Japan-based Sumitomo Pharma Co., Ltd (TYO: 4506) and Otsuka Pharmaceutical Co., Ltd (FRA: OS1) have revealed a setback in late-stage clinical trials for the potential first-in-class trace amine-associated receptor 1 (TAAR1) agonist, ulotaront, as a treatment for schizophrenia. Topline data from the Phase III DIAMOND 1 and DIAMOND 2 studies indicate that ulotaront, dosed once-daily in acutely psychotic patients, did not achieve the primary endpoint.
Design and Results of the DIAMOND Studies
Both DIAMOND 1 and DIAMOND 2 were multicenter, randomized, double-blind, parallel-group studies. DIAMOND 1 assessed ulotaront at 50 mg/day and 75 mg/day versus placebo over six weeks in 435 patients, while DIAMOND 2 evaluated ulotaront at 75 mg/day and 100 mg/day in 464 patients, also over six weeks. Ulotaront demonstrated a reduction in the Positive and Negative Syndrome Scale (PANSS) total score over time, with larger mean reductions than placebo in DIAMOND 2, but these did not achieve statistical significance. The molecule was found to be safe and well-tolerated.
Challenges and Next Steps
Sumitomo and Otsuka’s statement notes that the placebo effect was a significant factor, particularly in DIAMOND 1, and the trials were conducted during the COVID-19 outbreak, which may have affected the data. The companies plan to discuss the data with the US FDA to consider how to proceed based on existing results. The FDA had previously awarded ulotaront breakthrough therapy designation (BTD) for its potential use against schizophrenia.
Discovery and Mechanism of Ulotaront
Ulotaront is a TAAR1 agonist with 5-HT1A agonist activity discovered by Sumitomo in collaboration with US CRO PsychoGenics. Identified using PsychoGenics’ SmartCube platform, which applies in vivo phenotypes and associated artificial intelligence algorithms, TAAR1 is expressed in brain areas involved in psychiatric disorders and areas that regulate energy metabolism. TAAR1 has been shown to affect dopamine, serotonin, and glutamate signaling. Ulotaront is the first TAAR1 agonist to enter Phase III clinical studies for schizophrenia and is also the first to enter Phase II/III studies in generalized anxiety disorder (GAD) and as an adjunctive therapy in major depressive disorder (MDD).-Fineline Info & Tech
