All right. Good afternoon, everyone. Welcome back to the Canaccord Global Healthcare Conference. My name is Rick Pinkoski. I'm an analyst here on the biotech team, and it's my pleasure today to be hosting Dr. Daniel Vitt, CEO of Immunic. Welcome.
Hi. Happy to be here. Thank you.
All right, so I'd like to begin with just a little bit of level setting for the audience, if you can introduce us to the company and the lead program.
Yeah. Immunic is developing new oral therapies for treating chronic autoimmune and inflammatory diseases, and we have two clinical stage programs and one preclinical stage, and from the clinical stage program, the most advanced is vidofludimus calcium, which is in phase 3 development for relapsing multiple sclerosis, and also in an advanced phase 2 program in progressive MS, and it has shown activity also in ulcerative colitis in a phase 2 study, and then the second program, IMU-856, is a new target SIRT6 modulator for treating GI disorders, and for that molecule, last year we have shown clinical proof of concept in patients with celiac disease.
Very fantastic, and to begin, we could just jump right into some of the news of the day. There was a press release issued this morning by the company, highlighting four presentations at the ECTRIMS conference. I was hoping you can just give us an overview of what those presentations are, and what some of the key takeaways were from those presentations.
Yeah, I think ECTRIMS is by far the largest MS meeting in the world. It started this morning in Copenhagen, and we're very pleased we got four posters and presentations accepted from the organizers. I think ECTRIMS these days really talks a lot. There's a lot of talk about what's the medical need, what's the remaining medical need in multiple sclerosis. What can we do to improve things? There's a lot of discussions on neuroprotecting from neurodegeneration, so specifically a word called PIRA, so progression of MS patients independent of relapse activity. We have posters and presentations around all of these things. From the clinical side, we have some biomarker details from our ongoing CALIPER study in progressive MS. We have mechanistic data on immune response.
We have data on neuroprotection and our target Nurr1, which I think is by itself an exciting thing, because it's a first-in-class approach on neuroprotection with activating Nurr1. So there's a lot there.
All right. Well, since you brought up the mechanism, let's just start there with vidofludimus. So there is actually a dual mechanism of action here. There's the Nurr1 activation and also the DHODH inhibition. Could you discuss this mechanism of action broadly and the validation here?
Yeah. Initially developed as a DHODH inhibitor, and really with the goal to have a safe, good, efficient treatment for multiple sclerosis. Two years ago, and based on clinical data, we have seen impressive clinical effects on, for example, slowing down disability worsening in our phase two EMPHASIS study, and also interesting NfL biomarker data, which hint to something which goes beyond preventing inflammation and these things which are related to DHODH inhibition. So we were searching for the root cause of that. So what's the reason? What's the target? And we're very lucky that together with our academic collaborators at University of Munich, we found that vidofludimus calcium is a very potent activator of Nurr1. Nurr1 is a nuclear receptor involved in neuroprotection.
To draw a simple picture, it's known that Nurr1 is a differentially regulated gene, for example, in MS patients, in young female MS patients getting pregnant. So for example, during pregnancy, Nurr1 is upregulated, so it seems to really have a protective effect against the disease also on a genetic level.
Right. I know you said that there is an increasing focus on neuroprotection.
Right.
So I'd like to focus in on the opportunity you see for vidofludimus calcium. And I guess to start at a high level, how do you see the unmet need and the role of disability independent of relapses across the various forms of MS?
Yeah, this is maybe the most important thing. So still, in if you look on current MS therapies, the daily situation in discussions with between treating physician and patient is: How can we slow down or stop disability worsening? And there were a lot of progress in the last years, and I think namely the introduction of anti-CD20 therapy was a major step to stop relapses and also to stop inflammation. But obviously, that's not sufficient to stop the disability worsening over time. So there's something else going on, and today we know, we call this PIRA, or this progression independent of relapse activity, something going on there, which is not related, not linked to the lesions in the brain, not linked to focal inflammation.
That's the second problem, and this is 50% of disability, I think, is believed to come to originate from this PIRA process. And, yeah, long story short, with Nurr1 we target this effect, whereas with the others we target the RAW, so the relapse-associated worsening. We think vidofludimus calcium bears the unique opportunity to have really this, this double shot on goal to target both problems in MS progression.
Got it. And if we can focus in on non-active secondary progressive MS, if you could maybe just explain what exactly this form of MS is, what are the hallmark features, and how is it currently managed?
Yeah, MS is a big bandwidth of different things. It usually starts with relapsing MS, and at younger age, usually in the age of twenty, thirty. There you have relapses there, and you don't, maybe don't feel, don't figure out there's another process ongoing, which is below the relapses, is this PIRA process. If patients progress, then over time, their, the relapses go down, so there is a little bit of a stop over time of the relapse activity. Patients still progress on disability scale, they still worsen on cognitive functions, and this is then called non-relapsing secondary progressive. So the problem is there is no treatment approved for non-relapsing secondary progressive, and there are a lot of treatments for the relapses.
