Are we good? We're on? Okay, good. Thanks. Okay, everybody, thanks for joining us for our next session at the Leerink Partners Global Healthcare Conference. I'm Marc Goodman, one of the Biopharma Analysts, and we are lucky to have Immunic with us. We have Daniel Vitt, who is the CEO, and Jason Tardio, who is the Chief Operating Officer, Commercial Officer, getting ready to. A lot of discussion around how exciting this product is gonna be for multiple sclerosis, the different niche markets and stuff, and I wanna get into that. But I think it probably makes sense to kind of begin with just the unique mechanism in talking about how this product is differentiated. Maybe I'll just give you a chance to kind of start. Yeah, good starting point. Yeah, yeah. I think because what matters to patients in MS is neuroprotection. Patients with multiple sclerosis, living with multiple sclerosis, really are afraid of progression, and therefore this mechanism is unique. A molecule, Vidofludimus Calcium, is activating protein called Nurr1. Nurr1 is a nuclear receptor which is directly involved in neuroprotection. We think that direct neuroprotective effect makes the difference in the world of MS treatments and also makes the difference for the patients. On top of that, it's also an inhibitor of DHODH, which is an established anti-inflammatory mechanism in multiple sclerosis. I think that combination is quite unique and specifically having the Nurr1 activation really differentiates it from everything else which is going on in that space. Yeah, just to be clear, it's a dual impact, and you were saying the second part is the DHODH. Right. It was originally developed as a more selective DHODH inhibitor t o avoid the kinase inhibition of Aubagio and the toxicities associated to this kinase inhibition, but which was successful. It was also found that the drug has neuroprotective effects seen in the clinics, and we investigated where does this comes from, and we found it's a very potent activator of Nurr1. That's from the Nurr1 activation. That's from the Nurr1 activation. I think also with the CALLIPER data we have reported last year, we have also translated that into a clinical benefit, which is, I think, of course, the most important feature. Yeah. Walk us through, you know, just kind of the history of the molecule and, you know, kind of the work and the phase II, and then we can get to the design of the phase III and what to expect. Yeah, I think it was initially developed as a more selective DHODH inhibitor in my first company at 4SC in Germany at that time. We switched over and bought it out at Immunic when we started Immunic as a company in 2016, switching over to the calcium salt. With that, we started development phase I, phase II in multiple sclerosis in parallel to UC. The first clinical study done in MS was the EMPhASIS study, which was a very successful thing. On the one hand, we have confirmed the very good anti-inflammatory activity, p-value of less than 0.0001 and 0.0002 respectively on suppression of inflammatory lesions, as primary endpoint of the phase II study of the EMPhASIS study. On top of that, we have seen that the drug has two things. We have seen a very nice dose-dependent reduction of neurofilament light chain. Secondly, we have seen a numerical reduction of disability progression of CDW already in that small phase at the half-year treatment, phase II part by more than 50%. We investigated the reason why we've seen these effects on top of the anti-inflammatory effects, and this led us to Nurr1. What does- Unique What does that mean, the CDW event? Like, explain that. Well, slowing down disability. That's the thing. Basically, there are two reasons why patients with multiple sclerosis progress. One is related to relapses and related to an acute inflammation. That's the inflammatory part, maybe contributing 40%, 50% maximum, and the rest is PIRA, so progression, which is independent of relapse activity. For example, if today a patient is on a treatment with an effective anti-CD20 therapy, patients still progress. The question is, where does it come from? What's the reason for that, and what can we do against it? This is, I think, the unsolved problem in multiple sclerosis, which we address with Nurr1 activation. Right. Talk a little bit more about the phase II data, the EMPhASIS trial. Talk about, you know, just some numbers and help make comparisons to, you know, just standards of care, just so we have an idea how it performed. Yeah, it was pretty nice. We have seen primary endpoint, as I said, with accumulated active lesions and gadolinium-enhancing lesions. Really what you measure as focal inflammation in the brain is MRI-based endpoints. We have seen 76% reduction on cumulative active lesions, 78% reduction on gadolinium-enhancing lesions, both in 30 and 45 mg doses, so the two high