Pictured: Woman in mental anguish/iStock, Marina Demeshko

Sumitomo Pharma and Otsuka Pharmaceutical announced Monday that two Phase III studies of ulotaront failed to meet primary endpoints for acutely psychotic adults living with schizophrenia.  

The studies, DIAMOND 1 and DIAMOND 2, pitted the trace amine-associated receptor 1 (TAAR1) agonist against a placebo. After six weeks, the studies showed improvement on the Positive and Negative Syndrome Scale (PANSS), but results were not superior to placebo.  

A “large placebo effect” was present in both studies “which may have masked the molecule’s therapeutic effect,” according to the press release. 

While placebo responses are frequently higher in psychiatric studies, Sumitomo CEO Hiroshi Nomura pointed to COVID-19 as a potential culprit for the high placebo effect as the studies were conducted throughout the pandemic.

The molecule was part of a four-compound deal forged between Otsuka and Sunovion, a subsidiary of Sumitomo, nearly two years ago. The former made an upfront payment of $270 million to the latter with another $620 million on the line in milestone payments.  

Ulotaront is also in Phase II/III clinical studies as an adjunctive treatment for major depressive disorder as well as generalized anxiety disorder. Another asset from the deal, SEP-4199, is in a Phase III study for bipolar I depression. 

The TAAR1 agonist was safe and well-tolerated in both schizophrenia studies. The companies plan to further analyze the data and discuss next steps with the FDA, who had already granted Breakthrough Therapy Designation to ulotaront for a schizophrenia indication. 

Hopes had been high for ulotaront for its potential to treat both the positive psychosis symptoms in addition to the elusive negative symptoms of schizophrenia. Negative symptoms essentially zap patients of their motivation and zeal for life, affecting their ability to function normally.  

Recently, Roche had to axe a second Phase II trial of its investigational schizophrenia drug ralmitaront, leaving the future of its program uncertain.  

“In a preliminary analysis, the primary endpoint was negative, and ongoing portions of the study have therefore been discontinued,” said an update on the second Phase II trial posted to the ClinicalTrials.gov website. 

Karuna Therapeutics’ combination drug, KarXT, appears to treat both positive and negative symptoms of schizophrenia. It has not been specifically tested for negative symptoms. Since the drug is a non-dopamine D2 receptor antagonist, it does not cause many of the typical side effects of schizophrenia medicines like sedation and weight gain. 

An NDA is anticipated for the investigational M1/M4-preferring muscarinic agonist by the middle of this year. If approved, KarXT will be the first new class of drug for schizophrenia in over 50 years. 

Sumitomo Pharma’s stock dropped about 10% in Monday trading on the news. 

Published: Jul 31, 2023 By Kate Goodwin