AAN 2025: Pridopidine Shows Sustained Benefits on Progression, Cognition, and Motor Function in Patients With HD

In patients with Huntington disease (HD), pridopidine (Prilenia Therapeutics) demonstrated benefits on clinical progression, cognition, and motor function in patients who were not taking antidopaminergic medications (ADMs), according to study results presented at the 2025 American Academy of Neurology Annual Meeting in San Diego, California. Additionally, these positive effects were observed long-term, with pridopidine showing sustained efficacy for up to 2 years in patients.

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Currently, pridopidine is an investigational therapy that is undergoing development for HD, amyotrophic lateral sclerosis, as well as other neurodegenerative diseases. It is a selective and potent sigma-1 receptor (S1R) that is administered orally. HD is a rare neurodegenerative disease that causes nerve cells in the brain to decay over time, leading to movement, cognitive, and psychiatric complications. There is currently no cure; therefore, treatments are needed to help patients manage their symptoms and improve their overall quality of life, said presenter Andrew Feigin, MD, chief medical officer at Rho, Inc., and adjunct professor of neurology at New York University Grossman School of Medicine.

“Today, I'm going to be speaking about the prespecified subgroup analysis that we had in the protocol for patients who are not on ADMs. Many patients with these are treated with either neuroleptics or with VMAT inhibitors, and for reasons which I'll get into, we prespecified an analysis for the subgroup of patients in the trial who are not on ADM, roughly about 50% of the patients in the trial,” explained Feigin during the presentation. “So, what was the justification for having this prespecified analysis for patients not taking ADMS? Well, literature in HD…shows that ADMs can be associated with worse function, clinical progression, and cognitive performance, and so, and I will show you today, that the placebo group within the PROOF-HD trial confirmed that patients in the placebo group who are on ADMS performed less well over the course of 78 weeks [compared with] patients who were not on ADMS.”

PROOF-HD (NCT04556656) is a randomized, double-blind, placebo-controlled phase 3 clinical trial that enrolled patients with HD to assess the efficacy and safety of pridopidine compared with placebo. To be included in the study, according to Feigin, patients must have a diagnosis of HD based on clinical features and the presence of 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, a diagnostic confidence level of 4, stage 1 or 2 HD with a Total Functional Capacity score of 7 or higher at screening, and adult-onset HD with signs and symptoms beginning at 18 years or older. In the randomized controlled phase (RCP) of the trial, a total of 249 patients were randomly assigned to receive either 45 mg of pridopidine (n = 250) or placebo (n = 249), both of which were administered twice per day.

The primary end point was change from baseline in the Unified Huntington Disease Rating Scale-Total Functional Capacity (UHDRS-TFC) score in both the modified intention to treat (mITT) and ITT subgroups. The secondary end point was the change in the composite UHDRS (cUHDRS) total score.

“Following the double-blind phase of the trial, there was a 26-week open-label [extension] phase of the trial, and it's important to mention that patients continued in the double-blind phase until 78 weeks, until the last patient completed 65 weeks for the final end point,” explained Feigin. “So, there was a substantial number of people in the trial who [were] on pridopidine for 78 weeks, plus 26 weeks of the OLE, [which is a total of] 104 weeks or 2 years.”

The investigators confirmed that in the PROOF-HD trial, patients taking ADMs while receiving treatment with placebo had statistically worse outcomes when compared with patients who were not taking ADMs while receiving placebo. Further, pridopidine without ADMs demonstrated clinically meaningful cUHDRS benefits in patients of about 0.26 to 0.60 points, slowing decline, compared with patients receiving placebo without ADMs. Additionally, these benefits were also observed in cognitive and motor scales in the same population.

In the OLE analyses, pridopidine continued to demonstrate persistent beneficial effects in patients with HD who were not taking ADMs, according to Feigin. Specifically, persistent effects were shown in cUHDRS at week 104, or 2 years (week 26 of the OLE phase), as well as TFC, Q-Motor FT IOI, and SWR. These were present in the pridopidine-to-pridopidine group and were comparable to the propensity-matched controls as shown in the Enroll-HD and TRACK-HD clinical trials.

These positive and sustained effects of pridopidine on clinical progression, cognition, and motor function in patients with HD not taking ADMs is significant, noted Feigin. In a landscape in which HD has no curative options, it is imperative that there are strong therapeutic agents that can slow the progression of HD-related complications.

“I didn't show you the safety and tolerability data,” acknowledged Feigin at the presentation’s conclusion, “but I can tell you that the safety and tolerability of pridopidine [were] comparable to placebo in the PROOF-HD trial, and importantly, the positive effects of pridopidine were maintained with lower doses of ADMs.”

REFERENCE

Feigin A. Clinical Trials Plenary Session—The Phase 3 PROOF-HD Trial Demonstrates Meaningful Benefits of Pridopidine on Function, Cognition, and Motor Signs in Huntington's Disease. Presented at: American Academy of Neurology Annual Meeting; San Diego, California. April 5-9, 2025.