Good morning, ladies and gentlemen, and welcome to Immunic's webcast to discuss a wonderful update from our MS Development Program, the top-line data of our phase II CALLIPER trial for vidofludimus calcium in progressive multiple sclerosis. My name is Jessica Breu, Vice President of Investor Relations and Communications here at Immunic, and I will be the moderator for today's webcast. Please note that all participants will be in listen-only mode, and this event is being recorded. During today's presentation, there will be an opportunity to ask questions. If you joined the webcast via the Zoom platform, there are two ways to submit questions. You can either submit your questions in writing via the Q&A tool of the Zoom portal, or if you would like to speak with us directly, please use the raise hand function in the Zoom portal to queue your question.
Before we begin, I would like to remind you that this presentation may contain forward-looking statements. Such statements can be identified by words such as may, will, expect, anticipate, estimate, or words with a similar meaning, and such statements involve a number of risks and uncertainties that could cause Immunic's actual results to differ materially from those discussed here. Please note that these forward-looking statements reflect Immunic's opinions only as of the date of this presentation, and it undertakes no obligation to revise or publicly release the result of any revision to these forward-looking statements in light of new information or future events. Please refer to Immunic's SEC filings for a more detailed description of the risk factors that may affect Immunic's results and these forward-looking statements. Speaking on the call today are Dr. Daniel Vitt, our Chief Executive Officer; Jason Tardio, our President and Chief Operating Officer; and Dr.
Andreas Muehler, our Chief Medical Officer. I would now like to turn the call over to our CEO, Dr. Daniel Vitt, to share the updates from our CALLIPER trial. Daniel?
Yeah, thank you, Jessica, and also a warm welcome from my end to our call to present wonderful and potentially groundbreaking data we obtained from our CALLIPER phase II clinical study. Just to reiterate, it's really great data. The CALLIPER study is an integral part of our global development program of the vidofludimus calcium for patients with different forms of multiple sclerosis. After the successful completion of the EMPhASIS phase II trial in patients with relapsing-remitting MS in 2021, the medicine is currently being tested in relapsing MS patients in our pivotal twin phase II studies, ENSURE-1 and ENSURE-2. We expect completion of those studies during the next year. Last October, we already announced a very positive interim analysis from the ENSURE program. Our goals go beyond relapsing MS.
Our overall goal is to develop vidofludimus calcium for a broad range of patients suffering from MS, including relapsing MS, primary progressive, and secondary progressive MS, leveraging the drug's unique dual mode of action. Vidofludimus calcium is the first-in-class Nurr1 activator, making it a drug candidate with neuroprotective effects. Secondly, being a potent and selective DHODH inhibitor makes it a smart and safe tool to lower overshooting inflammation. On top of this, vidofludimus calcium has shown a very attractive safety and tolerability profile to date. Moreover, it is convenient and easy to use, expected to give people living with MS a better future treatment choice. Let's have a look on the progressive MS indication and our CALLIPER study.
Progressive MS has two main indications: primary and secondary PMS, with approximately 120,000 patients diagnosed with primary PMS and 175,000 patients with secondary PMS in the U.S. and the EU five countries. In contrast to relapsing MS, both PMS indications are mainly driven by smoldering neurodegeneration processes and less by focal inflammation. So far, only one drug, OCREVUS from Roche and Genentech, is approved to treat primary progressive MS, and no treatments are available for non-active secondary progressive MS. Being the first and only Nurr1 activator in clinical development for MS, vidofludimus calcium represents a completely new approach to directly target neurodegeneration and not just focal systemic inflammation. So, what is the real unmet medical need in MS? After 30 years of drug development, the key unmet medical need is still slowing down or even stopping disability progression.
That means we need to stop worsening of disability of people suffering from all forms of MS on the so-called EDSS scale, a measurement of physical ability status of patients. While over 15 anti-inflammatory treatments exist for relapsing forms of multiple sclerosis, there is no therapy available that directly impacts the neurodegeneration driving disability progression. It is Immunic's ambition to address this gap with a new innovative treatment option aiming to directly address the degeneration of neurons. Here, vidofludimus calcium comes into play. Why did we conduct the exploratory phase II CALLIPER trial in patients with progressive MS? First of all, we wanted to prove the direct neuroprotective effects of vidofludimus calcium via activation of Nurr1. In particular, answering the question, we see if we see clinical benefits in patients without focal inflammation.
Secondly, we wanted to check to what extent this new medicine can reduce disability worsening in PMS patients. Thirdly, it was our goal to identify which subpopulation benefits most and should be the first progressed into a full-blown phase III clinical study. I would now like to hand over to my co-founder colleague and Chief Medical Officer, Dr. Andreas Muehler, to walk you through the study design and most important exciting results from the study. Andreas, please go ahead.