So, that’s defining the medical problem, and we have round about a hundred and seventy-five thousand patients diagnosed with SPMS, non-relapsing SPMS, which is a huge set of patients who need help.
All right, still focused in on this patient population, I guess, can you say why B-cell depleters aren't used in this population? And on the flip side of that, given what we know about the disease, why do you think the neuron activation mechanism of action would be a good fit here?
No, because exactly, it's targeting the problem, so we want to prevent this continuous demyelination and destruction of neurons. With Nurr1 activation, we act on two things. We act on the neurons themselves in an anti-apoptotic fashion, but also, and that's quite impressively strong effect, even at very low concentration on microglia. Microglia produce a lot of neurotoxic cytokines and other things. Activation of Nurr1 seems to very effectively upregulate the respective target genes. One example is VMAT2, which is a transport protein for a neurotransmitter. That's why I think Nurr1 activation is exactly targeting these neurodegenerative part, obviously. More or less, the perfect solver of that problem.
There were also some recent competitive updates here in the field. I know that Sanofi reported data from their BTK inhibitor. I believe their top line was earlier in the month, and they will be giving a full presentation later this week. So what are your thoughts on the data, and what are the implications for Immunic?
Yeah, there are different effects of that. I think they published data for two studies, the phase three study, or even more studies, two phase three studies in relapsing MS and one in progressive. I think their data, together with the evobrutinib data last December from Merck Serono, showed that BTKs will have a little bit of a difficult time in relapsing MS to get approval. That's our conclusion based on what was reported. On the other hand, and in contrast to evobrutinib, tolebrutinib has shown obviously a signal on neuroprotection. So, yeah, I think it's a little of both worlds, some good and some bad news. For us, clearly, that, the little bit cleansing of the space.
When we started the program three, four years ago, it was a quite competitive field, five BTKs against us. And I think that is no longer a bigger challenge. And also, I think, thinking about the safety and clinical hold of most of the BTKs, at least in the U.S., also comparing that with our very good safety and tolerability profile, makes vidofludimus calcium quite interesting molecule for the next months and years to come.
Got it. Another question I wanted to focus on was just how disease is measured in clinical trials for NASPMS, and I know when we began the conversation, you spoke about the neurofilament data that will be presented at ECTRIMS or has been presented on a poster.
Yeah.
Could you discuss the role of neurofilaments as a biomarker also, and its role in neurodegeneration?
Yeah, I think we first need to address one thing. The regulators want to see clinical endpoints, so and therefore, in all our study, we have clearly focused to have the relevant clinical endpoints covered as secondary endpoints in the study or as primary endpoints. But there's good progress on using biomarkers in multiple sclerosis as well, and NfL really made substantial progress. It's not yet an established marker in general, but I think this is a work in progress. But it's very helpful to help us in designing studies and also managing our own expectations. And one example is we measured NfL in an interim analysis in our progressive MS study in last October, and we were really excited about a 22% NfL reduction after 24 weeks, in half of the patients which have been evaluated.
Which really shows there is a strong effect on NfL. And on the other side, the scientific progress also shows us that NfL, if you isolate the non-inflammatory patients, NfL baseline levels are predictive of future disability outcome. That gives us a tool to understand that, to correlate the data with expectations on the outcome of the study on the clinical endpoints. We are excited about that because NfL data was great, and we believe that also speaks for a likely positive outcome of the CALIPER clinical data in next April.
All right, and speaking of clinical data, I did want to review some of the earlier EMPHASIS data from the phase 2. I guess, you know, could you walk us through this trial, and I guess just starting with the patient population that was studied and what was found in this trial?
In the EMPHASIS study, this was the first MS study we did. The study was big enough, so we recruited 268 patients in the study, and the goal was really to measure everything we can, starting with the clinical primary endpoint of the study, which was lesion reduction, gadolinium enhancing lesions and cumulative active lesions in the brain based on MRI imaging. That was very successful. We had around about 75%-78% reduction in the lesions with very high statistical significance. But also secondary endpoints in the study were NfL reduction, and there was a dose-dependent reduction between 10, 30, 45 milligram, whereas in the lesion reductions, it was really for the two higher doses.
You could see already a difference in this relapsing population, that if it comes to inflammation, thirty milligrams seemed to be sufficient to help do the job. Whereas for NfL reduction, which also includes PIRA effects, so neuroprotective effects, there is even a better effect at forty-five milligram, which drove the decision to go into progressive MS with forty-five and to a relapsing MS with thirty milligram dose.
