"Improved" PDE10A Inhibitor Exhibits Antipsychotic Effect

Alofropodect (Celon Pharma), an investigational phosphodiesterase 10A (PDE10A) inhibitor drug, has demonstrated an antipsychotic effect in a phase 2 clinical trial,¹ distinguishing it from compounds in the class that share its preclinical promise but have not met clinical criteria.

Joanna Sierzputowska-Prarat, MSc, of Celon Pharma SA, Łomianki/Kiełpin, Poland, and colleagues characterize alofropodect as a "second-generation" PDE10A inhibitor, with an "improved" pharmacological profile.

The trial results, they indicate, "suggest that PDE10A is a viable but pharmacologically demanding target: one where the magnitude and pattern of enzyme inhibition, the choice of dose and the quality of trial execution may all influence the likelihood of detecting a clinical signal."

The PDE10A inhibitors have been considered potential candidates for neuropsychiatric product development since 1999 when it was determined that the PDE10A enzyme, which hydrolyzes both cAMP and cGMP, is highly expressed in the striatum region of the brain, and exclusively in the striatal medium spiny neuron (MSN).^2,3

"This localization prompted an intensive effort to determine the role of PDE10A in regulating striatal function and to investigate the potential therapeutic utilities of PDE10A inhibitors," recounted Frank Menniti, PhD, of the George & Anne Ryan Institute for Neuroscience, at the University of Rhode Island, in Kingston, RI, and colleagues.⁴

Menniti et al explain that the striatum serves as a gateway for input and processing cortical information by the basal ganglia circuit, and that the MSNs receive "dense" dopaminergic input from the substantia nigra and ventral tegmental areas. Dysfunction in the circuitry has been linked to a range of neuropsychiatric and neurodegenerative conditions; and, in the current focus, inhibition of D2 receptors on indirect pathway MSNs is the putative action of D2 dopamine blocking antipsychotics.

Preclinical studies have linked PDE10A inhibition with behavioral effects that are similar to those associated with the D2 dopamine blocking antipsychotics, as well as potentiation of D2 dopamine blocker antipsychotic effect. However, despite favorable preclinical indications, 3 candidate compounds from different manufacturers failed to demonstrate antipsychotic efficacy in clinical trials conducted in the period between 2017 and 2019.

In a 2021 publication,⁴ Menniti et al suggested that there are lessons from the failed trials which might guide development of "improved" compounds for clinical effect. "Moving forward from these disappointing results, comparing and contrasting the effects of PDE10A inhibitors with D2 antagonists provides a new opportunity for back translational research to gain insight into factors critical to the molecular basis of antipsychotic drug action," they asserted.

Menniti et al proposed, for example, developing compounds to target indirect over direct pathway MSNs, noting the intrinsic differences in excitability. They also point out that inhibitor compounds with faster rates of dissociation from the PDE10A enzyme have greater impact on indirect pathway activation.

In reporting the current trial, Sierzputowska-Prarat and colleagues attribute favorable results, in part, to alfropodect having such attributes, "with an improved pharmacological profile...including a fast dissociation rate and high activity..."

"Alfoprodect exhibits a unique pharmacodynamic profile, with dose-dependent catalepsy in preclinical studies, unlike other PDE10A inhibitors. This observation suggests a shift in the activation balance towards the indirect pathway, potentially indicating an extended and more pronounced therapeutic efficacy window," the investigators said.

Dose-Dependent Improvement in Acute Schizophrenia

Sierzputowska-Prarat and colleagues randomized 189 adult patients hospitalized with acute schizophrenia (157 completed) on a 1:1:1 ratio to receive oral alofropodect 20 mg, 40 mg, or placebo daily for 4 weeks in lieu of their standard-of-care antipsychotic treatment. A medication washout period of ≤7 days was instituted prior to baseline, with patients resuming their medication if needed on day 29.

The diagnosis of schizophrenia by DSM-V criteria was confirmed with the mini international neuropsychiatric interview (MINI) for schizophrenia and psychotic disorders studies. Participants had scored ≥4 on the clinical global impression scale-severity of illness (CGI-S); and had experienced an acute exacerbation, defined as PANSS total score ≥80 and a score of ≥5 in 3 or more PANSS items during screening and the day before baseline.

The primary study endpoint was change from baseline in the PANSS positive subscale score at week 4. Secondary endpoints included that measure as well as PANSS total and negative subscale scores at weeks 1, 2, and 3.

The investigators reported that both the 20 mg and 40 mg doses of alofropodect were effective in improving the primary endpoint measure of PANSS positive subscale score at week 4 compared with placebo (-3.70 [90%CI -5.51 to -1.89] and -6.35 [-8.12 to -4.57], respectively). They also reported that most secondary efficacy endpoints were met, and that clinical response, defined as decrease in PANSS total score of ≥30%, was achieved by 15.4% in the 20 mg group and 42.3% with 40 mg, compared with 3.8% of those receiving placebo.

Sierzputowska-Prarat et al characterize the investigational agent as well tolerated, with similar discontinuation rates in the placebo and active treatment arms. There were no increases in blood glucose, total cholesterol or triglycerides associated with active treatment compared with placebo. However, extrapyramidal symptoms and somnolence were reported with active treatment.

"To our knowledge, we present the first evidence of the successful completion of a phase 2 trial with a PDE10A inhibitor in patients with schizophrenia," the investigators said.

"Keeping in mind the limited number of study participants, alofropodect appeared to effectively target the PDE10A pathway, showing promising therapeutic potential for schizophrenia and possibly other psychiatric and neurological disorders," they concluded.

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Wieczorek M, Waszkiewicz N, Gromniak-Haniecka E, et al. PDE10A inhibition in schizophrenia: a randomised, placebo-controlled phase 2 study of alofropodect (CPL'36) in patients experiencing acute schizophrenia. CNS Drugs. 2026;40(9):1295-1305.

2. Fujishige K, Kotera J, Omori K. Striatum- and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A. Eur J Biochem. 1999;266(3):1118-1127.

3. Fujishige K, Kotera J, Michibata H, et al. Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem. 1999;274(26):18438-18445.

4. Menniti FS, Chapple TA, Schmidt CJ. PDE10A Inhibitors—clinical failure or window into antipsychotic drug action? Front Neurosci. 2021;14:600178.