Thank you, Daniel. Let me start with a general overview of the CALLIPER phase II study. We allowed primary progressive MS patients, referred to as PPMS, and secondary progressive MS patients referred to as SPMS, and in the SPMS case, both with active and non-active SPMS to enter the trial. CALLIPER was designed to focus on progressive MS patients with non-active disease and with as little as possible focal inflammatory disease to test our hypothesis that the neuroprotective mechanism of vidofludimus calcium via Nurr1 activation is able to provide benefits in such non-active patient population and therefore differentiates from treatments with pure anti-inflammatory mechanisms that show less or minimal benefits in patients without substantial inflammatory components. All of the progressive MS patients, irrespective of disease subtypes, were not allowed to have any evidence of relapse events in the last 24 months before randomization.
Therefore, this study was exclusively performed in a non-relapsing patient population, even for active SPMS patients. This is one of the main differences to some of the historical studies in progressive MS. The other difference to historical studies is that we allowed patients from 18 years- 65 years to enter the study, which is a higher age than most of the larger progressive MS trials allowed. For example, HERCULES for tolebrutinib and EXPAND for Siponimod only enrolled patients until 60 years old, and ORATORIO for ocrelizumab only until 55 years old. In agreement with these other studies, CALLIPER enrolled patients with a baseline EDSS score between 3- 6.5. Patients in CALLIPER were randomized one-to-one to 45 mg of vidofludimus calcium and placebo. The double-blind treatment period lasted up to 120 weeks, meaning a little bit more than two years.
The study was closed when the last randomized patient reached at least 72 weeks, close to one and a half years of follow-up. The follow-up period and the double-blind treatment period was therefore somewhere between 72 weeks- 120 weeks for all patients. Today, there are more than 375 patients that are continuing to be treated in the open label extension with 45 mg of vidofludimus calcium. Next slide. Let's dive into the baseline and patient characteristics of the CALLIPER study. As communicated before, a total of 467 progressive MS patients were randomized into CALLIPER. Hence, this is quite a large patient population for a phase II study. We recognize that such patient numbers may not achieve statistical significance in study endpoints and outcomes, which was not the goal of such a phase II trial.
The main goal of the CALLIPER study was to provide a large enough patient population to provide a clinical proof of concept or proof of clinical activity of vidofludimus calcium in this non-active progressive MS population with a neuroprotective treatment mechanism, in particular as we included both PPMS and SPMS patients. The relatively large sample size will allow reliable point estimates for important endpoints for better and more precise planning of future phase III trials. The CALLIPER trial included roughly two-thirds of non-active SPMS patients and about one-third of PPMS patients. There was no particular quota for these two larger disease subtypes, but we used disease subtypes for stratification during randomization together with baseline EDSS to carefully have carefully balanced treatment arms in this study.
SPMS patients who showed evidence of gadolinium MRI lesions in the brain or spinal cord in the last 12 months before study entry were classified as active SPMS, and roughly only 10% were characterized in these disease subtypes. We will show additional data for non-active subgroups, in particular one that excludes roughly 16% of CALLIPER patients without gadolinium-enhancing lesions at baseline MRI. Enough said, you all are probably waiting for the more detailed study results. I need to point out that the results we have received are top-line results focusing on the key endpoints as well as top-line safety data. We ourselves have not seen all data from all endpoints yet, and we will continue to receive them over the next weeks and months to come.
In particular, we are still waiting for some of the clinical endpoints such as full assessment of the functional outcomes, fatigue, and treatment satisfaction, for some of the MRI endpoints such as slowly expanding lesions, for some of the biomarkers such as neurofilament light chain and EBV reactivations, for some of the more detailed safety analysis such as for laboratory abnormalities, vital signs, and EKG, and we're still waiting for pharmacokinetic data. However, we believe that all relevant data are already available to make an overall assessment of the activity of vidofludimus calcium, especially based on confirmed disability worsening, including for the disease subtypes and non-active disease subgroups, important MRI outcomes, as well as top-line adverse event data. Let's look at those data points now. We will start with the confirmed disability events observed in this study based on the worsening of the EDSS neurological score.
This is traditionally the most important study endpoint in progressive MS and most relevant to regulatory authorities for approval of treatments in progressive MS. Overall, we believe that the data highlights that vidofludimus calcium has shown a substantial decrease in confirmed disability events as compared to placebo control. This slide summarizes the main and most relevant results of the CALLIPER study. This table shows the rate of EDSS disability worsening events confirmed at 24 weeks following the trigger event for the vidofludimus calcium and placebo treatment arms and calculated from these event rates the relative risk ratio. In the overall CALLIPER population, we have observed a 20% decrease in the relative risk of experienced 24-week CDW events for vidofludimus calcium as compared to placebo.
