AAN 2023: Pridopidine Phase 3 trial misses goal, but benefits seen for some

Potential for slower progression evident in patients not using certain treatments

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An illustration for the AAN conference showing a scientist studying features of a human brain.

The Phase 3 PROOF-HD trial failed to meet its main goal of showing that pridopidine, Prilenia Therapeutics’ experimental therapy, could slow functional decline compared with a placebo for adults with Huntington’s disease.

However, preliminary top-line data indicated a potential slowing of disease progression among patients who were not on other Huntington’s treatments to help manage disease symptoms.

Andrew Feigin, MD, the study’s North American lead principal investigator, discussed these findings at the recent American Academy of Neurology (AAN) annual meeting, in the talk “Topline Results of the PROOF-HD Pivotal Phase 3 Trial: PRidopidine’s Outcome On Function in Huntington Disease.”

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Potential for slower progression ‘warrants further investigation of pridopidine’

Feigin is a professor of neurology at New York University’s Grossman School of Medicine and the chief medical officer for the Huntington Study Group, a cooperative therapeutic research organization focused on the neurodegenerative disease.

“We are pleased to see initial results of PROOF-HD that suggest pridopidine provided meaningful benefits to certain HD [Huntington’s disease] patients,” Michael Hayden, PhD, Prilenia’s CEO and founder, said in a company press release.

“While of course we are not satisfied by not reaching the primary endpoint of this study, PROOF-HD has provided key findings that will be important to patients and families with HD and offer hope for progressing pridopidine for this devastating illness,” Hayden added.

The potential for benefits seen in a select patient group “warrants further investigation of pridopidine,” Feigin said, especially as the disease lacks “an approved treatment that slows its clinical progression.”

Pridopidine is an oral therapy that works by activating sigma 1 receptor, a protein of the brain and spinal cord involved in promoting nerve cell function and survival.

“Activation of the sigma 1 receptor by pridopidine positively influences multiple neuroprotective pathways that we think are relevant to multiple neurodegenerative diseases, and specifically for Huntington’s disease,” Feigin said.

Pridopidine showed promising effects in animal models, and data from a previous Phase 2 trial called PRIDE-HD (NCT02006472) suggested that the therapy may slow functional decline in patients.

Based on these findings, Prilenia launched the Phase 3 PROOF-HD trial (NCT04556656) in collaboration with the Huntington Study Group.

The trial enrolled 499 adults with early-stage Huntington’s at sites across North America and Europe. Participants were randomly assigned to pridopidine (45 mg) or a placebo taken twice a day. A final patient study visit took place in late March.

PROOF-HD’s main goal was to assess whether pridopidine could slow the rate of functional decline, as measured by the Unified Huntington Disease Rating Scale-Total Functional Capacity (UHDRS-TFC) scale, after 65 weeks of treatment.

UHDRS-TFC measures a person’s ability to function independently in life, such as working, managing finances, and handling household chores. Lower scores indicate poorer abilities.

Secondary goals included changes in composite UHDRS scores — which combines scores of certain measures of functional capacity, motor skills, and cognitive skills — as well as in each of these and other measures.

PROOF-HD participants were allowed to continue with stable doses of antipsychotics (also called neuroleptics), antidepressants, and therapies for chorea, or involuntary muscle contractions.

But in the PRIDE-HD trial, analyses suggested that “exposure to neuroleptics, and potentially exposure to anti-chorea meds, dampens the ability … to demonstrate” treatment benefit, Feigin said. As such, PROOF-HD took that into consideration when randomly assigning participants to either regimen and in analyzing the results.

“We felt it would be too difficult to enroll 480 patients … if we excluded people who were on neuroleptics, so we decided to deal with this by stratifying it and then by prespecifying” that data would be analyzed according to medication use, Feigin added.

Less than 10% of PROOF-HD participants left the study early, and nearly everyone who finished the trial’s main and placebo-controlled phase have elected to continue in its open-label extension phase, where all are being treated with pridopidine.

Benefit seen in treated patients not on antipsychotics or chorea therapies

Trial results showed no significant difference in the rate of decline in UHDRS-TFC scores between patients given pridopidine and those on a placebo capsule, failing to meet its main goal.

Analyses excluding patients on antipsychotics or anti-chorea medications found UHDRS-TFC scores tended to be slightly better in pridopidine-treated patients, though again the difference was not statistically significant.

Among those not taking these medications, “you can see … a suggestion that there might be some benefit [of pridopidine], but not statistically significant at any of the timepoints,” Feigin said.

Changes in composite UHDRS scores also did not significantly differ across the entire pridopidine and placebo patient groups.

However, when patients on antipsychotics and/or chorea treatments were removed from the analysis, pridopidine was associated with a significantly slower decline in scores relative to a placebo.

Similar findings were seen for score changes in a measure of motor function called Q-Motor, and on a measure of cognition called the Stroop test.

“Pre-specified analyses excluding patients on neuroleptics and/or anti-chorea medications showed beneficial effects on multiple [measures] including the composite UHDRS, which may reflect the progression of Huntington’s disease,” and in motor and cognitive function, Feigin said.

Safety data supported pridopidine being well tolerated overall, with no reports of serious treatment-related side effects. Two patients on pridopidine died during the study, one of a heart attack a year after stopping pridopidine’s use, and one due to an accident. Neither cause of death was related to treatment.

“These preliminary findings reflect the potential of pridopidine across a variety of important clinical measures, for a large subset of patients in the study,” said Ralf Reilmann, MD, PROOF-HD’s European lead principal investigator.

“The Q-Motor findings in PROOF-HD replicate what was seen in the prior Phase 2 PRIDE-HD study and are highly correlated to [composite] UHDRS and TFC. The totality of these data will hopefully bring pridopidine closer to becoming a new treatment for HD,” Reilmann said.

Prilenia plans to share additional PROOF-HD results at future scientific meetings.

“We are deeply grateful to the global HD community, study investigators, and most importantly, the people who participated in this study and their families for making this important research possible,” Hayden said.