doses had almost the same effect there. Basically, based on that, we picked 30 mg for the relapsing MS phase III studies going forward. We also tested 10 mg, which has a borderline activity there, so I think we found the right dose in the study. Second important outcome of that study was that the safety and tolerability data was really almost the same for the placebo control and the active treatment group. There is really a pretty outstandingly good safety and tolerability profile came out of that study, which is. If you look on the unmet medical need, and maybe Jason can talk a little about that, the unmet medical need is not only having more efficacious drug and targeting neuroprotection, but also having safer and easier to use drugs as well. Those types of metrics that you were just quoting, how do those compare to other products? If you compare it with other drugs, typically in the oral space or in the early development phase, these varied from 30%-40% for glatiramer acetate, then 50% for Aubagio, for example. Fingolimod data was in that same ballpark. ozanimod had an 80% reduction or 82% reduction in the phase III study. I think the anti-CD20s are in the 80s or even up into the 90s. It's kind of right there. Look, they all do something there. It's the same level of activity basically. We know we have a robust good reduction of inflammatory activity, and also that translates usually in a linear fashion into reduction of relapses then in the phase III studies. Yeah. You mentioned NFL. What other, I guess, biomarkers or whatever, what else did you discover, you know, that was helpful? Well, I mean, I think. Look, the MRIs themselves are a good biomarker. The reason that companies in the phase II study for an inflammatory disease use focal MRI reduction as a primary endpoint because there's a direct correlate to that to future impact on the clinical outcome of relapse reduction. The biomarker, again, we also used, as Daniel mentioned, a reduction in serum neurofilament light. We know that serum neurofilament light reduction is correlated to future disability progression in MS as well. We saw a 20% reduction at the 30 mg dose, a 26% reduction at the 45 mg dose. I think in totality, we have a clear robust signal on reducing inflammatory disease activity via the MRI. We show a clear dose-dependent reduction in serum neurofilament light. There's some clinical outcomes that show a clear sign of benefit. In totality, the safety and tolerability is highly differentiated. Very, very clear signals here. Talk about that a little more, the safety and tolerability being differentiated. Just give us a sense of if you're on these other drugs? And y ou're getting those type of high metrics on efficacy. Here's what you're sacrificing on the safety side. Here's what you don't have to sacrifice here. Yeah. Well, the vast majority of medicines approved for multiple sclerosis are immunosuppressant in nature. Given this approach, you see serious safety concerns, right? Risk of infection like progressive multifocal leukoencephalopathy or PML, which is a brain infection that can lead to death. You see increased risk malignancies, etc. There's always this continued trade-off between the potential benefit associated with the medicine and the potential concerns around long-term safety. Tolerability is also a concern, right? A medicine is no good if a patient cannot tolerate and take the medicine. We know that there's very, very high discontinuation rates across many of the approved therapies. For example, dimethyl fumarate, which was Biogen's blockbuster, did $4 billion-$5 billion in peak sales. Roughly, you know, in a real world setting, 50% of patients that can't tolerate that medicine. They get GI, they get flushing issues, etc. This is a big concern. In fact, when you poll patients and you survey patients and you ask them why they haven't started a disease-modifying therapy, the number one concern is long-term safety and tolerability issues. Even with 15+ available therapies in relapsing disease, there is still a need for a better benefit risk profile. Again, with Vidofludimus Calcium, we think we're gonna offer unique advantages on the efficacy side, balance what we think could be a best in disease safety and tolerability profile. You take this in totality. We think we have a winner on our hands. What are the adverse events that you even see? I mean, they're so low. I mean, in the first generation non-selective inhibitor of DHODH, Aubagio or teriflunomide, some of the most common side effects were GI tox, alopecia, around 15% of patients had alopecia, in a disease of young women, not a very good side effect to have. Liver enzyme elevations, that product does have a black box for drug-induced liver injury, etc. We see none of that with our medicine, right? Again, as Daniel mentioned, it's due to the selective