Clinical Implications of WVE-004 for C9-ALS and C9-FTD

Michael Panzara, MD, MPH

This is a 2-part interview. To view part 1, click here.

The phase 1b/2a FOCUS-C9 trial (NCT04931862) aims to evaluate the safety and tolerability of a new investigational treatment, WVE-004, for C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD). Dosing has recently commenced for multiple patients, with investigators hoping to enroll a total of 50 participants. 

The adaptive study was designed alongside experts in each field, generating a unique, basket-like study plan. The design further lends itself to evaluating both ALS and FTD as 2 phenotypes of a single disease. Despite ALS and FTD possessing a common underlying genetic problem, there have not been ample combined research efforts, making the FOCUS-C9 trial unique, according to Michael Panzara, MD, MPH. 

Panzara, who is the chief medical officer and head of therapeutics discovery and development at Wave Life Sciences, spoke with NeurologyLive on the clinical advantages of WVE-004, as well as key takeaways for the clinical community. He further discussed his hopes for the treatment of both ALS and FTD, as both are diseases that have limited treatment options for patients. 

NeurologyLive: Does WVE-004’s design offer any potenital clinical advantage for patients in FTD and ALS? 

Michael Panzara, MD, MPH: Right now, there is really nothing that works. So [WVE-004] could have dramatic impacts on the course of disease for patients and their families. One of the unusual things about this molecule is that, at least in the animal models, the effect lasts for many months. Actually, all of our preclinical studies to date suggest that WVE-004 has long-lasting effects and widespread distribution throughout the central nervous system (CNS).

With a treatment for these diseases, you want a drug that can impact the spinal cord, but also the cortex and other areas of brain, as all of these diseases are really whole brain diseases, whole CNS diseases. The idea that we can give infrequent doses with long-lasting effects, such that we can alter the course of the disease, potentially by 1, 2, or 3 administrations in a given year, that changes how people think about [these diseases], from universally fatal to diseases that can be managed, hopefully through the slowing of disability progression. 

The promise here is not just to show a biomarker effect, but that the biomarker effect tells us we are on the track to lead to clinically meaningful effects. The potential advantages of this particular compound are that we would not have to administer it as frequently as some of the older generation compounds, and that infrequent intrathecal administration can still have long lasting effects. There’s a lot of potential for patients with this compound, and the FOCUS-C9 study will help tell us if we're on the right track.

What do clinicians need to know about this trial?

The study was designed in collaboration with the numerous investigators in FTD and ALS, and we’ve gotten a lot of good feedback from people in the patient community. What I've learned from this experience has been, first of all, how even though ALS and FTD have this common underlying genetic problem, the 2 groups—the physicians who work on ALS and the physicians who work on FTD—really haven't worked that much together to tackle this as 2 phenotypes of a single disease. Our approach has always been to bring both groups together. The study was designed with both groups in the room, making sure that each group had what they were looking for in a clinical trial. 

In terms of the clinicians out there, thinking about this as a spectrum of a single underlying disease is going to be somewhat new to them. Thinking about approaching the treatment like you would a spectrum of phenotypes of a single underlying disorder, to us, that is something that, when we've worked with the two ALS and FTD communities, they have appreciated us bringing to the surface. 

As physicians look at this, and as they see their patients and think about how they might approach a patient with this underlying condition, [they should], first of all, test for it so that they can offer them potential for inclusion in FOCUS-C9 or other studies. Also, they should be prepared that there are going to be different manifestations because of this underlying genetic defect. It’s also important to think about the implications for patients’ families; these are autosomal dominant disorders, and they're fully penetrant. It is important for physicians to think about counseling that a family needs, once they you understand that they have this underlying condition.

The optimistic part of all this is that us and others having are recognizing the potential to identify these patients, and hopefully, through clinical trials, identify new treatments. There should be some optimism, because the innovation in ALS and FTD in general is quite high right now. There's a lot of people interested in it, and there's a lot of opportunities for patients to be involved in trials, and generally eventually lead to treatments, which not that long ago, was not something we could even think about.

When are you anticipating reading out interim and/or topline data?

We just started dosing, [and] we announced a few weeks ago that we just started seeing our first cohort, which is really the beginning of the FOCUS-C9 adaptive study. Because the study is adaptive, there are multiple points between now through the end of 2022 where there could be opportunity—depending on what our independent data safety monitoring board suggests—to inform the community about our progress. 

With every dose escalation, with every assessment of the cohort, the independent committee will be advising us how to proceed. If there are big changes to the study, as a result of that, it will be our obligation to inform the community. This could happen at any time between now and throughout 2022. That's what makes this exciting, because at any one of those points, we could end up rapidly converting or expanding our program into a more focused study on clinical endpoints. That would be great news for the community, that we have a hit and we're ready to move forward. 

In closing, this is not the only genetically targeted disease we're working on at Wave Life Sciences, it is representative of what we're trying to do. We have our Huntington's disease (HD) program, focusing on a very selective approach to HD, we have a DMD program we're going to be dosing in the next few weeks, which builds upon learnings from our previous program. The approach we've always taken is, through these innovative platform chemistries, we try to tackle these diseases, and then through some of the innovative clinical development, like the FOCUS-C9 study, which we heard from our investigators, is getting a lot of praise for its basket-like design and its adaptive nature, we're always trying to push things to try and accelerate things safely in a way that allows us to target the underlying genetic origins of these diseases, and what's leading to them from a pathophysiological standpoint, and hopefully, really move the field forward as well as develop treatments for patients.

Overall, I think where we are now in this space is where I was 20 years ago, when I was starting in MS. If things happen like they did in MS, all of the innovation of biomarkers, trial design, gene transcript targeting, is going to lead to an explosion of approaches these diseases, and that's really why that's why I came to Wave Live Sciences, and that’s what I wanted to bring. Hopefully, Wave Life Sciences and others are going to be pushing things forward to bring on new medicines that 5-10 years ago, we couldn't even imagine doing.

Transcript edited for clarity.