Okay, and if you could just elaborate more on some of the findings. I guess I wanted to dive into those MRI findings for the active lesions.
Mm-hmm.
What did you see there from a, I guess, an efficacy standpoint? And I guess, what does that tell you about what we may see in later trials?
Yeah, it is accepted and known that MRI lesions correlate clinically with relapse frequency. So therefore, we use these numbers to project on a numerical basis in a simulation, how they translate into relapse activity in the patients, and therefore, in the phase 3 study, we use time to first relapse as the primary endpoint of the study. The quantitative effects were simulated on computers based on the MRI lesion count. And as I said, in the three doses tested, 30 and 45 milligram had almost the same activity. We believe that you just need to reach a threshold to have the effect. And 10 milligram, which was the lower dose, did not have a strong effect on the lesions. So, that drove the decision to go forward with 30 milligram, there.
Okay, and if we can go back to the NfL findings. So trying to summarize what you said before, so this is still a developing biomarker. It's predictive of potential benefit as far as neuroprotection goes. But can you help contextualize this, the benefit you saw in decrease in NfL, and how you think this might translate into efficacy benefits or I guess, a signal in the phase 3?
Now we enter the speculation area. NfL is-
It's a perfect area for Fireside Chats, so.
Yeah, I think we have seen this 22% reduction in the PMS study. And I think that the same level, by the way, in the RMS study, so emphasis had also a in the 45 milligram more than 20% reduction of NfL. Comparing that with historic data, so and there's not unfortunately, there's not too many data published on this from other studies. But comparing NfL versus benefit on preventing disability worsening would lead to a projection of something like 0.7 hazard ratio. We asked the experts who are dealing with that every day, what would be perceived as a success for the sub-indications of non-relapsing or primary progressive MS?
And I think the around the room where we had our expert meeting, the consensus was 15% benefit is okay, 20% is good, and everything better than 20% benefit on hazard ratio is excellent. So that's how we think about it, and, but don't forget, this study is statistically powered for the primary endpoint. So you're talking about a CALIPER study, in April, which is brain atrophy, so another MRI imaging-based endpoint, which is more sensitive and statistically easier to predict, and disability change is a key secondary endpoint in the study.
Got it. And thank you for entertaining my question. So if we could switch gears a little bit and talk about the CALIPER trial. This trial has been fully enrolled? And I believe there is guidance for the data release in April. So if you can just give us a brief review of CALIPER, and I guess specifically how it differs from EMPHASIS?
Yeah, CALIPER is focusing on progressive MS patients, so we have non-relapsing secondary progressive, primary progressive, and active secondary progressive patients in the study. So these patients should, in a normal world, not have any relapse activity anymore or any MRI lesion activity. Of course, some patients have that, but we test that, and we also evaluate them separately in the study. So therefore, this study allows to selectively analyze the effect on PIRA, more or less, because those patients don't have a lot of interfering other RAW effects or some of these things. So this would enable us to really completely separate the PIRA activity in this challenging population. We have 467 patients enrolled in the study. It's big.
Just the non-relapsing secondary progressive cohort is more than 230 patients, so we expect that the data set is good enough to give us answers, which indication is the most promising? Where do we see the strongest data? Do we see correlation between brain atrophy and biomarkers? Do we see a correlation with clinical disability prevention, so it will be a very information-rich phase 2 study and should guide our decision how to continue with the study into phase 3, also should give us all the information to talk to potential partners on that, because this is a huge unmet need. Everybody knows it. There's little in development, so it's a hot area, and we think that this study could be transformative for the company.
Got it, and just because this is a different patient population, I was hoping maybe we can compare and contrast the two different patient populations, maybe on the level of how high the prevalence is for each one?
Yeah.
And also, just any differences in how the disease is currently being treated, what the standard of care is?
Yeah. Usually, we talk about incidence rates and all of these things. The point is that secondary non-relapsing secondary progressive patients prior had RMS, so there's the sum of the parts, not 100%, it's 120%. So we roundabout think that today we have 900,000 patients with relapsing MS. Approximately 40%-50% are not on a treatment, usually, on average. And mainly because of safety issues, concerns, or lack of efficacy of other drugs, or pausing during treatments. In non-relapsing MS, we have roundabout 175,000 patients affected, and in primary progressive, it's believed to be something like 125,000 patients. But in current drugs, we target relapsing MS, and just Ocrevus is approved for primary progressive.
In relapsing MS, a market share of 5% would be a blockbuster, would mean $1 billion sales. In the progressive MS diseases, there's little or nothing. We have Ocrevus in PPMS. That's it. There's no oral drug in PPMS, and there's no drug in non-active secondary progressive, so that defines a huge market by itself.
