Hello. Good morning, and welcome to Immunic's Third Quarter 2021 Earnings Call. My name is Jessica Breu, Head of Investor Relations and Communications at Immunic. I will also be the moderator on today's call. [Operator Instructions]. And this event is being recorded. Speaking on today's call are Dr.

Daniel Vitt, our Chief Executive Officer and President; as well as Glenn Whaley, our Vice President, Finance and Principal Financial and Accounting Officer. After today's presentation, there will be an opportunity to ask questions.

[Operator Instructions] 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 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. I now would like to turn the call over to our CEO and President, Dr. Daniel Vitt, to start with the presentation. Daniel, please go ahead..

Yes. Thank you, Jessica, for opening the call. I also would like to welcome everybody on Immunic's Third Quarter 2021 Earnings Call. Earlier this morning, we announced our financial results from the third quarter of 2021, and highlighted recent milestones as well as upcoming updates to our clinical development pipeline.

During today's call, we will talk through our third quarter 2021, and subsequent highlights, financial and operating results as well as anticipated milestones. Before we close the call, you will have the opportunity to ask questions.

During the third quarter, we continued to make great progress in advancing our 3 product candidates through the clinic, setting the stage for several important data readouts in the fourth quarter of 2021 and '22. Most importantly, we expect to start patient enrollment in our Phase III program in relapsing multiple sclerosis still this quarter.

Another major milestone will be the top line data from our Phase II trial in ulcerative colitis, which we anticipate in the second quarter of 2022. We just recently announced completion of patient recruitment with 263 patients randomized in total.

For our second program, IMU-935, we expect unblinded safety data from the single and multiple ascending dose parts of the Phase I trial later this year. Additionally, we just have started Part C of the Phase I trial in psoriasis patients and expect initial human data from this patient population in the second quarter of next year.

Finally, we also hope to see first clinical data from the ongoing Phase I trial of IMU-856 in the third quarter of next year. But let me walk through the third quarter 2021, and subsequent highlights in more detail first.

In July, we hosted a virtual R&D Day to provide an update on the preclinical and clinical development of our RORgamma t inverse agonist, IMU-935.

We presented very encouraging preclinical data showing that IMU-935 may inhibit both the generation of Th17 cells and the production of IL-17 cytokines that are responsible for the development of autoimmune diseases without impairing thymocyte development.

We think that this may avoid a potential risk for lymphoma that has complicated third-party programs in this space. At the R&D Day, we also presented further new preclinical data highlighting the potential of IMU-935 for the treatment of metastatic castration-resistant prostate cancer.

Based on the strength of this data, we expect to initiate an open-label Phase I dose escalation trial in CRPC during the fourth quarter of this year. Also in July, we successfully completed a $45 million follow-on offering, which extended our cash run rate through multiple value inflection points into 2023.

In September, we signed an in-license agreement with the University Medical Center Goettingen in Germany, covering the combination of DHODH inhibitors and nucleoside analogues to treat viral infections.

At the same time, we published remarkable preclinical data showing that certain DHODH inhibitors, including IMU-838, strongly synergized with selected nucleoside analogues to inhibit SARS-CoV-2 replication in vitro.

This powerful reduction was demonstrated across multiple SARS-CoV-2 variants, including alpha, beta and delta and thereby highlighting the independence of this approach to mutant virus forms.

I once again would like to thank our research partners at the University Medical Center, Goettingen, Ruhr-University Bochum, Universitätsklinikum Erlangen, Utah State University, and MBM ScienceBridge for their tremendous work. In September, we enrolled the first patient in our Phase II CALLIPER trial of IMU-838 in patients with progressive MS.

The trial will run concurrently with our twin Phase III ENSURE trials in relapsing MS and is thought to be a supportive trial to underline IMU-838 neuroprotective potential.

We believe that if the trial is successful in showing a beneficial neuroprotective effect of IMU-838, we may be able to clearly differentiate IMU-838 versus other oral MS medications and carve out a very attractive commercial positioning in the MS landscape. In October, we are very pleased to welcome Patrick Walsh as our new Chief Business Officer.

Patrick is a seasoned BD executive, and I very much look forward to leveraging his experience here at Immunic. In October, we also dosed the first psoriasis patient in Part C of our ongoing Phase I trial of IMU-935. This represents the first time patients are treated with our oral IL-17 inhibitor, IMU-935.

