NeuroVoices: Rita Sattler, MD, MSc, on 2024 MDA Conference and Advances in ALS Research

Rita Sattler, PhD, MSc

An annual event, the Muscular Dystrophy Association’s (MDA) Clinical and Scientific Conference is a way for clinicians in the neuromuscular field to stay up to date on the latest developments in research and clinical care. Beginning on March 3rd and running through the 6th, the conference will include over 50 sessions, 180 speakers, 56 exhibitors and patient advocacy organizations, and 16 industry forums. The event is comprised of 6 major tracks, focusing on Clinical Considerations, Lab to Life, Clinical Approaches to Streamlining Care, Practical Consideration in Gene Therapy, Disease Mechanism & Therapeutic Strategies, and New, Novel, and Noteworthy: Neuromuscular Disease Highlights.

Rita Sattler, PhD, MSc, a professor in the Department of Translational Neuroscience at Barrow Neurological Institute, will lead a session on translational research in amyotrophic lateral sclerosis (ALS). Over the years, the research for ALS has continued to mount, capped off by the FDA approvals of AMX0035 (Relyvrio; Amylyx) and tofersen (Qalsody; Biogen) in 2022 and 2023, respectively. In addition, there are several emerging biomarkers that have shown promise in preclinical settings that are now being translated into drug development trials.

In an interview with NeurologyLive®, Sattler discussed the upcoming track session in detail, including some of the educational takeaways clinicians can lookout for. In addition, she provided thoughts on several other ALS-related topics, including the emergence of biomarkers, a greater understanding of the epidemiology of the disease, and improvements to clinical care. Furthermore, she spoke on the approval of tofersen based on surrogate neurofilament light and whether future drug development will mirror this approach.

NeurologyLive^®: Can you provide an overview of what your track will entail?

Rita Sattler, PhD, MSc: We're really excited to be present at the Muscular Dystrophy Association conference that's coming up in a few weeks. And what we were hoping to do was really build on the excitement in the field of ALS, in particular about trials that have happened in the past that were successful, and led to approval of new drugs for individuals with the disease. But also for a lot of ongoing trials that are happening right now that many people in the audience, clinicians, but most importantly, the individuals affected by the disease, are really excited about. So based on that background, we thought it would be really important to highlight some of the technology advancements that have been made over the last year that have led to where we are right now, and will lead to where we go from here. And that includes novel technologies regarding how to remodel the disease, gene therapy, genetic analysis, and genetic discoveries that will lead to gene therapy approaches, and really provide an overview of just the highlights of what has been done, what has been worked on. What are we putting into the clinic right now? How do we monitor clinical success during clinical trials by using novel biomarkers that are being developed? And then really, at the end of our track, we decided that we want to put together a panel discussion about two very new consortia that have been founded and put together. One is called AMP ALS. The other one is called ALL ALS. And the idea behind those consortia is to really utilize a platform of facilitating a coordinated multi-institutional approach to collect big data on persons with ALS, but also those that are at risk with ALS and regards to clinical and biomarker data. We're really excited that these individuals who are having these consortia have agreed to come and discuss their ideas and what they want to do, and to highlight to the audience how the audience could potentially participate in these efforts.

Among the emerging biomarkers, what excites you?

That's a loaded question, but I'm happy to see how I can filter it down. I think the most important thing and the exciting thing that we see in the market development is that it's an emerging field. It's not just focusing on one sort of functionality of biomarkers, but starting to encourage integrating multiple biomarkers, and multiple modalities. And so I would probably categorize them into three categories. There's the traditional as I would see fluid-based biomarkers, where we collect CSF or blood recently, also urine, where we're looking at changes in protein or RNA levels that we can detect in those fluids that we can collect from individuals who are generous enough to participate in these clinical studies and allow us to do this research. But there is also a lot happening in the imaging field. There are a lot of new ideas on how we can utilize MRI and PET to diagnose or really also follow the progression of disease of individuals and persons with ALS.

Lastly, there is also what people most often refer to as neurophysiological measures and methods where you're going to measure sort of electromyography-based measures where you measure muscle strength, but also extra motor cortical biomarkers where you do EEGs or MEGs, that could be sort of really providing either a pharmacodynamic biomarker to see what changes in the circuitry in the muscle strength, but potentially also diagnostic biomarkers. And so having said all that, I think there's not going to be one single one [biomarker] that is going to be the golden ticket for all of us. I think what we need to understand is that we're probably going to need a combination of biomarkers. And depending on what clinical trial is being designed, we may pick one biomarker that sort of measures the overall changes in the outcome and the progression of the disease and we might pick another biomarker that would be more of a pharmacodynamic biomarker to sort of see, do we have targeted engagement of the intervention that we're giving to the individuals?

Tofersen was approved based on a surrogate biomarker of neurofilament light, do you believe this will become more of the standard going forward?

