BioBiz Buzz

15. Targeting Misfolded SOD1 in ALS: A First-in-Class Antibody Shows Promise

• https://biobizbuzz.com/ • Season 1 • Episode 15

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This episode of BioBiz Buzz explores AL-S Pharma's pioneering approach to treating amyotrophic lateral sclerosis through AP-101, a first-in-class monoclonal antibody targeting misfolded SOD1 protein. Host Mike Ward speaks with Dr. Michael Salzmann, CEO of AL-S Pharma and COO of Neurimmune, and Professor Angela Genge, CMO of AL-S Pharma and Professor of Neurology at McGill University.

The conversation examines the devastating impact of ALS, a progressive neurodegenerative disease that typically leads to death within three to five years of symptom onset, and the profound unmet need for disease-modifying therapies. Dr. Salzmann explains how AP-101 was discovered using Neurimmune's proprietary Reverse Translational Medicine platform, which leverages human immune responses to identify antibodies that selectively bind misfolded and aggregated forms of SOD1 while sparing normally folded protein. Professor Genge discusses the intriguing evidence that misfolded SOD1 may play a role not only in familial ALS patients with SOD1 mutations but also in sporadic ALS patients without known genetic causes, potentially expanding the therapeutic opportunity to a much broader patient population.

The Phase 2 study enrolled 73 ALS patients, both sporadic and SOD1 mutation carriers, and met its co-primary safety and tolerability endpoints while demonstrating clinically meaningful changes in exploratory outcome measures, including survival, ventilation requirements, and neurofilament biomarkers after 12 months of treatment. The guests explore the unique collaborative ecosystem that enabled this progress, including the partnership between Neurimmune and TVM Capital Life Sciences, and discuss AP-101's Orphan Drug Designation from the FDA, EMA, and Swissmedic. 

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SPEAKER_01:

Welcome to BioBiz Buzz, the podcast where we explore the cutting edge of life sciences innovation. I'm your host, Mike Ward, and I'm also the global head of thought leadership for life sciences and healthcare at Clarivate, which is a multinational provider of intelligence, insights, data that the life sciences industry actually uses to accelerate its innovation. Amitrophic lateral sclerosis, or ALS, uh remains one of the most devastating neurodegenerative diseases affecting patients worldwide. It's a progressive disease that uh attacks motor neurons in the brain and the spinal cord, leading to uh paralysis and uh typically death within uh three to five years of uh symptoms onset. For decades, uh the ALS community has been searching for disease-modifying therapies that could actually genuinely alter the course of this relentless condition. So today's episode actually focuses on a Swiss biotech that's actually taking a novel approach to tackling ALS by actually targeting a key pathological protein. The company ALS Pharma was created in 2016 through a unique partnership between Neuroimune and the venture capital firm TVM Capital Life Science. And it was created to specifically develop a compound called AP101, which is a first-in-class monoclonal antibody that is targeting misfolded SOD1 protein. And in fact, in September 2025, the company actually announced some positive phase two results showing that AP101 not only met its primary safety tolerability endpoint, but also was able to demonstrate clinically meaningful changes to other exploratory outcome measures. So joining me today are actually two of the leaders who are driving this groundbreaking research. So we have Dr. Michael Salzman, he's the chief executive officer of LS Pharma, and actually he's also the chief operating officer of Neuromune. He has a PhD in biophysics from ETH Zurich, where he actually studied under the Nobel laureate Kurt Vutri. And Michael has got more than 15 years of industry experience from companies that actually include Roche and Brooker. Also with us is Professor Angela Genj. She recently joined ALS Pharma as the chief medical officer. So Dr. Genj is the Professor of Neurology at McGill University in Montreal, Canada, and is also the head of the ALS Global Centre of Excellence for Research and Patient Care at McGill. Professor Genj is in fact an internationally recognized leader in ALS clinical research, having served as a global principal investigator, pivotal ALS trials, and has participated in more than 80 global clinical advisory boards and trial steering committees. So an absolute wealth of experience. Her contributions have been recognized with prestigious awards, including the Forbes Norrie Award and the Wings Over Wall Street Diamond Award. So, Michael, Angela, thank you very much for joining us on BioBiz Today.

SPEAKER_02:

Thank you for having us.

SPEAKER_01:

It's all my pleasure. So actually, I've got to sort of get a sort of a grasp of what the ALS landscape and unmet need looks like. So, Angela, I'll start with you. You've dedicated your career to ALS research and also patient care. So, can you paint a picture for our listeners as to what the current landscape actually looks like for ALS patients and also their families?

