Examining the efficacy, safety, and tolerability of pridopidine in Huntington disease through a phase II, double-blind, placebo-controlled, dose-ranging study
Imagine a devastating genetic disorder that gradually erodes your control over movements, thoughts, and emotions—a condition passed down through families, with each child of an affected parent facing a 50% chance of inheriting it. This is the reality of Huntington's disease (HD), a rare, inherited neurodegenerative disease that affects approximately 100,000 people worldwide 9 .
For decades, treatments have focused only on managing symptoms, offering no hope of slowing the disease's relentless progression. The PRIDE-HD trial represented a beacon of hope in this landscape, testing a promising investigational drug called pridopidine to see if it could change this reality.
Huntington's disease is caused by a single genetic error—an expanded repeat of three DNA letters (CAG) in the huntingtin gene. This mutation leads to the production of a toxic mutant protein that slowly damages nerve cells, particularly in a deep brain region called the striatum, which is crucial for coordinating movement, thought, and motivation .
The disease typically manifests between the ages of 30 and 50, and over 15-20 years, it progressively strips away a person's independence. Patients experience a triad of symptoms:
While medications exist to help manage chorea, nothing has been proven to tackle the underlying progression of the disease that affects all aspects of a person's life.
Pridopidine started as a puzzle for scientists. Initially classified as a dopamine stabilizer, it was thought to work by fine-tuning dopamine signaling in the brain—calming hyperactivity when dopamine levels were too high and boosting function when they were too low 3 . This mechanism held promise for addressing the complex motor symptoms of HD without the severe side effects of traditional antipsychotics.
However, further research revealed a more intriguing story. Scientists discovered that pridopidine is actually a potent and selective sigma-1 receptor (S1R) agonist 1 . Think of the sigma-1 receptor as a cellular guardian—a protein located in key areas of nerve cells that helps manage stress, maintain calcium balance, and support overall neuronal health .
By activating this receptor, pridopidine was found to trigger multiple neuroprotective pathways in laboratory models of HD, potentially helping nerve cells survive and function better despite the presence of the toxic mutant huntingtin protein .
Primary Target: Sigma-1 receptor (S1R)
Action: Agonist (activator)
Effect: Neuroprotection, cellular stress management
The sigma-1 receptor acts as a protective mechanism within cells, helping to:
Prior to PRIDE-HD, earlier clinical studies had provided hints that pridopidine at a dose of 45 mg twice daily might improve motor function in people with HD, though these studies didn't meet their primary endpoints 3 . The PRIDE-HD trial, a phase 2 study, was designed to answer a critical question: Could higher doses of pridopidine produce stronger, dose-dependent benefits while remaining safe for patients? 3 8
The trial enrolled 408 adults with early- to mid-stage Huntington's disease across 53 research centers in 12 countries 3 8 . To qualify, participants had to have genetically confirmed HD (36 or more CAG repeats) and noticeable motor symptoms.
Participants were divided into five groups, receiving either a placebo or one of four twice-daily doses of pridopidine: 45 mg, 67.5 mg, 90 mg, or 112.5 mg 3 8 . The treatment continued for 52 weeks, with the primary evaluation at the 26-week mark. The main goal was to see if pridopidine could improve motor function, specifically measured by the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS). This comprehensive assessment evaluates various aspects of motor control, from eye movements to gait and involuntary movements 3 .
| Characteristic | Placebo (n=81) | Pridopidine 45 mg (n=75) | Pridopidine 67.5 mg (n=79) | Pridopidine 90 mg (n=81) | Pridopidine 112.5 mg (n=81) |
|---|---|---|---|---|---|
| Mean Age (years) | ~50 | ~50 | ~50 | ~50 | ~50 |
| Female, % | Information combined across groups: Approximately 50% female 3 | ||||
| Baseline UHDRS-TMS | Comparable across groups 3 8 | ||||
| Reduced Independence (Independence Score ≤90%) | 100% of participants 8 | ||||
When the data were unblinded, the results were disappointing. None of the pridopidine doses, including the higher ones, showed a statistically significant improvement over placebo on the primary endpoint of UHDRS-TMS at 26 weeks 3 8 . The trial did not achieve what it set out to prove.
However, a deeper look revealed more to the story. The drug demonstrated a favorable safety and tolerability profile across all doses. The most common side effects were gastrointestinal issues (like diarrhea and vomiting), nasopharyngitis, falls, headache, insomnia, and anxiety 3 8 . While serious adverse events (including falls and suicide attempts) did occur, they were only observed in the pridopidine groups and were relatively rare. One death in the highest dose group was considered possibly related to the study drug 8 .
