Once-daily schizophrenia treatment falls short of endpoints in two phase 3 trials

Key takeaways:

• Ulotaront was not superior to placebo in improving mental status of adults with schizophrenia.
• Researchers said the COVID-19 pandemic may have boosted placebo responses, muting the drug’s therapeutic effects.

Two phase 3 studies of a once-daily treatment for schizophrenia failed to meet their primary endpoints, with developers pointing to placebo effects and disruption from the COVID-19 pandemic to possibly explain the drug’s performance.

According to a joint press release from developers Sumitomo Pharma and Otsuka, topline results show ulotaront reduced adult participants’ schizophrenia symptoms in two multicenter, randomized, double-blind trials, but not to a statistically significant degree compared with placebo.

Both studies, DIAMOND 1 (n = 435) and DIAMOND 2 (n = 464), measured the efficacy, safety and tolerability of ulotaront, a trace amine-associated receptor agonist with 5-HT_1A agonist activity, compared with placebo over 6 weeks in acutely psychotic adults with schizophrenia. DIAMOND 1 enrolled two treatment arms at 50 mg per day and 75 mg per day, and DIAMOND 2 studied ulotaront at 75 mg per day and 100 mg per day.

According to the release, ulotaront and placebo resulted in similar reductions in schizophrenia symptoms, as rated using the Positive and Negative Syndrome Scale (PANSS).

In DIAMOND 1, the mean PANSS score reduction from baseline to week 6 in the placebo arm (least-squares [LS] mean = –19.3) was greater than the lower-dose ulotaront arm (LS mean = –16.9) but less than the higher-dose ulotaront arm (LS mean = –19.6).

And in DIAMOND 2, numerically greater score reductions in both treatment arms did not reach statistical significance compared with placebo, with researchers reporting an LS mean reduction of –14.3 in the placebo arm vs. –16.4 and –18.1 in the lower-dose and higher-dose treatment arms, respectively.

The release stated that Ulotaront, which received breakthrough therapy designation from the FDA in May 2019 for treatment of schizophrenia, was generally safe and well-tolerated in both studies.

The companies’ preliminary analyses of the data lead them to “believe that a high placebo response may have masked the therapeutic effect,” Hiroshi Nomura, president and CEO of Sumitomo, said in the release, calling the placebo response in DIAMOND 1 “particularly high.” He added the analyses “suggest an impact of COVID-19 on the placebo responses that were seen.”

Makoto Inoue, president of Otsuka, said the companies still believe ulotaront can address unmet needs in schizophrenia “as a new, potential treatment option in the future.”

“Based on these study results, Otsuka and Sumitomo Pharma will continue to collaborate to explore the full range of possibilities for ulotaront, as well to develop other drug candidates in the neuropsychiatric area, in order to contribute to patients suffering from psychiatric disorders worldwide,” Inoue said.