Insights on the Potential of WVE-004 for C9-ALS and C9-FTD

Michael Panzara, MD, MPH

Both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remain diseases with few treatment options; although, multiple patients with C9orf72-associated ALS (C9-ALS) and FTD (C9-FTD) have recently received the initial doses of WVE-004, an investigational treatment developed by Wave Life Sciences, as part of a new clinical trial.

Dosing began as part of the phase 1b/2a FOCUS-C9 trial (NCT04931862), with investigators expecting to enroll 50 participants. According to Michael Panzara, MD, MPH, the FOCUS-C9 study was designed to be adaptive, with dosing frequency and escalation subject to monitoring by an independent data safety monitory board. Additionally, the study adopts a basket-like design, as investigators are looking at patients with C9-ALS as well as patients with C9-FTD. Clinical data is expected to be generated through 2022, and Panzara remains hopeful that, like studies in oncology, investigators will be able to see if WVE-004 influences underlying pathologies, and if so, move the treatment along as quickly as possible. 

Panzara, chief medical officer and head of therapeutics discovery and development at Wave Life Sciences, spoke with NeurologyLive about the study, outlining its design, desired outcomes, and the potential WVE-004 could have for patients and their families.

NeurologyLive: How was the trial designed? 

Michael Panzara, MD, MPH: FOCUS-C9 builds upon some of our learnings from our earlier development programs in Huntington’s disease, and it deploys a new type of oligonucleotide backbone molecule that employs a new type of technology, which appears to increase the amount of oligonucleotide that can get into tissues and engage targets.

The possibility of single doses leading to durable effects is something that we've seen in our animal studies. On that foundation, the FOCUS-C9 study is targeting C9-associated ALS (C9-ALS) and FTD (C9-FTD). These are patients who have a hexanucleotide repeat expansion, which leads to several secondary effects that ultimately need to lead to neurodegeneration. These effects are, first of all, an insufficiency of normal C9orf72 protein, which is important in neuronal function and immune function. In addition, the expansion of the mRNA transcripts leads to the production of very long RNAs, which in and of themselves, are toxic. You have the toxicity of these extra-long mRNAs, which are also translated into toxic proteins called dipeptide repeat proteins (DPRs), and these proteins themselves are also toxic, and in fact, there's a sense translation and an antisense translation that leads to again, these toxic proteins. 

In this form of ALS and FTD, you have this haploinsufficiency, you have the toxic RNA, you have the toxic protein, and all of this through some mechanism leads to gradual neuronal cell loss and death. Our approach is to try to target the disease at that transcript origin and target that extended transcript it in a way that brings down all the toxic effects without impacting the normal C9orf72 proteins. You can do this by targeting different variants of the transcript, because there are several variants produced during transcription; one of those produces toxic effects, the others produce normal effects. The approach is to bring down those toxic transcripts, bring down the toxic protein, and leave the normal protein intact. You do this with an oligonucleotide, and you administer a short strand of DNA, RNA that is modified at the backbone level to be a little bit more stable and have other features, including this new PN Chemistry, which helps in its potency and durability. We do that by introducing it intrathecally, getting it into the cerebrospinal fluid (CSF) and then distributed throughout the central nervous system (CNS), engaging these transcripts in the brain and spinal cord.

The FOCUS-C9 study is designed to assess the impact of this intrathecal-administered oligonucleotide on the DPRs and 1 protein in particular, polyGP. The idea is, if we hit those toxic RNAs, we're going to lower the toxic proteins, and that is something we can measure in the CSF. 

We’re asking for patients who have C9-ALS or C9-FTD with this expansion, treating them intrathecally, and doing 4 cohorts of escalating doses. We administer a dose to a group of patients, we do lumbar punctures several times around each of the doses, and as part of those measurements, we're able to see whether the drug is affecting the polyGP protein.

