Drug developers targeting schizophrenia are aiming to enhance the efficacy and reduce side effects of existing medications by exploring new brain targets. Unfortunately, the future of one such therapy developed by Sumitomo Pharma seems uncertain after its small molecule, discovered using artificial intelligence technology, failed in two Phase 3 studies.
In the initial Phase 3 trial involving 435 adults with schizophrenia, Sumitomo reported that its once-daily pill, ulotaront, led to a reduction in symptom severity scores according to a scale used to assess the disorder. However, neither of the treatment groups demonstrated superiority over the placebo in achieving the main objective of changing scores from baseline after six weeks of treatment. In the second Phase 3 study with 464 patients, both ulotaront groups showed numerically larger reductions in scores compared to the placebo. Unfortunately, these changes measured at week six were not statistically significant.
It is common to observe high placebo responses in clinical trials of psychiatric drugs, and this effect was also seen in the ulotaront studies. Hiroshi Nomura, the CEO of Sumitomo Pharma, suggested that a high placebo response may have masked the therapeutic effect of the innovative molecule. Additionally, the studies were conducted during the Covid-19 pandemic, and initial analyses suggest that the pandemic might have influenced the placebo responses.
Traditional schizophrenia drugs typically target and block dopamine D2 receptors in the brain, aiming to dampen psychotic symptoms associated with dopamine neurotransmission dysfunction.
Ulotaront, on the other hand, is a small molecule agonist designed to target trace amine-associated receptor 1 (TAAR1), a receptor that modulates neurotransmitters. It emerged from a partnership between Sumitomo subsidiary Sunovion and PsychoGenics, a contract research organisation with an AI-based drug discovery technology platform. The goal was to find a drug that does not target dopamine D2, differentiating it from existing schizophrenia drugs. Ulotaront showed potential for improving negative schizophrenia symptoms in Phase 2 results reported in 2018 under the name SEP-363856.
Ulotaront is the most advanced candidate resulting from the collaboration between Sumitomo and Otsuka Pharmaceutical, which began two years ago. Otsuka paid Sumitomo subsidiary Sunovion $270 million upfront and committed up to $620 million in milestone payments to share in the development and potential commercialisation of four drugs. Sumitomo is looking to find a successor to Latuda, an antipsychotic targeting dopamine and serotonin receptors, as it is losing patent protection in the U.S.
Nomura stated that Sumitomo will closely collaborate with Otsuka to analyse the data from ulotaront's schizophrenia studies and discuss the results with the FDA to determine the next steps for the program. Ulotaront is also in early clinical development for psychosis related to Parkinson's disease, and the partnership's other three programs are in preclinical development for bipolar disorder, treatment-resistant depression, and agitation in Alzheimer's disease.
Click here to read the original news story.