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LOS ANGELES — The novel phosphodiesterase 10A (PDE10A) inhibitor known as CPL'36 (Celon Pharma) is effective and generally safe in acute exacerbations of schizophrenia, new research suggested.

In a phase 2 trial of 189 patients with acute schizophrenia, compared with the placebo group, the groups receiving CPL'36 20 or 40 mg once daily both met the primary endpoint of a significant improvement from baseline to day 28 in scores on the positive subscale of the Positive and Negative Syndrome Scale (PANSS).

Both active treatment groups also showed a significant improvement in total scores on the PANSS, and the 40-mg group showed a significant improvement in scores on the negative subscale of the PANSS.

The most commonly reported adverse events for all groups included anxiety, insomnia, and somnolence. In the active treatment groups, no significant increases were observed in the levels of glucose and total cholesterol or in hepatic parameters.

“The drug is effective, and it has a very mild safety profile, with no metabolic side effects and limited extrapyramidal effects,” study co-investigator Maciej Wieczorek, MD, CEO of Celon Pharma, Łomianki, Poland, told Medscape Medical News.

Asked to comment, John Torous, MD, associate professor of psychiatry at Harvard Medical School, Boston, told Medscape Medical News that this study “felt more substantial and more convincing” than other phase 2 trials he typically sees.

“I think these were very impressive results. We’re always looking for things with new mechanisms of action in schizophrenia, and it had a favorable safety profile. So it was impressive they brought all that evidence to bear at once,” said Torous, who was not involved with the research.

The findings were presented on May 18, 2025, at American Psychiatric Association (APA) 2025 Annual Meeting.

Dopamine Modulator?

PDE10A hydrolyzes cyclic adenosine monophosphate and cyclic guanosine monophosphate “and is highly expressed in striatal medium spiny neurons (MSNs),” the investigators wrote. Its inhibition can lead to a modulation of MSN activity, upping the drug’s potential as a treatment for psychosis, they added.

“It’s completely different from other drugs. We don’t block dopamine receptors; rather, we modulate the release of dopamine. And from the molecular point of view, it’s very selective,” Wieczorek said.

After CPL'36 showed good safety and tolerability in a phase 1 clinical trial they conducted, the investigators sought to assess its safety and efficacy in a phase 2 study. Although top-line results were released by the drug development company last year, more detailed findings were presented at this year’s APA meeting.

Interesting, the drug is also being developed for levodopa-induced dyskinesia in Parkinson’s disease.

In the current double-blind, dose-ranging, multicenter, randomized controlled trial, 189 adult patients with schizophrenia were randomly assigned to receive either a 20-mg (n = 58; mean age, 41.3 years; 55% men) or a 40-mg (n = 66; mean age, 42.1 years; 62.1% men) dose of CPL'36 once daily as powder in a hard gelatin capsule or matching placebo (n = 65; mean age, 41.5 years; 70.8% men). All treatments were taken over 28 consecutive days.

For inclusion in the study, all participants had to have experienced exacerbation of psychotic symptoms within the previous 2-month period and have a total score of ≥ 80 on the PANSS. At baseline, the mean total score on the PANSS for all participants was 105.

Safety measures included ECG; the Extrapyramidal Symptom Rating Scale; and various physical, neurologic, and dermatologic exams.

‘First In The World’

Results showed a significantly greater improvement from baseline to day 28 in scores on the positive subscale of the PANSS for CPL'36 20 mg/d (reduction, 3.7 units; P < .001; Cohen d, 0.73) and 40 mg/d (reduction, 6.3 units; P < .001; Cohen d, 1.38) vs placebo.

In addition, significant improvements in scores on this subscale were seen for both doses as early as week 1 and continued through weeks 2, 3, and 4.

Compared with the placebo group, both active treatment groups also had a greater improvement in total scores on the PANSS at all timepoints (day 28 reductions, 9.7 and 16.4 units, respectively; P < .001 for both).

There was a 2.6 unit reduction in scores on the negative subscale of the PANSS for the 40-mg/d group vs the placebo group (P < .001) at day 28, with a significant improvement starting at week 2 and continuing through weeks 3 and 4.

Plasma testing showed that levels of glucose and total cholesterol remained constant throughout the study.

Somnolence was the most common adverse event, reported by 15.8% of the 20-mg group, 12.3% of the 40-mg group, and none of the placebo group.

In addition, anxiety was reported by 10.5%, 13.8%, and 9.2% of the groups; insomnia by 7.0%, 7.7%, and 7.7% of the groups; and worsening of schizophrenia symptoms by 7.0%, 10.8%, and 3.1% of the groups, respectively.

Additionally, five members in the 20-mg group, eight in the 40-mg group, and none in the placebo group reported extrapyramidal symptoms, which could include akathisia, extrapyramidal disorder, dystonia, or tremor and were considered by the researchers to be mild to moderate. They added that extrapyramidal symptoms are “typical side effects for already marketed antipsychotics.”

Treatment-emergent adverse events of any type were reported by 51% of the 20-mg group, 57% of the 40-mg group, and 34% of the placebo group. Treatment-emergent serious adverse events were reported by one member in each of the 20-mg and placebo groups and by two members in the 40-mg group.

There was also one episode of status epilepticus in the 40-mg group, but the investigators were unsure if it was treatment-related.

“This is the first study in the world demonstrating robust efficacy of PDE10A inhibition in the treatment of schizophrenia with positive primary and secondary endpoint readouts,” the company noted in their statement last year.

Wieczorek said they are now preparing for a meeting with the US Food and Drug Administration (FDA) later this year about creating a phase 3 trial. The current plan is to include both the 20-mg and 40-mg doses, but flexible dosing may be included in other future studies.

Desperate for New Options?

Torous noted that the field went years without a new schizophrenia medication before the FDA’s approval of xanomeline/trospium chloride (Cobenfy, Bristol Myers Squibb) last year.

However, as reported at the time by Medscape Medical News, its company announced in an April statement that the drug fell short as an add-on therapy in the phase 3 ARISE trial.

Torous said that, overall, there is still a real need for more options when it comes to treating patients with schizophrenia.

“It makes me think that for patients who haven’t responded to classical treatments, [CPL'36] is something that is different and has a different mechanism. That certainly could provide a lot of hope,” he said.

Asked whether he’d consider adding this drug to his medical toolbox if further research is as impressive and if it gets approved, Torous answered “definitely.”

“The field is hungry, if not desperate, for new treatments that have favorable side effect profiles and that would work for people who are in a more agitated state. So this could have real importance if it bears out,” he concluded.

The study was funded by the drug’s developer Celon Pharma, and Wieczorek is the CEO of the company. Torous reported having no relevant financial relationships.