We’re doing a basket-like study because we're studying ALS and FTD patients at the same time. Through the adaptive design, where we're dose escalating, and changing the dose frequency based upon an independent committee's review of the data for FTD and ALS patients, the objective is again to see, are we impacting these toxic proteins? Are we impacting other biomarkers like neurofilament light chain—which is a marker of axonal injury—and are we affecting other measures of disease activity, clinical imaging, etc.? Depending on the results of this study, this would inform our ability to do a registrational study in each of these populations, which would hopefully result in the measurement of positive effects in the clinical endpoints and thus allow it to become a treatment. 

The study is designed to be adaptive and change depending on the data and hopefully, accelerate as quickly as possible, because these are two areas, two devastating diseases with a lot of impact on patients and their families. The study is going to be driven similar to how studies are done in oncology, as oncologists look to see if drugs have an effect on the underlying pathology, and if so, they move them through the process as quickly as possible. We view these diseases to be just as devastating as cancer, so we tried to apply this approach, like our colleagues in oncology, and we're hopeful that we'll see a benefit.

What are you looking to observe, based on the outcomes being measured?

The key end point here is of course, safety and tolerability, because it's the first time the molecules have been administered to human beings. The key biomarker outcome we're looking for is this effect on these DPR proteins, in particular, polyGP.

PolyGP is the same biomarker that we measured in animal studies that had led to the development of the drug we're using, WVE-004. When we gave WVE-004 to an animal model (back transgenic mouse model) that had the hexanucleotide repeat gene in it, we saw dramatic reductions in polyGP, we saw a reduction in the mRNAs, and we saw that after 2 doses in a mouse, you can get this effect for 6 months. PolyGP is a very sensitive biomarker to reduction of these hexanucleotide repeat transcripts and proteins, so we chose that as the key endpoint to see if we can replicate what we saw in the animal models in humans. We’ll be measuring that throughout the course of this study, and with each cohort being dosed, that’s one of the key variables that the independent committee will be looking at, along with other things like safety and concentration of the drug, to determine how we should adjust the dose or whether no additional dose adjustment is necessary.

Can you speak to overall plans for WVE004, as well as future trials?

The immediate plan for WVE-004 is to get this biomarker outcome; the importance of this biomarker outcome can't be overstated. One of my earlier experiences was with multiple sclerosis (MS), and one of the big transformational moments that happened in MS was the realization that if you could impact an important biomarker on MRI, gadolinium enhancing lesions or T2-bright lesions, it was predictive of a beneficial effect on a meaningful clinical endpoint, and in the case of MS, that was relapses. 

For ALS and FTD, the ability to measure a biomarker that is so central to the pathophysiology of the disease, opens a huge amount of possibility to accelerate drug development, just like in MS. There are lots of MS drugs now because there was a biomarker that was indicative of effect of those treatments early in the course, which then allowed them to go to bigger studies. Should we see a change in the biomarker here, where the only explanation for that reduction is that we have done it with our drug and reduced an actual component of the pathophysiology of the disease, that would tell us that we are doing exactly what we set out to do, we are altering the natural course of this toxin, which will tell us that this is very likely to predict clinical effects in larger studies and longer studies. Sometimes it takes a little longer to see clinical effects versus a biomarker; typical MS studies take 2 years, [ALS/FTD] studies tend to be about 18 months to 2 years. 

If we see a positive effect here, this study will help us refine the dose level and how often we have to give it, with the potential to give it a couple of times a year, depending on the effect that we are seeing—the animal models suggest that is a possibility. Once we have the framework from this study that tells us the parameters of dose level, frequency, and degree of polyGP knockdown, that leads to larger studies that are focused on having a meaningful impact on patients.

The future holds here that if we can show that association between that polyGP knockdown and those clinical effects, future studies can be done faster; it opens a whole world of potential drug development for a C9-ALS. We’re excited not just that we hopefully have a drug that can improve the disease and slow down the progression, but that it opens up another approach to how other people and us can build upon that to develop additional treatments for this disease, as it has to start somewhere. We think that the structure of the FOCUS-C9 study and what it could trigger could have a dramatic impact on future drug development for these patients.

Transcript edited for clarity.