Neumora Therapeutics, Inc announced on January 2, 2025, results for The KOASTAL-1 Study, the first of 3 replicate phase 3 studies that comprise the pivotal KOASTAL program. The study did not demonstrate a statistically significant improvement on the primary endpoint of change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6 or the key secondary endpoint of a change from baseline in the Snaith-Hamilton Pleasure Scale (SHAPS) scale.

KOASTAL-1 Study Summary
The KOASTAL-1 study enrolled 383 adult patients with major depressive disorder (MDD). Topline efficacy results failed to show improvement on the MADRS or SHAPS but signaled possible improvement in female patients.

Navacaprant was shown to be safe and generally well-tolerated, and no serious adverse events were reported. There was no signal for increased suicidal ideation or suicidal behavior compared to placebo, as measured by the Columbia Suicide Severity Rating Scale (C-SSRS). Rates of treatment discontinuation due to treatment-emergent adverse events were low (navacaprant 80 mg: 2.1%, placebo: 3.1%).

A significant proportion (83.3%) of navacaprant 80 mg-treated patients who completed 6 weeks’ treatment elected to enroll in KOASTAL-LT. The phase 3 KOASTAL-2, KOASTAL-3, and KOASTAL-LT studies are ongoing.

About the KOASTAL Program
The KOASTAL program includes 3 replicate phase 3 randomized, placebo-controlled, double-blind studies, KOASTAL-1, KOASTAL-2, and KOASTAL-3, designed to evaluate the efficacy and safety of navacaprant monotherapy in adult patients with moderate-to-severe MDD who have a MADRS total score ≥25 at baseline. The KOASTAL-1 Study was conducted in the United States. The KOASTAL-2 and -3 studies include sites in the United States and other regions. The primary endpoint of these studies is a change from baseline in MADRS total score at week 6. Key secondary endpoints include change from baseline on the SHAPS at week 6, a measure of anhedonia.

The KOASTAL Program also includes an open-label extension study, KOASTAL-LT, designed to evaluate the long-term safety of navacaprant. As noted above, a significant portion of patients who received navacaprant 80 mg (83.3%) in the KOASTAL-1 study elected to enroll in KOASTAL-LT. Patients will also have the opportunity to enroll in the KOASTAL-LT study following participation in the KOASTAL-2 and KOASTAL-3 studies.

About Navacaprant
Navacaprant is a highly selective, novel kappa opioid receptor (KOR) antagonist being developed as a potential monotherapy treatment for MDD. Navacaprant is an investigational once-daily oral 80 mg medication designed to modulate the dopamine and reward processing pathways, which play an important role in regulating mood, cognition, reward, and behavior.

Dr Clayton –

Importance to Science: 5
Importance to Molecule: 8
Importance to the Medication Class: 8

Navacaprant is a KOR antagonist with 300-fold selectivity for the Kappa receptor vs the Mu receptor (the latter is associated with addiction). MOA is anticipated to modulate dopamine reward processing and plays a role in regulating mood, reward, and behavior.

KOSTAL-1 is a phase 3 trial without significant difference vs placebo on the primary efficacy endpoint of change in MADRS score or secondary endpoint on SHAPS (anhedonia scale) at week 6 in the total population (n=383). Women with MDD (2/3 of patients with MDD) on navacaprant were much more likely to separate from placebo than men on MADRS (p=0.72) and SHAPS (p=0.015) change from baseline. Eighty-three percent of completers at 6 weeks entered the open-label extension study. There is no report on differences in younger (those <45 years old) vs older (those >45 years old). The probability of success was decreased to 5%. No information was provided on comorbid anxiety or pain.

Common adverse events (AEs) of headache, diarrhea, pruritus, and discontinuation AEs were similar between active treatment and placebo. These are not the most common AEs seen with FDA-approved antidepressants, especially related to dopamine and reward (sexual dysfunction evaluation may be particularly helpful). There is no access to phase 1 and phase 2 trials, so it is unclear if the dose was too low, especially with women responding better than men and having minimal AEs. Placebo response rates are not specified, but there was no numerical mean difference between drug and placebo for change in MADRS. There is a concern for a high placebo response rate, especially in men, so dosing needs to be re-evaluated. They might consider looking at an indication for treatment for fibromyalgia.

The negative findings suggest the need to reassess dosing. The industry underdoses to keep AEs low. They need to find an ineffective dose, minimal therapeutic dose, and maximum tolerated dose in phase 2, especially for adjunctive treatment. High placebo response rates suggest poor site selection/monitoring (it only takes a few sites with high placebo response rates to tip the balance against the drug). Pharmaceutical companies, rather than contract research organizations, may need to be the final monitors of site-specific placebo-response rates across trials in current studies to inform the selection of sites in future trials. Potential for addiction risk appears higher for aticaprant than navacaprant due to the selectivity ratio in Kappa vs Mu opioid receptors. Studies may have been loaded with patients with anhedonia (which may be more difficult to treat) or with emotional blunting from the standard-of-care antidepressant medication (mistaken for anhedonia), which remained constant across the trial. (They might be able to tease this out with the Oxford Depression Scale). The meaning of sex differences is unclear without information about reproductive status in women (eg, premenopausal, perimenopausal, postmenopausal) or the use of age as an initial proxy. Sex differences may actually be related to dosing (too low in men).

Dr Thase –

Importance to Science: 5 
Importance to the Molecule: 9 
Importance to the Medication Class: 7 

There are a lot of putative targets for novel antidepressants, and that’s why my rating for science is less than for the other 2 parameters.  I was never thrilled with the target for this program—MDD monotherapy—but this study and the subsequent developments spelled the end for this compound and set the stage for the subsequent disappointing news about aticaprant. 

Dr Mattingly –

Importance to Science: 6 
Importance to the Molecule: 7 
Importance to the Medication Class: 7 

As the first of three phase 3 trials (KOASTAL-1, 2, and 3), the negative results are worrisome for this molecule. This may represent a high placebo response, a difficult-to-treat population in those with high anhedonia, or a lack of true clinical response for this molecule and potentially for the Kappa opioid mechanism.