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

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.