Transcript
[00:00:00] Intro: Welcome to Neurology Disease Deep Dive. In this episode, Dr. Merit Cudkowicz, MD, the Julianne Professor of Neurology at Harvard Medical School in Boston, Massachusetts, discusses the evolving landscape of treatment for amyotrophic lateral sclerosis, including FDA-approved disease-modifying therapies, the importance of genetic testing, the emergence of gene therapies, and the promising clinical trial pipeline targeting genetic and sporadic forms of ALS
[00:00:53] Host: Hello, everyone. I'm Joe Rusko, editor-in-chief of Practical Neurology, and I'm fortunate to speak with [00:01:00] Dr. Sukovitch today. Dr. Cudkowicz, please introduce yourself and tell us about your work in ALS.
[00:01:07] Dr. Cudkowicz: First of all, Joe, thank you for having me. I'm happy to be here. So I'm a neurologist. I'm-- I work at Mass General Hospital.
[00:01:13] I'm now the executive director of the new MGB Neuroscience Institute. I see people living with A- ALS, and my research is on, on, uh, ALS as well. Excellent. In thinking about DMTs in clinical practice, how are you currently approaching prescribing treatments for s- for someone who's newly diagnosed? Can you walk us through that, newly diagnosed with ALS?
[00:01:39] Uh, so the good news is that there are several FDA-approved drugs for people with ALS. So for someone newly diagnosed, I go through what those options are. So there's Riluzole, wh- uh, which has been around since mid-1990s and has reproducibly in many, many studies shown that it's safe and lowers-- slows the [00:02:00] progression by about 10%.
[00:02:01] So that's one. Uh, the second is Radicava, also known as Edaravone by MT Pharma. That one's only been approved since, I think, 2017. That one I have more of a discussion with because some studies have positive and some that weren't positive. So I go through a little bit about the pros and cons of that drug and which group it might work better in.
[00:02:22] The third one is a more recent drug, Qalsody or Tofersen, and that is a gene therapy for people who carry a gene mutation called SOD1 that causes their illness. And so we do do gene testing for all our patients. And if someone carries that gene mutation, then we try to get them on that drug as soon as possible.
[00:02:42] Host: Excellent. Thank you. What about managing patient and caregiver expectations about treatment options and delivering those type of messages? Any insights that you can share for someone who is perhaps not a specialist in this area?
[00:02:58] Dr. Cudkowicz: Yes, I think first of all, [00:03:00] there are things that we can do to help people with ALS today, and then there's a lot of research that we have a lot of hope for, but less certainty about how whether those drugs work or not.
[00:03:09] So I try to tell people what we know with confidence, the marketed drugs, and also that going to a multidisciplinary clinic, paying attention to your diet, your breathing, your exercise, all, uh, have been associated with better quality of life and longevity. So we can do all that now, and then to start to learn about the research, because there's many ways to be part of research, whether that's in a clinical trial, in a compassionate use study, or just in an observation study.
[00:03:36] Um, but it takes time. I mean, the good news is there's a lot of options, so it takes time to go through them and for people to decide if that's right for them and which one, and we work through that usually in person as well as phone calls. It takes some time. Excellent. Now I'm gonna jump to Qalsody. So you mentioned that it's approved for those who are s- SOD1 mutant, and you do [00:04:00] genetic testing for all your patients?
[00:04:03] Yes, we do. So we're very fortunate, at least in the United States, that the cost of genetic testing for ALS is free for the patient. It's covered by some pharma companies. They don't get your results, but they cover the cost, so we can do it right the day that we meet people, uh, if they want to do that, and then we get the results back in two or three weeks.
[00:04:22] And that's important because we don't want to miss anybody who carries an SOD1 mutation in particular. But also, there's other trials starting for the other genetic forms of it, so we really don't want to miss it in anybody. Excellent. That treatment is delivered intrathecally. So what about some of the challenges of delivering that therapy for folks who aren't used to doing that on a weekly or monthly basis, and, and then the burden's on the institution as well in having to kind of deliver that kind of care?