We have also observed medically relevant increases in the disability event risk throughout the two main disease subtypes: a 30% disability event reduction in PPMS patients and a 15% disability event reduction in non-active SPMS patients. This slide illustrates the differences between the baseline characteristics of PPMS patients as well as the relative risk reduction in these PPMS patients for the main historical phase III study in this patient in the PPMS patient population called ORATORIO, which led to approval of ocrelizumab in the PPMS population. While age and baseline EDSS characteristics are very similar between the ORATORIO and the CALLIPER studies, there's a clear difference in the inflammatory activity between these studies. There were clearly more PPMS patients in the ORATORIO trials that showed gadolinium-enhancing MRI lesions at baseline, about 27%. There were less PPMS patients with such lesions at baseline for the CALLIPER study, about 18%.
This provides some reference for the 30% of relative risk reduction in 24-week CDW events in the CALLIPER study, despite being in a less active PPMS population than ORATORIO. It has been shown in historical progressive MS trials, including in the ORATORIO study subgroups, that less active subgroups tend to have less benefit in reducing disability events. In this slide, we dive deeper into the non-active subgroup of the overall CALLIPER population to test whether the same is true for vidofludimus calcium, that non-active subgroups have less benefit in reducing disability events. In total, 391 of 467 patients in the CALLIPER study had no evidence of gadolinium-enhancing MRI lesions at baseline, indicating a lack of focal inflammatory activity at this time point.
When we analyze the confirmed disability events in these 391 patients without gadolinium lesions at baseline, we observe a roughly 20% rate of 24-week CDW events in the placebo treatment, but only about a 14% rate of such events in the vidofludimus calcium treatment arm. This corresponds to a 29% relative reduction of 24-week CDW events in this subgroup and is in line and larger as the same for the overall CALDOSE population with about a 20% relative risk reduction. The population without gadolinium lesions at baseline is the patient population who usually much less benefits from current anti-inflammatory therapies.
We believe this preservation of benefit for risk reduction in the subpopulation without gadolinium at baseline is a great testament to the mechanism of action of vidofludimus calcium, as basically all or almost all disability events in a non-active progressive MS population are progression independent of relapse activity or PIRA, which are known to be very little affected by anti-inflammatory treatments. We believe that the results in a subpopulation of CALLIPER without gadolinium lesions at baseline speak to a clinical neuroprotective effect of vidofludimus calcium observed in this study. This is likely the most important conclusion from these top-line data that vidofludimus calcium may establish the first MS treatment with direct and indirect neuroprotective effects.
In conclusion, we believe the CALLIPER top-line data regarding confirmed disability events successfully demonstrated the neuroprotective potential of vidofludimus calcium in progressive MS patients with medically relevant reductions in the relative risk for 24-week CDW events that also expands to subgroups not showing evidence of focal inflammatory activity. We also believe that the available MRI data provides mechanistic insight for the observed disability benefits of vidofludimus calcium. The ECTRIMS graph in this slide shows the effect of vidofludimus calcium on whole brain volume change as compared to placebo. The CALLIPER data confirms the recent findings of the HERCULES study for tolobrutinib that there's an at most modest benefit of the MRI endpoint of whole brain atrophy. There's a roughly 5% reduction in the annualized rate of whole brain atrophy for vidofludimus calcium compared to placebo at 24 months, almost identical to tolobrutinib at the same time point.
It further feeds the ongoing discussions over the last years in the medical MS community whether the more crude endpoint of whole brain atrophy is the right screening marker for treatments in progressive MS. Whole brain atrophy is now discussed to be better used in a patient population with more active and relapsing disease only. Lately, there was increasing support that atrophy of more selective brain regions such as the thalamus or the gray matter, with both usually showing less signs of focal inflammatory disease than the white matter, are more sensitive MRI markers in progressive MS. In addition, studies in thalamus have shown strong associations between thalamic atrophy and clinical disability progression. This is supported by the CALLIPER data where vidofludimus calcium reduced the thalamic volume loss by 20% as compared to placebo. A similar magnitude of effect was also seen in gray matter atrophy in CALLIPER.
This slide shows the changes in the volume of new or enlarging T2 lesions on MRI. These T2 lesions reflect the permanent footprint from previous diffuse inflammation and from focal inflammatory lesions that developed in the interval between two MRI scans. The volume assessment of the entirety of these T2 lesions is believed to correlate with the amount of ongoing diffuse or focal inflammation in the brain. The curves of the volume change for new or enlarging T2 lesions show a very different picture for vidofludimus calcium and placebo treatment arms. While the T2 lesion volume continues to increase over time for the placebo arm, the volume of T2 lesions remains stable over time or even slightly decreased for the vidofludimus calcium treatment arm.