nature o f our inhibition of this enzyme. We don't broadly bind to other kinases. We see comparable levels compared to placebo, for example, of many of these concerning side effects of the first generation. It's remarkably, you know, to date, based on the data we've seen, it's remarkably clean and. GI's low. Very low, comparable to placebo. Yeah. Yeah. That's pretty amazing. No liver issue. You don't expect to have any type of black box or anything around liver or. Look, the data to date supports a comparable liver enzyme changes either on ALT or AST compared to placebo. Okay? The data itself clearly states that we don't see the signal. Again, you never know what the FDA is gonna do. You know, the Aubagio does have a black box. It was largely driven by the fact that it's the active metabolite of leflunomide, which was the first DHODH inhibitor approved in rheumatoid arthritis that had a black box. Again, given the correlation between these two molecules, there was a carryover of the black box for that respective medicine. We don't believe based upon the data that we have to date that we see a clear liver signal. We'll continue to work with the authorities over time to ensure that they understand the data with our product and why it's differentiated. Yeah. Let's talk about the phase III program. Give us an idea of the design of the studies and what you know. First talking about the first thing, the phase IIIs, the ENSURE studies in relapsing MS, we kicked them off in 2021. They're two identical studies, twin studies, enrolled 1,100 patients, fully enrolled since mid of last year. Primary endpoint is time to first relapse. It will be because it's in relapsing MS, the endpoint, the primary endpoint need to be a relapse related endpoint. But of course, in the secondary endpoints, we also test the MRI biomarkers. We will test NFL, but also, of course, we will test disability progression as an endpoint. We confirmed disability progression as a secondary endpoint, which is important of course, because we think with a neuroprotective effect, that should translate into a good effect as well there. The study, as I said, is fully enrolled. We did already an interim analysis in the study in late 2024, when approximately half of the events occurred. It was pretty nice. It was a futility analysis. The IDMC was unblinded, and we asked them two questions, basically. Is the study futile? Clearly not. I mean, it was not expected to be futile. It's good to know that. The more interesting part was we had three scenarios of potential upsizing the study if the power of the study is not maintained in the first half. Good news was that the IDMC suggested to continue as planned. Right. It's good news. I think we're on track on the primary endpoint readout with the study. Both studies should read out. End of this year. End of this year. Together. Right. Together. Yes. As said, I think we are believing that has a high likelihood to be a positive study outcome. The assumptions basically are also important. The statistics were based on a 90% power with a effect size of a hazard ratio of 0.67 for time to first relapse. Got it. I wanna talk about the market for relapsing first, and then we can kinda go back to progressive and then talk about that study the program, and then we can talk about the market. That's important because I think it's a holistic view. It's MS, but of course. We have those two things ongoing, and I think our drug being the first potential treatment for all of those indications. I wanna make sure I just got it. Jason, let's flip to kinda how you see the opportunity for the product. Let's just presume the data's good. Check the box, we have an approved product. You're the commercial guy, where do you see the opportunity in this big competitive market? Well, the misnomer here is that relapsing multiple sclerosis is solved for, right? As Daniel's mentioned earlier, there's continued need to find medicines that address the totality of the underlying biology that drives disability accumulation. No medicine does this today. We think we will. There's also continued need, as we've discussed, for safer and better tolerated medicines, right? When we think about this medicine and a go-to-market strategy specific to the relapsing segment, we think that we have opportunity in two particular segments. The first would be the oral class in general, right? It's still a large market. It represents about 35%-40% of total prescriptions today. So even with the success of the CD20s, a large sizable percentage of the market still prefers oral therapies. As we've discussed, all those oral therapies come with an Achilles heel. They come with a trade-off largely related to safety. We believe we will offer a better benefit risk profile, and therefore, for a clinician, a patient who raises their hand that says that oral