Okay, let's go ahead and get started. Welcome, everybody, to our third day of Evercore ISI's HealthCONx in Miami, Florida. Pleasure to have with us today the management team from Immunic Therapeutics. With us today is Daniel Vitt, CEO, and Jason Tardio, President and Chief Operating Officer. Gentlemen, welcome. Thank you for making time to be with us at our conference. I would love to, before we get into the nitty-gritty Q&A, I would love to kind of give your overview of the business and what we could possibly look forward to in the next six to 12 months.
Yeah, thank you for having us here at that wonderful conference. Yeah, in general, I think at Immunic we are aiming to transform the MS market, which is a big thing, several indications, and a very exciting time for us because next year, so in a year from now, we should have data from our Phase 3 studies in relapsing MS, two big Phase 3 studies reading out. On top of that, I think earlier this year we read out wonderful data from progressive MS Phase 2 study, the CALLIPER study. Exciting times with a new mode of action in an area of huge unmet medical need and huge market potential as well. Very exciting times at Immunic right now.
Excellent. So just from following you guys in the past, you described this period as kind of a real inflection point for Immunic with the ENSURE phase three trial now fully enrolled in relapsing MS and the CALLIPER primary progressive trial, Phase 2 trial completed. How do you define where the vidofludimus this program stands today and what this phase really is about for the company?
Let me focus that a little bit on the unmet need. There are two things in all of these MS indications. And one is we should do better. We should have better treatments aiming specifically on slowing down disability progression. And that means in relapsing MS, the so-called PIRA or progression, which is independent of relapse activity. And in progressive MS, we should just improve or reduce the risk of disability worsening, which is the same thing at the end. And therefore, strategically, they really are very nicely connected to each other. And with the CALLIPER data and our study results of, for example, showing a dramatic reduction of disability worsening, specifically in those patients which don't have active inflammation for PPMS population, 34% in the study. I think this is the best number so far shown in any clinical trial. We are very excited about that.
Yes. So when people at face value, when they look at the CALLIPER data, they see P values that were not stat-sig, but was the trial powered or to detect stat-sig disability or not?
No, that would have been a Phase 3 study if they would have been powered for that. So this was never the goal. But as you may have seen, we reported recently data at ACTRIMS that we achieved statistical significance on the change of disability score from baseline already after 60 weeks with P value of down to 0.01 after 120 weeks. And very exciting additional endpoint here confirmed disability improvement as well. So giving our neuroprotective mode of action of neuron activation, we not only protect patients from disability worsening, we also have shown a statistically significant confirmed disability improvement in that study, which goes beyond what so far was done and was shown. And just as an example for a number, in the primary progressive MS population, the hazard ratio was 2.8, so a 3x higher likelihood to benefit on an improvement compared to placebo.
And that's kind of the main driver. If you had to pick one, stopping disability worsening or disability improvement, the latter is probably.
I think we should a little bit change our view on that. In the past, drugs did not show anything reasonable there. So this is an aspect of treatment which, if I would be a patient, would matter to me.
Right, so in future discussions with the FDA and EMA, if those future discussions kind of point to 24-week confirmed disability worsening as the pivotal endpoint for progressive MS, how are you thinking about the elements of a Phase 3 design that could maximize the ability to demonstrate a clear effect on that measure?
Actually, I think that will be the case, likely that regulators will ask for 24-week confirmed disability worsening, but I think this is a strength of the molecule, so we have no problem with that. This will be the primary endpoint of a potential Phase 3 study, and given what I have seen in our CALLIPER data, I think it's just a question of scaling of the study. I think to confirm that statistically, the study needs to be a little bit larger. It likely will be an event-driven study, and if you take our hazard ratio, we have seen around about 0.7 assumption for such a study, you may end up with 800, 900 patients in such a study. It's an ongoing discussion we are having, but this could be kind of a good design for such a study.
Makes sense. That kind of stepping back, kind of a broader MOA type of question for folks not as familiar with the story. I mean, one, clearly solid data kind of showing its potential role in neuroprotection. Why is no one else pursuing this target?
Actually, it's not easy to find an activator. It's a nuclear receptor, and you need to find an activator for that molecule. This is more a scientific technical issue so far, and it's a target which is known for quite a while, and I know that a lot of companies worked on it, but vidofludimus calcium is a potent activator. It activates up to five times of target gene transcription, which is a huge effect, and also at low concentrations, so at very low effective concentrations, so it's a very unique thing, and the main difference between Nurr1 and what else was done so far in MS is this is a direct neuroprotective effect, so it's expressed in neurons themselves. You can treat neuronal culture with toxic agents, cytotoxic agents, and vidofludimus calcium is potently protecting cells from cell death in that design.
That makes a difference compared to other approaches, which are mainly immunosuppressive so far or treating some immunological subpopulation of cells, whereas this one really adds a direct neuroprotective component, which I think makes a difference and also makes the concept attractive in other indications as well.
