The “Black Monday” for CNS drug-developing companies. Is the placebo “going wild and uncontrollable”?
Jinsong Guo (Founder of DrugTimes)
Founder of DrugTimes（药时代）, Co-President and Secretary General of China Alliance of New Drug Development for Liver Diseases
March 3, 2025: The “Black Monday” for CNS drug-developing companies.
Biohaven, Neumora, and Lexicon all announced clinical failures or adjustments on the same day. Biohaven’s share price plummeted by 13.77%, Neumora’s by 9.94%, and Lexicon’s by a staggering 58.17%.
The collective drop in share prices reflects the tug-of-war between the market and the drug companies, as well as the fierce competition between therapeutic drugs and placebos. The underlying dilemma faced by the industry as a whole has come to light—
When the placebo group demonstrates pain-relief, anti-manic, or anti-depressant effects comparable to those of therapeutic drugs, is our understanding of brain disease mechanisms still at the stage of groping in the dark like blind men feeling an elephant?
Table of Contents
Biohaven: A Setback in the Sand
On March 3, 2025, Biohaven announced that its potassium channel activator, BHV-7000, failed to meet the primary endpoint in a Phase II/III clinical trial for the acute treatment of manic episodes in Bipolar I Disorder.
It is reported that the study enrolled 256 patients who were randomly assigned to receive either BHV-7000 or placebo once daily for three weeks. The primary endpoint was the improvement in scores on the Young Mania Rating Scale (YMRS).
The YMRS is a commonly used scale for assessing Bipolar Disorder, primarily evaluating the severity of manic symptoms. It includes 11 items such as elevated mood, increased activity, and increased libido, with higher total scores indicating more severe symptoms.
The results showed no statistically significant difference in YMRS score improvement between the treatment group and the placebo group. However, the safety profile was good, with no dose-limiting toxicity or serious central nervous system adverse events observed. Detailed data are expected to be presented at an upcoming academic conference.
Bipolar Disorder is a common mental illness characterized by episodes of mania and depression. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the disease is categorized into five major types, including Bipolar I, Bipolar II, and Cyclothymic Disorder.
Bipolar I Disorder indicates the presence of at least one manic episode. Statistics show that patients with this type spend approximately 40% of their lifetime in the depressive phase and 15% in the manic phase. The exact etiology of the disease remains unclear.
BHV-7000 is a selective activator of the Kv7.2/7.3 potassium channels. The Kv7.2/7.3 channels are a subtype of voltage-gated potassium channels (Kv channels) and are mainly expressed in the central and peripheral nervous systems.
Theoretically, activating the Kv7.2/7.3 potassium channels helps stabilize neuronal membrane potential, reducing neuronal hyperexcitability, thereby treating Bipolar Disorder. Currently, no drugs targeting this pathway have been approved.
The clinical failure of BHV-7000 suggests that the pathogenesis of manic episodes in Bipolar Disorder is far more complex than anticipated. The therapeutic strategy of inhibiting neuronal hyperexcitability by activating Kv7.2/7.3 potassium channels needs further validation. Of course, the clinical trial design, patient population selection, and sample size may all impact the trial results, and the complete data readout is awaited.
Currently, BHV-7000 is also being investigated in clinical trials for epilepsy and depression.
Neumora: Repeating the Same Mistakes
On March 3, 2025, Neumora announced adjustments to its clinical trial strategy for navacaprant, a novel kappa-opioid receptor (KOR) antagonist. The company decided to resume two previously suspended Phase III studies for Major Depressive Disorder (MDD) while pausing a Phase II study for Bipolar Disorder.
The resumed MDD studies are named KOASTAL-2 and KOASTAL-3. In January of this year, navacaprant failed to meet the primary and key secondary endpoints in the KOASTAL-1 study. The KOASTAL-1 study enrolled 383 patients with a male-to-female ratio of 172:211. The primary endpoint was the change from baseline in the Montgomery-?sberg Depression Rating Scale (MADRS) total score at Week 6, while the key secondary endpoint was the improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score.
