Results from the phase 3 PROOF-HD trial presented at the 2025 American Academy of Neurology Annual Meeting in San Diego reveal that pridopidine shows significant benefits for Huntington's disease (HD) patients, particularly those not taking antidopaminergic medications (ADMs).
The investigational therapy, developed by Prilenia Therapeutics, demonstrated sustained positive effects on clinical progression, cognition, and motor function in this patient subgroup for up to two years, potentially offering new hope for managing this devastating neurodegenerative condition.
Significant Benefits in Non-ADM Patients
Dr. Andrew Feigin, Chief Medical Officer at Rho, Inc. and adjunct professor of neurology at New York University Grossman School of Medicine, presented the prespecified subgroup analysis focusing on HD patients not taking ADMs—approximately 50% of trial participants.
"Literature in HD and several large observational studies show that ADMs can be associated with worse function, clinical progression, and cognitive performance," Dr. Feigin explained during his presentation. "The presence of ADMs seems to mask the beneficial effects of pridopidine."
The PROOF-HD trial (NCT04556656) confirmed this observation, showing that patients in the placebo group who were taking ADMs performed worse over the 78-week study period compared to those not on ADMs.
Trial Design and Patient Population
PROOF-HD was a randomized, double-blind, placebo-controlled phase 3 clinical trial that enrolled 499 patients with HD. Participants were randomly assigned to receive either 45 mg of pridopidine (n=250) or placebo (n=249), both administered twice daily.
To qualify for the study, patients needed:
- A diagnosis of HD based on clinical features and ≥36 CAG repeats in the huntingtin gene
- A diagnostic confidence level of 4
- Stage 1 or 2 HD with a Total Functional Capacity score of ≥7 at screening
- Adult-onset HD with symptoms beginning at age 18 or older
The randomized controlled phase (RCP) was followed by a 26-week open-label extension (OLE), allowing some patients to receive pridopidine for a total of 104 weeks (2 years).
Meaningful Clinical Improvements
While pridopidine did not meet primary and secondary endpoints in the full analysis, the prespecified subgroup analysis revealed significant benefits in patients not taking ADMs:
At one year, pridopidine demonstrated significant improvements compared to placebo in:
- Composite UHDRS (cUHDRS) with a difference of 0.43
- Stroop Word Reading (SWR) test with a difference of 4.22
- Q-Motor finger tapping inter-onset interval with a difference of -22.84
These benefits were maintained through the 104-week mark (including the open-label extension). Compared to propensity score weighted controls from the Enroll-HD and TRACK-HD clinical trials, pridopidine showed:
- cUHDRS improvement (difference of 1.48)
- Total Functional Capacity improvement (difference of 1.01)
- SWR improvement (difference of 7.9)
- Q-Motor finger tapping inter-onset interval improvement (difference of -110.0ms)
- Total Motor Score improvement (difference of -4.4)
Mechanism of Action and Safety Profile
Pridopidine is a selective and potent sigma-1 receptor (S1R) agonist administered orally. It is currently under development not only for HD but also for amyotrophic lateral sclerosis and other neurodegenerative diseases.
Importantly, Dr. Feigin noted that "the safety and tolerability of pridopidine was comparable to placebo in the PROOF-HD trial, and importantly, the positive effects of pridopidine were maintained with lower doses of ADMs."
Implications for HD Treatment
Huntington's disease is a rare neurodegenerative disorder causing progressive decay of brain nerve cells, leading to movement disorders, cognitive decline, and psychiatric complications. With no current cure available, treatments that can slow disease progression and manage symptoms are critically needed.
The sustained benefits of pridopidine observed in this study—particularly in patients not taking ADMs—represent a potentially significant advancement in HD management. The drug's ability to slow clinical progression while maintaining a favorable safety profile makes it a promising candidate for further development.
As research continues, pridopidine may offer new hope for patients with HD, a condition where therapeutic options have been limited. The findings suggest that careful consideration of concomitant medications, particularly ADMs, may be important in optimizing treatment outcomes for HD patients in the future.
