied in Phase III for major depressive disorder (MDD) with anhedonia, with data expected this year.
KOR antagonists are “a brand-new class for depression,” Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace in a previous interview. With data initially expected in the fourth quarter of 2024, Mizuho was bullish on navacaprant’s prospects due to de-risking Phase II data, a positive reception from key opinion leaders on the KOR class and a large MDD market, Suvannevejh wrote in a July 8 investor note.
But on Thursday, Neumora revealed that navacaprant failed to demonstrate a statistically significant improvement on the Phase III KOASTAL-1 study’s primary endpoint of change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6. Navacaprant also missed the trial’s key secondary endpoint of a change from baseline on the Snaith-Hamilton Pleasure Scale.
“We are disappointed by the results from KOASTAL-1 as they were not consistent with the body of evidence supporting this mechanism in MDD,” Rob Lenz, executive vice president and head of research and development at Neumora, said in a statement. Lenz noted the “contrast” in drug and placebo responses in depressed mood and anhedonia in female participants compared to male participants. The change from baseline on MADRS was -14 for female patients taking navacaprant vs. -10.6 for males.
Navacaprant was safe and “generally well-tolerated” with no serious adverse events reported, according to Neumora.
Neumora is far from the only biopharma company to suffer a recent failure in MDD. Last month, Relmada Therapeutics halted two Phase III trials of its MDD candidate REL-1017 after an independent Data Monitoring Committee determined the drug was unlikely to succeed. And in October, Alto Neuroscience reported that a trial of ALTO-100 failed to improve symptoms in a Phase II trial. Alto CEO Amit Etkin said in a statement at the time that the company was “disheartened” by the result “as the unmet need in this patient population is immense.”
For Neumora, the ballgame is far from over, as the company is anticipating results from two identical pivotal Phase III studies, KOASTAL-2 and KOASTAL-3, both of which are expected to read out in the first half of this year.
In an investor note Thursday, Stifel analysts expressed doubt regarding the potential of these trials. “Ultimately this is a significant blow to the NMRA bull case and investors are likely to remain very skeptical,” regarding the upcoming readouts, they wrote.
