Insights on Pridopidine From the HEALEY ALS Platform Trial

Melanie Leitner, PhD

The HEALEY ALS Platform Trial (NCT04297683), a first of its kind, phase 2/3, multicenter, randomized, placebo-controlled, multi-arm trial, is assessing several agents in development for amyotrophic lateral sclerosis (ALS). This specific type of designed study allows for perpetual trial infrastructure and shared placebo data, thus accelerating drug development.

The primary endpoint of the trial is change in disease severity over time, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), with additional endpoints that include respiratory function, muscle strength, survival, and safety, among others. Between July 2020 and Dec 2021, a total of 653 patients with ALS were randomized within the first 4 regimens of the HEALEY ALS Platform Trial (regimen A: zilucoplan; regimen B: verdiperstat; regimen C: CNM-Au8; regimen D: pridopidine). At the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, results for primary, secondary, and exploratory endpoints from the 4 regimens were reported by lead author Sabrina Paganoni, MD, PhD, an associate professor at Harvard Medical School.¹

Recently, Melanie Leitner, PhD, consultant and founder of Accelerating NeuroVentures, and program director for regimen D on the Healey ALS Platform Trial, shared her insights from the pridopidine substudy (NCT04615923) and the significance of the findings. She provided a brief overview of the Healey-ALS Platform Trial and the set up for regimen D of the platform trial. Also, she spoke about exciting innovations in the field of ALS and the importance of early diagnosis.

NeurologyLive®: Can you provide an overview of the HEALEY Platform trial?

Melanie Leitner, PhD: The HEALEY platform trial for ALS is an exciting innovation in the clinical trial space. A platform trial allows for the testing of multiple compounds, where each arm of the platform shares the placebo group. It's a very patient-friendly format, in the sense that because of the ability to share placebo groups, patients can be randomized 3:1 to drug and are therefore more likely to receive an active compound compared with a traditional, 1:1, double blind study. There's that important benefit for patients but also, because it's a perpetual trial, this means that the time to get the clinical study up and running is much shorter than for a traditional clinical trial where you need to build all the clinical infrastructure. The platform trial is basically a plug and play situation where there are sites, protocols, and trial agreements already in place. The main time constraint is to customize the design for a specific regimen that will go on to join the ongoing trial.

Can you provide an overview of the current regimen D and how it differs from the other regimens?

At this point, there are 6 arms to the study. There were first 3 regimens A, B, and C, which all joined around the same time and read out earlier this year. Then, regimen D was the fourth drug to join in, and regimens E and F are currently still active. Regimen D completed recently, and top line results just read out. Regimen D was for a compound called pridopidine, a specific and selective sigma-1 receptor agonist, which is a different mechanism of action than any of the other compounds that have been tested through the platform. For the first 5 regimens, all of them interrogated very different targets using different approaches. The pridopidine study started enrolling in the beginning of 2021 and, like regimens A-C, it was a 6-month, double-blind, placebo-controlled study that rolled over into an open label extension. The top line results from the 6-month placebo-controlled study were presented at the recent AAN Annual Meeting. The OLE data have not yet read out for any of the Healey platform regimens, as these are all ongoing.

What were the results from regimen D and their significance?

The results were really interesting. Unfortunately, the study did not meet the primary endpoint, which was looking at a change in the ALSFRS-R between baseline and 24 weeks. When you looked at the entire population, there wasn't an obvious, statistically significant change in total ALSFRS-R slope; however, there were some interesting findings around speech. This study tested a novel set of speech measures, in collaboration with the company Aural Analytics, and showed benefits in speech across the entire population (the full analysis cohort). Even using this very conservative statistical approach, the treatment group showed significant changes in measures of articulation rate and speaking rate, as well as almost reaching significance in articulatory precision. These are key speech metrics that correlate with the speech question in the ALSFSR-R. The implication is that treatment with pridopidine delayed the loss of speech in patients in the treated population. This result is super important because losing the ability to communicate is one of the hardest things I think for many patients with ALS. A delay in that loss could be really profound for maintaining quality of life.

What are the next steps from here after exploring regimen D?

Remember, this study itself was only a 6-month study. That's a short period of time to see an impact of a drug on the ALSFRS-R (functional rating scale). I think the first thing will be the analysis of the open label extension data, which will cover a larger, longer period of time. With the addition of this data, we’ll be able to answer questions around survival, and also assess functional changes over a longer time window of treatment. The next thing will hopefully be the design and launch of a follow-up study, which will build upon the learnings from the platform. The goal of all the Phase 2 studies, conducted using the HEALEY platform, is to assess if there is enough of an efficacy signal to warrant designing a Phase 3 trial, and if so to take advantage of the Phase 2 learnings in the design of any follow-on Phase 3 confirmatory studies.. The platform itself will continue to advance and enroll new arms and new drugs into this study. Right now, as I mentioned, there have been 6 drugs enrolled in the platform, and there's a seventh drug that has already been approved for the platform, which will hopefully start enrolling later this year.

This has been such a crazy and exciting time to be in ALS [field] with the approval of AMX0035 (Relyvrio; Amylyx Pharmaceuticals), and then the recent and accelerated approval of tofersen (Qalsody; Biogen). We’ve also had so much momentum with the HEALEY platform study, enabling the testing of multiple potential ALS therapies much more quickly and cost-effectively. I've been in the ALS space for a long time now and it's been very difficult over that time. There have been many [agents] that failed and I just read recently that another drug failed a Phase 3 ALS trial. But in general, I think there's a sense of hope and momentum in the space that at last, there are additional potential therapeutic options for newly diagnosed patients with ALS. There's certainly been enormous strides in terms of understanding the biology behind the disease. This means that the drugs that are coming along earlier in the pipeline, I think, also have a strong chance of being effective. We're making slow but important strides.

What do you think is exciting in the ALS field now and what is currently being talked about?

One of the things that I think a lot about, and I think the field has really been thinking a lot about more recently, is early diagnosis, and how important it is to diagnose patients earlier. It seems like the therapies that are being approved are more effective when they're given earlier in the disease. One of the organizations, a foundation that I'm working with, is trying to identify novel diagnostic markers so we can diagnose ALS definitively earlier in disease. It typically takes, on average, 12 months to definitively diagnose an ALS patient in the US, but part of that is because of the delay in getting people to an ALS clinic where they can receive that definitive diagnosis. One of the things I'd be interested in telling general neurologists is that if you really think a patient might have ALS, rather than waiting a long time to exclude everything else, try to have that patient get to an ALS clinic, or at least yourself try to consult with an ALS clinic. It’s better to send your patient sooner rather than later, because if it is ALS it's extremely valuable for those patients to find out sooner so that they can potentially take advantage of the new therapies, participate in clinical trials, and avoid unneeded (and potentially harmful) surgical interventions. Hopefully, in the near future we'll be in a better position to provide the general neurologist with tools so that patients can receive a definitive ALS diagnosis earlier.

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REFERENCES
1. Paganoni S, Berry J, Quintana M. Results from the first four regimens of the HEALEY ALS Platform Trial. Presented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts.