Good morning, everyone. Welcome to our Piper Sandler Healthcare Conference. Today is day three of our conference. My name is Yasmeen Rahimi. I'm a Senior Biotech Analyst here at Piper. Excited to have the team from Immunic here, and Daniel, I was your first analyst covering you. It's been an incredible journey.
Absolutely.
And, you know, as I said, so much, and I can't wait for 2025 and 2026, as it's been really key pivotal years ahead of us. So, lots to cover. Let's get started. Let's go in chronological order of the upcoming catalysts, right? So, I think one of the key milestones is going to be the CALLIPER data here in April of 2025. And how do you think about the venue in April? Like, are you hoping to wait for getting this presentation at a medical meeting to present, or do you just expect your typical, you know, call and release of the information? Like, or, like, that's something we would love to get your thoughts on.
First of all, thank you for having us here. It's always a pleasure to be here. And, as you said, as a first analyst, you have a certain role for us as a company.
You're like my baby, yeah.
No, and.
For a while.
As you said, I think things are progressing nicely since we started. And now, seeing all the milestones of the next two years coming, it's maybe the most important time for the company, not only next year, but also the year after, with the phase three data from the ENSURE studies in relapsing MS, where we just had that wonderful interim readout. But coming to the next milestone. So, CALLIPER is an interesting study. It's a phase two study, yeah. And the reason why we started that study was we have seen in our phase two in relapsing MS that the drug has neuroprotective properties. And on top of that, we recognized, working with our collaborators, that the drug is the first activator of a pretty cool target called Nurr1, which, from a biological side, really makes a lot of sense why we see these neuroprotective effects.
So, really going beyond what the current drugs can do just on preventing relapses. That's why we started that study. When we designed the study, we said, well, what should we put in? We said, okay, all forms of PMS are difficult or impossible to treat right now, so it's a huge unmet need. We said we want to do a phase two where we can learn what form of progressive MS can best benefit from the drug. Secondly, on the end points, we decided, okay, let's look at everything which would make sense. We added biomarkers. We had brain atrophy as an end point.
But also, we said, why not looking on the most important clinical end point, which, going forward towards approval, will be the major important thing: can we slow down, can we inhibit disability worsening in MS patients and progressive MS patients, which currently don't have any choice there? So, that's why this is an excited time, and we want to release the full top-line data once we have it. So, this likely will be in April. So, this is the guidance we give. And we don't want to wait for a conference to show the top-line data. There are more detailed data, which we will have later, which then will be presented as a comprehensive summary.
What will you have at top line? Will you be able to do the subgroup analyses looking in the various populations?
Yes, I think. And this is, I think, what investors and also our potential pharma partners want. They want to see specifically disability protection. So, the 24-week confirmed disability worsening end point and the EDSS-Plus score, it's a key secondary end point of the study, are definitely the most important and the most relevant end point of the study. And we will have the data for the complete study, but also for the three subgroups. Actually, they're not subgroups. They're independent indications. So, for the FDA, it's a different indication. So, it's primary progressive MS. To remind everybody, that's an indication where there is currently only one drug approved, which is an infusion OCREVUS from Roche.
And then, in the highest unmet medical need, clearly, is in the non-active secondary progressive MS patients where there's no treatment approved, which also may give us some tailwind on discussing with the regulators how we could use it and how we can get it to the patients as early as possible.
As we head into the data, as you noted, brain volume, but more importantly, key disability worsening is going to be a critical end point. How do you foresee the various scenarios, given the heterogeneity of the population that you have with progressive MS?
That's not.
Like, walk at scenario one, two, three?
I think it's not a big problem, I think, because the study is huge. So, we have 467 patients in the study. So, just the non-active secondary progressive population, it's more than 230 patients. That's enough to learn, really to conclude, does the drug work? What is important is you can't power a phase two for significance on disability worsening in a reasonable size. So, that's why it's a secondary end point. And we picked brain atrophy as kind of like a surrogate primary end point for the study, just to have a reasonable size of the study, which gives us all the information, but don't overdo it for a phase two study. So, what was the question?
I guess the question is, when we think about the scenarios, just to kind of maybe pull that back, is it's powered for brain atrophy. What change and what do you want to see? And you guys have said that you want to be at 20%-30% brain volume, sort of as the bar for success there. For disability worsening, it isn't powered because you want to see a trend that allows you to then power and select the right population. But what type of a signal in disability worsening do you need to detect that could be informative to say, this is enough for us to move forward to a phase III?
That's really the important question. Brain atrophy is a surrogate. Actually, I doubt that this is decisive for future decisions for the drug. It's really the secondary end point, as I said. The benefit on preventing disability worsening in each sub-indication is, I think, similar, but given the absence of any treatment in non-active secondary progressive MS, any signal which is medically meaningful would be a success. We asked the experts, and they said something like 15% is maybe the lower bar of success for such cases.
That's placebo-adjusted?
Placebo-adjusted 15% slowdown of disability worsening compared with placebo would be definitely a medically accepted effect. Then the question is, what do you need to go further into a phase III study? I think then brings us more to, if you have a reasonable sample size, maybe you want to have a 20% there. But I think the bar is, from my point of view, 15%. The higher the difference, the better for the drug. It makes it easier to go forward because the study size for phase III would be definitely depending on that. That's, by the way, confirmed disability worsening will be the primary end point for the phase III study anyhow.
Okay. And given that investors are new to progressive MS, as well as disability worsening, what is an acceptable placebo response that we should, you know, of course, we don't expect to be powered, but we don't want to be surprised?
The placebo response on confirmed disability worsening, I expect, is nothing because usually it's just worsening. So, it's, and look, the end point is recorded after 120 weeks of follow-up time in a patient. It's more than two years we're looking at that. So, the random fluctuation is not a problem at all.
Okay. And we'd love to talk about what the implication of the CALLIPER data is post the results. So, let's say you end up exactly what you communicated at 20%-30% brain atrophy and 15% placebo-adjusted disability worsening trend, right? I guess, do you think, when you look at progressive MS, which population is the larger market that you would want in your subgroup to show a difference to really build out a registrational path forward?
Yeah, I think this study covers all the three forms of progressive MS, so, non-active secondary progressive MS, which is the untreatable part. Those patients did not have relapses going into the study in the last two years, and they also did not have active lesions at baseline screening, so, the reason for their worsening of disability is really neurodegeneration. And that has the highest unmet need, and we have 60% of the patients in the study have that indication, and this is, of course, one of the big interesting high unmet medical need indications with a market potential definitely in the $1 billion-$2 billion range just for that, because if you were there, you would just own the market. The second one is primary progressive, where it's only OCREVUS approved, and there's no oral drug available, and there's also little in development.
So, that also would be an interesting indication. And both have shown the similar effect on the biomarker interim analysis on reducing NfL. So, I think the likelihood that we see something is pretty similar. So, each of those would be a good way to go forward. So, we just look on the data, and we will pick the highest likelihood of success thing to go forward. The only thing which I would exclude is the active secondary progressive indication, because that is more kind of relapsing MS than progressive MS, at least in the United States.
Could you maybe also educate us what a developmental path looks like? Because I have the fear that investors think that past positive data, you will have to run a similar sort of ENSURE-like trials in this population. So, you talked about disability worsening being a key primary, but what would the duration and potential size of the study look like?
Yeah, size depends on the hazard ratio. But clearly, this will not need two phase three studies. So, a single pivotal study will be sufficient to be done. We learned that from the FDA discussions, and also historically, that was not required for that high medical need indication. On the sample size, I think typically these studies have something like 800 to 1,000 patients. So, and they are somehow easier to recruit because of the high unmet need. There are a lot of patients. We have a diagnosed set of patients in the U.S. of 100,000, or in the Western countries, of 120,000 patients with PPMS and 175,000 patients with non-active secondary progressive MS. So, huge indications, and there's no treatment. They're both good business cases.
