Immunic, Inc. (IMUX) Earnings Call Transcript & Summary

Good morning, and welcome to Immunic's webcast to present the, and I'm very happy to say this, positive outcome of the interim analysis of our Phase III ENSURE program of vidofludimus calcium in relapsing multiple sclerosis. My name is Jessica Breu, Vice President, Investor Relations and Communications at Immunic, and I will be the moderator for today's webcast. Speaking on the call are Dr. Daniel Vitt, our Chief Executive Officer; and Dr. Andreas Muehler, our Chief Medical Officer. [Operator Instructions] And this event is being recorded. [Operator Instructions] Before we begin, as always, 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 the 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 revisions 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. I would now like to turn the call over to our CEO, Dr. Daniel Vitt, to begin the presentation. Daniel?

Yes. Thank you, Jessica. I also would like to welcome everybody on today's call. I'm delighted to report today on the positive outcome of the IDMC meeting for the interim analysis of our ENSURE Phase III clinical trials with a recommendation to continue the studies as planned. The ENSURE studies are twin Phase III studies in which we are testing the activity of vidofludimus calcium in patients with relapsing MS. The studies were initiated in 2021 based on excellent Phase II clinical trial results from our EMPhASIS study in relapsed and remitting MS. We plan to complete ENSURE studies in 2026. Vidofludimus calcium is a first-in-class dual mode of action medicine designed to address the full spectrum of multiple sclerosis disease. Nurr1 activation provides a direct neuroprotective effect. And on top of this, the profound and selective DHODH inhibition is associated with strong effects targeting an overshooting inflammation. Vidofludimus calcium aims to be best-in-class oral DMT with an outstanding risk/benefit profile by combining strong efficacy with very good safety, tolerability and once-daily treatment convenience. The absence of monetary requirements during initiation or on treatment makes it an easy to start or switch to therapy. And no black box warnings or serious infections risks like PML or malignancies are anticipated based on our current data from thousands of patients and unique mode of action. Let me now hand over to my co-Founder colleague and Chief Medical Officer, Andreas Muehler. Andreas, please go ahead.