We expect initial psoriasis data in the second quarter of next year. October was a month of clinical milestones for Immunic. We also completed patient randomization in our Phase II trial of IMU-838 in moderate-to-severe ulcerative colitis. In total, 263 patients were randomized.

We now eagerly await the top line data of the trial in the second quarter of next year. For the next part of our presentation, I would like to hand over to Glenn for the financial overview..

Thank you, Daniel. We will now review the financial and operating results for the third quarter of 2021. Let me start with the cash overview. We ended the quarter with $110 million in cash and cash equivalents, which we anticipate to be sufficient to fund operations into 2023. Now let's review the operating results.

Research and development expenses in the third quarter were $15.5 million as compared to $11 million for the same period in 2020. For the 9 months ended September 30, R&D expenses were $42.7 million as compared to $27.5 million for the same period in 2020.

The increase in costs for both periods reflect the continued ramp-up of our clinical expenses related to our 3 clinical programs as well as increased personnel expenses as a result of hiring more people to support the company's growth.

The increases were partially offset by decreased costs related to our Phase II clinical trial in COVID-19 that was finished in the first quarter of 2021 and decreases in drug supply costs for IMU-856. General and administrative expenses were $2.9 million for the 3 months ended September 30 as compared to $2.5 million for the same period last year.

For the 9 months ended September 30, G&A expenses were $10 million as compared to $7.3 million for the same period in 2020. The increase in costs for both periods was primarily due to noncash stock compensation expense as well as smaller increases in costs across numerous categories.

Net loss for the third quarter 2021 was approximately $19.3 million or $0.76 per share based on 25.3 million weighted average common shares outstanding compared to a net loss of approximately $12.9 million or $0.70 per share based on 18.4 million weighted average common shares outstanding for the same period in 2020.

Net loss for the 9 months ended September 30 was approximately $71.8 million or $3.33 per share based on 21.6 million weighted average common shares outstanding compared to a net loss of $32.9 million or $2.35 per share based on 14 million weighted average common shares outstanding for the same period in 2020.

I would like to remind everybody that our year-to-date net loss was impacted by the settlement agreement of our subsidiary in Immunic AG signed with 4SC AG in March of 2021. Immunic AG settled its remaining obligation of 4.4% royalty on net sales of IMU-838 for $17.25 million. The payment was made 50% in cash, 50% in shares of Immunic's common stock.

No further payment obligations remain between Immunic and 4SC AG. With that, I'll turn the call back over to Daniel for an outlook on our upcoming clinical milestones.

Daniel?.

Yes. Thank you, Glenn. As mentioned in the beginning of the call, we have the wealth of milestones coming up in the next couple of months, and I'm happy to walk you through these.

Still in the fourth quarter of this year, we anticipate advancing IMU-838 into active Phase III development with the first relapsing MS patients expected to be dosed very soon. The ENSURE program comprises twin Phase III design to evaluate the efficacy, safety and tolerability of IMU-838 in RMS patients.

We have targeted an enrollment of approximately 1,050 patients in each trial. Dosing will be either 30 milligram daily dose of IMU-838 or placebo. The primary endpoint for both trials is time to first relapse after 72 weeks.

One of our biggest milestones in 2022 will be the readout of our Phase II trial in patients with moderate-to-severe ulcerative colitis. We currently expect the top line results of the induction phase to be available in the second quarter.

For our Phase I trial of IMU-935, we recently completed the experimental phase of the multiple ascending dose part in 15 healthy volunteers. We anticipate to receive safety, pharmacodynamic and pharmacokinetic data from both single and multiple ascending dose parts still in the fourth quarter of 2021.

Also for IMU-935, we expect initial patient data from the third portion of the Phase I trial in moderate-to-severe psoriasis to be available in the second quarter of 2022.

For IMU-935, we will be -- this will be a major value inflection point as the data will provide us the first time hit about IMU-935's safety and efficacy profile in the patient population. Staying a little bit with our IMU-935 program.

In July, we announced that we anticipate to begin an open-label Phase I dose escalation trial of IMU-935 in patients with progressive metastatic castration-resistant prostate cancer.