[00:04:53] The Qalsody's given monthly, so p- people do have to come back, and so it is nice for the patients to have [00:05:00] centers reasonably close to them. Some states I know and some areas have tried to consolidate and maybe built one clinic in a certain t- area that provides it, because it's a rare form of a rare disease.
[00:05:13] So for example, we, we have a clinic, it's actually every week now, and we see people from all over New England who have SOD1 mutations that come there. And so the more people you see, the easier it is actually to be able to do this. I call it, to be honest, our happy clinic. It's a really powerful clinic because you're giving a drug to people that makes a huge impact on, on them.
[00:05:33] The burden is, is figuring out, like, with your pharmacy, how to make it and, and deliver it, because you have to make it pretty much same day, the insurance. So again, having a few places that do it is good. But I'll say what really excites me is, is this innovation in neurotherapeutics, because there's now three other companies working on other ways to tackle SOD1 ALS, and, and one of them, Unicure, is doing a trial with an AAV [00:06:00] approach, a gene therapy approach, which is a one-shot treatment.
[00:06:03] Regeneron and Anym have a, another antisense oligo that's given, I think, every three months, and then there's a company in China, Retagen, that has another antisense that I think is given a little less frequently. So I don't know that they'll be better or the same as Qalsody, but there is a need to develop an approach that can be given a little less frequently.
[00:06:22] Host: Exciting to hear about these more options, and that leads me to my next question, which is all about the pipeline, and a- as you've discussed previously, there's lots going on in this field. What are some of the promising new therapies that you're looking at that are in clinical trial stage?
[00:06:39] Dr. Cudkowicz: I'd probably divide them up into the ones for the genetic forms and then for the non-genetic forms.
[00:06:45] I, I think for the genetic forms, there's a global trial, for example, of a gene therapy against the gene mutation F-U-S, or FUS. That work has really been pioneered by Dr. Neil Shneider at Columbia, but now it's in the Phase III, and, and we're very hopeful [00:07:00] for that. There's also a program called Silence ALS that Dr.
[00:07:04] Shneider is leading, that is, has some federal support to custom make gene therapies for people who carry a gene that maybe is, is rarer and doesn't have a, a commercial partner behind it. So another reason to test everybody is if you f- if you find someone with a gene mutation that maybe there isn't a trial for, you can approach the Silence ALS program to see if that might be an option.
[00:07:27] So that's one group. And then for the sporadic, for people without a known gene, I'm excited about a couple things. So our Healey ALS platform trial we're about to launch, we've publicly shared with two companies, Transposon and Neuryson. They both have drugs ready for phase II, III, and we have a third one that we're working with.
[00:07:47] One of the drugs works on something called autophagy or the cell death pathway. Another works on, on this idea of skips in your DNA that might cause proteins to be, be made incorrectly and can [00:08:00] fix that problem. Those are coming this fall. There's also a couple companies with really targeted approaches against the protein TDP-43 that is in the wrong place in the cell in ALS and aggregated.
[00:08:13] So it's really one of the most important targets. There's a company, Vectory, that's developed an antibody that they deliver using gene therapy, goes into the motor neurons to try to disrupt that aggregate and get the TDP-43 back in the right place. They're planning a phase I trial. And another company, Celosya, that has a g- another gene therapy approach targeting also that same protein, TDP-43.
[00:08:38] So those get me excited because I think they're getting closer to one of the fundamental things that's going wrong in the motor neurons. What about some of these other therapies that aren't necessarily DMTs but also could be used for su- supportive reasons, like the stem cell therapies? Some of them look promising, and how would you discuss with the clinician how to interpret [00:09:00] the early signals from those trials?
[00:09:01] I, I think that, that some of the early signals in stem cell trials have been not that clear. So there's two companies, for example, that use mesenchymal stem cells. Those are the cells from your bone marrow or from your fat that turn into your red or white cells, and they use them as a way to deliver proteins that can block inflammation, and they've had some mixed results.
[00:09:23] So, like, Brainstorm had, overall the trial was negative, but they had some hopeful signals in people early in the illness. And then an- the other company, Corestem in South Korea, they also overall had a negative study, but they also s- think that there might be a subset of patients that responded. So it brings up this really key question in ALS, is that it might not be all the same in everybody.
