The research, “Safety and efficacy of pridopidine in patients with Huntington’s disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study,” appeared in The Lancet Neurology.
Teva Pharmaceuticals’ Huntexil is a type of compound called dopamine stabilizer because it regulates dopamine-dependent behaviors. It has high affinity for the sigma-1 receptor (S1R) chaperone protein, which is believed to be implicated in several cellular pathways impaired in Huntington’s and other neurodegenerative diseases.
S1R affects neuroprotection by increasing the production of brain-derived neurotrophic factor (BDNF), whose levels are reduced in people with Huntington’s. Through its binding to S1R in the brain, Huntexil may ultimately increase BDNF production.
Two prior clinical trials — MermaiHD (NCT00665223) and HART (NCT00724048) — showed that twice daily Huntexil 45 mg led to small, but consistent, motor improvements compared to placebo, as assessed with the Unified Huntington’s Disease Rating Scale (UHDRS)-total motor score (TMS). Of note, TMS assesses eye movements, dysarthria (slurred or slow speech), tongue protrusion, voluntary hand function, involuntary motor signs, and gait. All Huntexil doses — up to 45 mg — were generally well-tolerated and safe over a maximum of three years.
These results prompted the team to conduct the Teva-sponsored PRIDE-HD Phase 2 study (NCT02006472) to assess whether higher Huntexil doses than those previously used would ease Huntington’s motor symptoms, while maintaining a positive safety profile.
The international, multi-center, double-blind dose-ranging study included patients 21 years of age or older, randomized to either placebo or the treatment candidate twice daily (three capsules in the morning and three more in the afternoon) for one year. All patients included had Huntington’s disease onset when adults, 36 or more CAG repeats in the HTT gene (the hallmark genetic alterations in people with Huntington’s), a minimum UHDRS-TMS score of 25 points, and reduced independence – meaning a UHDRS independence score not greater than 90%.
The full analysis set included 397 patients, 81 of whom received placebo while the remaining were treated with Huntexil — 75 with 45 mg, 79 with 67.5 mg, 81 with 90 mg, and 81 with 112.5 mg. Huntexil’s dose had been adjusted gradually over the initial four weeks. Mean age of the 408 enrolled patients ranged from 47.5 years in those receiving 112.5 mg of Huntexil, to 51.9 in patients receiving 45 mg of the investigational treatment.
Treatment with any dose of Huntexil failed to provide significant motor benefits over placebo at both weeks 26 and 52. Scores of a modified physical performance test, which addresses activities of daily living, also revealed no differences.
Of note, a large placebo effect was found in TMS, a common finding in trials of Huntington’s possibly due to high expectations of participants and investigators, researchers noted. This may have precluded detection of motor benefits with Huntexil.
At 52 weeks, Huntexil showed a benefit in function, as assessed by total functional capacity scores. This was observed only with the 45 mg dose and was most evident in the early clinical stages of Huntington’s. However, the scientists cautioned this effect may have been due to chance and needs to be replicated.
All Huntexil doses were well-tolerated, with most adverse events (AEs) being mild or moderate. The most common across all groups were diarrhea, vomiting, nasopharyngitis (inflammation of the pharynx and nasal cavities), falls, headache, insomnia, and anxiety. In turn, the most frequent treatment-related AEs were insomnia, diarrhea, nausea, and dizziness. A mild dose-dependent increase in heart rate was observed.
Serious AEs were reported only in patients treated with Huntexil and included falls (five), suicide attempt (four), suicidal thoughts (three), head injury (three), and aspiration pneumonia (also three). Although noting that suicidal thoughts and attempts would be expected in this patient population, the scientists said they should be carefully monitored in future studies of Huntexil. Overall, 35 Huntexil-treated patients had at least one serious AE and the therapy led to treatment discontinuation more often than placebo (53 vs. 6).
No new safety or tolerability concerns were found. One man treated with the higher dose of Huntexil died due to aspiration pneumonia, which was considered possibly related to the therapy.
Overall, “pridopidine (Huntexil) does not have detectable motor benefit,” researchers wrote. However, they believe that its positive safety profile and the benefit seen with the lower dose at 52 weeks may warrant further investigations.