The discovery and the development of neurofilament was really an incredible advancement. For us to diagnose and follow individuals in their disease progression by using this very easy non-invasive, fluid-based biomarker—because we do not only develop or detect it in CSF—but we can detect it in plasma, which is a much easier, non-invasive way for us to collect a biofluid. Neurofilament has been shown in other neurodegenerative diseases. It's not very specific to ALS, that's one sort of slight disadvantage of it. However, it tends to be much higher in patients with ALS over other neurodegenerative diseases. That’s as an advantage for us to utilize this either in combination with drug trials, but also in potentially diagnosing individuals that are at risk for ALS to see whether they convert into an individual that is now at least on a molecular level, showing signs of having a manifestation of the disease.

The mechanisms of what happens with neurofilament when it's released into those bioflow is not yet quite understood. We tend to think it's because of the destruction of the axonal structure and the integrity of the neuron that we see an elevation of neurofilament as a consequence, but there are a lot of ideas and thoughts that an increased expression of neurofilament could also be sort of protective mechanism of the cells as a response to the stress and the pathology that the neurons undergo. I think a lot needs to be done to really truly better understand what these increases in neurofilament really mean biologically. Meanwhile, having said that, I firmly believe that having NFL measures in clinical trials is incredibly helpful. But what I see is happening, as I alluded earlier, I think we need to use it in combination with other biomarkers. We can use it as a biomarker to see changes overall, but we need a more specific biomarker that gives us target engagement information, and potentially is really sort of targeted towards the individual therapeutic that we're utilizing that we're trialing in those clinical trials that are ongoing. Don't know whether that answers your question, but that's sort of where I am at.

Where have we improved the most in the understanding and biology of ALS?

I think our biggest improvements or advancements were based on I think, for now, two technologies that have really changed how we study ALS, how we research earliest and how we then develop novel therapeutic targets and developments. And that is genetic analysis and sequencing abilities. I think that has changed the field completely the fact that we have better technology to find genetic variations, and variants that are responsible and that are triggering ALS, or that present a risk factor for anybody to developing ALS. And the other one is how we model these diseases. In addition to the traditional animal models that have been developed, when we first started looking at ALS when SOD1 was uncovered and degenerated mouse models based on that mutation. I'm a strong believer that the human model system using induced pluripotent stem cells that are derived from patients that are reflecting the disease pathogenesis, but are very easy, manipulated, and really reflecting a human disease model system that still have the genetic background that comes with the individuals that have this disease. I think the combination of those two really allowed us to dive into the cellular and molecular changes of the disease more so than studying the behavioral changes, utilizing an animal model. And this that comes, I think, an education on what potentially triggers the disease early on, what molecular changes are happening before we see clinical symptoms in patients. And that in turn, spirals down to the biomarkers that we develop by having this knowledge. TDP-43 and the cryptic exons are a perfect example for this.

Without understanding the biology of TDP-43 and its dysfunction, we would have never uncovered RNA splicing defects that lead to this very atypical change of RNA structure and the cryptic exon inclusion, which in turn can lead to the translation of what we call cryptic peptides, which in turn, we can now detect in as biofluids of patients with ALS. The goal and the hope is that we can detect this very early on in the disease, which means we can intervene earlier if we have an appropriate therapeutic strategy. But having said that, I think if you would ask me a year from now, [we are] probably [going to] add two more new developments to this. One of these for sure is artificial intelligence. I think this is going to make a huge impact on how we utilize all of the data that we're generating right now and how we look at this. And the other are new approaches and new ways of using gene therapy approaches. Probably at some point CRISPR based, once that is fully understood and developed, there are really incredible opportunities that might allow us to—I'm always afraid to say this—actually have an opportunity to potentially cure this disease by genetic approaches.

Do you envision studies in the future assessing the prodromal phases of ALS?

I absolutely do, 100%. I'm really excited about opportunities that we have now to integrate and include individuals that are at risk of developing ALS, which for the most time, means that these are individuals that have been genotyped and know that they have a genetic variant that is causative of ALS, not 100%. But there's a high probability that if you have a genetic variant, depending on which one there's, at now, we're probably at about 50 variants that have been identified that are causative of ALS, if we can integrate those individuals into our clinical trial design, and utilize the knowledge that we now gain of identifying early molecular changes, where we can say we see a conversion of An at risk person to somebody who is now developing a molecular change that is indicative of ALS, and immediately, including these individuals into the clinical trial design, that is going to be a life-changing event. And I know a lot of these individuals very well, that are genetic carriers, that are really at risk of developing the disease. And I know the community is very excited about the opportunities that are now available, that they can be included in the clinical trial design. And we see this with so the one mutation carriers that now we have a first what we call pre-symptomatic clinical trial designed for these individuals that are at risk with SOD1 to be included based on their neurofilament level changes to be involved in the antisense oligonucleotide treatment for sad one. And I think this is only going to be the beginning. And I'm extremely hopeful and positive that this will become a much more common theme.

Transcript edited for clarity.