Got it. Well, I think in the past, you said that in terms of neuron activation and neuroprotection, it still kind of warrants further investigation. As you kind of think ahead, what are the things you want to see maybe in the next stage of development that kind of really firm up this part of the story?
Actually, we need to link this biological unique thing with our clinical outcomes. It's all about neuroprotection and what does it mean for the patient. For the patient, it means we prolong his time or her time of independence. So give patients right away from the early start to give the patient a treatment which is safe and well tolerated, where patients can continue with their normal lives. Don't be worried about increased cancer risk or other stuff or liver tox or whatever. Don't need to go to the doctor's office every week for screening. So just continue with your life, but having the feeling that I protect myself from disability worsening. So I think this is our goal, and this would change the life of patients.
Excellent. Now kind of pivoting to the relapsing-remitting part of the disease. So with the Phase 3 ENSURE program kind of reading out in a very competitive relapsing-remitting landscape, how do you think about the level of efficacy that vidofludimus needs to show to be meaningfully differentiated just beyond safety and convenience advantages that you've highlighted before?
Yeah, so I'll take that question. So I think the first thing when talking about competition is you need to define the competitive set. And so vidofludimus calcium, if approved in relapsing disease, would compete in the oral disease-modifying therapy segment of the market. Now, this is a large segment. It represents 40% of total prescriptions today and will continue to represent about 35%-40% of prescriptions over time. So that's where we'll laser focus our initial efforts. If you think about that segment, we think that we will have clear advantages over the currently marketed products. We will have a strong effect on relapses. That is the primary endpoint of our ongoing trial.
But as Daniel alluded to during the course of this conversation today, where we really think we'll be differentiated from an efficacy perspective over other oral products is vidofludimus calcium's ability to address both relapse-associated worsening or inflammatory-associated worsening that contributes to disability progression, but also impact this PIRA, this progression that's independent of relapse activity. And all the available orals today are anti-inflammatory in their approach. So we will have a unique mechanistic advantage. And given that, we think we will have a more robust impact on disability progression than the currently available oral products. Now, you've asked a question specific to efficacy, but we can't just focus on efficacy, right? Because remember, multiple sclerosis is a chronic lifelong disease. Individuals diagnosed with multiple sclerosis need to be on these medicines for life. And so safety and tolerability concerns are real.
And when clinicians and patients alike think about treatment selection, they don't just think about a focus on efficacy. It's a focus on the total value proposition of a respective medicine. And where we will have clear advantages over the rest of the oral products is in our safety and tolerability profile. The Achilles heel of all oral products today is they have serious safety concerns. They come with serious safety risks for infection, like progressive multifocal leukoencephalopathy, increased risk of malignancy, increased risk of hepatotoxicity. And so we think vidofludimus calcium will offer a better benefit-risk profile because we'll have none of that in our respective labels. So we think we'll compete and compete quite strongly within the oral disease-modifying therapy class.
Excellent. I mean, clearly an unmet need. When you speak, when you're out in the field, Jason, when you speak with practicing neurologists and KOLs, where do they tell you that vidofludimus would be particularly a natural fit if ENSURE positive? And in what situation do they expect to stay with the current options?
Yeah. Well, so again, focusing again on the oral market, when a clinician chooses to prescribe or a patient themselves raises their hand and says, "I want an oral administered product," that's where we want vidofludimus to be considered and to be considered first. Clearly, for newly diagnosed patients, this would be a wonderful option. Early in the disease, both patients and clinicians alike value safety and tolerability equal to overall efficacy. And so again, we think we'll have the best benefit-risk profile of any oral product we think will win in that respective segment. Given our unique impact on disability progression, again, this dual mechanistic approach, nuclear activation for neuroprotection, highly selective inhibition of DHODH for anti-inflammatory benefits, if a patient is having continued disability progression and wants to stay in that oral class, we will be the logical switch to therapy.
Given our highly differentiated safety and tolerability profile, any patient that's having safety or tolerability concerns on an existing product that needs to switch, we would be a logical switch to. And then one segment of the market that I think is underappreciated that we think we will own if approved is the patient sequencing off of anti-CD20 therapy. So remember, broad B-cell depletion over time brings increased risk of serious infection. And we're seeing that. You've had CD20s available in the market for, what, seven, eight years now with Ocrevus, and there's a clear correlate between duration of B-cell depletion and increased risk for serious infection. By our estimates, it's about 5% of the class of medicines need to discontinue on an annual basis because of infection. At the higher end, it could be as high as 10%.
When you stop a B-cell depleting product, it takes two years to replete those B-cells, so a patient has an infection, you stop it, it takes two years. For those two years, you cannot put those patients on any medicine that's immunosuppressant in nature, which by and large, all of the medicines today are. The value and benefit of vidofludimus calcium is the medicine is an immunomodulator, not an immunosuppressant. Given its neuroprotective benefits, given its wonderful safety and tolerability profile, all of our market research suggests that the market will sequence those patients coming off of CD20 because of infection to vidofludimus calcium, and just to quantify that opportunity, in the United States alone, that's anywhere between $500 million and $1 billion opportunity just for those patients, so we think these are some clear patient segments that we will win.
