Background

Pridopidine, formerly called huntexil, is a selective agonist of the sigma1 receptor, a molecular chaperone located in the endoplasmic reticulum in association with mitochondria. Sigma1Rs are highly expressed in the central nervous system, and regulate calcium signaling, ion channel function, and the ER stress response. In various experimental systems, sigma1R agonists have been reported to be neuroprotective by improving mitochondrial function and neurotropic signaling, clearing toxic proteins, and decreasing neuroinflammation. The companies NeuroSearch and then Teva Pharmaceuticals originally began developing pridopidine for Huntington’s disease; Prilenia took over the program in 2018.

In preclinical work, pridopidine was studied extensively in cell-based mouse models of Huntington's, and was also reported to show beneficial effects across models of ALS, Parkinson's, and Alzheimer's diseases (reviewed in Ryskamp et al., 2019). For example, in the PS1 knock-in mouse model of Alzheimer's, pridopidine rescued synaptic damage induced by Aβ42 (Ryskamp et al., 2019). It promoted synaptogenesis in primary neurons and improved spatial memory in APP/PS1 transgenic mice; it increased BDNF availability in a microfluidic model of striatal neurons, and it modified the disease phenotype but did not extend survival in an ALS mouse model  (Estevez-Silva et al., 2022; Lenoir et al., 2022; Estevez-Silva et al., 2022). Effects facilitating autophagy in cell-based models have been reported, as well, as have effects on endoplasmic reticulum stress, and neuroprotective effects on retinal ganglion cells in glaucoma models (Wang et al., 2023; Shenkman et al., 2021; Geva et al., 2021).

Other compounds with sigma1R agonist activity are in clinical trials for Alzheimer's disease; they include blarcamesine, edonerpic, and the dextromethorphan formulations AVP-786, AVP-923, and AXS-05.

Pridopidine was originally postulated to act through dopamine receptors, and was therefore developed initially for the treatment of motor symptoms in HD. However, in vitro binding assays, as well as studies in preclinical models, showed its effects occur specifically through sigma1Rs (e.g., Ryskamp et al., 2017). In a human PET imaging study, at clinical doses, pridopidine selectively occupied a large fraction of sigma1Rs in the brain, and not D2/D3 receptors (Grachev et al., 2020).

Findings

Based on its dopaminergic activity, pridopidine was originally tested to treat symptoms of Huntington’s disease. In a Phase 2 study of 58 patients, four weeks of 50 mg/day improved voluntary motor symptoms, including balance, gait, and hand movements, compared to placebo (Lundin et al., 2010). The drug was deemed safe and well-tolerated.

Between 2008 and 2010, TEVA ran two larger studies. Beginning in April 2008, the Phase 3 MermaiHD trial compared six months of 45 or 90 mg pridopidine daily to placebo in 437 people with HD. The primary outcome was a modified motor score comprising a subset of items from the Unified Huntington Disease Rating Scale Total Motor Score that focused on voluntary movements. The Phase 2/3 HART study began in October 2008 to test doses of 10, 22.5 or 45 mg twice daily for 12 weeks against the same primary outcome of the modified motor score. In both studies, pridopidine was well-tolerated up to 90 mg, but did not affect the modified motor score (de Yebenes et al., 2011; Huntington Study Group, 2013). Both studies detected a three-point, nominally significant, improvement in the pre-specified endpoint of the UHDRS Total Motor Score with treatment.

An open-label extension to HART enrolled 118 people to receive 45 mg twice a day for up to five years. After three years, participants had declined in motor function as seen in previous observational studies (McGarry et al., 2017). At four and five years, 40 and 33 participants remained, respectively. Their total motor and functional scores stabilized, i.e., did not show the decline expected from historical controls (McGarry et al., 2020).

In February 2014, TEVA began PRIDE-HD, a 6-month Phase 2 trial testing higher doses of pridopidine, using the UHDRS-TMS as a primary outcome. The study included an open-label extension that ran for up to 2 years. The PRIDE-HD study compared twice-daily doses of 45, 67.5, 90, or 112.5 mg to placebo in 408 people with HD. Treatment was originally planned for six months, but a mid-trial change in protocol extended the placebo-controlled period to one year, and added UHDRS-Total Functional Capacity (TFC), which is measured annually, as a secondary endpoint to measure disease progression. The UHDRS-TFC is a 13-point scale that encompasses ability to work, handle finances, do domestic chores and activities of daily living, and care level. 

A peer-reviewed paper reported no statistically significant effect compared to placebo of any dose on the primary motor symptoms outcome at six months; all dose groups showed numeric improvement from baseline (Reilmann et al., 2019). Serious adverse events seen most frequently in the pridopidine groups were falls, suicide attempts or ideation, head injury, and aspiration pneumonia. No dose response was observed. One death in the highest-dose group due to aspiration pneumonia was considered possibly related to study drug. On the functional outcome, the TFC showed a benefit for 45 mg pridopidine twice daily at one year in all randomized patients (p=0.0032). Post hoc analysis indicated the effect on TFC was strongest in the patients with early HD (TFC 7-13 p=0.0003) (McGarry et al., 2020). A safety analysis of electrocardiograms taken during this trial reported a concentration-dependent effect of pridopidil on QT-interval, but noted a favorable cardiac safety profile at the therapeutic dose of 45 mg twice daily (Darpo et al., 2023).

In October 2020, Prilenia started PROOF-HD. This Phase 3 trial compared 65 weeks of 45 mg twice-daily pridopidine to placebo in 480 people with early HD defined as a line UHDRS-TFC of seven or greater. The primary endpoint was change from baseline in UHDRS-TFC. The trial missed its primary endpoint, according to an April 2023 press release of top-line results. The company claimed effects of pridopidine were reduced by the concomitant use of Huntington’s medications. More results were presented at the May 2023 American Academy of Neurology annual meeting (news report).

Pridopidine was also tested to treat ALS, as part of the Phase 2/3 Healey Platform. This multicenter trial is testing four investigational treatments in a parallel, standardized platform protocol. In December 2020, the study began to enroll 160 participants in the pridopidine arm; they will be randomized to 24 weeks of 45 mg twice daily pridopidine or placebo in a 3:1 ratio. The primary outcome is disease progression measures on the ALS Functional Rating Scale-Revised. Secondary measures include changes in the ability to talk or swallow, respiratory function, muscle strength, and survival. On February 23, 2023, the company announced negative top-line results (press release). Pridopidine did not significantly change the primary endpoint of ALSFRS-R total score, or key secondary endpoints. The company claimed that the drug did slow decline on the ALSFRS-R, and decrease  neurofilament light concentrations, in a subset of faster-progressing patients early in disease. Pridopidine improved quantitative speech measures in the group as whole. An open-label extension continues.

In July 2021, the FDA granted pridopidine orphan drug status for ALS (company press release). Meta-analyses are starting to compile pridopidine trial results (Mostafa Asla et al., 2021; Chen et al., 2021). 

In May 2019, a Phase 2 study evaluating two doses of pridopidine for its effect on levodopa-induced dyskinesia in Parkinson's disease began enrolling for its target population of 135 (McFarthing et al., 2019). It had enrolled 23 participants when it was terminated in November 2020 due to the COVID pandemic; results are posted on Clinicaltrials.gov.

For details on pridopidine trials, see clinicaltrials.gov.