The trial is designed to establish a recommended Phase II dose and to assess safety, tolerability and to tumor activity, biomarkers and pharmacokinetics of IMU-935 in CRPC. We were very honored that Professor Johann de Bono from Royal Marsden Hospital in London agreed to be the principal investigator of the trial.

Just recently, we received approval by the relevant authorities in the U.K. to conduct the trial, which we expect to start in the fourth quarter of this year. Finally, we anticipate underlining safety data from the single and multiple ascending dose parts of IMU-856 in healthy volunteers in the third quarter of 2022.

Initiation of patient part of the Phase I trial in intestinal barrier function associated diseases is expected in the first half of 2022. This brings me to the end of the presentation. Jessica, please open the call for the Q&A session..

Thank you, Daniel and Glenn, for walking us through the third quarter 2021 earnings presentation. [Operator Instructions]. For the Q&A session, we also have our broader management team on the call. In addition to Daniel and Glenn, we have Dr.

Andreas Muehler, our Chief Medical Officer; Patrick Walsh, our newly appointed Chief Business Officer; and Inderpal Singh, our General Counsel. [Operator Instructions]. The first question comes from Yasmeen Rahimi at Piper Sandler..

I have A number for them. Maybe we would like -- I would like to start off as we think about the CALDOSE study that is upcoming. So I think a frequent question that we're getting from our clients is to understand how we should be thinking about the composite endpoint, which is symptomatic remission endoscopy healing.

So if you could provide us some color on what bar in your view is considered success? And then second, I would love to also learn a little bit more in terms of the clinical execution of reporting these histological in an endoscopy reading. And then I have a follow-up..

Thank you, Yas, for the question. This is Andreas, the Chief Medical Officer. Regarding the -- our CALDOSE-1 trial in moderate-to-severe ulcerative colitis patients, yes, I think you're absolutely right. I think we use a composite endpoint that entails both symptomatic remission and endoscopic remission to be achieved at the same time at week 10.

So when we designed this study, both regulators and also international clinical experts that we worked with had really indicated that we needed to find an endpoint that reduces the variability of the outcomes in placebo.

It is known from the history of trials in IBD that there is some variability between trials in a placebo response, and patients actually can get better even under placebo or no treatment in this indication. And this variability has contributed to some of the failures of clinical trials in the past of drugs that we know to be active.

So when we designed this drug, this composite endpoint was designed to minimize any placebo response. So we do expect a very low treatment response in the placebo group.

But also, I think we -- this will have influence in what to expect in terms of the response in the active dose groups for IMU-838 when we have 3 dose groups, 10, 30 and 45 milligrams in this trial. So I think there should be the expectation.

That's very similar to very recent trials that were also used on the composite endpoints of very similar, even identical composite endpoints, where you see that the placebo response is below 10% or much below 10% and the active treatment arms of these drugs that we know are active been found somewhere in the range of 15%, 20%, 25% for the active treatment arms.

And I think that's also our expectation that this would be a desired outcome and a good outcome for this kind of trial where we use this very stringent composite endpoint in order to reduce the variability of placebo. So that's your first question, Yas. And the second question, the clinical execution of endoscopy and histology.

So as with many other trials, I think it's now a state-of-the-art that the endoscopy, the screening endoscopy, but also we have endoscopies, of course, at week 10 for the primary endpoint and we have an endoscopy at week 50 at the end of the double-blind's maintenance period after the induction -- after remission was achieved, that all of those endoscopies are done by a central blinded reader.

So this is not done locally but this is done by the central blinded reader. And the -- there was also an adjudication of the week 10 endoscopy. That means that they have been read at least twice. And if they are not concurrent, then adjudication was done.

So I think this is what we've done, I believe, is really state-of-the-art to what's currently done in IBD trials.

In terms of histology, we have a histology assessment at screening at week 10 and at week 50 that will allow us to do EDSS, that's also the histology score that's used and, of course, this is also done in a blinded fashion, which is, of course, much easier because it's done often by a -- it has to be done by a central app that is completely independent of the execution of the trial.

Hopefully, Yas, I addressed your questions..

No -- that was perfect. Andreas.

