Sumitomo-Otsuka schizophrenia drug flunks pair of phase 3 trials amid 'high placebo response'

Sumitomo Pharma and Otsuka’s plan to turn ulotaront into a blockbuster growth driver is on the ropes. A pair of phase 3 schizophrenia clinical trials of the candidate missed their primary endpoints, leaving the partners looking to a “high placebo response” for evidence that the asset has a future in the disease. 

Otsuka bought into the program in 2021, paying $270 million upfront for rights to a set of candidates led by ulotaront. By that time, the AAR1 agonist with 5-HT1A agonist activity was already in phase 3 trials as a treatment for schizophrenia. With depression and anxiety on the R&D road map, Sumitomo identified (PDF) the asset as a potential blockbuster that can mitigate the loss of sales of its antipsychotic Latuda.

The first phase 3 readouts raise doubts about the prospects of ulotaront. The trials randomized 435 and 464 acutely psychotic adults with schizophrenia to receive one of two doses of ulotaront or placebo and measured changes in symptoms after six weeks. The partners tested different doses in the two trials.

None of the doses beat placebo. In the DIAMOND 1 trial, Sumitomo and Otsuka saw reductions in scores on a schizophrenia symptom severity scale at both daily doses, 50 mg and 75 mg. The problem? Scores in the placebo arm fell, too, and neither ulotaront dose performed significantly better.

The DIAMOND 2 trial tested different doses, 75 mg and 100 mg, but delivered similar results. Both doses achieved numerically larger mean reductions than placebo, 16.4 and 18.1 in the ulotaront arms versus 14.3 in the placebo group, but the difference fell short of statistical significance. Why ulotaront failed to outperform placebo is the next question, and the partners suspect they know the answer.

“We believe that a high placebo response may have masked the therapeutic effect of this innovative molecule,” Sumitomo CEO Hiroshi Nomura said in a statement. “The placebo response in DIAMOND 1 was particularly high. These studies were conducted throughout the COVID-19 pandemic and initial analyses of these data suggest an impact of COVID-19 on the placebo responses that were seen.” 

High placebo response rates are a recurring problem in psychiatric clinical trials. Sumitomo and Otsuka think the pandemic may have added to the problem. In a pooled analysis (PDF) of data enrolled in the two DIAMOND trials before the pandemic, “ulotaront showed a similar trend in efficacy as seen in the phase 2 study.”

The partners are continuing to analyze the data and plan to talk to the FDA about how to proceed. Both companies have a lot resting on the program, with Otsuka listing (PDF) it as a next-gen growth driver and Sumitomo predicting sales across all indications could top revenues from its fading blockbuster Latuda.