Thank you, Daniel. Let me explain -- first of all, good morning, everybody, and thank you for your interest in today's announcement. Let me explain a bit more about this preplanned interim analysis of our ENSURE Phase III program for vidofludimus calcium in relapsing multiple sclerosis. When we planned the entire program, the intent of this interim analysis was to evaluate the futility of this program in general and to investigate whether our prestudy sample size assumptions were in line with actual data. Please understand that for this interim analysis, we had to protect the blinding of the studies for Immunic and ensure the full significance level, or alpha, is still maintained for the full analysis at the unblinding of the studies in the future. This leads to some of the framework used in this interim analysis. Just a short reminder of what the Phase III ENSURE program looks like. The program consists of 2 separate and independent studies with identical protocols. Hence, they are called twin studies by us. First of all, Immunic set a follow-up period of 72 weeks, guiding efficient patient recruitment in these large placebo-controlled relapsing MS studies. Together with making pre-study assumptions that will be discussed later and with a maximum follow-up period of 72 weeks, Immunic determines an anticipated sample size to power the study. For this reason, each ENSURE study was planned to a sample size of 1,050 patients randomized 1:1 to 30 milligrams vidofludimus calcium and placebo. Immunic has been communicating that recruitment for the ENSURE studies is progressing according to projections. Again, this interim analysis was to reassess the required sample size for each of the studies based on data from the ongoing studies. The primary endpoint, which would be the main determinant for approval by regulatory agencies in the future, is the comparison of time to first relapse between the 30-milligram vidofludimus calcium and placebo treatment arms. Time to first relapse is a statistically efficient clinical endpoint accepted by regulators as primary endpoint in MS studies. You can think of this analysis similar to other endpoints where the results are displayed in Kaplan-Meier curves, and one could see a difference in the survival curve of the 2 treatment arms, and treatment effects are usually communicating as hazard ratios. We would also like to reiterate that given the mechanism of action of vidofludimus calcium with combined neuroprotective anti-inflammatory and antiviral properties, Immunic believes the key secondary endpoint of 12-week confirmed disability worsening is an equally important outcome to support the medical relevance of the treatment effects of this medication. This key secondary endpoint will be investigated as a pooled analysis over both ENSURE studies, which was discussed and the precondition for such pooled analysis agreed with the FDA at the start of the program. So let's talk now about the main pre-study assumptions that went into planning of the sample size for the ENSURE program. There are 2 main determinants that drive the statistical power of the ENSURE studies. These are the general event rate and the hazard ratio. As you are quite aware from recent study readouts, the presence of a sufficient event rate is a quite important precondition for even having the opportunity to show potential treatment effect. We have planned for a relapse rate of 31% for placebo patients over the 27-week follow-up period. The other determinant of statistical power would be the degree of treatment effect of 30-milligram vidofludimus calcium versus placebo commonly communicate as hazard ratio in such time to event analysis. The ENSURE studies are powered to detect a hazard ratio of 0.67 between vidofludimus calcium and placebo. This resulted in a required minimum of 262 first relapse events. In broad terms, the interim analysis was preplanned to see whether these 2 main determinants of statistical power differ from pre-study assumptions. To do this, the relapse rates and hazard ratio were not calculated directly, but both combined are used to calculate a conditional power. Conditional power estimates the power of a study given the results observed so far and projected to the end of recruitment with certain assumptions. The calculation of conditional power and the use of it in interim analyses is quite common and well described in statistical literature. The preplanned interim analysis was preplanned to occur when approximately half of the planned first relapse events have occurred in a double-blind treatment period. The conditional power was only available for review by an unblinded independent data monitoring committee, or IDMC, and was used by this IDMC to make nonbinding recommendations based on the preset criteria regarding futility and additional criteria to evaluate a potential sample size increase. If both criteria were not met, the IDMC would then return a response of continuous plans. I would like to reiterate again that Immunic has remained blinded during the interim analysis and has not seen any of the unblinded data and conditional power evaluations available to the unblinded IDMC to make the recommendations. Immunic has only received the recommendations from the IDMC. For question one, the IDMC responded that the futility criteria have not been met at this time of this interim analysis in the ENSURE program. For question two, the IDMC recommended to continue both studies as planned without recommending an increase in the sample size of either study. Of course, now everybody would like to know how we as a management team feel about this outcome of the interim analysis and, I would, therefore, reference the quote in our press release from this morning. We see this as very positive event for the ENSURE program and are enthusiastic about this best case outcome of this interim analysis. With the IDMC's recommendations that the study -- the studies continue as planned without changes, we are continuing to target completion of the ENSURE studies in 2026. We believe today's results provides reassurance that the studies have the statistical power to address the primary endpoint of time to first relapse based on the original planned sample size. On this note, I would like to hand back to Jessica for her to start the questions-and-answer section of our webcast.

Yes. Thank you, Daniel and Andreas, for presenting this positive interim outcome for our Phase III ENSURE program of vidofludimus calcium in relapsing MS. [Operator Instructions] Our first guest today is William Wood from B. Riley.

Congratulations on the very nice results here. Really great to see that -- the progress going on. So just thinking about ENSURE-1 and 2, based on clinical trials and then Slide 3, sort of the timing for the expected readout, these trials would be slightly staggered, so presumably on at least slightly different time lines. The futility analysis occurred though on a pooled basis, so how should we think about these potential timing differences? And also just as a side commentary, it seems like IDMC commented on both trials. So just any color on the potential timing differences and how we should think about these being separate but full trial analysis? And then an additional follow-up.

