Pridopidine may slow Huntington’s progression for some patients
Trial suggests benefits for those not taking antidopaminergic treatments
Pridopidine may safely and effectively slow Huntington’s disease progression in patients who aren’t taking antidopaminergic medications, which are commonly used for psychiatric symptoms and chorea, or involuntary movements.
That’s according to full results from the Phase 3 PROOF-HD clinical trial (NCT04556656), which tested pridopidine against a placebo in nearly 500 adults in the early stages of Huntington’s.
While the study failed to meet its main goal of showing pridopidine slowed a measure of Huntington’s progression, pre-specified subgroup analyses found statistically significant effects among participants not on antidopaminergic treatments.
The study’s complete results were published in Nature Medicine, in a study titled “Pridopidine in early-stage manifest Huntington’s disease: a phase 3 trial.” The work was funded by pridopidine’s developer, Prilenia Therapeutics, which has announced plans for a new trial aiming to confirm pridopidine’s beneficial effects, with the ultimate goal of supporting applications for its regulatory approval.
“These data provide a clear path forward for next year’s planned global confirmatory study in early HD [Huntington’s disease] patients, aimed at confirming pridopidine’s effect and supporting ongoing global regulatory discussions,” Michael Hayden, PhD, CEO of Prilenia, said in a company press release.
Hope for treatments beyond symptom control
“These results provide hope that there are therapies that can go further than just symptom control, and hope that we can take a step forward toward availability of a disease-modifying treatment able to slow down the inexorable march of this dreadful disease,” said Dina de Sousa, who carries a Huntington’s-causing mutation and is a member of the European Huntington Association board.
Huntington’s is a genetic disorder marked by the death and degeneration of nerve cells in the brain, leading to Huntington’s disease symptoms such as movement problems, psychiatric problems, and cognitive difficulties. No therapy has been proven to slow the progression of Huntington’s, though there are treatments available that can help ease symptoms.
Many of these treatments, including those approved for chorea and antipsychotics used for mental health problems, are antidopaminergic medications (ADMs). These work by suppressing the activity of dopamine, a brain signaling molecule.
Pridopidine is an oral therapy thought to support nerve cell health by activating a protein called sigma-1 receptor.
Prilenia launched the PROOF-HD trial to assess whether pridopidine was superior to the placebo at slowing functional decline in Huntington’s patients, as assessed with the Unified Huntington Disease Rating Scale-Total Functional Capacity (UHDRS-TFC) scale.
Results, however, showed no clinical benefit, failing to meet the study’s main goal. In fact, after slightly more than a year of treatment, average UHDRS-TFC scores worsened slightly more in pridopidine-treated participants than in those on the placebo.
Scores on the composite UHDRS (cUHDRS) — which combines scores from TFC and other measures of motor and cognitive skills — showed no significant difference between the pridopidine and placebo groups. This meant the trial failed to attain its key secondary goal.
Patients were allowed to continue ADMs to help with symptom management during the study. “However, mounting evidence suggests ADM-related side effects may interfere with accurate measures of disease progression, especially in outcomes like cognition and function widely used in HD clinical trials,” the researchers wrote.
To address this potential interference, the trial’s design included pre-specified analyses of data from participants who had not received ADMs at any point during the trial. This included 39.7% of those on pridopidine and 45.3% of those on the placebo.
These analyses showed that the pridopidine group had a significantly lower decline in cUHDRS scores than the placebo group, suggesting slower disease progression.
Score differences between the two groups were 0.41 after one year and 0.27 after slightly more than a year. “Annual reductions in cUHDRS of 0.1–0.3 points have been associated with a clinically meaningful benefit in HD,” the release stated.
The decline in TFC scores also tended to be slower in the pridopidine group. However, this difference did not reach statistical significance, meaning it could be due to random chance.
Trends suggest ‘treatment effect,’ researchers say
A variety of assessments of cognitive and motor function consistently showed trends favoring pridopidine over the placebo, though not all were statistically significant.
“Overall, participants treated with pridopidine in the off-ADM subgroup showed less decline than participants treated with placebo across multiple outcomes, but the subgroup size was limited, and the findings were not powered to support definitive conclusions,” the researchers wrote. “Nonetheless, the consistency of trends across function, motor and cognition suggests a treatment effect.”
Safety data from PROOF-HD were positive overall. There were no reports of serious adverse events related to pridopidine, and fewer than 1% of participants discontinued the trial due to adverse events.
“The published data represents the first Phase 3 HD trial to deliver consistent and meaningful benefits on progression across multiple clinical domains of HD such as function, cognition and motor performance,” said Ralf Reilmann, MD, the study’s first author and the founding director of the George Huntington Institute, in Germany.
Future studies “can now refine patient selection and account for the impact of ADM exposure, which obscured the true drug-related benefits,” Reilmann said. “Appropriate stratification and dosage strategies will control for this [influencing] factor and allow demonstration of pridopidine’s positive treatment effects on clinical progression of symptoms.”
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