In a significant setback for schizophrenia treatment development, Sumitomo Pharma America announced that its investigational drug ulotaront (SEP-363856) failed to meet its primary endpoint in two pivotal Phase 3 trials. The studies, conducted in partnership with Otsuka Pharma, evaluated the drug's efficacy in treating adults with acute psychotic symptoms of schizophrenia.
Trial Results and Design
The DIAMOND 1 and DIAMOND 2 studies assessed ulotaront's ability to improve symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) total score over six weeks. While the drug showed numerical trends favoring treatment, it failed to achieve statistical significance compared to placebo. The companies noted that an unusually high placebo response may have obscured the drug's therapeutic effects.
Novel Mechanism of Action
Ulotaront represents an innovative approach to schizophrenia treatment as a trace amine-associated receptor 1 (TAAR1) agonist with additional serotonin 5-HT1A agonist activity. Unlike traditional antipsychotics, the compound demonstrated a favorable safety profile in earlier studies, notably avoiding common side effects such as:
- Metabolic complications (weight gain, blood pressure elevation, cholesterol increases)
- Movement disorders resembling Parkinson's disease
- Restlessness associated with dopamine-targeting medications
Future Prospects and Market Context
Despite the disappointing results, Sumitomo and Otsuka have not abandoned the program. The companies plan to discuss next steps with the FDA, citing the common challenge of high placebo response rates in schizophrenia trials and potential COVID-19 pandemic impacts on study outcomes.
Competitive Landscape
The schizophrenia treatment pipeline remains active with several promising candidates:
- Karuna Therapeutics' KarXT, a muscarinic agonist combination therapy, has shown positive Phase 3 results and is preparing for regulatory submissions with potential launch in late 2024
- Minerva Pharma's roluperidone, targeting negative symptoms through serotonin, sigma, and α-adrenergic receptor blockade, is under FDA review with a decision expected by February 26th
Clinical Implications
The development setback highlights the ongoing challenges in advancing new treatments for schizophrenia, a condition that has seen limited therapeutic innovation for decades. While ulotaront's tolerability profile showed promise for maintenance therapy, the efficacy results underscore the complexity of developing new psychiatric medications and the need for continued research in this field.