We believe that these data on thalamic atrophy and volume change of T2 lesions provide a mechanistic rationale to explain the medically relevant reduction in confirmed disability events. This concludes our presentation of the CaLLIPER top-line data on clinical endpoints and MRI outcome. Let's summarize now the available top-line safety data from the CALLIPER S tudy. In short, in these top-line safety data, the CALLIPER Study did not identify any new safety signals for the progressive MS population or for the 45 mg dose of vidofludimus calcium. As you can see from the upper left table on this slide, treatment emergent adverse events and serious adverse events occurred with similar frequency in both treatment arms. The lower two tables show the most common treatment emergent and serious adverse events observed in the CALLIPER S tudy. All of these events are mainly non-specific events that correspond to common events in this patient population.
I would also like to add that we did not observe any Hy's law cases for liver enzyme elevations during the entire double-blind treatment period of CALLIPER. I think here I would really like to personally thank all of the patients that choose to enter our CALLIPER study, as well as all of our investigators and site personnel at more than 70 sites in North America, as well as Western, Central, and Eastern Europe, for their willingness to support Immunic in this important research in a largely underserved patient population in MS. We, as an Immunic team, are humbled by their kind collaboration with us. From here, I would like to hand over to our President and CEO to elaborate more on the commercial considerations related to the CALLIPER Study population. Please take over from here, Jason.
Thank you, Andreas.
The development of a safe, effective, and convenient therapeutic option for the treatment of primary progressive MS remains the Holy Grail of drug development in the MS space, as primary progressive multiple sclerosis represents a significant unmet need within the multiple sclerosis landscape. This subset of disease, which affects approximately 10%-15% of all MS patients, is associated with more severe symptoms and greater functional impairment than relapsing forms of multiple sclerosis. Furthermore, patients with primary progressive MS experience higher rates of unemployment, increased hospitalizations, and a more profound reduction in quality of life, all of which translates into a greater economic burden on individuals living with this disease and the healthcare systems. Across the U.S. and EU5, approximately 120,000 people have been diagnosed with primary progressive MS. Yet, despite the burden, only about 45% or 54,000 patients are currently being treated with disease-modifying therapies.
This low treatment rate reflects a broader issue. Primary progressive MS remains significantly underdiagnosed and undertreated due to a lack of safe, effective, and convenient treatment options. Therefore, it should not come as a surprise that current market research and physician surveys underscore a clear consensus: there is a pressing need for a new, more effective therapy to manage this segment of the disease. Unfortunately, the one currently approved therapy does not address the totality of patient needs within primary progressive MS. The limited use of ocrelizumab in primary progressive MS is due to several factors, but the two most common reasons include safety and risk considerations and lack of convenience.
From a safety perspective, it is important to remember that treatment with ocrelizumab carries immunosuppressant risks, including increased susceptibility to infections such as herpes virus, progressive multifocal leukoencephalopathy, and more, and also has the potential for an increased risk of malignancies. Unfortunately, these risks can be particularly concerning in older or more disabled primary progressive MS patients who are more vulnerable to these complications. Within the PPMS segment, these patients often experience difficulties with mobility and fatigue, which can make it harder for this population to travel to and from infusion appointments and to adhere to the complex monitoring requirements associated with therapeutic intervention with ocrelizumab. For Immunic, this presents a clear opportunity.
The combination of high unmet medical need, substantial disease burden, and limited therapeutic competition creates a compelling business case, and we believe that if we are successful in primary progressive MS, it could represent a large market opportunity. We estimate that the total global market for primary progressive MS therapies is currently $6 billion, and this number is expected to grow with the approval and increased availability of new medicines. As a reminder, we believe that there are approximately 120,000 diagnosed primary progressive MS patients in the U.S. and EU5 alone, but less than half of these patients are currently treated, many with off-label therapies. Current market estimates assume that approximately 35% or roughly $2.7 billion of OCREVUS's revenues today are being driven by PPMS sales.
An indication for primary progressive MS would build upon our previous market assumptions for vidofludimus calcium in relapsing MS and would represent a large global opportunity for this asset. In relapsing MS alone, our research supports that the product profile associated with vidofludimus calcium could drive peak sales in the $1 billion-$2 billion CALLIPER trial, we believe that vidofludimus calcium could become the cornerstone of care in the primary progressive MS segment, representing an additional $2 billion-$3 billion in peak sales. In summary, vidofludimus calcium has the opportunity to transform the MS market, and we believe may be the first and only oral disease-modifying therapy approved to treat both relapsing and progressive forms of the disease.
