Pridopidine Shows Clinically Meaningful Results in Huntington Disease for Patients Not on Neuroleptics, Chorea Medications


Q-Motor, an objective measure of motor function, showed robust beneficial effects for individuals treated with pridopidine in PROOF-HD at various time points.

Andrew Feign, MD, professor, Department of Neurology, NYU Grossman School of Medicine

Andrew Feign, MD

Findings from the phase 3 PROOF-HD study (NCT04556656) showed that pridopidine (Prilenia), an investigational agent in development for Huntington disease (HD), did not meet its primary end point; however, investigators observed improved clinical outcomes among patients not taking neuroleptics and/or chorea medications.

These data were presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, by lead investigator Andrew Feign, MD, professor, Department of Neurology, NYU Grossman School of Medicine. All told, pre-specified analyses that excluded patients on neuroleptics and/or chorea medications resulted in beneficial effects on multiple end points of overall progression, motor, and cognition. Feign noted that additional analyses are currently ongoing.

The main study included a 6-week screening period, 2-week titration period, 53-week double-blind, full-dose treatment period, followed by a 2-week follow-up. A total of 500 individuals with HD were randomly assigned 1:1 to pridopidine, a highly selective and potent sigma-1 receptor (S1R) agonist, in doses of 45 mg BID, or placebo. Patients in the trial had CAG repeats of more than 36, Unified Huntington’s Disease Rating Scale (UHDRS)-IS levels of less than 90%,and were allowed antipsychotic, antidepressant, chorea, or other psychotropic medications.

In total, 458 (91.8%) patients completed 65 weeks of treatment. In the modified intend-to-treat population, pridopidine showed no favorable benefit over placebo in change of Total Functional Capacity (THC), a composite of the primary end point UHDRS. At 26 weeks, pridopidine showed a beneficial effect vs placebo on TFC (Δ 0.55; P = .058), but showed an even greater effect when excluding neuroleptics (Δ 0.86; P = .02).

In the whole sample, which included those taking neuroleptics and/or chorea medications, investigators observed mean difference of change of –44.4 ms (P = .03) on Q-Motor pronation supination inter-tap-interval (ITI) between pridopidine and placebo groups. When excluding neuroleptics, pridopidine showed a stronger effect, as demonstrated by differences of ­–69.3 ms (P = .02) at 52 weeks.

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"The potential represented in these preliminary results warrants further investigation of pridopidine given the highly complex nature of HD, the 100,000 patients affected by it worldwide, and the lack of an approved treatment that slows its clinical progression," Feign said in a statement. "PROOF-HD marks the first time in HD that we have had a study suggest benefit on multiple important clinical measures, including progression, cognition, and motor findings."

When excluding both neuroleptics and chorea medications, investigators observed Q-Motor pronation supination ITI mean differences of Δ –23.92 ms (P = .039) between the placebo and pridopidine groups. Exclusion of these patients also led to greater differences in cUHDRS change. Statistically significant differences were seen at weeks 26 (Δ 0.38; P = .0147), 39 (Δ 0.48; P = .0085), and 52 (Δ 0.37; P = .06), with nominal differences seen at week 65 (Δ 0.17; P = .4).

Similar findings were observed for Stroop Word Reading Test (SWR), a secondary end point of cognition, when excluding neuroleptics and chorea medications. Investigators observed statistically significant differences between the 2 groups at week 65 (Δ 1.53; P = .44), with the greatest difference observed at week 39 (Δ 3.87; P = .03).

"We are pleased to see initial results of PROOF-HD that suggest pridopidine provided meaningful benefits to certain HD patients,” Michael Hayden, chief executive officer and founder of Prilenia, said in a statement.2 "While of course we are not satisfied by not reaching the primary endpoint of this study, PROOF-HD has provided key findings that will be important to patients and families with HD and offer hope for progressing pridopidine for this devastating illness."

Click here for more coverage of AAN 2023.

1. Feign A, et al. PRidopine outcome on function in HD: preliminary topline results. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Clinical trials plenary session PL5.
2. Prilenia shares preliminary topline results from phase 3 PROOF-HD clinical trial in Huntington’s disease and data from phase 2 HEALEY ALS platform trial of pridopidine at the 75th American Academy of Neurology (AAN) Annual Meeting. News release. April 25, 2023. Accessed April 27, 2023.
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