Pridopidine shows long-term benefit for some Huntington’s patients
Trial: Therapy continues to slow disease progression in those not taking ADMs
Up to two years of pridopidine treatment continues to slow Huntington’s disease progression among patients not taking certain standard treatments called antidopaminergic medications (ADMs).
That’s according to a new analysis comparing long-term outcomes from pridopidine-treated people with Huntington’s in the Phase 3 PROOF-HD clinical trial (NCT04556656) against data from untreated patients in natural history studies. Significant benefits were seen with pridopidine in terms of functional capacity, motor skills, and cognitive function.
Prilenia Therapeutics and Ferrer, which are codeveloping pridopidine in Europe and certain other markets, presented the findings in a poster at the 2025 HSG HD Clinical Research Congress, held Oct. 10 to 13 in Tennessee.
The companies are already making plans for a new Phase 3 study aiming to confirm the therapy’s effects in this subgroup of Huntington’s patients. The trial is expected to start in the first half of 2026.
“It is clear that the HD [Huntington’s disease] community needs access to new therapies that improve multiple independent clinical [measures] that matter most to people with HD and their families, including function, disease progression, cognition, and motor function,” Oscar Pérez, Ferrer’s chief scientific officer, said in a joint press release from the companies. “We have a carefully designed [road map] aimed at paving the way to availability of pridopidine as an oral and easy to administer disease-modifying therapy capable of significantly slowing down clinical progression of HD.”
Pridopidine activates protein thought to promote nerve cell survival
Huntington’s is a genetic disorder marked by the progressive death of nerve cells in the brain, leading to symptoms such as movement problems, psychiatric issues, and cognitive difficulties. Currently available treatments can help ease Huntington’s symptoms, but none actually slow the disease’s progression.
Pridopidine is an oral therapy that activates the sigma-1 receptor, a protein thought to promote the function and survival of nerve cells. It received orphan drug designation in both the U.S. and European Union, as well as fast track designation in the U.S. for treating Huntington’s. These statuses are meant to speed pridopidine’s clinical development and regulatory review.
PROOF-HD tested the therapy at a dose of 45 mg twice daily against a placebo in nearly 500 adults in the early stages of Huntington’s. The global trial hoped to show that pridopidine slowed the decline in functional abilities as measured by the Unified Huntington Disease Rating Scale-Total Functional Capacity (UHDRS-TFC) scale.
However, results at just over a year showed no difference in UHDRS-TFC scores between participants given pridopidine or a placebo, failing to meet the study’s goal.
Measures of motor, cognitive function indicate slower worsening
Most of PROOF-HD participants were taking ADMs, a class of medications commonly used to manage certain Huntington’s symptoms like mental health problems and chorea, or involuntary movements.
Although ADMs can help ease symptoms, there’s evidence that they can make standardized scales like the UHDRS-TFC less accurate. To account for this, the PROOF-HD study included prespecified analyses that only looked at patients who weren’t taking ADMs.
These analyses showed that those given pridopidine had significantly better scores on the composite UHDRS (cUHDRS), which measures total functional capacity alongside other measures of cognitive and motor skills.
Scores on the UHDRS-TFC and other measures also tended to favor pridopidine over the placebo in people not taking ADMs, though the differences weren’t always statistically significant.
After PROOF-HD’s placebo-controlled portion ended, participants had the option to continue into an open-label portion, where all are being treated with pridopidine and monitored for long-term outcomes.
The newly announced findings come from comparative analyses between two-year data from PROOF-HD’s placebo-controlled and open-label portions and data from external groups of matched, untreated patients in natural history studies.
The data show pridopidine’s ability to deliver consistent and sustained slowing of disease progression and significantly less decline across multiple [measures] of function, cognition, and motor features.
Results showed that, in the subset of patients not taking ADMs, the decline in UHDRS-TFC and cUHDRS scores was significantly slowed, by 65% and 59%, respectively, with long-term pridopidine. Measures of motor and cognitive function likewise indicated a 78% to 88% slower worsening.
“The data show pridopidine’s ability to deliver consistent and sustained slowing of disease progression and significantly less decline across multiple [measures] of function, cognition, and motor features … and compared to both placebo and two natural history [groups], in HD patients not taking antidopaminergic medicines,” said Michal Geva, PhD, Prilenia’s head of research.
Other posters presented at the conference highlighted how ADMs may influence outcomes.
PROOF-HD data demonstrated that the effects of pridopidine were similar between participants taking low doses of ADMs and those not taking ADMs at all, while those taking high-dose ADMs tended to have faster disease progression. This link between high-dose ADMs and worse outcomes was also seen in the placebo group.
These data emphasize the importance of carefully considering how ADMs may affect results when designing Huntington’s trials, the companies said.
Additional PROOF-HD analyses identified factors, such as performance on a finger-tapping task and a score based on age and genetics, that may help predict Huntington’s progression. These findings may help inform future clinical trial design, according to the companies.
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