This is a medicine that is uniquely designed to address the full spectrum of multiple sclerosis through inhibition of the enzyme DHODH for neuroinflammatory benefits and via activation of the nuclear receptor Nurr1 for direct neuroprotective effects. The data to date supports a differentiated profile that will provide a best-in-class benefit-risk profile within the oral disease-modifying segment by combining strong efficacy with a best-in-disease safety and tolerability profile. If approved for both relapsing MS and primary progressive MS, we believe this could represent peak global sales in the $3 billion-$7 billion range. With that, I will now pass it to Daniel for a few concluding remarks.
Yeah, thank you, Jason, and also Andreas for the insights you gave us here. What a great success, I think. Let me shortly draw some conclusions here from our end. Let me phrase it in that way.
We're delighted about the Phase II CALLIPER results showing that vidofludimus calcium outperformed historic trials in PPMS regarding numerical reduction of disability progression events. It goes even further. The data impressively confirmed the main objectives of this exploratory phase II clinical trial. With today's results, we believe it paves the way for a potential registrational study in progressive MS, looking at the data likely starting with PPMS first. We believe that the CALLIPER trial achieved unprecedented proof of concept, in particular regarding the key medical and future phase III endpoint of confirmed disability progression, not only for primary progressive multiple sclerosis, but also for non-active secondary progressive multiple sclerosis patients. I would like to highlight that vidofludimus calcium addresses a more than $6 billion market in PPMS alone. As I said earlier, only one therapy is currently approved for PPMS.
As one of the next steps, we will discuss the CALLIPER results with healthcare authorities to determine appropriate next steps for further development and a potential approval track in progressive MS, including a potential application for breakthrough designation. With this, I would like to hand back over to Jessica to open the Q&A session. Jessica, please go ahead.
Thank you, Daniel, and also Andreas and Jason for presenting these exciting news for vidofludimus calcium in progressive MS. It's now time to open the call for questions from the audience, so we will now begin the Q&A session. As a reminder, if you join the webcast via the Zoom platform, there are two ways to submit questions.
You can either submit your questions in writing via the Q&A tool of the Zoom portal, or if you would like to speak with us directly, please use the raise hand function of the Zoom portal to queue your question. The first one in the line here today is Faisal Khurshid at Leerink Partners. Faisal, please unmute yourself and welcome to the call.
Hey, thank you for taking the question. Just wanted to ask, how should investors think about the sort of discordancy between the disability outcomes and the brain volume outcome?
Yeah, not unexpected question, Faisal. Thank you for that. I think this is just a very good impression of how science is progressing and understanding that, obviously, the whole brain volume is more directed to white matter, and therefore it's relevant for those cases where focal inflammation plays a role. This is more relapsing MS.
If we deal with progressive MS, and also maybe shown in all the difficulties of immunosuppressive drugs to show effect in these progressive patients which do not have inflammation, that gray matter and, for example, thalamus are more relevant for the link between disability on the long run and volume change. I think we are at the forefront of science and, of course, a little bit of a pity, but honestly, this is all in line with the scientific results of the study and the huge potential of the drug. I think thank you for the question here.
Got it. Thank you. If I could slip in one more, could you just comment on the next steps here, both from a development perspective and then also from a sort of corporate and financing perspective as well?
Yeah, you see, I was hopefully very delighted today.
This is really the best thing that you can hope for from such a study, in particular recognizing not only that very, very good reduction of disability, but also what Andreas has shown, this strong activity on disability protection here in the patients without gadolinium lesions makes it a quite unique new approach. This could be a game changer, specifically focusing here on patients which have progression without inflammation. Therefore, this is, I think, of high interest to the whole MS community, but also companies with active businesses there. We will definitely enter into detailed discussion with current players there and to see where synergies arise and where potential partnerships could come from. On financing, I think you're aware that we entered this very nice staggered financing last year in the PIPE transaction we did in January 2024.
We also think that likely the second tranche of that deal may come in very, very soon. I think all in all, a very good day for the company and very bright outlook for the company.
Great. Thank you so much for taking the question.
Thank you, Faisal. Thanks, Faisal. Next one here in the queue is Yasmeen Rahimi from Piper Sandler. Yas, please unmute yourself. Welcome.
Yeah, great. Congrats to the data team. Can you hear me?
Yes.
Yes.
Hi. Okay, thank you. Sorry. Team, congrats on the data. I think the first question is, I think before this data came in, you had obviously spoken about the opportunity about really fostering this data would be very important for partnering discussion.
Given that the brain atrophy showed not a statistical separation, could you maybe comment on whether that's going to be handicapping your discussion with strategics given this data on disability worsening? That's sort of question one. Question two is for Andreas. If you could just maybe talk about, obviously, the study wasn't powered for statistical separation, but how did the placebo perform in terms of disability worsening, especially in the progressive population, which will be the target population for phase III? Maybe the third one is back for Daniel around just broad strokes of the phase III study could be really, really helpful. I'll jump back for the queue, sorry, for the multi-part questions.
