PRIDE-HD
Pridopidine preserves functional capacity in early Huntington disease: Analysis of 52-week data from the PRIDE-HD study
Clinical Question
Does pridopidine at a dose of 45 mg twice daily preserve functional capacity in early Huntington’s disease over 52 weeks?
Bottom Line
Pridopidine did not improve UHDRS Total Motor Score in HD: -0.7 (45mg BID) vs -0.2 (placebo); P=0.32. Phase 2, 52-week, dose-finding. Published JAMA Neurol 2019. 408 patients, 4 dose groups. Sigma-1 receptor agonist mechanism explored post-hoc.
Major Points
- Primary endpoint not met: UHDRS-TMS change -0.7 (45mg BID) vs -0.2 (placebo); P=0.32.
- No dose group (22.5, 45, 67.5, or 112.5 mg BID) significantly improved TMS.
- 408 HD patients. 52-week, double-blind, placebo-controlled, dose-finding (Phase 2).
- Secondary endpoints also negative: TFC, UHDRS-IS, CGI-C all non-significant.
- Post-hoc: possible signal in TFC preservation at 45mg dose — explored in PROOF-HD (Phase 3, failed).
- Pridopidine: initially developed as dopamine stabilizer, reclassified as sigma-1 receptor agonist.
- Well tolerated: AEs similar across groups. Falls, nausea, diarrhea most common.
- Teva Pharmaceutical sponsored. Published JAMA Neurol 2019 (Reilmann et al.).
- Sigma-1 mechanism may target neuroprotection rather than symptomatic motor improvement.
- PROOF-HD (Phase 3, n=499) also failed primary endpoint — pridopidine development halted for HD.
Design
Study Type: Randomized, double-blind, placebo-controlled, phase 2 trial with post hoc subgroup analysis
Randomization: 1
Blinding: Double-blind (patients and investigators)
Enrollment Period: 2012–2015
Follow-up Duration: 52 weeks
Centers: 57
Countries: USA, Canada, Europe, Australia
Sample Size: 408
Analysis: Mixed-model repeated measures for TFC and cUHDRS; responder analysis using logistic regression
Inclusion Criteria
- Manifest Huntington's disease
- TFC score between 7 and 13 at baseline (early-stage)
- Age 21–65 years
- Ability to provide informed consent and participate for 52 weeks
Exclusion Criteria
- TFC <7 or >13
- Unstable psychiatric or medical illness
- Use of investigational drugs within 60 days
- Prior participation in certain other HD trials
Arms
| Field | Pridopidine 45 mg BID | Control |
|---|---|---|
| Intervention | Oral pridopidine 45 mg twice daily | Oral placebo twice daily |
| Duration | 52 weeks | 52 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change in Total Functional Capacity (TFC) score from baseline to 52 weeks | Primary | Greater decline in placebo group | Mean difference +1.16 vs placebo | 0.0003 | |
| Responder analysis (stable or improved TFC) | Secondary | 48.8% | 81.1% | 0.2 | 0.002 |
| cUHDRS | Secondary | Decline | Mean difference +0.6 | 0.04 | |
| Any adverse event | Adverse | 64.5% | 59.3% | ||
| Serious adverse event | Adverse | 1 patient | 1 patient |
Subgroup Analysis
Consistent functional benefit across all five TFC domains; analysis limited to early HD subgroup (TFC 7–13)
Criticisms
- Primary analysis was post hoc and not pre-specified
- Study not powered for clinical outcomes in early HD subgroup
- No imaging or biomarker data to support disease-modifying claims
- Functional scales may be prone to subjective interpretation
Funding
Teva Pharmaceuticals
Based on: PRIDE-HD (Neurology, 2020)
Authors: Ralf Reilmann, Herwig Lange, Dana Kayson, ..., and others
Citation: Neurology. 2020;95(6):e805-e814. doi:10.1212/WNL.0000000000009823
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