The results showed that both the treatment and placebo groups experienced a 12.9-point reduction in MADRS total score from baseline (p=0.993). The SHAPS score decreased by -5.8 points in the treatment group and -5.5 points in the placebo group (p=0.648). Among female participants, the treatment group saw a 14.0-point reduction in MADRS score compared to 11.4 points in the placebo group (p=0.072), while the SHAPS score improved by -7.2 points in the treatment group and -5.5 points in the placebo group (p=0.015). In contrast, no statistically significant differences were observed in the male subgroup.
Gender differences are thus noteworthy. The KOASTAL-2 and KOASTAL-3 studies are essentially replications of KOASTAL-1, with broader geographic coverage. According to Neumora’s official website, after the suspension of the Bipolar Disorder study, navacaprant’s remaining indication under investigation is now limited to MDD.
In response, Neumora has decided to learn from the failure of KOASTAL-1 by implementing an independent review mechanism (SAFER) and screening tools to ensure that enrolled patients meet the criteria and exclude those who have participated in multiple clinical trials.
Lexicon: A Last-Ditch Effort
On March 3, 2025, Lexicon announced that its AAK1 inhibitor, pilavapadin, failed to meet the primary endpoint in the Phase IIb PROGRESS study for the treatment of moderate-to-severe diabetic peripheral neuropathic pain (DPNP).
The PROGRESS study enrolled 496 patients, who were randomly assigned to four treatment groups: 10 mg once daily, 20 mg once daily, 20 mg for seven days followed by a reduction to 10 mg, or placebo. The primary endpoint was the change in the average daily pain score (ADPS) from baseline to Week 8.
It is worth noting that the study allowed patients to continue using a stable DPNP treatment medication (such as gabapentin, pregabalin, or duloxetine) without discontinuation.
The results showed that at Week 8, the 10 mg once-daily group experienced a 1.74-point reduction in ADPS from baseline, significantly better than the 1.31-point reduction in the placebo group, and achieved a clinically meaningful separation from placebo early in the treatment course. However, the 20 mg dose group (including the dose-tapering regimen) did not show a significant improvement over placebo (ADPS reduction of 1.38 vs. 1.31), leading to a failure to achieve statistical significance for the primary endpoint (p=0.11).
In terms of safety, the 10 mg group experienced mostly mild-to-moderate adverse events (AEs), with a 50% lower incidence of dizziness and nausea compared to the 20 mg group. As a result, Lexicon selected the 10 mg once-daily group as the optimal dose and advanced it to Phase III.
It is important to note that the primary endpoint of the PROGRESS study required demonstrating superiority over placebo for all dose groups. The failure of the 20 mg group led to a broken signal chain. To illustrate, if the total score of an exam equals the sum of math and language scores, even if math is perfect but language is failing, the total score remains unqualified. Therefore, the study was deemed a failure. In response, Lexicon explained that if only the data from the 10 mg group were evaluated, the results would show significance. Detailed data are planned to be presented at an upcoming medical conference.
Additionally, a key piece of data in this study deserves attention: the number of patients receiving background therapy. What is the impact of these patients on the final clinical data?
Summary
The concentrated failures in clinical trials have led to starkly different responses from the three pharmaceutical companies. Neumora is focusing its resources on optimizing patient stratification and continuing to tackle the MDD indication, despite previous failures. Lexicon, on the other hand, has undeniable doubts about its dose escalation but is determined to advance the drug to Phase III.
In the “dark forest” of CNS, where mechanisms are still unclear, the traditional development paradigm that relies solely on scale scores and dose increases is fraught with danger. To explore more efficient and stable clinical trial protocols, these “failures” are inevitably part of the cost.
【Editor’s note】The above content (~7500 words) is a quick translation of a Chinese article (posted on 2025-03-04) by DrugTimes team. To read the original article, please click here. All comments are warmly welcome. Many thanks!