Prilenia presented the preliminary topline results of the PROOF-HD clinical trial (PRidopidine Outcome On Function in Huntington Disease) at the end of April. Last year, the Moving Forward team wrote a news piece about this trial.

Now, we look at the first findings of PROOF-HD and share our expectations for the near future. PROOF-HD enrolled 499 participants with early manifest Huntington’s disease (HD) in the U.S., Canada, Austria, Czech Republic, France, Germany, Italy, the Netherlands, Poland, Spain and the United Kingdom. The goal of this trial was to evaluate the efficacy and safety of Pridopidine (a 45 mg oral capsule taken twice daily, in the morning and in the evening) in people with early manifest HD.

Pridopidine is an oral, small molecule, highly selective and potent investigational drug that binds and specifically activates a receptor called Sigma-1. Pridopidine has exhibited a safety and tolerability profile similar to placebo in previous clinical studies. The S1R regulates several key processes that are often impaired in neurodegenerative diseases such as Huntington’s disease. The hypothesis is that the activation of the S1R by Pridopidine will stimulate multiple cellular protective pathways which are crucial for neurons to function and survive and thus may lead to neuroprotective effects.

Unfortunately, the trial did not meet its primary endpoint, which was a change from baseline compared to placebo at 65 weeks in the functional capacity of people with HD (as measured by the Unified Huntington’s Disease Rating Scale-Total Functional Capacity score). The TFC – Total Functional Capacity assesses the person’s ability to work, manage finances, perform domestic chores and activities of daily living and handle self-care. Hence, the main goal of PROOF-HD was to demonstrate that people with early manifest HD taking Pridopidine would show a change in the rate of decline of their functional capacity compared to people with early manifest HD not taking Pridopidine after 65 weeks. Regrettably, it failed.

The study also did not meet its key secondary endpoint, which was for the participants on Pridopidine to maintain a stable score (no worsening) on a specific measure throughout the trial, the Composite Unified Huntington’s Disease Rating Scale. This composite includes measures related to the TFC, motor skills, cognitive status, and quality of life. The secondary endpoints of a trial support the claim of efficacy of the drug being investigated. Again, the trial failed to achieve this goal.

Nevertheless, the first analysis of the PROOF-HD results has provided several positive findings:

• Pridopidine showed benefits in a sub-group of people with early manifest Huntington’s disease that was not taking neuroleptics (neuroleptics are used for symptoms such as psychosis, irritability, or chorea) and chorea medications (e.g., tetrabenazine) during the clinical trial. This group included 40% of the trial participants on Pridopidine and it showed positive results compared to placebo on measures of disease progression, motor, and cognitive function.
• In terms of disease progression, Pridopidine showed the potential of delaying HD progression in participants not taking neuroleptics or chorea medications.
• In terms of cognitive symptoms, there were benefits in the cognition of participants taking Pridopidine but no neuroleptics or chorea medications who were assessed with the Stroop Word Reading Test at various timepoints in the trial.
• In terms of motor symptoms, Q-Motor, an objective measure of motor function, showed robust beneficial effects for all the trial participants treated with Pridopidine in PROOF-HD at various timepoints.
• Pridopidine was well-tolerated by the trial participants, having a safety profile similar to placebo.

Thus, these preliminary findings suggest that Pridopidine is safe and well-tolerated by people with early manifest HD and may have a positive impact in multiple important clinical aspects of Huntington’s disease, namely disease progression, motor and cognitive function. This positive impact seems to be particularly significant in people who take less concomitant medication.

Importantly, Prilenia intends to continue providing trial participants with access to Pridopidine as part of the current PROOF-HD Open Label Extension. Additionally, Prilenia will continue to analyze the PROOF-HD results, to understand which sub-groups may benefit more from the drug and substantiate further efforts to bring this treatment to HD families across the world.

From the HD community perspective, it is important to first and foremost emphasize the role of the patients and families who relentlessly committed to this clinical trial – especially during the COVID-19 pandemic. The Moving Forward team considers that, even though the study was not a success, there were important findings that came with it that are important to take forward. Each trial is a step forward in learning more and more about possible treatment options and pathways in HD.

In fact, while failing to meet the trial’s main objectives obviously is not good news, the preliminary data obtained from specific sub-groups of participants does keep the door open. Since no two HD patients are alike, having different research paths (not only based exclusively on the reduction of Huntingtin levels) is a good starting point to achieve a personalized therapeutic approach tailored to the stage and symptoms of each patient. A treatment may not be effective for some, but can be effective for others, and this will benefit hundreds of HD families.

So, if a drug helps a certain cohort of study participants, why is the trial considered ineffective?  – this is on the back of the mind of several family members. We believe that one of the answers to this question may lie in the study’s endpoint – what is used as a measure of effectiveness. Most likely, if we change these measures and/or shift the focus of the study, pridopidine will be found effective in treating certain symptoms of Huntington’s disease and will move forward in the drug development pipeline.

For that to happen and progress is made on the bumpy road to find an effective treatment for HD, the engagement of HD families in clinical trials is critical. All in all, the Moving Forward team believes it is essential that the HD community doesn’t see this as a defeat, but rather as an opportunity to move forward with the research.