Okay. And what would be the duration? Would it be like a sort of event-driven study of like?
It's an event-driven study, and you measure confirmed disability worsening rate. Time to first confirmed worsening of disability based on EDSS score. The timeline for such a study typically is in the range of three years plus minus treatment time. It depends on the statistics. If you have a shorter follow-up time, then you need more patients.
Okay. And what is the implication of course, you noted that CALLIPER being positive could signal a path forward of very high unmet need? How fast can you engage with the agency to get the regulatory feedback, and how important is that in M&A discussions and partnership discussions?
I think the business base case of most of our potential pharma partners is based on they do a phase three study for PMS. There is a possibility to, depending on the data, yeah, there's a possibility that we may discuss in the end of phase two meeting that we use the data also for an expedited approval pathway. But that's not the base case for the business here. It's a little of an upside potential for this. Generally, I would say for deal-making, you need to put that in the context of the relapsing MS phase three study as well, because that will read out a year later with the first of the ENSURE studies, and seeing any neuroprotective effect here has a clear halo effect on relapsing MS. You've seen that with OCREVUS.
If patients know that a drug can go beyond just avoiding relapses and preventing the relapse-associated disability worsening, it makes it a very attractive treatment. And together with the outstanding safety and tolerability profile we have so far generated, this would make that drug really a disruptive new treatment. Yeah. And this is also important for the potential partnering discussions, because any partner would be interested in having a drug which works in all of these forms of MS. So far, there is nothing which does that.
Does CALLIPER de-risk the ENSURE one-two studies that could lead to this partnership ahead of the ENSURE readouts? Or would that be why take the risk? Why not wait? Unless it's more clear than that.
I don't think it's de-risking. It's pimping the program. So, we kind of like.
I'm not in a way to thinking about it.
No, because you know, the phase III study, the readout is really based on we want to have a rock-solid end point, which we definitely will. So, we think we will achieve here. And with the recent interim data, we have more confidence in that. Just to get approval. So, therefore, the primary end point of the phase III study is time to first relapse. So, we really want to slow down time to first relapse. But for the patients, of course, it is important to know that the drug is not just only doing that, because you can solve that with other drugs as well for the price of maybe a safety or tolerability problem or convenience problem. But knowing that a drug there has some neuroprotective features, and this is even a 15% advantage in a secondary progressive population, would make a huge difference.
That could make it a unique drug. And therefore, there is a spillover for relapsing MS. But I don't think it's de-risking because it's not needed. Yeah.
I guess maybe what, like you said, I think is correct, like CALLIPER being positive would mean that you could work on a test-to-treat population. I think when we're going to talk, we're going to transition to ENSURE-1 and ENSURE-2. This is a DHODH inhibitor for which we have already existing data of a validation. Unless there's something goes wrong from an execution perspective, it carries a high POS of success. So, I guess could one say that the CALLIPER success, as well as ENSURE, could basically establish vidofludimus calcium is one of the key? It's not a DHODH inhibitor. It's a put it into a novel, like before the thought would be it's best in class in DHODH, but it would be best in class in MS in totality by having that broad spectrum of activity.
Yeah, best in indication. Yeah. And first in class on Nurr1 activation. I think this research around Nurr1 and finding that vidofludimus calcium is the first potent activator of Nurr1 as a chemical molecule really brought it into a totally different world, really making the DHODH inhibition more kind of like a rock-solid base fundament for the drug, for the activity in RMS. But Nurr1 really brings it beyond the old paradigms in RMS treatment. But of course, you're right. And considering the good DHODH activity and the absence of off-target toxicities we know from other drugs really makes it a simple-to-use and likely successful phase three study. And therefore, I like ENSURE-1 and ENSURE-2 because it's not these typical, I have no clue what comes out of phase three study product.