Maybe I start with the first question, Yas. As I said before, nobody, I can clearly say today that really nobody should care at all about whole brain volume change anymore.
This is a little bit of a leftover of our design of the study we did five years ago. This is really not an issue of everybody who's skilled in what's going on. If you remember the Hollywood-intended paper from Sanofi, there was a discussion already arising there. It was already clear at that time point that there is this difference. It is more a good thing and more linked to the neuroprotective features of the drug in the population, which just does not have a lot of inflammatory activity. These are the difficult-to-treat patients we have here. We see the disability protective effects we want to see. This is the clinical outcome. This is the phase III o utcome.
I think the idea was and the MRI endpoints to have a little bit easier way to show something in a phase II study, that's no longer the challenge. I think here we need to plan forward to look for a phase III study. This is all about disability and more or less nothing else. Every other data point in the study we have looked at so far supports that direction and corroborates the neuroprotective features and the clinical benefit for the patients. Clearly, this is a very, very clear positive-only outcome. I think industry sees this from the same point of view. That's our conviction here. If you look back, we said that to people before we had the data, because that was a shift which took place in the last 12 months, maybe.
Second question, maybe Andreas, you take over the placebo baseline question here.
Hi, Yas. I think it's a good question. I think we also, of course, we had monitored the overall confirmed disability event rate during the trial, which was in line with our assumptions that we had done. Also, when you look at the placebo disability event rate, it's probably in the lower range of what historical trials have done in the same patient population. I think it has to do a little bit that we have a patient population that basically does not have any focal inflammatory activity, has very little relapse activity in this trial. You can see this in our slides that we made public today.
I think you would expect that we are in the lower range of the placebo disability event rate, I think, as compared to historical trials who also had focal inflammatory activities and were, for example, the disability may also have come from reducing focal inflammatory activity or the disability events from reducing focal inflammatory activity. I think it is even more so, I think, a testament to the mechanism of action, especially the Nurr1 activation, that despite this, we see basically a relative risk reduction despite this more lower rate of placebo disability events here in this trial in a very medically relevant and meaningful reduction range, which is, I think, important to say. This will translate. You asked about, again, about the statistical significance. Of course, this is a phase II trial, especially for a secondary endpoint in this trial of confirmed disability worsening.
You would have to power the study similar to a phase III trial to really expect something here. This was not the goal and the purpose of this trial. When we power a phase III trial, we can now really take the very good point estimates of relative risk reduction and power the study accordingly so that we achieve statistical significance in a phase III. This was quite important for us to really understand the performance of the drug in different subtypes of diseases. For example, PPMS versus non-active SPMS, but also in the different subgroups in the trial, patients with and without gadolinium lesions. We will also have further subgroup analyses down the road that will allow us to really basically design the phase III trial in a way that we are sure we are reaching statistical significance here.
In principle, the only thing I can say about the phase III study at this point, we all know that the 24-week confirmed disability worsening that I've shown you here today is basically the registration endpoint in this patient population, PPMS and non-active SPMS that regulators would like to see. We had the discussions, of course, with the regulators while we're doing the CALLIPER trial so that we already understood a lot about the design of the phase III trial. Of course, we also now execute the end of phase II trials with the regulators to get more detailed information. I think we are very much aware that in which direction the phase III trial will have to go in order to get approval.
Thank you, Andreas. Maybe to complete the picture here on the phase III, it's a perfect result we got today.
We know what to do. PPMS is our first thing. We will kick off on active SPMS, maybe then the second point. That also will be part of our discussion with our potential partners. All in all, great time. I think we are prepared to kick it off very soon. Yas, does that answer your question or anything else?
No, that was perfect.
Thank you, Yas. The next one in the queue here is William Wood at B. Riley. Good morning, William. Please unmute yourself.
Thank you, Jessica. Congratulations, team, on the results today. A couple of questions from us. I was wondering if you could first speak to how the improvements you've seen today, specifically in CDW, support sort of the benefit of Nurr1 targeting of your drug.
Since that may be having an effect on the smoldering sort of PIRA underlying MS, which also resides in RMS, how you sort of see the benefit today reading through to phase III ensure later on next year?
Yeah, sure. That's a perfect question. Thank you for this. I think specifically the data we have shown on the 30% reduction here on the patient with gadolinium lesions, that's for us more or less the perfect PIRA population. As you said, Faisal, this is the big issue also in relapsing MS to target early.
