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SAN DIEGO — The investigational drug pridopidine has demonstrated consistent, sustained, and clinically meaningful improvements in function, cognition, and fine motor skills in patients with early-stage Huntington disease (HD) who are not taking antidopaminergic medications (ADMs) or who are on low doses of these medications.

“These updated data suggest that pridopidine may be beneficial for patients with Huntington’s disease who are either taking low doses of antidopaminergic drugs or not taking these drugs at all,” study investigator Andrew Feigin, MD, adjunct professor of neurology, NYU Grossman School of Medicine, New York City, and chief medical officer, Rho, Inc., told Medscape Medical News.

The findings were presented on April 8, 2025, at the American Academy of Neurology 2025 annual meeting.

Rare, Fatal Disease

HD is a rare, inherited neurodegenerative disorder characterized by uncontrolled movements, cognitive decline, and progressive functional loss and is ultimately fatal. It is caused by a mutation in the huntingtin (HTT) gene, and each child of an affected parent has a 50% chance of inheriting the condition.

The only currently available treatments for HD focus on symptomatic relief and palliative care. No approved therapies affect measures of overall disease progression.

Pridopidine is an oral investigational therapy in development for HD and is not yet approved. It is a potent and selective sigma-1 receptor (S1R) agonist. The S1R protein is highly expressed in the brain and spinal cord where it regulates key processes commonly impaired in neurodegenerative diseases. The activation of the S1R by pridopidine may lead to neuroprotective effects.

The phase 3 Pridopidine Outcome on Function in HD (PROOF-HD) trial was a multicenter, double-blind study that enrolled 499 patients with mild to moderate HD with a Unified Huntington Disease Rating Scale – Total Functional Capacity (UHDRS-TFC) score of 7-13.

Participants were randomly assigned to receive either pridopidine (45 mg oral capsule, twice daily) or placebo for 65-78 weeks, followed by an open-label extension through week 104.

The primary endpoint was the mean change at week 65 in UHDRS-TFC. Secondary endpoints included change at week 65 in measures of TFC, Stroop Word Reading (SWR) test, Total Motor Score, Symbol Digit Modalities test, and the Q-Motor test which uses accelerometers to measure speed and accuracy of movements. Participants were permitted to use ADMs because these medications are considered part of the standard of care.

Key Endpoints Not Met

While the study did not meet its primary or key secondary endpoints, it included a prespecified analysis of participants who were not taking ADMs, which include neuroleptics, antipsychotics, and vesicular monoamine transporter-2 inhibitors.

The rationale for conducting this analysis is that research shows ADMs can be associated with worse function, clinical progression, and cognitive performance in patients with HD, said Feigin.

The key endpoints for the new analysis, which included roughly half of the original cohort, were change in TFC and progression as measured by the composite UHDRS (cUHDRS) which is a composite of four measures, including total motor score, TFC, and two cognitive measures.

“It turns out that the combination of those four elements in a composite score is very sensitive to measuring changes in Huntington’s,” said Feigin.

Results showed that pridopidine showed clinically meaningful benefits in cUHDRS (least square mean differences of 0.26-0.60).

Feigin pointed to the significant improvement with pridopidine compared with placebo in cUHDRS at week 52 (Δ0.43; P = .04).“This delta of.43 is well in excess of what would be functionally meaningful for a patient,” he said.

Slowed Clinical Decline

The consensus, he said, is that a treatment that slows clinical decline of 0.2-.0.3 points per year “is equivalent to about 2.4-3.5 months per year of time saved from progression and can be used to define a clinically efficacious treatment.”

Researchers also found important results for subcomponents of the cUHDRS as well as for separate measures. These included SWR test at week 52 (Δ4.22; P = .02) and Q-Motor finger tapping (FT) inter-onset interval (IOI) at week 52 (Δ-22.84; P = .04).

The Q-Motor FT IOI measures both speed and accuracy of finger tapping and has been found to be sensitive to motor impairment and progression in HD, noted Feigin.

The treatment group showed similar improvement in cUHDRS compared with placebo among patients taking low doses of certain ADMs. Feigin noted that this benefit is not observed in patients taking higher ADM doses.

Researchers also investigated the benefits of pridopidine in terms of progression (cUHDRS), function (TFC), and cognition (SWR) compared with matched cohorts from two longitudinal observational studies, including TRACK-HD, which monitored disease progression over a year in “pre-manifest” patients carrying the HTT gene, those with early HD, and matched control individuals.

Pridopidine demonstrated benefits through week 104 in cUHDRS (Δ1.48; P = .0089), as well as certain cognitive and motor outcomes compared with propensity score weighted control individuals from TRACK-HD.

In clinical studies of the drug to date, pridopidine “has been extremely well tolerated,” said Feigin. “In terms of safety, it was kind of analogous to placebo.”

The company behind the drug (Prilenia Therapeutics) holds Orphan Drug designation for pridopidine in HD and amyotrophic lateral sclerosis in the United States and European Union. Pridopidine has received Fast Track designation by the US Food and Drug Administration for the treatment of HD.

Commenting on the study for Medscape Medical News, Anindita Deb, MD, a neurologist specializing in neuro-movement disorders and associate professor of neurology, UMass Chan Medical School, Worcester, Massachusetts,, said it’s “exciting” to have a drug that may actually slow disease progression.

The new data are promising, said Deb, but her optimism is tempered by the fact the drug was studied in those not taking ADMs. “Many of our HD patients are on these medications for symptom control.”

Doctors should get a better idea of the drug’s impact once they can start using it in their clinical practice, she said.

This study received support from Prilenia Therapeutics. Feigin received grant support for his role as North American Principal Investigator for the PROOF-HD study.Deb reported no relevant conflicts of interest.