SPEAKER_00:

Thanks, Mike. Great question. I have spent a lifetime on this. The current landscape is probably the strongest that I've ever seen in terms of drug development in ALS. And we'll probably talk about this again later. For patients, the immediate situation is that there are three approved drugs, not approved consistently around the world, but most jurisdictions have Rilazol, which was actually first approved in 1995, and some jurisdictions have Raticava. But what we see happening is a tremendous interest and a much better, more targeted approach to ALS in terms of targeting proven pathology that triggers the disease. So the reality is patients want to join clinical trials and drug development. They understand that this is where oncology was 30 years ago, and they want to get in on these therapeutics that could change the future for them and for their families.

SPEAKER_01:

Right. So we will definitely dive in a little deeper. So, Michael, so ALS Pharma, it was created as essentially a single asset company specifically to develop AP101. And you create that company alongside TVN Capital and Neuromune. So can you actually explain how the partnership came about and actually how it works?

SPEAKER_02:

Yeah, sure. So Alice Pharma was co-created in 2016 by Neurimune, which is a successful biotech company, mainly in the neurodegenerative phase and TVM Capital Life Science, with the objective to develop AP101 for the treatment of ALS. So both investors, I think that's important, not only provided funding, but they also provided development expertise. I mean, this certainly is true for Neuroimune, as this is a biotech company, but also TVM Capital. You know, there are a lot of these partners, they have a background in science, a lot of history in biotech. So I think that was a key asset to uh developing AP101. The antibody was originally discovered with uh Neuromunes technology, which is a clinically validated platform for identifying human antibody therapeutics to target and deplete misfolded proteins in uh protein aggregation diseases. And I have been the CEO of Alice Pharma, as you also laid out in the uh introduction, in addition to my main assignment of being the COO at Neuroimune. So I think the model overall proved to be highly effective in advancing a preclinical stage acid through phase one and phase two clinical development.

SPEAKER_01:

Right. Let's sort of take a deeper dive into the science. Angelo, for our listeners who aren't familiar with molecular basis of ALS, can you explain what SOD1 is and also why actually misfolded SOD1 has become such an important therapeutic target?

SPEAKER_00:

Thanks, Mike. So SOD1 is a protein that is ubiquitous around the human body, uh, but became identified with ALS in 1992 when the gene, the first gene was discovered as a genetic mutation causing a dominant form of ALS. A number of big families, people researching big families got together, identified SOD1. When it was identified, the decision was, the research then focused on whether this abnormality in the SOD1 gene creating an abnormality in the SOD-1 protein was causing what we call a loss of function or a gain of function toxicity. And in the end, what was what has been discovered is that the SOD-1 mutation creates abnormal forms of SOD1 that misplod, and then the toxic conformers, particularly the oligomers, become toxic to the motor neurons and they directly cause motor neuron cell death. The next step in the understanding of the biology occurred in around 2010, but has progressed since then, in which it was identified that not only did misfolding occur in this mutant or genetically modified forms of SOD one, but also in what we call wild type SOD 1, which is the SOD one we have already in normal people, and that if that wild type SOD 1 misfolds, it can also trigger motor neuron cell death, which is the underlying cause of ALS. So that really is a basis for what we're doing with ALS pharma after recognizing that misfolded SOD one could trigger death of motor neurons and therefore this disease in first in the familial cases with the mutation, but now also in the sporadic cases, we come at a target that we can now treat with our drug that occurs in many patients with ALS, not just a select few.

SPEAKER_01:

I mean, that's interesting. I think I'll come back, sort of explore that. But but Michael, you you mentioned in your introductory remarks about how AP101 was actually discovered using sort of neuroimmunes proprietary reverse translational medicine platform. Now, that's clearly a sort of a different approach from sort of you know traditional drug discovery. So can you sort of walk us through uh how that technology works and how it helped you find AP101?

SPEAKER_02:

Yeah. So the RTM, that's how we called it, platform is based on analyzing human immune responses to disease-related proteins in selected populations. So selected populations may be, for example, healthy individuals or healthy elderly people with absent diseases, although they have a certain risk factor for diseases such as neurodegeneration, which of course occurs in at old age. So the RTM process translates genetic information from human memory B cells into selective high affinity antibody candidates. And the advantage of that approach is that the antibodies are optimized by human affinity maturation and the tolerance selection mechanisms in the human biology, and these antibodies can therefore discriminate between a target protein in its physiological conformation and a misfolded toxic conformer that plays a very different role, right? So, in the case of AP101, when I relate to what Angela just explained with SOD1, we discovered an antibody that is highly selective for misfolded conformers of SOD1 that are believed to be toxic. And the antibody does not bind the physiological protein, which is actually a very important protein in the human biology.