It's really something where, based on very good data from a big phase II study, we more or less transform that into that phase III concept. And just to prove that we are on the right track, we did that interim analysis recently to evaluate whether our statistical assumptions are still correct for that.
I concluded to go as is and let the data so we'll be reading out. So, when you look at the ENSURE-1 and ENSURE-2 studies, just remind us, what is the timing of the data? One. And then two, is your bar for ENSURE-1 and ENSURE-2 to be given all the differentiations with CALLIPER, the lack of hepatotoxicity, the broad activity of less infection? Like there's just a lot of differentiation aspect. Do you need to be equal to other DHODH inhibitors in terms of efficacy, or do you need to be better?
I think you clearly want to reach statistical significance in the study and to show the drug works in that study design. The differentiation is more coming from the aspects you mentioned, because it goes beyond just stopping relapses. And as I said, this is more a regulatory end point thing. We want to get approval, and approval will be based on the relapse activity. And there's a question, is the study successful? Do we reach statistical significance in the two ENSURE studies? Yes, we check the box, go to the FDA, get approval. But talking to the doctors and patients really is a different thing, because we have the secondary end point. So, also in the ENSURE study, to remind you, we also record the impact on preventing or slowing down disability. And that is done in a pooled fashion.
We pool the data from ENSURE-1 and ENSURE-2 for that purpose. And given the biological activity I've seen in EMPhASIS and also in our preclinical work, we believe we have a good chance to really be a game changer on slowing down that for that population in ENSURE. And this will be the reason, will be part of the label, and will be the reason why patients want to go on such a treatment, and doctors want to have their patients on that. And you mentioned safety. That's an important piece, because when we started working in the MS space, we talked a lot of KOLs on what is needed. And one of the things which surprised me a little was we need an easier drug, because so far there's always this difficult point when patients are first diagnosed with multiple sclerosis.
In the discussion with the treating physician, it comes to, okay, these are the options you can use. And then at the end of that discussion, the doctor needs to say, okay, that could be a good option, but, and then you have a risk of getting PML. You may die from that. You may get cancer because you get that treatment and these things. So, there's not an easy-to-use drug, which perfectly hits this risk-benefit profile patients deserve and they want to have. And therefore, our drug can also on that end, not just neuroprotection, but also on the safety side, could really be a game changer.
Okay, and what's the timing of ENSURE-1 and ENSURE-2, as well as vidofludimus calcium and IMU-856?
Yeah. So, timing on ENSURE-1 and ENSURE-2. So, we kept our guidance now for two years on that. So, we expect completion of ENSURE-1 in the second quarter of 2026, and followed by ENSURE-2 a couple of weeks or months later in the second half of 2026.
The patent estate?
Oh, that's a wonderful thing. So, we did a huge effort on extending protection of the molecule with several patents, specifically for MS. And last year, we got three or four patents granted around that. So, meanwhile, we have a portfolio of eight families of patents. And there are two kind of basic patents which protect such a molecule. One is the molecule we use itself. So, specifically, the polymorph we use in the production has a granted patent, which is important because it's an NCE to defend that situation and the data exclusivity as well. So, not only the patent itself. And secondly, to really cover all the potential ways of our friends from generic companies to keep them out of the game here. We also have a couple of patents on dosing regimen of the drug, but also dose strength for treating MS patients.
And recently, we filed another patent on the neuroprotective features of the molecule. This was before we came out with the Nurr1 story to also have an indication protection. So, we also hope to get that granted and to have a protection on using the drug for treating PIRA, so progression independent of relapse activity.
What's the total? What's the patent extension with all of these eight families?
We think at least at 2041 is our thought. The last patent I mentioned would protect us until 2044, and the 2041 does not include PTE or SPC. Any business calculation can easily be done with a 10-year exclusivity, which usually the pharma companies do.
Great. I want to say thank you for Daniel for being here, and we have an amazing 2025 to look forward to.
Yeah, thank you, Yas.
Yes.