Phase 3 clinical trial of pridopidine in

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On the heels of promising HEALEY-ALS Phase 2 trial data, Prilenia Therapeutics plans to launch a pivotal Phase 3 study of pridopidine, its candidate amyotrophic lateral sclerosis (ALS) treatment, in the second half of this year.

Relative to a placebo, pridopidine was associated with slower disease progression, a better life quality, and a potential to prolong survival in patients in early disease stages. These recently diagnosed ALS patients with rapidly progressing symptoms saw particular benefit in terms of respiratory health and speech, although better speech was evident across all treated patients.

Prilenia reports it has completed discussions with global regulatory agencies regarding the next stage of pridopidine’s development.

“Based on the clinical data generated to date, pridopidine has the potential to become a meaningful treatment for ALS,” Michael R. Hayden, PhD, a physician, and CEO and founder of Prilenia, said in a company press release.

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“We believe it is important for Prilenia to advance our clinical program in ALS, and we are actively planning a single, global, pivotal Phase 3 clinical trial,” Hayden said.

Pridopidine is an oral small molecule designed to selectively bind to and activate the sigma-1 receptor (S1R), a protein involved in several processes critical to the function and survival of nerve cells.

Essentially, pridopidine aims to slow ALS progression by boosting the clearance of toxic molecules, increasing energy production, reducing cellular stress, and limiting inflammation.

The HEALEY ALS (NCT04297683) platform trial is designed to simultaneously evaluate multiple experimental ALS treatments against a shared placebo group. It is being led by researchers at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in Boston.

The Phase 2/3 pridopidine arm (NCT04615923) enrolled 163 adults with clinically possible, probable, or definite ALS, whose symptoms had started within the last three years.

Participants were randomly assigned to oral pridopidine (45 mg) or a matched placebo taken twice daily for 24 weeks, or about six months. This was followed by an open-label extension study, where all participants received pridopidine.

The pridopidine trial failed to meet its main goal of demonstrating that treatment could slow functional decline relative to a placebo, reflected by changes in ALS Functional Rating Scale-Revised (ALSFRS-R) scores. Secondary goals related to muscle strength, respiratory function, and survival also were not met.

However, pridopidine led to significant improvements in certain speech measures, including speaking rate (how fast a person can speak) and articulation rate, or how quickly and clearly someone pronounces a word, after six months.

Additional analyses indicated that pridopidine’s use slowed ALSFRS-R declines in a subgroup of patients with definite ALS who were in an early disease course — within 1.5 years of symptom onset.

These patients experienced a significant, 2.4-point slower decline in ALSFRS-R scores compared with those given a placebo. Pridopidine was particularly effective at slowing changes on the ALSFRS-R respiratory domain, mainly on questions related to shortness of breath (dyspnea).

Early ALS patients also experienced significantly slower declines in overall life quality compared with a placebo, with particular benefits in the eating/drinking and communication domains.

Particular benefit seen in HEALEY trial for those with fast progression

Even greater benefits were observed in the subset of probable or definite ALS patients who were early in the disease course but also considered to have fast-progressing disease. In this group, pridopidine was associated with a significant slowing of ALSFRS-R declines starting at week eight of treatment, and with a 5.2-point difference from a placebo after 24 weeks, corresponding to a 41% slower decline.

This subgroup of early, fast-progressing patients also showed the greatest improvements relative to a placebo in terms of changes on the ALSFRS-R respiratory domain, dyspnea, and speech.

Survival analyses spanning the main trial and its extension phase showed that pridopidine may increase survival time for those with definite or probable ALS in early disease phases.

Specifically, participants treated with pridopidine from the main trial’s start experienced a median survival of about 600 days (around 1.5 years), compared with a 300-day median survival for patients first randomized to a placebo, amounting to a 57% lower risk of death.

Pridopidine also was well tolerated with no serious treatment-related side effects reported.

Support for pridopidine’s continued development also may come from an ongoing expanded access program. This study, (NCT06069934), is enrolling about 200 ALS patients in the U.S. who are not eligible to participate in clinical trials of pridopidine, all of whom will receive the therapy for up to two years.

“Our sincere appreciation to the many ALS patients, caregivers and healthcare providers who have contributed so much to our clinical studies as well as to those who will participate in future trials,” Hayden said.

Pridopidine has been designated an orphan drug in the U.S. and Europe for the treatment of ALS, a status that intends to help speed its clinical development. Prilenia is also developing pridopidine for Huntington’s disease.

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