And maybe one more follow-up for you would be, will you be reporting a top line also just the individual rates for clinical remission? And then the second question is, as we are awaiting the data from the SAD and MAD portion of 935, should we be looking at certain biomarkers that will help us sort of provide translation into the Ib psoriasis cohorts?.

Yes. No, that's fine, Yas. So I think for -- we will -- for the UC trial, the CALDOSE-1 trial, we will, of course -- the top line data will not only include the primary data but it also includes the individual rates of clinical remission, clinical improvement and endoscopic improvement, endoscopic remission.

So I think there will be these individual data as well, not just the composite data. I think because also I think it provides a better understanding of comparability to other UC drugs and Phase II trials. So I think that for us was important as well to be part of the top line data. In terms of 935, that's a very good question.

Do we have in the Part A and B that includes healthy volunteers, any chance to have biomarkers that will hint on efficacy or an activity in the psoriasis part later on. I have to say that's very difficult.

We have thought about this quite a lot, and it's very difficult to do because you wouldn't have to look at, for example, cytokines or some other biomarkers that are not elevated in these healthy volunteers because they're very carefully selected to be really healthy volunteers and have no medical history so on and so forth.

So unfortunately, I have to say, I don't think with the data that we will present to you before the end of the year in terms of the safety, pharmacokinetics, unblinded, laboratory findings and so forth, I don't think that we'll give too much credence on efficacy activity readouts.

So I don't think that's possible with this healthy volunteer population..

Our next question comes from Gobind Singh at JMP..

So 2 for me. First, on IMU-838 in progressive MS.

Wondering if there's -- if you have any comments about the recent hype from large pharma to kind of develop their own BTK in this space and also RMS, of course, but if why BTK is in MS and now? And is there any relation to neurofilament? And what are we seeing there? And is there any way to kind of use that as a bar for what could be coming from the interim readout from the CALLIPER trial? And then one follow-up for me..

Gobind, thanks for the question. This is Andreas again, Chief Medical Officer. So I think in terms of the BTK, we're carefully looking, of course, at the BTK inhibitors and how they present themselves in this space, especially in progressive MS, but also in general in the MS space.

And to be quite honest, I think I've seen the presentations by the companies developing it.

And at the moment, they are focusing very much on still the immune component of their reaction and the upregulation of the BTK in immune-related cells in the brain, which surprised a little bit because I think if you have to -- if you want to develop this for secondary progressive you have to, to my mind, or to our mind, you have to address also mechanisms of disability worsening that are unrelated to -- primarily unrelated to the immune system.

So I think the BTK inhibitors have focused on microglia, for example. This is -- we believe that the mechanism of action of IMU-838 is much broader than that and can address different things that of course, involves, for example, antiviral effects.

It involves also having an effect on -- which is known for other DHODH inhibitors on actually the metabolic status, especially mitochondrial stress in actually neuronal cells, so nonimmune-related cells, which I think we believe is contributing to efficacy in a phase of MS that's not primarily driven by immune mechanism.

So in that respect, I see a clear difference in the way that IMU-838 can act in secondary progressive MS or in primary progressive MS than the BTK inhibitors.

On the other thing, I also -- I feel very strongly that our safety profile that we have shown in Phase II in the relapsing-remitting and also that we see now in the continued open-label phase of this Phase II study. And we have more than 200 patients of this Phase II trial still on drug, still on treatment in this open-label portion.

We see very little drop-off in basically patients on treatment, which we take as a very good sign in terms of the general tolerability profile for this drug. So I think we feel very strongly that we can achieve a very good differentiation versus BTK inhibitors, even in this progressive MS population..

One follow-up on that. Have we seen with any of the BTKs, what it's doing on neurofilament? And then on the open-label part of the trial, might we see any updated data longer term, perhaps improvements in neurofilament? I believe the last results you guys presented there was almost about a 20% reduction compared to placebo.

Why would we see an update in the open label this year? And then one follow-up on COVID-19.

With everything going around with Merck and the excitement there and the data that you guys have presented in the combo setting ex vivo for the potentially improved reduction in SARS-CoV-2, is there anything there that you -- you can comment on at this point about maybe resuming clinical development or otherwise?.

Yes. Gobind, just a question for you, basically neurofilament. I have to hear in public present ignorance on my part that I don't really have a good understanding of what neurofilament is doing in BTK inhibitors. So I know you're very interested in it, and I'll do my best to update myself a little bit better next time.