modality is what fits their lifestyle, it's what they're looking for, we expect and hope to win that patient. The second segment that we hope to go after is the anti-CD20 market, but more specifically, patients that need to sequence off of anti-CD20 therapies. Anti-CD20s are broad B-cell depleting therapies. All of these medicines carry a serious warning for infections. There is a direct correlation between prolonged exposure on those therapies and an increased risk of serious infection. We believe this is an underappreciated segment of the market. In the United States alone, we estimate it's between 5% and 10% of patients need to sequence off those class of medicines annually because of serious infections. When you have a serious infection on a CD20, remember, it takes two years to replete those B-cells when you stop the therapy. For two years, you cannot put these patients on any medicine that's immunosuppressant in nature, otherwise you're gonna exacerbate the situation. Our medicine is immunomodulator. It's not immunosuppressant. It's neuroprotective, as we've discussed, via Nurr1 activation. It shows great safety, great tolerability. It's antiviral, also via its DHODH inhibition. We take all of this in totality based on the research we've done, suggest Vidofludimus Calcium could be a wonderful medicine to sequence those patients too. To put into context what this 5%-10% of patients means from a potential sales perspective, just that small segment alone is worth $1 billion in the United States, right? If you think an approach to market which we hope to be the oral disease modifying therapy of choice based on our value proposition, combined with being the medicine to sequence patients coming off of CD20 patients, CD20 therapies too, we think it potentially is a multi-billion-dollar opportunity just in relapsing disease alone. Yeah. Yeah. What kind of pricing are you considering for this product? Way too early to discuss pricing. Wh at I can give you generalities in the market. I mean. The average cost of a branded oral disease modifying therapy today in the United States is about $110,000 WAC. Companies on average take about a 5% year-over-year price increase. By the time we launched, you know, the oral class will probably be in the $120,000-$125,000 WAC range. The numbers that you were referring to before about a billion-dollar opportunity was using just those numbers $ 110,000. Well, yeah, general assumptions and, yeah, I mean, look, I think another interesting point related to this market, and specifically the United States, is as follows. I mean, we would love a 30%, 40%, 50% market share capture, but it doesn't even take that much to drive $1 billion of sales in this market. It's roughly a 4%-5% total MS market share capture drives $1 billion. And so again, we believe we have a differentiated asset. We believe we're gonna find segments of the market to compete in quite heavily. We believe we have, again, a winner on our hands. As an oral therapy. That's first of all, so that fits into that 40% market. You kinda can fight it out for share within that. Just as an oral alone. I mean, you would think that a better oral, maybe some of the other therapies move to you just by that nature, right? Then you're talking about the CD20s who have been very effective drugs, and people just have to stop taking them, like you said 5%-10%. That's the other slot that you look at. Correct. Got it. Interesting. Okay. Good. We should talk about progressive. Yeah, I think this is the elephant in the room, right? What to do there. Just explain how it's different to our last person. I think. Let's talk about primary progressive because this is where we start with our phase III this year. Primary progressive is a disease which is a little bit diagnosed usually a little bit later in the age of patients, and it does not come with relapses. You just figure out that patients are worsening on their physical ability, and they go to the neurologist. Actually, from a diagnostic point of view, most of the patients don't have active inflammatory lesions on the brain. It's maybe just 15% on average who have that. But symptom-wise, it's very similar to a progressed relapsing MS patients, which is progressing then to secondary progressive MS, where the inflammation cools down, the relapses go down, but the patient still progresses on disability. There is an ongoing smoldering neurodegeneration going on in the brain of those patients which impacts the physical ability of these patients. Right now, in this space, there's only one drug approved for treatment, which is for primary progressive MS. It's Ocrevus, as an anti-CD20 therapy, and has shown activity specifically on majority coming from patients with active inflammation and at younger age. If you look on the details of the ORATORIO approval study from Roche