What Went Wrong? Top 6 Clinical Disappointments

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While science is all about trial and error, it can be easy to feel disappointed when a new potential treatment fails in the development process. Here, we highlight the most disappointing outcomes in the psychiatric treatment pipeline from the last year.

6. Roluperidone for Negative Symptoms of Schizophrenia

The US Food & Drug Administration (FDA) issued a complete response letter (CRL) in follow-up to the New Drug Application for roluperidone (MIN-101) as a treatment for negative symptoms of schizophrenia. In the CRL, the FDA cited several clinical areas for improvement necessary for future approval of roluperidone: (1) insufficient data to establish that the change in negative symptoms with roluperidone treatment was clinically meaningful, (2) a lack of data on concomitant administration of antipsychotic drugs in the NDA submission, (3) an inadequate number of participants exposed to the proposed dose (64 mg) of roluperidone for at least 12 months in the safety database, and (4) this study alone was insufficient to establish substantial evidence of effectiveness.

5. Navacaprant for Major Depressive Disorder

Just last month, the oral kappa opioid receptor antagonist navacaprant for the treatment of major depressive disorder (MDD) failed in a phase 3 study as part of Neumora Therapeutics' pivotal KOASTAL program. Investigators in the KOASTAL-1 trial enrolled 383 adults with moderate-to-severe MDD, who were randomized to receive navacaprant as a monotherapy at a dose of 80 mg or placebo. According to topline results, both navacaprant and placebo led to a 12.5-point improvement from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6, thus missing the study's primary endpoint. The study also failed on its key secondary endpoint: change from baseline in the Snaith-Hamilton Pleasure Scale (SHAPS) scale. The difference between navacaprant and placebo was 0.3 points; while this favors navacaprant, it was not a statistically significant improvement.

4. Emraclidine for Schizophrenia

Emraclidine—once-daily, oral monotherapy treatment for adults with schizophrenia experiencing acute psychotic symptoms—failed to meet the primary endpoints in the 2 phase 2 EMPOWER trials, or a statistically significant improvement in the change from baseline in the Positive and Negative Syndrome Scale total score compared with the placebo group at week 6. However, these results are important for our continued understanding of how the muscarinic cholinergic receptors interface with the symptoms of schizophrenia.

3. Pimavanserin for Schizophrenia

In another disappointment for schizophrenia, topline data from the phase 3 ADVANCE-2 trial revealed that pimavanserin, an inverse serotonin 2A receptor agonist, failed to separate from placebo in a phase 3 double-blind study of 454 adults with schizophrenia treated for 26 weeks. In April 2021, it was rejected for approval in dementia-related psychosis, followed by another rejection in August 2022 for hallucinations associated with Alzheimer disease psychosis. Following this failure, Acadia Pharmaceuticals discontinued research on pimavanserin for schizophrenia.

2. Iclepertin for Cognitive Impairment in Schizophrenia

Data from a phase 3 study for iclepertin in addressing cognitive impairment in adults with schizophrenia found that no statistically significant effects on cognition or functioning were observed in patients treated with iclepertin vs placebo at 6 months. Iclepertin (BI 425809) is an investigational oral inhibitor of glycine transporter 1 thought to influence brain biology and address cognition deficits in schizophrenia and potentially other disorders. It would have been a huge step forward if iclepertin demonstrated statistical clinical efficacy in the improvement of cognitive symptoms in schizophrenia, as this is a significant unmet need.

1. MDMA-Assisted Therapy for Posttraumatic Stress Disorder

The most disappointing clinical update of the past year has to go to midomafetamine (MDMA)-assisted psychotherapy, as its approval would have made it the first psychedelic-assisted therapy. Instead, the FDA issued a CRL for Lykos’s MDMA-assisted psychotherapy for PTSD, noting it could not be approved based on the data submitted. The FDA requested an additional phase 3 trial examining safety and efficacy. Despite this setback, researchers shared they will continue to work diligently to address the FDA’s questions.

What update were disappointed by? Let us know at PTEditor@mmhgroup.com!