With Roche's recent announcement that their BTK was successful in primary progressive, we still have yet to see the data next year, especially the safety data. But any initial thoughts on how vidofludimus may compete with the BTKs?
Look, we think an introduction of a BTK inhibitor into the market doesn't change our value proposition, doesn't change our opportunity, and doesn't change where we would go. I think clearly there will be different physician segments and different patient segments that we will be focusing on, given, again, the total profile of our respective product versus what a BTK inhibitor will. But again, I go back to this continued discussion about a benefit-risk profile. And what we know, we haven't seen any data, so it's hard numerically to discuss the overarching impact on efficacy of the BTK inhibitors. What I would say is that what we know is that BTK inhibitors don't offer direct neuroprotection. We know that Nurr1 activation with vidofludimus calcium offers direct neuroprotection and prevents neuronal cell death. So I think that's a clear differentiator between the two.
Again, benefit-risk, there's a clear liver toxicity signal with the BTK inhibitors. All of them, I believe, will have a black box for liver toxicity that will require constant monitoring. The expectation is at a minimum three, if not for the first six months that a patient is on those therapies, they'll have to do weekly blood draws for liver monitoring. That's going to be cumbersome for the patient. It's going to be cumbersome for the physician. All of that said, remember, this is a large market. It's a $23 billion market. It's growing 2%-4% over a year. It's going to be a $30 billion market. So there's plenty of space for multiple products to play. We welcome innovation. We welcome new therapeutic advances for the MS community. But we would stay true to our strategy.
Again, we believe the value proposition and the benefit-risk profile of vidofludimus calcium will make it the oral of choice within that segment.
Excellent. Excellent. So kind of stepping back a bit. So with the Phase 3 ENSURE program running through to 2026, how are you thinking about supporting your various programs over the next couple of years in light of your cash position and outlined in your recent filings?
Yeah, so well, we did the raise back in June, which brought $65 million into the company. As part of that raise, there are a series of cash warrants that could come in by the end of the year, which would bring up to another $65 million into the company, but beyond that, as you can imagine, we are having a multitude of conversations today with a variety of different parties about how we would fund not only the remaining clinical development program in relapsing MS, again, which is expected top-line data Q4 of next year, but also how we would think about funding a Phase 3 PPMS study, and I think probably most importantly is how do we begin to prepare for commercial preparation and commercial launch.
I think you kind of started to answer my next question, Jason, about potential partnerships. How are you thinking about the role partnerships or other strategic options that may play in helping you balance the execution of the ENSURE trial with the longer-term opportunities you see in progressive MS?
So there's a lot of interest in this program. As you can imagine, we have a phase 3 program in relapsing disease that we believe is de-risked, and we think will offer clear differentiation. And that opportunity alone, we think, is $1 billion plus a peak. Clearly, if we continue to show success on the progressive side of the business, that's ample upside. We believe it's at least $2 billion plus upside per each of the respective progressive indications for this molecule. So given all of that, you can imagine there's a lot of interest from a partnership perspective, and we continue to have those conversations. The question is, when would be the right time to do a partnership? Do we consider a partnership now? Perhaps. Do we consider a partnership after the Phase 3 ENSURE readout, again, in Q4 of next year? Perhaps.
But rather, our focus is continuing to prepare to launch this medicine ourselves. I think the wonderful thing about a recent analog in the market with TG Therapeutics. It shows that a small biotech company with a laser-focused approach can have commercial success in this space. And we believe, again, the differentiation of our respective molecule with some of the institutional expertise and experience that we have within the company that we could build a similar commercial plan and execution strategy that would offer a similar level of success that TG and others have had. So it's about optionality. We're going to continue to seek optionality. And if a partner comes along and offers an opportunity that we think is the best interest of shareholders and the best interest of the molecule and of the patients, then we'll certainly consider that.
Excellent. Maybe in the last minute and a half, could you maybe pivoting away from Vito and into your other programs and maybe a brief update into where IMU-856 and IMU-381 stand?
Great molecule. As you may remember, we have shown proof of concept in celiac disease. So just to summarize, this mode of action is a unique thing. IMU-856 is restoring a proper epithelial layer in the gut wall, so restoring a healthy gut, basically. And we have shown proof of concept in celiac disease by histology, for example. We protected with a statistically significant effect in just 30 patients protection of the villous structure in these patients and also have shown functional improvements there. On top of that, we have also shown that by restoring a proper healthy gut, you also restore a proper GLP-1 secretion from these L-cells, which is an interesting finding and maybe also is linked that mode of action to protecting patients from weight gain because I think actually celiac disease patients somehow have a weight issue that's maybe coming from that.
There's a lot of exciting things going on. For now, I think the priority is execution of the MS program first. We are prepared to really go forward with that development as well if the funding is available.
Excellent. Well, unfortunately, we're out of time. But gentlemen, thanks for such an excellent discussion. Lots to look forward to in the year to come. And I wish you the best of luck.
Thank you, Michael.
Thank you.