Genentech. This is the 15% of the population that you were re... Have Have inflammation. This is... Actually, yeah. I think this is more that they contribute substantially to the effect which led to the approval of the drug. Right. Okay, that's what it is. Now let's talk about, you know, your product and. Yeah. The wish would be to have a drug which does something in patients where there is no active inflammation, but they still progress because there is a destruction of neurons in the whole brain, basically. In that context, no immune activation seemed to be a good thing. We did a phase II study. I think this was actually the first real phase II study done in progressive MS. We enrolled patients with primary and non-active secondary progressive MS, also active secondary progressive, but we forget that for a while because they can be treated with RMS drugs in the United States. These two big cohorts, which are not treatable right now, non-active SPMS and primary progressive MS, were enrolled, and we have seen a pretty good reduction of disability progression in these patients. At 24% overall in the study, and a 31% reduction in the PPMS set, in that study that was based on 130 patients, with PPMS. That was a good starting point. The important question was, does that activity also come from the anti-inflammatory effect or not? We looked on patients without baseline gadolinium lesions, before starting the treatment. These patients have no active symptoms of inflammation in the brain. If you take them out, then we have the same activity in primary progressive MS of 31% this goes up actually from 31% to 34% on reduction of confirmed disability progression, whereas in the secondary progressive, non-active secondary progressive, it goes up from 20% to 30%, right? It's a quite dramatic result, and it's a first, I think, to our knowledge, the first study really showing such a strong numerical effect on this. What kind of metrics did Ocrevus have to get their approval? Actually, they achieved in the totality of the study, and they had 26% of patients had inflammatory activity in their study. It was 26.6% baseline gadolinium lesions. If you take them out, the effect size goes down from 25% in that population to 19% if you take out the patients with baseline gadolinium lesions. If you take out the patients with gadolinium lesions during the study, it goes down to 16%. If you then look on patients of age above 45, it goes down to 9%, right? It is an age and inflammation-related signal which they detect. Just to be clear, your overall was 24%. In the total population. Total. In the PPMS, it's 31. 31 was. 31. 31% of the PPMS. PPMS. That's the key. That's the difference. 25 on Ocrevus versus 31. Of course, this is phase III versus phase II, so we need to. Right. The apples to apples is 31.5. It's 31 to 25. Yeah. Right. That's a slight advantage. Yeah. The real test whether it's a real neuroprotection, I think, really comes from leaving out the gadolinium patients in that count which is, I think, really a breakthrough. Interesting. Yeah. The safety profile was no different in that. Safety profile was as good as the earlier study. As the RMS. We know no difference between treated and control. That's in place as well. We tested more endpoints, of course, in the study. That's another interesting part because if we believe in neuroprotection, then remyelination could also be part of that game. We also look for confirmed disability improvement. Could patients go back and improve their disability status, which is measured by EDSS scale? We have seen a statistically significant increase of CDI in the treated group. The hazard ratio was 2.44. You have a 2.4 x higher likelihood to experience confirmed disability improvement compared with the placebo patients. With that data, we've decided to move into pivotal. Talk about that. It is a no-brainer, I think, here to go into PPMS with that asset. Considering the competitive environment, it's even more rewarding now because all the challenges of other drugs in that indication. The BTK case, namely, I think, opens up an avenue for us where it's just us, right? What would that design look like as you're thinking about that? Well, the design will be very similar to what other companies have done recently, namely Sanofi with tolebrutinib and so really to look at confirmed 24-week disability progression as the primary endpoint. That's, I think, the most likely endpoint of that study. Given the historical control group activity, we expect to need to enroll something like 800-1,000 patients. It will be event-driven. We start enrollment, and we'll treat until end of the study until we reach enough events. Assumptions for statistics are too early to say exactly. I think we have observed a hazard ratio of 0.7, so we may use that as a starting point for our statistics. Study duration