PROOF in the Publishing: Slicing the Data on Pridopidine

Pridopidine has been under investigation as a treatment for Huntington’s disease (HD) since the early 2000s. The most recent Phase 3 trial testing to see if pridopidine might improve signs and symptoms of HD, a study called PROOF-HD, did not meet its key goals. Furthermore, this summer we learned that the European Medicines Agency (EMA) did not accept Prilenia’s application to market pridopidine for the treatment of HD in Europe. 

While we’ve known about the overall outcome of the PROOF-HD study for quite some time, it’s important to acknowledge a new major research milestone: publication of the trial results in a medical journal. Publishing clinical trial data can take a while – especially in a prestigious journal like Nature Medicine, where the PROOF-HD results appear. 

This is an important opportunity for the investigators involved in this clinical trial to lay out all the details, and to share detailed analyses that can help determine next steps for a drug. Let’s get into what the PROOF-HD investigators report. 

What the paper adds

Prilenia has publicly shared the data from the PROOF-HD study over the course of the last few years, at HD conferences and other research events. This recent paper reiterates the main points – overall, pridopidine did not improve how people with HD function or move, compared to a placebo. 

Like any clinical trial publication, this one examines the nitty-gritty of the data, including instances of safety issues and side effects. Importantly, pridopidine remains safe and is tolerated well by the vast majority of participants. 

What’s most notable about this paper is that it places a lot of emphasis on analyses that split up the participants into different groups, depending on the other types of medications they were taking while they participated. As with most HD trials, PROOF-HD allowed people to continue taking drugs to control chorea, like tetrabenazine and deutetrabenazine, and drugs that can help with both chorea and behavioral symptoms, like risperidone and olanzapine – among many others. These anti-dopaminergic medications (ADMs) are commonly used to manage various movement and psychiatric symptoms of HD. 

When Prilenia analyzed data only from those who were not taking ADMs (less than half of the participants), they observed some potential trends. Starting at about six months, up until about a year, those taking pridopidine and no ADMs seemed to do slightly better on some clinical tests of function, movement, and thinking than those taking placebo. But by the end of the study (about 18 months), this was no longer the case – the groups had both declined by about the same amount. 

This recent paper reiterates the main points – overall, pridopidine did not improve how people with HD function or move, compared to a placebo. 

Mining the data for more

This recent paper places strong emphasis on how the data was sliced, diced, and examined from multiple angles to check for any clues that pridopidine could have promise for some people with HD. They used specialized maths and statistics to ask more questions about the full group of participants, as well as only those taking ADMs. 

For example, looking at performance using a multi-pronged clinical score that combines information from multiple tests across the spectrum of HD symptoms (the uHDRS), what percentage of people improved by 5% or more? More people in the pridopidine group met this threshold than in the placebo group, but depending on the participants and time points they analyzed, this wasn’t always a clear cut result. From other mathematical angles, individual tests of movement and memory also had quite mixed results. 

Some of these analyses were planned from the start (pre-specified), while others were decided upon later (post hoc). The paper contains clear language that the results should be interpreted with caution – and interpretation is in fact challenging. There were some promising trends in a minority of participants who were not taking common medications to manage their HD symptoms. But because the group sizes were small, the authors state that “the findings were not powered to support definitive conclusions,” meaning that the results must be taken with a hefty pinch of salt. 

Progress in publication

The PROOF-HD study was designed to ask whether pridopidine is safe and whether it is effective at slowing decline of function and movement symptoms in people with HD. The study unfortunately did not meet its primary or secondary endpoints – its overall goals. Given the positive trends they observe in a portion of the folks in the trial, it’s possible that yet another study in a different segment of the HD population (those not managing their symptoms with ADMs) could have some promise, or that small changes could be more meaningful over time. This hope has buoyed pridopidine through 20 years of study, across trials varying in dosing regimens, HD participant populations, and outcome measures, in pursuit of evidence for benefit. This hope is driving Prilenia and their partner Ferrer to continue development plans. 

Even when studies of experimental HD treatments don’t turn out how we’d hoped, publication is the gold standard for responsible sharing of data within the scientific community. The publication process – which can sometimes take years – allows for careful review, analysis, and presentation of all relevant data. A clinical trial paper comes to fruition through the efforts of researchers, clinicians, and industry scientists who ran the study, as well as external reviewers and steering committees, which often involve community members. 

Starting at about six months, up until about a year, those taking pridopidine and no ADMs seemed to do slightly better on some clinical tests of function, movement, and thinking than those taking placebo. But by the end of the study (about 18 months), this was no longer the case – the groups had both declined by about the same amount. 

Hope and human variability

Publication is also an opportunity to craft a story that fosters momentum, in this case by focusing on a subset of the data. ADMs include quite a few drugs that are helpful for managing a range of HD symptoms, from unwanted movements and behaviors, to sleep disruptions and anxiety. Each individual responds differently to their prescribed medications, especially as a complex disease like HD progresses. This paper emphasizes that ADMs, while important for managing HD, introduce a degree of variability into tests designed to measure changes in movement, motivation, and problem solving. In short – humans and health are complex. 

The hope is that a truly effective drug would overcome that variability. Some scientists and doctors think that if certain subgroups of people may benefit from pridopidine, further research should clarify which ones and determine how best to measure meaningful change. Others question whether continued trials are justified. What’s clear is the tremendous contribution of the HD community: the many brave individuals who participated in PROOF-HD and other trials of pridopidine, some of whom felt that the drug made a difference in their lives. 

Summary

• Pridopidine has been tested for HD for 20+ years; the Phase 3 PROOF-HD trial did not meet its main goals
• The drug was safe and well-tolerated, but showed no overall benefit compared to placebo
• Subgroup analyses hinted at short-term improvements in participants not taking anti-dopaminergic medications, but these faded by 18 months
• Results were exploratory and not definitive, so must be interpreted with caution
• Publication in Nature Medicine makes the full data available, ensuring transparency and learning for the HD community