Prilenia Therapeutics – Pridopidine

Background

Pridopidine is an orally administered small molecule that crosses the blood-brain barrier, reaching the brain, and binds to the dopamine D2/D3 and sigma-1 (S1R) receptors. Pridopidine is owned by Prilenia, who describes it as a potent and selective S1R agonist (activator) that rebalances calcium, which reduces intracellular (endoplasmic reticulum) stress, and restores synaptic function. These actions collectively contribute to the hypothesized neuroprotective effects of pridopidine, potentially restoring connectivity between neurons and maintaining their viability (Ref: Gracehv, Meyer et al., 2020; Waters et al., 2018; Prilenia Therapeutics website).

Preclinical studies have shown beneficial effects of pridopidine in cellular and mouse models of several neurodegenerative disorders (Ryskamp et al., 2019). It was originally studied as a treatment for Huntington’s Disease. However, given its characteristics it was thought to potentially also have an effect on ALS/MND disease mechanisms. In SOD1 mice pridopidine showed improvement of motor symptoms but no effect on overall survival (Ref: Estévez‐Silvaet al., 2022; Alzforum).

Trial Design and Results

In 2022, a phase 2/3 clinical trial was conducted through the HEALEY platform in 163 people with ALS/MND. The trial was randomized at a 3:1 ratio to receive active pridopidine or a matching placebo. It was a 6-month, double-blind, placebo-controlled study that rolled over into an open label extension (Ref: Quintana et al., 2023).

The drug or placebo were administered orally twice a day. The measured primary endpoint was change from baseline through 24 weeks in the total ALS functional rating scale revised (ALSFRS-R) score (Ref: Shefner et al., 2024).

In February 2023, a press release from the Healey & AMG Center and the Northeast ALS Consortium (NEALS) indicated that the primary endpoint was not met; however, pridopidine was considered safe and well tolerated. A post hoc analysis revealed that within a very small subset of participants, with definite or probable ALS/MND combined with being early, fast progressors (pridopidine n=20; placebo n=14), those treated with pridopidine had less decline in speech. Additional post hoc analyses in the same subgroup demonstrated ALSFRS-R (Δ5.2, p=0.04) and quality of life measures that favoured pridopidine over placebo (Ref: Shefner et al., 2024). While these results are potentially intriguing, it is important to note that post hoc data from small subgroups can be misleading and require confirmation in larger studies. Furthermore, the SAC feels there has been unclear communication regarding these results and, until the data is released publicly and a larger phase 3 trial is completed, it is not possible to understand if these changes represent a real effect of pridopidine on disease progression.

A global phase 3 clinical trial for pridopidine in ALS/MND has been announced. The trial, scheduled to start in 2025, will examine the effectiveness of pridopidine in ALS/MND on a larger population (Ref: Studna 2024).

Summary

Data shows that pridopidine appears safe and well tolerated at the therapeutic dose. The efficacy of pridopidine was tested through the HEALEY ALS platform but did not meet its primary endpoint (Ref: Neurology live, 2023). Post hoc analyses from the trial suggests there may be some potential benefit to speech, quality of life, and ALSFRS-R score. Due to the very small subset of participants used in these analyses, this potential benefit should be interpreted with caution.

The Scientific Advisory Council believes that, to date, there is insufficient evidence to conclude that pridopidine provides any clinical benefit to people living with ALS and looks forward to the results of the Phase 3 clinical trial that will provide clearer evidence for/against its efficacy.