is then expected to be between three and a half and four years if these assumptions are valid we make right now. Yeah. Jason, talk about the opportunity in that space. I think Daniel's mentioned it, one of the biggest unmet needs, clearly the biggest unmet need in multiple sclerosis is progressive disease. Again, nothing approved for non-active SPMS and only one product approved for PPMS. Even that product is suboptimal. We've discussed it does not work in patients that are truly progressed. You know. These are patients without inflammatory disease activity. Remember, PPMS patients are usually a bit older in age. They're a bit more progressed in their disease, so oftentimes they have a accumulated disability. They may be in a wheelchair. They have increased comorbidities. Because they're older in age, they also have immunosenescence is just kicking in, so the last thing you really wanna do is put this population, this more fragile population, on a broad B-cell depleting immunosuppressant therapy. Combined with the fact that Ocrevus has limited benefit in this true population with inherent safety concerns, you can imagine that there's a wealth of opportunity within the PPMS segment. Even given that challenge, I think just to quantify, Roche has publicly commented about 35% of their global sales for Ocrevus comes from the PPMS segment. They did $9 billion in global sales last year, so over $3 billion of sales generated just in the PPMS segment alone, again, with a suboptimal therapy. You can imagine, if we replicate the data that we've seen in CALLIPER with a, you know, 30%+ benefit on time to 24-week confirmed disability progression, balanced with the safety and tolerability that we have, balanced with the convenience of just a tablet, these patients don't have to, you know, with limited mobility, don't have to get to a hospital or something. We believe it's a huge, huge upside. We Vidofludimus Calcium could clearly be the cornerstone of care in PPMS. I think the floor would probably be that $3 billion mark that Ocrevus is selling today and potentially, you know, even significantly above that. What's the potential timing of starting that study, would you think? We are actively working it. We did already some feasibility on the site, so it's going on right now. To kick it off, we have IDMC meeting, so we hope to really activate the study, this year, second half of this year. Good. In our last minute, what have we not hit? What else do we need to talk about? We don't talk about that. It will not happen. It will be successful, I'm pretty sure. Of course, I think somehow RMS and PMS, despite being both MS, are independent development tracks. You would definitely continue with the PMS as well if RMS is not hitting our expectations there? I think to summarize, what I think is, a, I think we have a de-risked clinical development program in relapsing disease. We have a clear line of sight to data, and we think a medicine that could be highly differentiated within that segment. That's a billion-dollar-plus opportunity, again, for a de-risked asset in relapsing MS. We'll kick off the PPMS study, as we've mentioned, and we'll find out the answer to that in a couple of years. If we can replicate the data we've shown to date, that's an enormous upside, $3 to $4 to $5 billion upside just in that segment alone. We're quite excited again about what we Yeah, one of the things you and I have spoken about is just how well Vumerity has done i n a generic Tecfidera market. It's got a benefit of GI. A little better, and it's 600 or. That's, yeah, I mean, so people get asked all the time and 'cause there are generic, you know, entries into the space here, and so people question oftentimes is there even room to maneuver through those, and clearly the answer is yes. Vumerity did $750 million in sales. For those that aren't familiar, Vumerity is a monomethyl fumarate. It's the active metabolite of dimethyl fumarate or Tecfidera, which has been generic in the market. In fact, Biogen used a 505(b)(2) pathway to approve that medicine, so they share the efficacy, they share the safety of dimethyl fumarate. There's a direct generic on the market to this respective product, and yet this branded product. From Biogen did $750 million in sales last year. It grew nearly 20% year-over-year. Again, Biogen has kinda waved the white flag and is barely in MS these days. Again, we think a highly differentiated product like ours with a very dedicated and aggressive push, commercial push into the market. We think again there's large opportunity. Yeah, it certainly makes you feel better about just the size of the opportunity. Sure. Yeah. It's pretty amazing. Yeah. Yeah. Thank you. Thanks for joining us. Thanks much. Looking forward to the data. Thank you. Appreciate it. Yeah. Thank you. Thank you. you. Thanks. See ya. All right.