And maybe for the question about the synergistic effect between DHODH with other drugs in the COVID setting, I would hand over to Daniel..

I think we just recently announced, we did -- you have seen we signed this collaboration or a licensing agreement with University of Göttingen and it was based on exactly that synergy observed. We think the potential is broad and goes typically beyond COVID-19.

So I think this principle should be used on a broader level on targeting antiviral or having a new antiviral, very potent antiviral treatments. However, clearly -- we've clearly said in the past already that we are not planning to go ahead in the Phase III and with 838 and COVID-19, and we didn't change our plans yet.

I think we are focusing the company really on the important things here. We are still interested in the combination and in the antiviral properties, but that should be done in a collaboration or in an independent way forward. And I'm not in a position to give more details on the discussion status here.

But I think clearly, there is an interest in this world in potent antivirals, and there will be way forward for that molecule. But it's unlikely that we started in clinical trials soon..

Our next question comes from Thomas Smith at SVB Leerink..

This is Mike on for Tom. Two on our end. The first is just can you provide some color on how you're thinking of the overall competitive landscape in IBD? And specifically, what kind of impact you see the recent labeling updates for the JAK inhibitor is having? And then I have a follow-up..

Well, it's a mixture of a question for Andreas and myself. Of course, it's an interesting time in that space. And specifically, given that -- and that's not a secret that the FDA had some questions around safety and tolerability of JAK inhibitors recently. So that's, of course, impacting the whole set of therapy developments in that space.

And for us, it underlines that there's a high unmet medical need we nicely fit in.

And just to repeat, and I mentioned that in our company presentation a couple of time, 838 provides something from a mode of action point of view, something new for patients with ulcerative colitis, which is, on the one hand, being a selective immune regulator and targeting specifically hyperactivated immune cells, on the other hand having antiviral properties protecting patients from viral reactivations.

I think these are 2 features which are urgently needed from patients in that space. I'm not sure, Andreas, if you want to add some more color on the competitive landscape from your point of view -- just from a medical point of view..

Yes.

And of course, when we started the Phase II program for IMU-838, there was -- when we talked to our medical advisers and experts, there was cause -- they had a lot of focus on the JAK inhibitors because they had an advantage to the market to -- in establishing this new category of this -- these novel immune modulators that are between the traditional immune modulators and the biologics.

And what I've seen now is really I think that there's more and more drugs coming. There was the hope that what's called more selective JAK inhibitors would behave differently or would have less challenges, which, I think, in general, didn't materialize.

And so I think the whole class of drugs really has to certain -- the different degrees, of course, the different drugs but have the same, I think, reputational problem then also for the medical community.

We also have seen that there was -- especially about the JAK inhibitors, a lot of discussions about the increases of infections during treatment and virus reactivations, special disaster reactivations.

And I think we clearly see here that our antiviral properties that really has helped us that we have in our clinical trials never seen an increase of infections and infestations versus placebo. We have not seen these viral reactivations.

And in that respect, we feel very strongly that the time advantage that these JAK inhibitors had coming into the market will not play out well for them to mind and we have a very good chance to, with IMU-838 to create a very successful drug in ulcerative colitis..

Got it. That's very helpful.

And then just quickly, with respect to the MS program, has anything changed recently in the Phase III trial assessment? And how do you plan on mitigating potential impact of COVID in the study?.

So I'm not sure anything has changed, no. I'm just thinking what you could mean because I -- we are just executing as quickly as possible the plans that we had. And so I think it's a very large form. It's also -- these Phase III programs are very complex in terms of the different assessments with different vendors that you have to do.

So I think our team does -- do an extremely good work in terms of preparing these Phase III trials, but nothing has changed in the execution of the Phase III trials..

Maybe just on COVID, I think we talked about it, given that we have seen antiviral properties of 838, we clearly see not a big issue with the ongoing COVID pandemic on recruitment. That's priced in basically in our estimates..

I think we have the experience from the CALDOSE trial, the IMU-838 trial in ulcerative colitis that, of course, had a lot of activity during the whole COVID period. And yes, there are a few sites usually that makes monitoring harder and also that we have accessibility problems for patients.

