Sumitomo's novel schizophrenia drug flunks phase 3 test

Milad Fakurian

After decades of stagnation in the drug treatment of schizophrenia, a handful of new therapies have raised hopes of improvement – but one of them has just failed a pair of phase 3 trials.

Sumitomo Pharma America (formerly Sunvion) has said that its ulotaront (SEP-363856), a novel trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity, was unable to meet its objectives in the DIAMOND 1 and DIAMOND 2 studies in acutely psychotic adults living with schizophrenia.

The two studies were run by Sumitomo in partnership with Otsuka Pharma, which said ulotaront was unable to show a statistically significant improvement over placebo on the primary endpoint – the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score after six weeks.

There were numerical trends in favour of the drug, and Sumitomo and Otsuka also pointed to an unexpectedly high response to the placebo, which could have masked the therapeutic effects of the drug, but the finding is clearly a big setback for the programme.

There were signs in mid-stage studies with the drug that its efficacy may not be as high as some of the current antipsychotics, but its tolerability was seen as giving it the potential to become a potential game-changer in schizophrenia, particularly for potential use as maintenance therapy.

The drug seems to lack the metabolic side effects that are associated with current antipsychotic treatments for the mental health disorder, including weight gain and increases in blood pressure and cholesterol. It also avoids the Parkinson-like symptoms and restlessness that can be caused by dopamine-acting drugs.

In a statement, Sumitomo and Otsuka gave no indication they are giving up on the drug yet, noting that high placebo response rates are common in schizophrenia trials, and also that the effect may have been exacerbated by the COVID-19 pandemic.

They said they would be discussing the next steps with the FDA, while continuing to "collaborate to explore the full range of possibilities for ulotaront, as well to develop other drug candidates in the neuropsychiatric area," according to Otsuka's president Makoto Inoue.

Other candidates approaching the market

Along with ulotaront, psychiatrists are also hopeful that other experimental drugs will offer stepwise improvements in schizophrenia treatment, including Minerva Pharma's roluperidone (MIN-101), which has been shown to block serotonin, sigma, and α-adrenergic receptors.

Roluperidone also failed a phase 3 trial in 2020 but subsequently showed evidence that it may be able to target the negative symptoms of schizophrenia – such as apathy and social withdrawal – that remain resistant to treatment with current drugs.

The drug was filed with the FDA, and while initially the regulator refused to accept the marketing application, a review has since started with a decision due by 26th February next year.

Karuna Therapeutics, meanwhile, is focusing on a muscarinic agonist approach with KarXT, combining a muscarinic agonist (xanomeline), which acts in the brain, with a muscarinic antagonist (trospium), designed to prevent side effects in peripheral tissues.

KarXT was shown to be effective in a phase 3 programme and is being prepared for regulatory filings, with a possible launch in the second half of 2024 if approved.

Photo by Milad Fakurian on Unsplash