This treatment also could be the perfect choice in relapsing MS, not only on the already proven anti-inflammatory activity, which we used for powering the phase III studies we are currently doing, insurance studies, but also for the key secondary endpoint of the insurance studies, which is basically slowing down disability worsening, which more or less where we want to demonstrate that we have this effect on PIRA also in the RMS population. This is a great point for the science team here at Immunic today to demonstrate that the science is relevant. Finding Nurr1 activation as a direct neuroprotective effect, a neuroprotective mode of action could be a game changer. This is why I like it. Thank you for the question.
I appreciate that answer.
I was actually curious in terms of the you evaluated non-relapsing and then PPMS, but I believe at least in your interim results, you also commented on sort of the active or I guess would be the relapsing in an NR-type population, the active nSPMS population. Could you provide any color there on how that population performed since I did not see too much data on it? Also, just to sort of provide one extra question, if I may, if you could comment in terms of the safety data overall, any elevations of liver enzymes that you may have seen that did not reach the level of Hy's law would be nice to know. Thank you. I will jump back in queue.
Yeah. Yeah. What was the first one?
It was the. From the active population.
The active population. Right.
The numbers are very small, so you can't really conclude anything on the disability numbers there. They're small, and there was no difference. I think you could, with three, five, four events, I think you can't really judge something based on that. In the published deck, you will also see in the backup some data on reduction of inflammatory lesions in these patients. In the small set of inflammatory patients, we also confirm that anti-inflammatory effect again. This is not the purpose of the study, and this is sort of a secondary positive effect on that population. Therefore, we don't focus on that right now in the presentation. For example, the subgroup analysis we've shown here for the totality of data always includes also these patients. Of course, they have gadolinium lesions at baseline, for sure.
The second was on liver enzyme elevations.
Yeah, I think give us time to, as I said, there was no new signal of side effects, toxicities here. As always, we will publish the whole thing. We will continue to be very open in publishing everything once it's time for that. There are a couple of good MS conferences later this year. Likely in the context of that, we will publish details once we have them. This is really changing wheels while driving. The data came in, and we just wanted to get it into April, as we promised. This is what we have. Therefore, give us a little bit more time on all the other details there.
Got it. Thank you.
Thanks, William. Next one in the queue is Myles Minter at William Blair. Good morning, Myles. Please unmute yourself.
Good morning.
Thanks for taking the questions. Yeah, just looking at the CDW data, it does look like you'd be competitive against ocrelizumab in primary progressive. Obviously in secondary progressive versus siponimod, by now doing cross-trial comparisons here. I shouldn't be, but maybe there's a little bit of gap to efficacy, at least from the six-week CDW data that we've seen from the HERCULES trial. Just curious as to whether or not that has played on your mind in terms of your decision to chase primary progressive first in a phase III versus non-relapsing secondary progressive MS and how you're sort of seeing the competitive landscape there.
The second question is actually on if you know or have intended to show the T1 lesion data, because I know that there's some pretty interesting telemarketing data out there suggesting that maybe that endpoint doesn't necessarily trend in the direction that we now predict for benefits from that compound. Thanks very much.
Good. Great question. Honestly, I think we are in a better place than you think, specifically when it comes to comparison to HERCULES. I think we just don't know to what extent HERCULES has really targeted patients with or where does the activity came from in that study. Their data was based on non-relapsing secondary progressive MS patients. We have non-active SPMS patients.
Traditionally, I would say any anti-inflammatory therapy without a direct neuroprotective mode of action had difficulties to confirm the activity in these non-inflammatory gadolinium-negative set of patients to show the same level of protection. We don't know the data yet. I think we are waiting for that. That was not even published in the Lancet paper recently. Therefore, we can't really compare our data. The 15% there is a good data point. Of course, in any phase III study, we need to really look, okay, what subpopulation is benefiting most? This is work of the next couple of months to come to identify what parameters make our drug great and what patients are responding best. Our preliminary judgment here is that we are good and we're difficult to treat patients. We are better where others are bad.
I also think, therefore, I have no worries about going against a BTK program clinically.
Yeah. Myles, this is Jason. Just a couple of general comments specific to the competitive profile. I mean, look, we'll have to see what plays out in the phase III here. But based on the data we have, if we continue to show a similar reduction in confirmed disability progression, for example, in a primary progressive population around the 30% benefit, clearly numerically, that would be in line, if not better, than what OCREVUS has shown to date. Remember, efficacy is just one part of the total consideration set when clinicians decide to prescribe a medicine. Beyond efficacy, you also look at the safety and tolerability profile of a medicine and general convenience.
As I discussed earlier in my slides, there is some reluctance from the market to broadly use B-cell depleting therapies in an older, more progressed MS population. Certainly, we know that the limits of this population to get to and from infusion centers as well impacts their quality of life. If you take the totality of what vidofludimus calcium could provide, a convenient once-a-day tablet, very effective and balanced with great safety and tolerability, again, we think it could be competitive, if not ultimately the cornerstone of care in primary progressive MS. Those same arguments would hold true in a non-active SPMS population as well. Obviously, tolerability, if approved, is an oral as well. You would have to balance the potential benefits of that medicine with the liver toxicity and safety concerns of which, again, we see none of those signals with vidofludimus.