But this was really, I think, very minimal on our part, the COVID impact on IMU-838 because we have been in very close contact with all of the investigators during the COVID period, highlighting the broad antiviral property at the time when we didn't know that we had actually activity in COVID-19, as we found out later on with the CALDOSE trial.

We focus that this does not put patients at risk like many other immune modulators that actually put patients at risk, which is very well known now for a more severe course of the COVID-19 disease.

And once we had to cover data in COVID patients, we actually also informed them that we have seen some activity in this trial that would support that we actually might be helpful for these patients in case they get infected.

So I think this all had very good, I think, assurance to the investigators that they should continue this trial and that's what we have seen at least in the CALDOSE trial. We, of course, take preventive matters, especially in terms of providing study drug to patients when they're not allowed to access the site.

But in terms of enrollment, I don't think we see a significant impact even with maybe a more robust infection numbers in the future here in this winter for COVID-19..

So our next 2 questions come from Zegbeh Jallah at ROTH Capital, and I will actually read them because they came in via the Q&A tool. First question, most of indications being pursued by Immunic, including MS, you see psoriasis, et cetera, and even your investigator-sponsored studies like MCRPC are all blockbuster indications.

However, there are also indications for which there are multiple competing drugs. You've shown success in MS.

How are you thinking about competitiveness of your programs in UC and psoriasis?.

Well, this is a very important strategic question for the company. And first of all, I agree with the success in the MS space, that's a good problem to have. They are big indications. And I think the company is addressing high unmet medical need. We may not be in a position to continue with other programs through Phase III our own.

So it's likely something where we would -- we are open for partnering. And in that context, you can also see that we just recently strengthened the team with Patrick Walsh joining us in October as Chief Business Officer to balance the exposure here and also strengthening our discussions here with potential pharmas for the future.

But of course, these are big markets, and they are driven by big unmet medical need..

The second question is about our interest in partnerships.

And are you likely to also independently take your UC and psoriasis programs into Phase III like you have with your MS program? Or are you open to partnering ahead of the initiation of pivotal studies?.

Patrick, would you like to comment on that?.

Yes, happy to, and good morning, everyone. This is Patrick Walsh.

I'll summarize it this way in that we are actively exploring many options across the portfolio, and we have not made any decisions with respect to the types of arrangements that we will or won't consider, but certainly excited about the evolution of the data for all of our programs here. So looking forward to that..

Thank you, Patrick. [Operator Instructions]. Our next question comes from Matt Kaplan at Ladenburg Thalmann..

Just one -- a couple of questions. First, a follow-up on Yasmeen's admin question in terms of the SAD and MAD data for 935.

I guess not that we're looking for a read-through to the psoriasis but can you describe the PD data that we should be looking for as that reads out later this year?.

So Matt, are you -- meaning what's in the Part A and B that we're....

No. Just from a pharmacodynamic point of view, what are some of the things you're looking for, not really beyond PK, I guess, in the SAD, MAD data..

So pharmacokinetic, of course, data, we will have extensively because we -- of course, in this Part A and B, we did single-dose pharmacokinetic. We had multiple-dose pharmacokinetic over 14 days in these patients, and these were healthy volunteers, sorry.

We also explored different dosing options once daily versus twice daily, I think, to see how they address certain needs, for example, or how they would allow us certain configurations for these patients. So both are done. And we also, in this part A and B, did evaluation of food effect, for example, on the pharmacokinetics.

So that's what you should expect all to come.

And I think I just have to stress what I told to, I think the amount of pharmacodynamic data that you can get this relevant to really our indication and that exceeds what we had done in vitro because we have done the in vitro data with human lymphocytes and release based on different concentrations of IMU-935. So this was done in vitro.

We felt that there's very little that you can do in healthy volunteers that would exceed really the value of the in vitro experiments that we have done with human lymphocytes..

Okay. That's very helpful. And then second question, just wanted to focus a little bit on your other program IMU-856, which targets the intestinal barrier function.

Can you give us a sense in terms of what this -- what role this molecule could play? And what indications you're excited about potentially pursuing after your -- after you announced the SAD and MAD data, I guess, in the third quarter of next year?.

Yes. I think Matt, that is a very good question. So the thing with the -- and you know this as well as I do, that we -- that the mechanism of action addresses the basic -- the barrier dysfunctions in the guts that is responsible for so many diseases, symptoms and pathophysiology for different diseases.

