PDE-10A Inhibitor For Huntington Disease Found Safe, Not Efficacious

Article

A phase 2 trial demonstrating a PDE-10A inhibitor to be safe but not efficacious for Huntington disease could be followed with the testing of a higher dose.

Dr Marielle Delnomdedieu

Marielle Delnomdedieu, PhD, the senior director of Neuroscience Clinical at Pfizer Pharmaceuticals

Marielle Delnomdedieu, PhD

Results from a phase 2 trial of an investigational agent for Huntington disease (HD) were presented at the International Congress of Parkinson’s Disease and Movement Disorders after the trial was discontinued for lack of efficacy.1

The AMARYLLIS trial, conducted by Marielle Delnomdedieu, PhD, the senior director of Neuroscience Clinical at Pfizer Pharmaceuticals, and colleagues, did demonstrate that the agent, a phosphodiesterase-10A (PDE-10) inhibitor (PF-02545920), was generally safe and that it appeared to have some beneficial effect.

The investigators suggest that there could still be a role for the PDE-10 inhibitor for HD and that further testing with higher dosage could be warranted.

"This study did not provide evidence of efficacy in primary or secondary clinical endpoints, but rater-independent improvements in pre-specified [quantitative motor] measures suggested proof-of-concept for a dose-dependent central effect on motor coordination of unknown clinical significance," the investigators reported. "Exploration of higher doses possibly in earlier stages of HD may be considered."

The rationale for investigating a PDE-10A inhibitor in HD is based on a determination that degeneration of striatal medium-spiny neurons underlies the corticostriatal dysfunction in HD. As PDE-10A is an intracellular signaling regulator that is preferentially expressed in medium-spiny neurons, inhibition of the enzyme could be expected to increase corticostriatal function, and possibly improve HD.

The manufacturer originally investigated PF-02545920 for use in schizophrenia. The inhibition of PDE-10A is linked to increased cAMP/PKA signaling in the basal ganglia, which in turn leads to potentiation of dopamine D1 receptor signaling and concomitant inhibition of dopamine D2 receptor signaling.

In the double-blind, placebo-controlled AMARYLLIS trial of the agent for HD, Delnomdedieu and colleagues identified 272 subjects with genetically confirmed, symptomatic HD in stages 1-II (Unified Huntington's Disease Rating Scale Total Motor Score [UHDRS-TMS] ≥10) and without neuroleptic treatment. In total, 216 subjects completed the 26-week trial after random assignment to receive either 5 mg (n = 79) or 20 mg (n = 56) of active medication, or placebo (n = 81).

The agent failed to demonstrate superiority over placebo on either the primary outcome of improvement on UHDRS-TMS, or secondary efficacy assessments with the UHDRS-Total Maximum Chorea Score or the Clinical Global Impression of Improvement (CGI-I). As noted, pre-specified exploratory Q-Motor measures did show consistent, and dose-dependent improvements.

Adverse events (AEs) were characterized as mild or moderate, occurring more frequently (90%) with the 20-mg dose (90%) than with 5-mg (86%) or with placebo (72%). The most common treatment-emergent AEs were somnolence, fatigue, and weight loss. Discontinuation rates from AEs were higher with the 20-mg dose (26%) than with 5-mg dose (14%) or placebo (6%). Serious AEs were not dose-related and emerged at a rate of <10% across groups.

"Despite the negative outcome, we've learned a great deal about HD and PDE10. The trial data will be a rich resource for HD research," Delnomdedieu remarked in comments at the time of the trial’s discontinuation to a co-investigator, Edward Wild, PhD, Principal Clinical Research Associate Neurodegenerative Diseases, UCL Queen Square Institute of Neurology.2

REFERENCES

1. Delnomdedieu M, Tan Y, Ogde A, Berger Z, Reilmann R. A randomized, double-blind, placebo-controlled phase II efficacy and safety study of the PDE10A inhibitor PF-02545920 in Huntington Disease (AMARYLLIS). Presented at: 2018 International Congress of Parkinson's Disease and Movement Disorders; Hong Kong; October 7, 2018. mdsabstracts.org/abstract/a-randomized-double-blind-placebo-controlled-phase-ii-efficacy-and-safety-study-of-the-pde10a-inhibitor-pf-02545920-in-huntington-disease-amaryllis.

2. Wild E. Pfizer Amaryllis trial ends in disappointment: no improvement in Huntington's disease symptoms. HD Buzz website. hdbuzz.net/229. Published December 16, 2016. Accessed October 24, 2018.

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