Okay, and if we could focus on the ENSURE trial, the phase 3 program there. Could you walk us through the current timelines, and the expectations there for potential differentiation, given how the market's currently being served?
Yeah, first of all, I think the key difference between EMPHASIS and CALIPER is CALIPER is an experimental trial. We try to find the right information to guide the final phase three or approval. There's maybe even a way for an expedited approval there, but it's a really science-driven thing. In the ENSURE phase three studies, we are repeating what we have learned from EMPHASIS and really trying to deliver a good data package to get approval from the FDA. And we really shied away from shortcuts, simplifications, and so forth. We didn't change comparator, so this trial is really designed to succeed and to get approval. And we have two identical studies, ENSURE one and two, to have the statistical confirmation, which we need for an approval.
But we also agreed with the FDA that we can pool the data of the two studies to evaluate neuroprotection in reading our 24-week confirmed disability worsening. And we think that our package is pretty attractive because it will highlight the role of PIRA in neuroprotection also in relapsing MS, which so far didn't play a big role in historic development, and now is a key thing we need to focus on. And given the design of the study and using a placebo comparison, we think it has a very good chance to succeed and to fill the space which was more or less opened or left because the BTKs are disappearing from that.
Right, and in the study, I do believe there is a futility analysis that may be planned here?
Yeah. I think this was because we have chosen an event-driven relapse endpoint for the study, so we measured time to first relapse between the thirty milligram and the placebo group. We said we need to check whether the disease activity in the population is sufficient to deliver enough delta and events in the study, and therefore, there's one futility analysis included, which will be done in the next quarter. So in the fourth quarter of this year, we expect to have that performed, and then, either get a sample size adjustment result or a proceed as planned. I don't think that we will see a futile situation.
If we could just elaborate on the futility analysis. I was hoping you could maybe elaborate on what specifically would lead to the trial stopping?
Yeah, if a trial is futile-
Um
... I think that would be a recommendation of stopping the study.
Okay, and, is there a timing for that analysis, potential timing?
Yeah. It's we the guidance is for fourth quarter. No more details there, but we don't wanna mess up Christmas, so...
Okay. Got it. And I guess if we think about the flip side of a futility analysis, is there any chance of the trial stopping early for success?
That was we was hoping for when we were discussing with the regulators, but the FDA doesn't like it and explicitly excluded that option because of the multiplicity problem of statistics. So therefore, we will not be able to stop, even if we overperform brutally.
Okay, understood. It looks like we only have about four minutes left, so I did wanna give you a chance to highlight the other pipeline assets?
Yeah.
I know there's an asset in celiac disease and also in Crohn's or in GI disease. So, please go ahead.
Yeah, I think I mentioned shortly in the beginning, IMU-856 is a first-in-class Sirtuin 6 modulator, and the molecule is quite unique. It's binding to Sirtuin 6 and has two effects. On the one hand is stopping the enzymatic functionality of the protein of Sirtuin 6, and on the other hand, stabilizing the protein, and therefore has a very unique function on the transcription control and the effects. Sirtuin 6 is highly expressed in the intestine, specifically in Paneth cells, goblet cells, and enterocytes, and it's interesting because it looks like activating Sirtuin 6 or modulating Sirtuin 6, I need to say, because of the stabilization and enzymatic inhibition, we observe a concerted activity in that tissue.
And what we observe is that the molecule triggers somehow the renewal process in the gut wall by activating intestinal stem cells, and leading to this asymmetric division, which then supplies new epithelial cells in the gut wall. So the concept is very easy. We want to fix the, or heal the gut wall, by that protecting insults from toxins, from proteins, from the outside. It could be gliadin, for example, and other things. And with that, improve the GI diseases at root, at the root cause, basically. And to show that, as part of our phase one program, we have not only looked on safety and PK, but also we included around about thirty patients with celiac disease in the phase one program.
And we did a four-week study in the celiac disease patients with two weeks just treating either with placebo or active molecule, and another two weeks where we gave six gram of daily dose of gluten to the patients. And then we looked for a lot of different clinical and biomarker endpoints in that study to see whether the drug can protect patients from the gluten insult, from damage on four dimensions, meaning histologic, functional, biomarker, and symptomatic. And we were surprised that specifically the challenging endpoint of histology, we had despite very small number of patients a statistically significant protective effect on the villous height, which is, I think, good because of an objective readout for such a study.
And secondly, very impressive functional improvement in the gut tissue, because we have seen a dose-dependent strong recovery or increase of vitamin B12 uptake, of citrulline biomarker, zinc uptake, and a lot of nutrients. So it looks like that despite we gave the patients six gram of gluten, they were in fact improving on disease and function of disease.
All right. And looks like we're about out of time. Thank you. This has been a pleasure, and hopefully, we see you soon.