Interestingly, when researchers extended their analysis to the full 52 weeks of the study and looked at other measures, they observed that pridopidine 45 mg twice daily was associated with a slower rate of decline in Total Functional Capacity (TFC) compared to placebo 1 . TFC measures how well patients perform daily activities like managing finances, household chores, and self-care. This potential signal, though not the trial's primary goal, offered a glimmer of hope and prompted further investigation.
No significant improvement in UHDRS-TMS at any dose
Primary endpoint not met at 26 weeks
Favorable safety and tolerability
Most common side effects were gastrointestinal issues, nasopharyngitis, falls
Slower TFC decline with 45 mg dose at 52 weeks
Not the primary endpoint but promising signal
| Outcome Measure | Result | Statistical Significance |
|---|---|---|
| Primary Endpoint: Change in UHDRS-TMS | No improvement at any dose (45 mg to 112.5 mg) compared to placebo | Not significant 3 8 |
| Key Secondary Endpoint: Modified Physical Performance Test | No improvement at any dose compared to placebo | Not significant 3 |
| Exploratory Outcome: Total Functional Capacity (TFC) at 52 weeks | Slower decline with pridopidine 45 mg | Not primary endpoint; seen in exploratory analysis 1 |
| Adverse Event | Frequency |
|---|---|
| Diarrhea | Frequent across all groups 8 |
| Vomiting | Frequent across all groups 8 |
| Nasopharyngitis | Frequent across all groups 8 |
| Falls | Frequent across all groups 8 |
| Headache | Frequent across all groups 8 |
| Insomnia | More common in pridopidine groups 8 |
| Anxiety | More common in pridopidine groups 8 |
Advancing the understanding and treatment of Huntington's disease relies on a sophisticated set of tools and assessments.
| Tool or Method | Function and Purpose |
|---|---|
| Unified Huntington's Disease Rating Scale (UHDRS) | A comprehensive battery of tests to assess motor function, cognition, behavior, and functional capacity in HD 3 . |
| Total Motor Score (TMS) | A component of the UHDRS that quantitatively measures motor signs, including chorea, dystonia, and eye movements 3 . |
| Total Functional Capacity (TFC) | A scale that measures a patient's ability to work, manage finances, perform domestic tasks, and self-care 1 . |
| Randomized Controlled Trial (RCT) | The gold-standard study design where participants are randomly assigned to treatment or control groups to objectively evaluate a drug's efficacy and safety 3 8 . |
| Sigma-1 Receptor (S1R) | A key cellular protein targeted by pridopidine; its activation is thought to promote neuroprotection and cellular health 1 . |
The negative primary outcome of PRIDE-HD was a setback, but it was not the end of the road for pridopidine. The potential functional benefit seen in exploratory analyses fueled the design of a larger Phase 3 trial called PROOF-HD 1 .
PROOF-HD shifted the focus from motor symptoms to functional capacity (TFC) as the primary endpoint 1 . While the overall results of PROOF-HD also did not meet its primary endpoint, a pre-specified analysis of participants not taking antidopaminergic medications (often used for chorea) showed favorable trends for pridopidine across function, cognition, and motor performance 1 9 . This suggests that concomitant medications might mask pridopidine's benefits in clinical trials 1 .
As of 2025, the journey for pridopidine continues. The European Medicines Agency (EMA) rejected an application for approval in Europe, citing the need for more robust data 4 . However, the drug's developer, Prilenia, has announced plans for a new global study aimed at securing regulatory approval 4 . The scientific community continues to be intrigued by pridopidine's unique mechanism of action as a sigma-1 receptor agonist and its potential to modify the course of this challenging disease.
The story of the PRIDE-HD trial is a powerful example of how scientific progress is often non-linear, filled with both disappointments and unexpected clues. While it did not demonstrate that high-dose pridopidine could improve motor function, it reinforced the drug's safety and provided a critical hint about its potential to preserve what matters most to patients—their daily functioning and independence.
This trial, and the research that has followed, has also highlighted the immense complexity of conducting clinical trials in Huntington's disease. The search for effective treatments for HD continues to be a relentless and collaborative effort between scientists, clinicians, and the courageous patients and families who participate in clinical studies. Their collective hope and perseverance ensure that the path forward, though winding, remains bright.