SPEAKER_01:

Right. So, Angela, I mean you you've been very much involved. I mean, I know you just recently joined the company as the CMO, but you've been involved in AP101 in the sort of the clinical development program since the beginning. I mean, you were there as a sort of the global principal investigator. So in the sort of the phase one and the phase two studies, can you sort of describe what was involved in the clinical trial design there? And specifically, what were you actually looking to see?

SPEAKER_00:

What we're really looking for in phase one is safety and tolerability of a new molecule, right? So we have with AP1, we have a very strong safety profile. We've not really seen any dose limiting side effects in the preclinical or the clinical program. But the phase one was done using an oncology design, really in recognition of how fatal this disease is, and really demonstrated a very safe molecule, and also gave us some information on the amount of the drug that penetrates into the brain and spinal cord where the pathology exists. It's the motor neurons die in your brain and spinal cord. With a very clean signal again, out of the phase one, we've embarked and now have completed our phase two. The phase two program really was to look at more long-term safety and toxicity. So it's a multi-dose study. And because of this evidence that misfolded SOD-1 plays a role in both SOD-1 ALS and sporadic ALS, we designed it to have two separate cohorts. One with sporadic ALS, meaning that there were none of the participants had a SOD-1 mutation. And one participant or couple had a very rare mutation, but it was purely those patients who had no genetic underpinning. And then a second cohort, which was people carrying the SOD1 mutation, one of several, we gave it wide open. Whatever SOD1 mutation you had, you could enter. And the ratio was two to one treated to untreated. With the program, we were able to follow people in a double-blind manner for 24 weeks and then extend it in an open label extension, giving everybody the drug for another 24 weeks. And then there was a period of 16 weeks in which we did safety follow-up. So all patients in the program received AP101 in the second phase. Only the first phase had groups that included placebo. And what we followed in that, because it's a phase two, we continue to follow safety and tolerability, but we also followed very closely the key clinical outcome measures in ALS. First survival, then function, which is the ALS FRSR, and the stags. But we also ensured that we looked at very specific biomarkers, one developed with AP101 as part, and the neurofilament story, we included it. And we have a couple more outcome measures, particularly quality of life, that the patients uh participated in throughout the duration of the program.

SPEAKER_01:

Right. And one of the things I want to sort of pick you on, you sort of mentioned earlier, is you know, around, for example, the SOD1 or SOD1 mutations, but you also sort of referred to the sporadic ALS patients who don't actually have sort of that known genetic cause. So I'm sort of thinking this seems to almost like challenge the traditional view of how SOD1 actually contributes to ALS. So can you sort of explain what's going on?

SPEAKER_00:

Yes, absolutely. So there has been a lot of uh work done actually that demonstrate that misfolded SOD 1, wild type misfolded SOD 1, actually is relevant in the sporadic, in the pathogenesis of sporadic ALS. And that information has been building over time. The most recent article was just last month, and it reviewed all of the data. It came out of Sheffield, reviewed all of the data regarding misfolded SOD 1 in sporadic cases, 15 different experiments, and their strong conclusion was to use these misfolded SOD 1 as a target in sporadic disease. We had that story much earlier, and what we, in part of what we did pre-starting the phase two, was doing a couple of studies where we looked at the presence of the misfolded SOD 1 that AP101 targets in sporadic cases and compared that to normal controls in SOD 1. And lo and behold, we saw a very significant number of patients deemed sporadic, no genetic mutation, that actually had clear evidence of misfolded SOD 1 with the AP101 target in their CSF. We repeated that at baseline in our patients in our phase two study, and it replicated the same results. So although the traditional old school way of looking at ALS is that misfolded SOD 1 is only relevant in familial disease, we have clear evidence now that it is relevant also in individuals with sporadic disease.

SPEAKER_01:

So but when companies are developing sort of your new medicines, I mean they like a biomarker. And so you're having a genetic mutation that you can look for is clearly an elegant way of identifying potential patients that you would have in clinical trials. So I'm sort of thinking that with the fact that also it's patients without those SOD-1 mutations, how do you go about identifying the potential patients? I mean, are there other biomarkers or other diagnostic tools that you're able to use?

