A "Black Monday" for CNS drug developers

March 3, 2025: A "Black Monday" for CNS drug developers.

On the same day, three pharmaceutical companies—Biohaven, Neumora, and Lexicon—announced clinical trial failures or adjustments. Biohaven’s stock price fell 13.77%, Neumora’s dropped 9.94%, and Lexicon plummeted by 58.17%.

This collective stock plunge reflects the ongoing battle between pharmaceutical companies and the market, as well as the fierce competition between treatment drugs and placebos. A deeper crisis within the industry has come to light:

When placebo groups demonstrate pain relief, anti-mania, or antidepressant effects comparable to actual treatments, does this suggest that our understanding of brain disorders is still at a primitive stage—akin to blind men feeling an elephant?

Biohaven: A Crushing Defeat

On March 3, 2025, Biohaven announced that its potassium ion channel activator, BHV-7000, did not meet its primary endpoint in a Phase II/III clinical trial for the acute treatment of bipolar I disorder mania episodes.

The study included 256 patients who were randomly assigned to receive either daily BHV-7000 or a placebo for 3 weeks. The primary endpoint was improvement in the Young Mania Rating Scale (YMRS) score. YMRS is a widely used assessment tool for bipolar disorder, primarily measuring the severity of manic symptoms, including elevated mood, increased activity, and enhanced libido across 11 items—higher scores indicate more severe symptoms.

The results showed no statistically significant difference between the treatment and placebo groups in terms of YMRS score improvement. However, the treatment showed good safety, with no dose-limiting toxicity or serious central nervous system adverse events. Detailed data is expected to be presented at an upcoming academic conference.

Bipolar disorder is a common mental illness that includes both manic and depressive episodes. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the disorder has five major types, including Bipolar I, Bipolar II, and cyclothymic disorder. Bipolar I disorder involves at least one manic episode. Statistics suggest that individuals with Bipolar I disorder spend about 40% of their lifetime in the depressive phase and 15% in the manic phase. The exact cause of the disorder remains unclear.

As for BHV-7000, it is a selective activator of the Kv7.2/7.3 potassium channels. Kv7.2/7.3 is a subtype of voltage-gated potassium ion channels (Kv channels), primarily expressed in the central and peripheral nervous systems.

Theoretically, activating Kv7.2/7.3 potassium channels helps maintain neuronal membrane potential stability and reduces excessive neuronal excitability, thus potentially treating bipolar disorder. Currently, no drugs targeting this channel have been approved.

The clinical failure of BHV-7000 suggests that the mechanisms behind manic episodes in bipolar disorder are more complex than expected. The approach of activating Kv7.2/7.3 potassium channels to inhibit neuronal overexcitability still needs further verification. Clinical trial design, subject population selection, and sample size could all influence the trial results, and full data analysis is awaited.

Currently, BHV-7000 is also being studied in clinical trials for epilepsy and depression.

Neumora: Repeating History

On March 3, 2025, Neumora announced adjustments to its clinical trial strategy for its novel κ-opioid receptor (KOR) antagonist, navacaprant. The company decided to resume two previously suspended Phase III trials for major depressive disorder (MDD) while halting a Phase II trial for bipolar disorder.

The two resumed MDD trials, KOASTAL-2 and KOASTAL-3, follow the same design as the earlier KOASTAL-1 study. In January, navacaprant failed to meet both the primary and key secondary endpoints in KOASTAL-1.

KOASTAL-1 enrolled 383 patients (172 males and 211 females). The primary endpoint was the change in the Montgomery-?sberg Depression Rating Scale (MADRS) total score from baseline at week 6. The secondary endpoint was improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score.

Results showed that both the treatment and placebo groups had an identical reduction of 12.9 points in MADRS scores (p = 0.993). SHAPS scores decreased by -5.8 in the treatment group and -5.5 in the placebo group (p = 0.648).

However, a gender difference emerged. Among female participants, the treatment group saw a MADRS score reduction of -14.0 compared to -11.4 in the placebo group (p = 0.072), and SHAPS scores dropped by -7.2 in the treatment group versus -5.5 in the placebo group (p = 0.015). In contrast, no statistically significant difference was observed among male participants.

The observed gender differences warrant further investigation. KOASTAL-2 and KOASTAL-3 are essentially replications of KOASTAL-1 but with a broader range of trial sites. Following the suspension of its bipolar disorder trial, navacaprant’s only remaining indication is MDD. In response to KOASTAL-1’s failure, Neumora plans to introduce an independent review mechanism (SAFER) and enhanced screening tools to ensure enrolled patients meet the study criteria and to prevent repeat clinical trial participants from skewing results.

Lexicon: A Do-or-Die Gamble

On March 3, 2025, Lexicon announced that its AAK1 inhibitor, pilavapadin, failed to meet its primary endpoint in the Phase IIb PROGRESS trial for moderate-to-severe diabetic peripheral neuropathic pain (DPNP).

The PROGRESS trial enrolled 496 patients, randomly assigned to four groups: 10 mg once daily, 20 mg once daily, 20 mg once daily for 7 days before tapering to 10 mg, or placebo. The primary endpoint was the change in the average daily pain score (ADPS) from baseline to week 8.

Notably, the trial allowed patients to continue using a stable background DPNP treatment (e.g., gabapentin, pregabalin, or duloxetine) without discontinuation.

At week 8, the 10 mg once-daily group showed an ADPS reduction of -1.74, significantly outperforming the placebo group (-1.31) and demonstrating an early clinically meaningful separation from placebo. However, the 20 mg group (including the tapering arm) failed to show a significant benefit over placebo (ADPS reduction of -1.38 vs. -1.31), leading to a lack of statistical significance in the overall primary endpoint (p = 0.11).

In terms of safety, adverse events in the 10 mg group were mostly mild to moderate, with dizziness and nausea occurring at half the rate of the 20 mg group. As a result, Lexicon selected 10 mg once daily as the optimal dose and decided to advance it to Phase III trials.

Importantly, the PROGRESS trial’s primary endpoint required all dose groups to outperform placebo. The failure of the 20 mg group disrupted the overall signal chain, leading to a technical failure. This situation is comparable to an exam where the final score is based on math and language—achieving a perfect score in math but failing language still results in an overall failing grade.

Lexicon explained that if the analysis had focused solely on the 10 mg group, the results would have been statistically significant. Detailed data will be presented at an upcoming medical conference. Additionally, a critical aspect requiring further analysis is the proportion of patients receiving background treatment and its potential impact on the final clinical outcomes.

Conclusion

The wave of clinical trial failures highlights the diverging responses of these three pharmaceutical companies. Neumora is concentrating its resources on refining patient stratification and pushing forward with MDD trials despite past failures. Lexicon, despite concerns over dose escalation, remains determined to proceed to Phase III.

In the murky “dark forest” of CNS drug development, where disease mechanisms remain poorly understood, traditional development paradigms—relying on rating scales and dose escalation—are increasingly under threat. To uncover more effective and reliable clinical trial strategies, failures like these may be an inevitable price to pay.