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EHDN 2022 | PROOF-HD: Phase III trial of oral S1R agonist pridopidine for the treatment of Huntington’s disease

Michael Hayden, MB, ChB, PhD, FRCP, FRSC, The University of British Columbia, Vancouver, Canada, & Prilenia, CEO, introduces pridopidine: a potent, highly selective, oral sigma-1 receptor (S1R) agonist currently under investigation in the Phase III PROOF-HD study for the treatment of Huntington’s disease (HD). Experimental studies have shown pridopidine to exert neuroprotective effects via activation of the S1R, which is highly expressed in the brain. For example, pridopidine administration in disease models reduced cellular stress and neuroinflammation, enhanced autophagy and toxic protein clearance, and increased BDNF secretion. In the Phase II PRIDE-HD (NCT02006472) investigation, twice daily pridopidine administration was associated with maintenance of functional capacity from baseline to 52 weeks, compared to placebo, in patients with early HD. Favorable safety and tolerability data was also demonstrated. The ongoing Phase III, randomized, placebo-controlled PROOF-HD trial (PRidopidine Outcome On Function in Huntington Disease; NCT04556656) has enrolled 499 patients since October 2020. Total Functional Capacity (TFC) will be evaluated as the primary study outcome. This interview took place during the European Huntington’s Disease Network 2022 Plenary Meeting.

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Transcript (edited for clarity)

Pridopidine is a highly selective and potent sigma-1 receptor agonist. There have been drugs in the past that have interacted with this receptor, but there’s been none that have been so selective and so clearly acting on this target at these therapeutic doses, with very little off target activity.

Activation of the sigma-1 has been shown in the past to have numerous impacts on neuroprotective approaches to therapy...

Pridopidine is a highly selective and potent sigma-1 receptor agonist. There have been drugs in the past that have interacted with this receptor, but there’s been none that have been so selective and so clearly acting on this target at these therapeutic doses, with very little off target activity.

Activation of the sigma-1 has been shown in the past to have numerous impacts on neuroprotective approaches to therapy. We also know here, for example, in Huntington’s disease and ALS in particular, what we see is that this drug has major activity on pathways that provide neuroprotection. This includes enhancing autophagy, decreasing ER stress, having impact on improving the connectivity in the brain with increasing spines, decreasing neuroinflammation, enhancing BDNF secretion, all of which are associated with neuroprotection in the past.

What we also know is that these effects are completely mediated through the sigma-1 receptor. How do we know that? We know that because if you delete in those experiments one gene, the sigma-1 receptor, you lose the neuroprotective effects completely. Also, if you use a highly selective sigma-1 receptor antagonist, you lose the effect completely. Remarkably, this really shows, in vivo. In studies that the neuroprotective effects are only mediated through the sigma-1 receptor.

Well, the drug was initially thought to interact with D2 and D3 dopamine receptors, but in fact, what we learned in vivo in human studies where we did in vivo target engagement in humans is that the primary affinity for this drug was for the sigma-1 receptor, 100 to 500 times more potent and more selective than to D2, D3.

This drug has been shown in a prior study, which was extended from six months to one year to be able to look at the impact on progression, has been shown to have impact on a single pivotal endpoint that’s accepted by the regulators, both in Europe and the US called TFC. TFC measures function, the ability of the patients and the subjects tp continue to manage their finance, stay employed, look after activities of daily living, participate in domestic chores, and also that they’re being able to be cared for on their own. This is a scale that’s been around for 40 years, now accepted as part of a single endpoint for pivotal trials, and this has been accepted both by the EMA and FDA in this single pivotal Phase III trial that is now underway.

This study started in October 2020 when the pandemic of COVID was on us and creating massive disturbance. We were worried that we would have some delays in recruitment. Our target for recruitment was 480 patients by the end of November 2021. To our pleasure and delight, we were able to recruit ahead of schedule, about six weeks to two months, and we recruited 499 patients ahead of target. This reflects two things. Firstly, the amazing support and enthusiasm of the Huntington’s community for the study, and secondly, the fact that it became apparent that this is very safe and tolerable.

Associated with that, we have a much lower than expected dropout rate. We powered this for a 22% dropout rate. At the moment, we are around 6%, so this is much lower than expected. The drug is safe and tolerable. There have been serious adverse events, but not a single serious adverse event ascribed to this drug by the investigator on that site. So, safe and tolerable, and of course a community that has been beset by particularly bad news in the Huntington space with failures, four big failures right now, and some coming back to look at other approaches.

At this stage, this is the only Phase III drug in clinical development for Huntington disease, which is looking to have impact on function. Impact on function is most important for patients. This is what they highlight as what is devastating for them as they see their family member be devastated by inability to work and unable to manage finances, unable to feed themselves, inability to be cared for at home or by themselves. This has impact on function, and our goal here is to assess whether pridopidine has any impact on delaying the progression of function. And of course, that would be very welcomed by the community.

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