SPEAKER_00:

So the diagnosis of ALS is done clinically and with the support of evidence from clinical tests like EMG. I think the question buried in your question is how would we identify which patients would respond to this drug, right? And at the beginning of our program, our main objective was to document that sporadic patients, other than safety intolerability, was that sporadic patients, patients with non-genetic forms of ALS, actually have misfolded SOD one that is circulating in their system and could very well be the cause of their motor neuron cell loss. And we've done that now in phase one and we've done it again in phase two. And then the question will be going forward is do we have a method of determining that which patients who are sporadic have the best chance of responding to a misfolded ASOD-1 therapeutic? And that is very much a part of our development program.

SPEAKER_01:

Right, right.

SPEAKER_00:

So we haven't stratified for anything in particular in the phase two program except the genetic mutation. And that has given us a very comprehensive look at what the opportunity is for treatment response.

SPEAKER_01:

All right. Yeah, and that's sort of yeah, interesting. And also clearly still a challenge. So, Michael, you you you were describing almost like an ecosystem. So where you you had TVM, you had neuroimmune, and you have LS Pharma. How does it work? What is the sort of the process of this model in practice? What advantages do you think that you've gained from having that relationship with both neuroimmune and TVM?

SPEAKER_02:

Well, I think as a single asset company, the complementary expertise that each partner brings to the table is probably the key. So neuroimmune's role, of course, is providing the antibody with discovery expertise, clinical validation expertise through the platform. TVM brings the capital, of course, the expertise in strategic guidance for drug development. So I think that is probably when it comes to the two founders of the company. However, as a small company, we uh collaborated with, for example, a very large uh CDMO for manufacturing the drug substance, drug product with a highly reliable process. We collaborated with many contract research organizations for clinical operations, statistics, biomarkers, whatever. But I think it also boils down a little bit to passion. You know, I think Alice Pharma has really a passionate team that is dedicated to develop AP101. And that also transmitted, I believe, uh somehow into our collaboration with our clinical investigators around the world, that basically without them the trial would not have been possible.

unknown:

Right.

SPEAKER_01:

I mean, is that your experience, Angela? I mean, you know, the fact that you're actually at the clinical coalface, that sort of that collaborative ecosystem. You know, how does it manifest itself in terms of facilitating the sort of the research in meaningful ways?

SPEAKER_00:

So I think it's been a tremendously effective, honestly. It's really played to the strengths of each individual partners. And it has then led to another key driver in this program, which is that it's a very international program, right? So there were no barriers because everyone was set up in one individual country, because TPM is international. ALS Pharma and Nirmune are based in Zurich, but they have a very international view. So we were able to essentially get an international trial run from a very small company. We have regulatory approval in the US, Canada, Europe, Asia. We have orphan drug designation in four regions for this molecule already, even as we're ending phase two. So we have experience in the Asian population, we have experience in Europe, we have the experience in the US and Canada in a relatively small project to date. So everyone will be waiting to hear the next round of results. And that I believe will make the next steps much more efficient because we are not starting from scratch in any major jurisdiction. We are going in on a basis that they already know the program.

SPEAKER_01:

Yeah, and then as we look at the sort of the almost like the international scale of what you're doing, I mean, the AP101 has achieved orphan drug designation from the FDA, EMA, Swiss Medic. So, Michael, so how, for example, does that orphan drug designation actually sort of just shaped your regulatory and commercial strategy?

SPEAKER_02:

Well, you know, the overarching idea of the orphan drug designations, mainly, of course, in the big jurisdictions like uh the US and the EU, is to support drug development in diseases that are not very frequent. And if you look at the disease, I mean, you you said it in the introduction, it's a devastating disease. ALS is really, I mean, it's such a bad disease, it's considered not that frequent. So I think that to go for, as a drug developer, to go for the orphan drug designation is not only to get the benefits that are associated with these labels, such as additional market exclusivities for a couple of years, or tax credits for clinical trial expenses, or exemption from certain FDA user fees and you know, uh, eligibility for expedited regulatory pathways. But it really facilitates the interaction with regulators and so the importance of these designations for a rare disease like ALS is that it really helps make development economically viable for a smaller patient population.

SPEAKER_01:

And Angela, I mean you mentioned earlier about the fact that the ALS therapeutic landscape has expanded. So we've got gene therapies, we've got antisense oligonucleotides, and there are other approaches. So when you're sort of thinking about AP101, how is that going to fold into that ecosystem? Is it is it going to be sort of complementary to some of these other approaches?

