Schizophrenia drugs mainly go after the same target in the brain, but drug developers are hoping to improve on the efficacy and side effect profile of such medicines by going after new targets. The prospects for one such therapy from Sumitomo Pharma are dimmer after the small molecule discovered with artificial intelligence technology failed in two Phase 3 studies.
In the first Phase 3 study, which enrolled 435 adults with schizophrenia, Osaka, Japan-based Sumitomo reported Monday that treatment with its once-daily pill, ulotaront, led to a reduction in score according to a scale used to assess the severity of the disorder. But the preliminary results showed that neither of the treatment groups was superior to placebo on the main goal of showing a change in score from baseline at after six weeks of treatment.
In a second Phase 3 study enrolling enrolled 464 patients, both ulotaront groups showed numerically larger reductions in scores compared to placebo. But those changes measured at week six were not large enough to be statistically significant.
High placebo responses are common in clinical tests of psychiatric drugs and that effect was also observed in ulotaront studies. Hiroshi Nomura, representative director, president and CEO of Sumitomo Pharma, said in a prepared statement that the company believes “a high placebo response may have masked the therapeutic effect of this innovative molecule.” Nomura also noted that the studies were conducted during the Covid-19 pandemic and initial analyses suggest that the pandemic affected the placebo responses.
The first generation of schizophrenia drugs target and block dopamine D2 receptors in the brain. Schizophrenia is associated with dysfunction of neurotransmission of dopamine, so blocking dopamine receptors is intended to dampen psychotic symptoms.
Ulotaront is a small molecule agonist designed to target trace amine-associated receptor 1 (TAAR1), a receptor that modulates neurotransmitters. The drug stems from a partnership between Sumitomo subsidiary Sunovion and PsychoGenics, a contract research organization that has developed an AI-based drug discovery technology platform. In an interview last week before ulotaront’s Phase 3 data were reported, PsychoGenics CEO Emer Leahy said the goal of the Sunovion partnership was to find a drug that does not target dopamine D2 like other schizophrenia drugs already on the market.
“We like to think about mental illness a little bit differently,” Leahy said. “We like to look at molecules that are not the me-too type of molecules.”
Sunovion brought compounds to the alliance that were then screened using PsychoGenics’s SmartCube technology, which employs computer vision to analyze and define behaviors of mice treated with a potential drug. Ulotaront emerged from this process showing potential for improvement on the negative symptoms of schizophrenia, Leahy said. In Phase 2 results reported in 2018, Sunovion and PsychoGenics said the molecule, then known as SEP-363856, met the main goal of showing statistically significant improvement measured according to the schizophrenia assessment scale after four weeks of treatment.
Ulotaront is the most advanced candidate of a psychiatry and neurology collaboration between Sumitomo and Otsuka Pharmaceutical that began two years ago. Otsuka paid Sumitomo subsidiary Sunovion $270 million up front and committed to up to $620 million more in milestone payments to share in the development and potential commercialization of four drugs. Sumitomo is looking to find a successor to Latuda, an antipsychotic that targets dopamine and serotonin receptors. That product is losing patent protection in the U.S.
Nomura said Sumitomo will work closely with Otsuka and to analyze the data from ulotaront’s schizophrenia studies and discuss the results with the FDA to determine the next steps for the program. In addition to schizophrenia, ulotaront is in early clinical development for psychosis from Parkinson’s disease. The three other programs in the partnership are in preclinical development for bipolar disorder, treatment-resistant depression, and agitation in Alzheimer’s disease.
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