[00:09:48] Maybe there are some people who respond better to a drug than another. For right now, I wouldn't recommend any of my patients go and get stem cell treatments, but I think if these trials come out in different subsets, I would [00:10:00] encourage them to think about that. Appreciate that. Thank you. What about SPG302, which recently entered clinical trials?
[00:10:08] Can you tell us a little bit about how this would work with ALS? Yeah, this is a new drug by Spinogenix, and I'm, I'm excited about their drug. So, so I put it in the class of what I call repair drugs. So the exciting thing in ALS is people are actually using the word repair. You know, could you actually help people get function back, which is really what people living with the illness want as well.
[00:10:35] So their drug works on something called dendrites, which are the connections between neurons, and we see those dendrites go away or retract in ALS as well as other neurodegenerative diseases, and that's their target. And so they've done a small study in Australia, 24 patients followed for six months at least, and also some compassionate use studies in the US, and so they have good safety signals, [00:11:00] and they haven't announced their results of the Australia study yet, but people are waiting for it and are excited about the science.
[00:11:07] And they've also have FDA approval for compassionate use program as well So it sounds like there may even be the potential for a cocktail of different therapies that, that might be used in certain patients depending on the outcomes of some of these studies. Yeah, absolutely. I think we're gonna be like cancer where maybe each drug has an effect, but it's really when you combine them, and you target different parts of the biology where, that you see the big effects.
[00:11:33] And I actually think that might be also where some of these repair drugs will really help. So, for example, go back in, back to the CalSadi, the gene therapy trial, we saw up to 40% of people get some improvement in one or more measures, whether that was breathing or strength- Right ... or function, but not everybody.
[00:11:52] And then the question is, could, could you layer on maybe drugs that work more on repair to that drug 'cause it slowed [00:12:00] it down, you have time
[00:12:00] Host: Now you mentioned the Happy Clinic that you're, that you're working with there. Mm-hmm. What about access and barriers that you see elsewhere in treatment of ALS?
[00:12:11] Are there programs that clinicians can connect their patients with, with care in other regions, for example?
[00:12:17] Dr. Cudkowicz: I, I think in ALS, and probably other neurological illnesses, multidisciplinary care has really been shown to make a huge difference on quality of life and longevity. So it really is good for people with ALS to get to ALS clinic, but they don't exist everywhere.
[00:12:34] And I think the number of people with ALS is going up, and so the wait times are actually going up. I'm hearing from, from people that it's getting harder and harder to get even appointments in the ALS clinics. So my advice would be, if you've seen someone with ALS, is to try to, try to get them to the closest ALS clinic.
[00:12:52] There's also a company started by some people living with ALS called Synapticure that provides more [00:13:00] virtual health to ALS care for people who might live in communities where there isn't an ALS center, so that's also an option. And then there's some really good foundations like Compassionate Care ALS, and the ALS Association, the Muscular Dystrophy that also do home visits and provide lots of access to equipment and other supports for patients.
[00:13:21] I might add that ALS has really grown as a field that wants to make sure that everybody living with ALS has options for new treatments. So there was this bill passed a couple years ago called Act for ALS, which funds compassionate use programs. And why that's important is that a lot of the clinical trials as, as we get to more smaller and smaller subsets of people, when we try to target the right person for the right drug It leaves a lot of people without options for trials, and that's where the compassionate use programs come in, so that they, uh, as long as it makes, you know, sense clinically and research-wise, that people can have that option if they can't [00:14:00] be in a clinical trial.
[00:14:01] And that's what the Spinal Genix folks are doing. The SPG302 drug, they're providing it now I think for up to 200 people on a compassionate use basis if they're not eligible for a clinical trial. I think that that's unique in the neurology world, the scale of it, but it's because of how serious an illness it is.
[00:14:20] Host: Excellent. Well, I appreciate your time today. Thank you so much.
[00:14:23] Outro: Thank you to Dr. Merit Cudkowicz for sharing her knowledge with our listeners in this episode of Neurology Disease Deep Dive. Be sure to visit practicalneurology.com for more podcasts in the field of neurology. Neurology Disease Deep Dive is brought to you by the editors of Practical Neurology.