And that's as much as good news as bad news because I think the company has to focus to find its indication where we believe we can show proof of concept relatively quickly with the 28-day dosing, similar to psoriasis where you have a medical need and where you also have the ability to execute quickly towards with -- endpoints that are accepted by the FDA.

And with -- this discussion is ongoing, but I think I can promise, we have a lot of these interesting discussions, and we will relatively soon present our plans for that. But at the moment, we haven't fully been able to make this public yet..

Next question comes from Boobalan Pachaiyappan at H.C. Wainwright..

Okay. Awesome. So just a few from our end. So just curious to hear your thoughts on NFL, especially these two questions.

So firstly, how do NFL levels in RRMS patients compared with healthy adults? And secondly, do you think utilizing NFL as a biomarker may streamline patient's recruitment for your upcoming ENSURE trial and maybe future pivotal trials in advanced MS patients?.

Boobalan, this is Andreas again, the Chief Medical Officer. So I think -- this goes way beyond the Immunic, yes, because I think the -- not only the MS community, but the community of doing clinical research on -- in neurodegenerate diseases, this is beyond MS.

I really found that the biomarker neurofilament correlates to the amount of damage to neurons and independent necessary -- independent of the disease process that's involved. And we have seen this in several diseases.

And in MS, also, we've seen a very good correlation, not just in our trial but also in other trials in the last years that the treatment effect in preventing the damage to neurons and neurons dying and having less lesions and having less relapse activity always translates into neurofilament.

So that -- and we have shown the stress with the ECTRIMS poster, I think, 2 months ago -- last month that correlated very well with the patients who had relapse, for example, in our Phase II trial had more of a -- more resistance to NFL decrease than patients who didn't have a relapse.

But you're also asking a good question because I think there's a predictability. It doesn't mean that there's no overlap in the individual patients. So I think NFL is a good marker for groups in terms of -- populations in terms of therapy control or therapy -- relation to success of therapy.

But we have also seen that -- and that we have also published in this ECTRIMS poster is that those patients who, at baseline, for example, at startup therapy have a relatively high neurofilament that they're having more activity in a trial, they tend to be -- have more activity.

But it's also a little bit more -- this is a prediction and may not help you on the individual patient level. But on the population, that's true.

We will not use a stratification or an inclusion/exclusion criteria for neurofilament in the Phase III because we believe, I think, also that what we have seen from the Phase II data is this -- and that was part of the as well -- part of the poster as well that the treatment effect of IMU-838 is independent of what baseline neurofilament level you have.

But -- so I think it would unnecessarily diminish our Phase III population or -- and also we don't need to basically enrich a more active or a more -- a population that is expected to have more relapses for this trial, we believe. So it's something that is a very good marker for damage to neurons.

And especially to you -- come back to your last question in terms of progressive MS. There are over the last 1 or 2 years, and this ECTRIMS again last month was also no exception.

There are now more data because I think the marker started with relapsing MS data, but we have no more data in progressive MS, and they absolutely mirror what we know from relapsing MS that neurofilament also is a very good treatment predictor and correlates with activity of drugs in secondary progressive and patients who have a more aggressive form of progressive MS, have a higher neurofilament in serum than those patients who have a less severe disability progression of brain atrophy.

And this has been shown over and over again, so that -- it thinks this is a real effect, and that's why we're also using neurofilament as part of our interim analysis for our CALLIPER trial. And we believe that this could be predictive in terms of the overall results to expect at the end of the trial..

Andreas, that's really, really helpful. So CALDOSE-1 study has completed enrollment.

So what are your baseline expectations for this trial? And what would be the minimum placebo-adjusted clinical remission rate you would like to see to carry the program forward? And do you think the CALDOSE-1 results impact the upcoming Crohn's disease trial?.

So I think -- I know that's a very good question in terms of whether you have a hard threshold or a hard parameter on which to decide whether to go forward in Phase III.

Usually, I think these Phase III decisions are not related to statistical significance or to a certain outcome or -- I think you need to justify it on the entirety of the data because I think there's also some benefit risk that you have to consider where you have to put the safety versus the gain and efficacy activity that you see.