Yes. So thank you, William. So I talked about that the primary endpoint of the study, time to first relapse is assessed for each study independently. And the second -- or the key secondary endpoint would be the second endpoint that would be a value is only done at a pooled analysis. So if the studies would read out in a staggered fashion. So this is kind of our anticipation based on the current projections of patient enrollment. But if they would read out in a staggered fashion, first of all, they wouldn't be far apart to be quite honest. And the other thing would be that we would communicate whether the primary endpoint would be met by each -- by, for example, a study that, for example, ENSURE-1 that reads out first. And then we would wait for the key secondary endpoints, for example, to wait for the other study to complete and then assess the key secondary outcome. So I think that's the way we would handle this because this key secondary endpoint of 12-week confirmed disability worsening requires a pooled analysis. So we would stop after the primary endpoint of the study.

Got it. And that's very helpful. Just thinking about, though, the actual futility analysis, though, since it was done sort of on this pooled analysis, is that -- is it -- if ENSURE-2 is slightly delayed beyond ENSURE-1 or maybe they're not delayed enough where you could be over representing in, say, ENSURE-1 over ENSURE-2 in your assessment?

Yes. So it is correct that there were slightly different numbers in this interim analysis contribution from ENSURE-1 and ENSURE-2, but it was not that unbalanced. And also we had set this interim analysis to occur basically for both studies at the same time, especially for the futility analysis had to be done on a pooled basis. However, we waited until both studies had reached about approximately half of the first relapse events. So you can be assured that both studies have already reported at least half of the first relapse events for this interim analysis, which statistically then assures that the data are relevant. And that's what -- how we planned this interim analysis that both studies had to reach half of the planned relapse events already.

Got it. That's very helpful. I appreciate that. And then one last one, if I may. In terms of baseline patient differences that you may be seeing, I understand that these were pooled and blinded, but maybe you could remind us in terms of patient differences or where you actually stand in terms of the full enrollment for each trial, if possible.

Yes. So maybe I'll start going with the last one is the easiest. We have not publicly guided to the current status of our patient enrollment, but we have guided at least half of the relapse events have already happened in the trial that we have planned. So that will maybe give you some idea where we are, yes, because you have to recruit patients and then give patients enough time to develop relapses in this study. And in terms of the baseline characteristics of this, we have not evaluated these 2 studies against each other, whether they have different characteristics. However, we really have used a stratification of the randomization, both in terms of EDSS at baseline and age at baseline, which we believe that those 2 characteristics of patients are really driving kind of the relapse rate in patient population. So it means that the -- that basically gives you 4 strata of young patients, older patients,with more and less disability. And these 4 strata differ in -- likely in the relapse rates that you will see. And that's -- it's very important that we make sure that they are well distributed. And with the -- these 2 patient characters used as stratification randomization, this very likely assures a very good distribution of these 2 important factors in these studies. And that's something that -- this is the reason why we use them as stratification for the randomization in these -- both of these trials.

Thank you, William. The next one in the queue here is Matt Kaplan from Ladenburg.

Just, I guess, congrats on the powering assumptions that you confirmed here in the interim analysis. Can you give us a little bit more detail in terms of what the futility aspect of the analysis was in terms of the futility criteria that were examined and how this could potentially give us a read-through for the positive outcomes of the 2 studies?

Thank you, Matt. Good to see you again, and good to hear you again. So we have not guided publicly exactly the criteria and has a little bit to do that it would enable a little bit more in terms of second guessing, I think, the interim analysis. But I think, basically, our futility criteria are set on this conditional power as well in this futility analysis. And it's a little bit more difficult to translate, for example, conditional power just in terms of hazard ratio or just in terms of relapse rate because it takes both into consideration. But in principle, it's very close to saying if you find that the study has almost no chances to reach a positive outcome with the current both relapse rates and hazard ratio, then, basically, the conditional power would be so low that we set this as futility criteria, but it's not easily translatable just into a hazard ratio or just into relapse rates. Sorry, this is a little bit more difficult than to express an equivalent of that.

Okay. Fair enough. And then in terms of the sample sizing of 1,050 patients, with the confirmation of that, I guess, there was a chance that you would have had to upside -- upsize the studies. Can you give us a little bit more detail what that means in terms of not having to upsize the studies?

