New Hope Schizophrenia Treatment: Drugs Targeting Different Mechanisms

Most new drugs in schizophrenia have relied on similar targets to antipsychotics first approved in the 1950s. But some up and coming late-stage therapies could make waves in what has previously been a stagnant space.

Many of these therapies have faced development setbacks, but experts are optimistic. “We could be on the precipice of something big in schizophrenia,” Columbia Schizophrenia Research Center director Dr Joshua Kantrowitz says.

Currently approved antipsychotics are agonists of the dopamine type 2 (D2) receptor, which can cause undesirable side effects like weight gain and metabolic disturbances. There is a significant need for schizophrenia treatments with new mechanisms and symptom targets, University of Maryland psychiatrist Dr William Carpenter adds.

Three schizophrenia treatments in development —Sunovion’s ulotaront, Minerva’s roluperidone, and Teva and MedinCell’s extended-release risperidone—are vying to disrupt the current paradigm. But, as these companies have learned so far, it can be a bumpy path to approval.

Ulotaront offers new mechanism

Ulotaront, a trace amine-associated receptor 1 (TAAR1) agonist, has a new mechanism that could make it a major game-changer in schizophrenia, Kantrowitz says. The drug does not appear to cause the same, troubling metabolic side effects as traditional antipsychotics, he explains.

“Overall, this medication represents a major change in our understanding of the psychopharmacologies of schizophrenia,” mental health service CBH Health medical director Dr Robert Litman adds. A Sunovion spokesperson says ulotaront could be the first approved schizophrenia treatment with a novel mechanism in over 60 years.

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However, despite mechanism and tolerability advantages, the magnitude of efficacy is only “midrange” in relation to available treatments, Kantrowitz notes. As a primary efficacy outcome measure, the 245-patient Phase II study (NCT02969382) used the Positive and Negative Syndrome Scale (PANSS). Patients in the ulotaront treatment group (n=125) had a PANSS improvement of 17.2 compared to 9.7 with placebo (n=120). More adverse events and serious adverse events were reported with placebo than ulotaront.

Sunovion is currently recruiting patients for a 525-patient Phase III ulotaront trial (NCT04072354) and subsequent open-label study. The long-term study of ulotaront has an estimated primary completion date of November 2022, according to

Roluperidone’s symptom target promising despite setback

Roluperidone’s focus on the “negative symptoms” of schizophrenia—such as social withdrawal and apathy—addresses a unique, unmet need, Kantrowitz says. While the drug recently missed a Phase III trial (NCT03397134), he is still optimistic of its long-term chances.

The drug’s primary endpoint is improvement in negative symptoms, though it may also reduce overall symptoms of schizophrenia, Carpenter explains. Roluperidone can block serotonin, sigma- and alpha-adrenergic receptors, leading to possible improvements in regulating sleep, mood, and anxiety. Most schizophrenia drugs focus on “positive symptoms”, such as hallucinations and hyperactivity, Carpenter adds.

Most schizophrenia drugs focus on “positive symptoms”, such as hallucinations and hyperactivity.

The Phase III trial missed its primary endpoint of change in the Marder negative symptoms factor score (NSFS). NSFS is a validated scale that incorporates parts of the PANSS but focuses on negative symptoms of schizophrenia. In the 343-patient study, patients on the highest dose of roluperidone had a NSFS improvement of 4.3 points compared to a 3.5-point improvement in the placebo group (p=0.064), according to a December 2020 press release.

But overall, Kantrowitz says the Phase III trial miss is not too discouraging given promising earlier results. “It was a pretty close replication of good Phase II data,” he says. “I’m hopeful that [Minerva] is going to continue to pursue it.”

A previous Phase IIb trial of roluperidone as a monotherapy (EudraCT-2014-004878-42) was associated with specific and significant improvements in negative symptoms. Yet, based on Phase IIb and Phase III data, the FDA has said it’s unlikely to grant approval for roluperidone at this time. The company said it plans to continue developing roluperidone with the FDA’s feedback in mind. 

Extended-release risperidone fails to impress

Risperidone was first approved as a daily pill for schizophrenia in 1993. Now, Teva and MedinCell have applied for FDA approval of monthly and bimonthly injectable risperidone formulations. But these new formulations could have a tough time gaining traction in a crowded market of long-acting injectables.

Numerous long-acting injectable antipsychotics for schizophrenia are already on the market. Most recently, Johnson & Johnson’s Invega Hayfera (paliperidone), an injection given every six months, gained FDA approval for schizophrenia in September 2021.

There are no meaningful differences between extended-release risperidone and Hayfera, Kantrowitz says. In a 544-patient Phase III trial (NCT03503318), the patients’ risk of relapse on a monthly and every-other-month version of subcutaneous extended-release risperidone injection reduced by 80% and 62.5%, respectively, relative to placebo. The companies reported no new side effects beyond what has been observed in previously approved formulations of risperidone.

But while the long-acting injectable field is full of options, there is still a market for long-acting medications. Insurers could significantly save on healthcare costs by prioritising long-acting injectables, which can boost compliance, Litman explains. The FDA has accepted extended-release risperidone’s NDA for the treatment of schizophrenia.