So I personally think that you need to look at the entirety of data. For example, I just want to remind you of the Phase II trial in tofacitinib by Pfizer. There was really, I think -- as far as I remember, there was no statistically significant outcome in the primary or key secondary outcomes. And clearly, it's an active drug in UC.

And Pfizer took it forward. So I think the expectation should be really to look at the entirety of the data and make an assessment of benefit-risk and also what the dosing level is that is supported by activity and the safety.

And so far, what we have seen, I think we have -- and that was true for the Phase II study in MS that we could have taken any of our doses forward that we had in Phase II in terms of safety, but then you have to decide what's the lowest effective dose that should be going to Phase III. That's how we chose the 30-milligram dose.

It was not an assessment of a certain statistical outcome from the Phase II that we put on.

So I think, more consideration spend, but I think the outcome, of course, in the main efficacy endpoints, of course, have a huge effect on how this benefit risk is, but I think it's wrong to have a -- it's not advised to have a very hard criterion for that to my mind..

Okay. Awesome. One last one from me.

So what are some of the gating items remaining to initiate the GBS program, Guillain-Barre syndrome? And where do you see opportunities for value creation given there are multiple players in the clinical development space?.

So maybe this is more an overall question for the pipeline in the band, and we decided to pocket for a little bit because we have identified CRPC as a very attractive indication and we prioritize CRPC a little bit over GBS.

And given that we will see data from the MAD safety part towards the end of the year and first efficacy hints from the psoriasis patient power in the second quarter next year coming from psoriasis, I think, this will help us to get the full picture and also will help us on supporting going forward, for example, in GBS as well..

Our next question comes from Andreas Argyrides at Wedbush..

Just a quick one. I know there's a nice segue from the prostate cancer program, 935.

Can you provide additional color on the study and such as how many doses will be assessed at the start of the trial? What biomarkers do you plan on measuring?.

Yes. Andreas, I think there's a little bit lower volume, I think, than the rest, so I'd just say we repeat the question for if somebody had a hard time hearing the question. So do you want a little bit more color how the study will be done in CRPC for IMU-935. So this -- first of all, in general, this study will have a dose escalation part.

That means that we have several cohorts where we try to escalate the dose and potentially find a dose-limiting toxicity. This is something that we have not done in the Phase I trial -- in a general Phase I trial for IMU-935 because we know that the dose-limited toxicity is way beyond the therapeutic necessary doses for immunology diseases.

So in that respect, this will be different, of course, for the oncology indication where you have to try to dose up to the dose-limiting toxicity. So this will be done with several cohorts. We don't know how many. So it depends a little bit, of course, how quickly you find that dose-limiting toxicity or whether you not find it.

We have a maximum dose also identified where we will stop because it's -- we believe that you don't need to go beyond that.

And then we have a second part that's an expansion part where we take 1 or 2 doses that we identified as potential Phase II doses or that basically are where we have seen maybe some hint of activity in the dose escalation part to expand cohorts to allow a more thorough assessment of activities in these dose parts.

The study will look at biochemical markets, of course, PSA, yes, as a biochemical output. We're looking at imaging, we're looking at circulating tumor cells. So everything that you know about prostate cancer, especially about castration resistant prostate cancer from the prostate cancer working group now recommendation 3, I think we have implemented.

So I think when you read the prostate cancer working group document, you basically find the biomarker that we're also looking at. We are following the recommendations as Johann de Bono is one of the offers of this prostate cancer working group document and really had set the guidelines. I think you more or less have to follow these guidelines then..

This concludes our question-and-answer session. I would like to turn the call back over to Daniel for any closing remarks..

Yes. Thank you, Jessica, and thank you all for the great questions and the lively discussion today here. Very much enjoyed that. I hope you can feel our excitement about the operational progress Immunic has made this year and the multiple catalysts to come in the next couple of months.

We very much look forward to seeing clinical data from our clinical programs next year, in particular, the Phase II data of IMU-838 in ulcerative colitis and the initial patient data from IMU-935, both in the second quarter of next year. With this, I would like to close today's call.

Thank you very much for joining, and we are very happy to answer any additional questions in one-on-ones..

Also from my side, thank you for joining Immunic's Third Quarter 2021 Earnings Call today. The conference has now concluded. You may now disconnect..