Given the totality of the profile, we believe that the value proposition for this medicine in either of the subpopulations of progressive disease would be very well received.
Maybe from my end, Myles, I think you asked about the T1 lesion. I assume that you mean gadolinium lesions in the tolerability trial because you're absolutely right. There was a tendency that actually the tolobrutinib arm had a little bit more gadolinium-enhancing lesions than placebo in the HERCULES trial. In the version of the basic data that we have filed today, there's a backup slide that actually highlights that we have a substantial decrease in gadolinium lesion as compared to placebo in the non-active active SPMS patients. I think that's really in stark difference to what you've seen in tolerability with these lesions.
Great. Thanks for answering the questions. Congrats on data.
Yeah, thank you so much.
Thanks, Myles. I got two questions here via the Q&A tool. The first question for PPMS, how long will the phase III trial for PPMS be? When do you expect to start and end?
Yeah, that's too early to say, honestly. We know the data for a couple of days. Let's do the homework there. I can tell you with the effect size we have seen, it will be a pretty convenient, manageable study.
Thank you. The second question, now for non-active SPMS with no available options for those patients, how do you evaluate the 15% reduction? Also, will there be a chance to negotiate expedited approval from this phase II to allow patients to benefit from Vido?
The second thing is something we need to discuss with the regulators. I think we need to see what the feedback will be there.
For example, next year, we expect the data from the insurance studies. Maybe a combined data set could also give us a little bit of an accelerated track here. Let's see on that end. What was the first part of the question?
The 15%.
The 15%, yeah. Look, this is still a medically meaningful outcome in an untreatable population. I agree. This deserves to be worked on further. We think this clearly makes it an attractive asset. Consider, please, that we had a population with only 6% of patients with gadolinium lesions. That is a so far believed untreatable patient set. This is a great data point for such patients. I think maybe we tend to undersell things here. We should maybe be a little bit more explicit on this is really great. We think it deserves to be followed up as well.
The only thing we can't do without a partner, I think, will be challenging to imperil the launch of both studies. So far, I think it's just from the timing point, the PPMS data maybe tells us we should consider going first there. Again, here, this is also subject of discussion with potential partners on the one end, but also with the experts, KOLs, and the regulators. All right.
Thank you, Daniel. Thank you for the questions. I don't see any more hands raised here. This concludes our Q&A session. I would like to turn the webcast back over to Daniel for a summary and closing remarks.
Yeah. Thank you, Jessica, and all of you on the call today for listening in, for dialing in, to our analysts for these very good questions today.
To summarize the key points here, vidofludimus calcium in this study reduced the relative risk of 24-week confirmed disability worsening by 20% in the overall study population, with an even more prominent 30% reduction in the high unmet need population of PPMS, which we believe is a great success. We have seen a remarkable outstanding 29% reduction of disability worsening in patients without inflammatory lesions at baseline in the overall study population with 391 patients counted here, which underlines Nurr1 activation as a new mode of action for preventing neurodegeneration in MS and substantiates the impact on disability accumulation by both progression independent of relapse activity PIRA and relapse-associated worsening role. The data also confirmed the favorable safety and tolerability profile of vidofludimus calcium already observed in previous clinical trials with no new safety signals identified.
In addition, the data further de-risked our ongoing phase III ENSURE program, which offers the potential to bring an oral, safe, and neuroprotective treatment to relapsing MS patients early in the disease. Finally, patients seem to really love this treatment, as right now, there are still more than 375 patients which continue to be treated in the open-label extension phase of the CALLIPER trial, a really low rate of treatment discontinuations. What is next? Regarding CALLIPER, we will continue with the evaluation of the full data set, including, for example, as Andreas mentioned, further clinical data, biomarkers, safety, and so forth. We are committed to publish additional data at upcoming scientific conferences. Please stay tuned on that. Regarding our ENSURE studies, we continue to work towards completion of the trials and believe to be able to complete both of them next year. Another great things to come.
All in all, today's set of data together with the wonderful RMS phase II data from 2021 lay a strong foundation to make vidofludimus calcium a real game changer in MS therapy. Of course, we are also actively discussing potential collaborations and partnerships with pharma companies around the world with a clear aim to leverage the real value and multi-billion market opportunity of vidofludimus calcium. With this, I would like to thank you once again for listening, dialing in today, and for continued support. I wish you a wonderful and great day. Bye-bye.
Thank you for joining Immunic's webcast today. The call has now concluded.