That's also very good questions, and we also have not guided to the criteria for the upsizing, of course. So in principle, the study, of course, was planned with -- which is usually done for Phase III trial with a 90% power. So you -- in principle, you're looking for a scenario given the current relapse rates, but also hazard ratio that maintains in that corridor of power to the end of the study, yes, and that's more or less what the criteria have done for, for example, a continuous plan and everything below this, which is kind of -- in these papers that we mentioned here is basically described there how the -- this zone below basically that value is then used to translate this into a number of patients that should be increased to maintain that 90% power calculation of the trial. So that's more or less what it is in layman's terms like for me.

Matt, are you still with us?

I'm still there, yes.

Sorry. This is probably a little bit convoluted, what I'm telling you, but it's a more convoluted story. And we -- I think, really -- we also have basically given you all the data that we have, more or less, yes, because the unblinded IDMC has seen a lot more data. But since we have to maintain the integrity of the trial, especially because it's a Phase III trial, we have to make sure that we're not receiving data that would endanger basically the scientific and statistic integrity of the study.

Maybe I can add one thing here because I'm listening to the details here and our discussion also in our presentation. The answer is basically very simple. I think it's this interim confirms that our assumptions were correct and as the drug works. I think this is my conclusion from that on the whole analysis. And we can't look more deeper into that because that would impact the integrity of the study. So therefore, sorry to not give you more numbers and these things on these assumptions. But we also, I think, as a company, are very happy that we had the best outcome of all the options we asked the IDMC.

Thank you, Matt. The next one here in the queue is Faisal Khurshid from Leerink Partners.

Congrats on the positive update. I have a couple of questions. One, just on enrollment, how are things going? And do you plan to provide an estimate of when you expect to conclude enrollment?

So I -- Faisal, unfortunately, we have not publicly guided the end of enrollment. We have publicly guided for the completion of the trials, which is, of course, somehow connected by 72 weeks a little bit, yes. And we have not publicly guided to the current status of our patient recruitment. But like I said earlier to William, I think if you know that the interim analysis is done, if you have it basically had approximately or at least half of the events have already occurred and that you know that you have to enroll patients and then give them time in the trial to develop these events, I think it tells you a little bit where we are with recruitment.

Got it. Understood. And then in terms of the -- I guess, the other question I have is, do you have visibility on the overall event rate? And is there anything to read into the timing of this futility analysis coming kind of earlier in the fourth quarter rather than later in the fourth quarter, either on what's happening in the trial or in terms of the patient population that you've enrolled?

So if I understand, of course, we, on a blinded basis, yes, on a combined of both treatment arms, we do get updates on the relapse rates that we see, and we know the number of events. We don't know the hazard ratio. We don't know which treatment aren't -- they belong to. But we continuously monitor the overall blended relapse rates that we have in these studies. And that's important. I think -- like I mentioned, I think there were 2 readouts in RMS now, the last 2 ones that had really suffered from a relatively low event rate and ARR. And that makes it really, really difficult for any drug to have the opportunity to show a treatment effect. We have basically monitored this, and we're -- we believed that the overall event rate was right on basically target what we believe with the assumptions. And I told you the assumptions, you can almost calculate it from this, what I gave you, if the hazard ratio is correct. So we believe that the event rate is pretty much also in line with our assumptions. You also asked about whether we know the -- where these events coming from. So the events are basically from all of the previously enrolled patients that we have until a cutoff date, which is not far from here, but not that far off from today. But in principle, this is all I can tell you, and the -- there is -- of course, this is a study that already is ongoing for 2 years. So it -- the -- all of the countries are activated, all of the sites are activated. There's -- so there's -- I don't believe there is a chance for a lot of bias between basically the periods that we have used for the interim analysis and the future recruitment. But of course, this is something that we couldn't evaluate here because we are still blinded.

Got it. That's helpful. And then just last quick one I had was, was safety considered at all in the interim? Or is safety considered by the independent committee? And do you hear back anything on that?