SPEAKER_00:

Another great question, Mike. So the thing about monoclonal antibodies is we know how to give them, we know how they work, we have a beautiful safety profile. And monoclonals can work very quickly, right? We don't have to wait six to nine to 12 months to have an effect with the monoclonal. If the target that it's removing from circulation is a primary disease driver, then AP101 removes that misfolded SOD one, protecting the motor neurons from further damage. And it doesn't take a long time to be active. You give it, and it's within the CNS, within 72 hours. And with the very clean safety profile, we have opportunities again in the dosing and other ways. But I think for patients living with this disease, the idea that you can give a drug and it will have an effect relatively quickly is a really big positive. Not having to wait for the mechanism to hit means that they can hope for response that will keep them stable now, not in six months from now. I think that's a really important part of what monoclonals have demonstrated in many different diseases, both neurodegenerative, and if you look into the work in other targets in other disease areas, monoclonals are well understood. They work fast. If they hit their targets and their targets are important, you see a result.

SPEAKER_01:

Yeah. So yeah, let's talk about the patients because we've sort of talked about, you know, sort of what are devastating and how quickly the sort of the disease progresses from sort of the initial onset to ultimately in many um it's it it does involve in death with three to five years. So with all this going on, in your conversations with patients, how are they sort of viewing the sort of the emerging therapeutic landscape that's taking place? And and also to the point of you know sort of being patient-centric, how has some of what you've learned from those conversations actually sort of helped shape what you're doing at Alice Pharma?

SPEAKER_00:

So the patients want treatments that work and for themselves initially, no question, right? They're motivated by, they may be motivated personally or by their families, or they want to see their kids growing up or something. They're motivated to have uh find a drug that has an effect right away. As the disease progresses, there's very, very frequently an additional altruistic component here, where they're also want to make sure they can do something for their families or they do something for their community so that no one else has to go through this. But we need to really respect the fact that if a drug is available that can have an effect relatively soon after they start the drug, they are more than willing to have that treatment. We're entering with an IV formulation at a time when giving drugs IV is now standard. It's been since the early 90s, since I've prescribed drugs IV every two weeks, every three weeks, every four weeks. So the formulation is not a barrier. Healthcare systems in most places in the world can handle it. And the idea that if you give something IV, you can get a response relatively quickly is certainly something that really helps the patient.

SPEAKER_01:

Right. So we're we're sort of getting really, really close to the end of the time. So, Michael, when we sort of look at you know what happened in the phase two trials, you know, what are the next steps? And particularly also other sort of other potential uses for AP101 into other neurodegenerative diseases.

SPEAKER_02:

So the path for the next steps is paved. I mean, it's of course the presentation of the full phase two data to the community at the upcoming ALS M and D conference in December by Angela. Uh, we engage with regulators in the US, Europe, and other markets to discuss late-stage development and to also to explore potential for accelerated approval pathways. We are engaged. Uh Angela, of course, I'm very happy she joined as the chief medical officer to design the pivotal phase three trials based on our learnings. And then also, of course, uh expand manufacturing capacity for larger trials and potential commercialization. So I think that's the path forward. I mean, it's an interesting question that you raise with potential, you know, indication extensions. Uh, SOD1 and misfolded SOD 1 is actually found in other diseases such as Parkinson's. Disease. I mean, this is something to explore, of course.

SPEAKER_01:

Yeah, okay. So that's all we've got time for today. So thank you both for your contributions. Thank you. Thank you. That was Dr. Michael Sulzman, the CEO of Alice Pharma, and Professor Angela Genj, who's the CMO of Alice Pharma, and also Professor of Neurology at McGill University. I mean, clearly their work on AP101 represents a genuinely innovative approach to targeting ALS by focusing on misfolded SOD-1 protein, a mechanism that could potentially benefit both familial and sporadic forms of this devastating disease. The positive phase two results that were announced in September 2025 represent an important milestone. And with AP101 meeting its primary safety and tolerability endpoints while showing clinically meaningful signals in exploratory outcome measures, it's clearly that we're moving in a place that for a disease with such a profound unmet need and limited treatment options, such a program offers genuine hope to patients and families facing this devastating diagnosis. So if you've found this episode interesting, please leave a review and also subscribe to BioBiz Buzz, you know, wherever you get your podcasts. So I'm Mike Ward. Thank you for listening and keep on innovating and goodbye until the next episode of BioBiz Buzz.