Pridopidine shows some potential in HEALEY trial, but misses main goal

Physical gains not always evident, but speech and other benefits merit study

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Pridopidine, an oral small molecule, failed to meet its primary goal of improving physical function across amyotrophic lateral sclerosis (ALS) patients who took part in a Phase 2/3 clinical trial.

Changes in secondary endpoints measuring muscle strength and respiratory function also did not significantly differ between people taking pridopidine and those on a placebo, Prilenia Therapeutics, the therapy’s developer, reported in a press release.

But significant physical benefits were reported in a subset of recently diagnosed patients — within 18 months or 1.5 years — whose ALS symptoms indicated rapidly progressing disease. And all treated patients showed “trends” toward better respiratory health, with significant gains seen in two measures of speech.

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‘Encouraging results’ seen with pridopidine ‘deserve further exploration’

The Phase 2/3 study (NCT04615923) is an arm of HEALEY ALS (NCT04297683), a platform trial where multiple experimental treatments are being tested at the same time against a shared placebo (control) group. It is being led by researchers at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in Boston.

“Pridopidine showed encouraging results for the potential treatment of ALS that deserve further exploration,” said Merit Cudkowicz, MD, principal investigator for HEALEY ALS, director of the ALS center, and chief of neurology at Massachusetts General.

The trial’s open-label extension is ongoing, and Prilenia will share full study data at upcoming scientific meetings.

Cudkowicz particularly saw as “notable” pridopidine’s impact on speech measures. “Speech is a highly clinically relevant endpoint in ALS studies, and more than 80 percent of ALS patients become speech impaired, which significantly impacts their quality of life,” she said.

Pridopidine is designed to act as an agonist, binding to and activating the sigma-1 receptor (S1R). S1R is a protein present at high levels in the brain and spinal cord that, among many roles, is thought to help keep nerve cells healthy.

As an S1R agonist, pridopidine aims to prevent nerve cell loss and improve the connections between these cells that are commonly impaired in neurodegenerative diseases such as ALS.

“Pre-clinical data in mice and other species strongly indicated that S1R activity can mitigate the features of ALS,” said Michael R. Hayden, PhD, CEO and founder of Prilenia. “This study showed for the first time in humans that S1R agonism with pridopidine has the potential to impact ALS.”

The trial enrolled 163 adults with ALS who were randomized to either oral pridopidine at 45 mg or a matching placebo taken twice daily.

Its primary goal was a change in overall physical function, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), from baseline or study start through 24 weeks. Higher scores on this scale reflect better function, indicating slower disease progression. However, changes between treatment and control patients failed to reach significance.

Physical function gains reach significance in recently diagnosed patient group

Among the prespecified group of people recently diagnosed with rapidly progressing and “probable or definitive” ALS, as per El Escorial criteria, patients taking pridopidine showed a significantly lesser decline in physical function (minus 7.51 points for total ALSFRS-R score) than those on a placebo (minus 12.71 points) in post-hoc analyses.

Significant benefits were also seen in speech measures across all treated patients, namely in terms of speaking rate (how fast someone talks) and articulation rate (how quickly and clearly someone sounds out each word), and positive “trends” in respiratory function were evident.

An analysis of neurofilament light (NfL) levels in the recently diagnosed patient group also found an average 40% reduction in the levels of this biomarker of nerve cell loss among treated patients relative to controls at 24 weeks.

Pridopidine was well tolerated, with a safety profile similar to that of the placebo, Prilenia reported.

“This study adds to the growing body of evidence that S1R activation has beneficial neuroprotective effects, and this gives us a compelling rationale for further development of pridopidine in ALS,” Hayden said. “Prilenia intends to continue its evaluation of pridopidine in ALS, and our future clinical program will build on the important learnings from the HEALEY ALS Platform Trial.”

The company holds orphan drug designations for pridopidine in ALS in both the U.S. and Europe, and is exploring next steps for its clinical development.