INTRANASAL FORALUMAB INFORM-MS KOL WEBCAST - TIZIANA LIFE SCIENCES LTD

Well, welcome, everybody. Today, we're here. It's a lovely day, November 9. We're here to talk about our Phase 2 results in the INFORM-MS trial, which was a Phase 2 placebo-controlled double-blind trial of intranasal feralumab in non-active secondary progressive multiple sclerosis. and we refer to that as NASPMS. I'm Ivar El-Rifi. I am the CEO of Tiziana Life Sciences, and today I have with me a number of our key opinion leaders. Before I get there, I have to just dispense with some legalities. So please, because we're a publicly traded company, read the forward-looking statements and govern yourselves accordingly. Let me introduce the presenters. The first is Dr. Tanuja Chitnis. Tanuca is the principal investigator for MS trial. She's a professor of neurology at Harvard Medical School and Brigham and Women's Hospital. We also have with us Dr. Tarun Singhal. TarUN is the founding director of the NeuroPet program at the Ann Romney Center for Neurologic Diseases, which is associated with the Brigham and Women's Hospital and Mass General Brighham. And he is also an associate professor of neurology at Harvard Medical School. And lastly, but not least, of course, is Dr. Howard Weiner. Dr. Weiner is the chair of Tiziana's Science Advisory Board. He's the Robert Kroc Professor of Neuroology at Harvard Medical School, and he's the co-director of the Anne Romney Center for Neurologic Diseases at BWH. So without further ado, I will turn it over to the investigators and the competing leaders to discuss the INFORM-MS trial and the events that led up to it. Howard, take it away. So thank you very much. It's great to be here. I've spent my whole life working on multiple sclerosis from a time that there weren't therapies to when we first did immunotherapy to our B-cell therapies. And what's really important is if you look at the stages of multiple sclerosis, multiple sclereosis has evolved over time. When I started, there was no treatment for MS or relapsing disease, we now have very good treatments. These are anti-B cell therapies. But what we discovered is that people who, I don't, can you see my arrow here? Is that seen by anybody? No. No. What we discovered ist people who have their relapses shut off, many of them become progressive. And that's now the major challenge in multiple sclerosis. And although there's many FDA-approved therapies for relapsing disease, there are no therapies for non-active secondary progressive disease. And there's a major unmet need. Dr. Chitnis, Dr. Single Online will tell you of all the patients who come to our clinic, are on the therapy, and they say, well, the therapy's supposed to help. Why am I getting worse. And 25% become progressive, and many are non-active. Non-active means there's no more attacks, no more MRI lesions. So it's a little silent in a way, but we discovered that you can see it by PET imaging, and you'll hear about that. Now, another very important thing, and Dr. Chitinous has pioneered this work, is that fatigue is a major symptom that impacts quality of life and daily function in MS. And one of the things we discovered, quite to our surprise, but very exciting for us and the patients, isthat the nasal paralysis helps fatigue. And you'll hear that in the INFORM MS trial, we even saw it after three months. So I spoke about the current therapies. And many of the people we've treated were on ocrelizumab and are still getting worse. And what's very exciting, and this comes out of work from my laboratory, is that the intranasal feralumab targets microglial-driven neuroinflammation. So what's going on in MS, in progressive MS, is microglia inflammation. And there have been no trials that have targeted microglial inflammation in the way we've done it, and certainly nothing as positive as what we've seen. Next slide, please. So a big question is, how does nasal feralumab work? So feralomab is a fully human monoclonal antibody. It binds to the T-cell receptor. One thing that some people think, well, you give it nasally, it goes into the brain. That's not how it works. It doesn't have to go into the brain. And in fact, it doesn't go intothe brain. When you give nasal feralumab, one of the reasons we give it nasally is that the most powerful immune regulatory parts of the immune system are the gut and the nasal and lung, because there, if you're exposed of the environment, you have to generate regulatory T cells. And so for allumab, which binds to T cells, it binds to it in the cervical lymph node. And what it does is it specifically activates regulatory cells. Now, why does it do it? That gets into some immunology. It has to do with the other cells that are in this particular area. But it's known that that's why you get regulatory cells. Now, most of you know that the Nobel Prize was just awarded to Shimon Sagaguchi for describing regulatory cells called T-Rex. And he got it. It was a basic discovery. He got it because it's so important in modulating the immune system and treating disease. In fact, I had dinner with him in Japan the night before he won the Nobel prize and then spoke to him here. He loves our approach of inducing Tregs by giving nasal anti-CD3, and there aren't any other ways as simple and direct as ours to induce Treg. So we induce the Treg in the cervical lymph node. They go into the bloodstream, okay? And after they go in the blood stream, they come back into the brain because regulatory T cells and T cells traffic throughout the body. They go into the grain, and that's where they dampen the microglial inflammation. And they do it by a cytokine or a chemical called IL-10, and we've shown that in animals. And so it's a very unique approach. We have enormous amounts of animal data, and now clinical data. And we'll talk a little bit about it in terms of the clinical effects, the dampening of microglial activation and affecting the immune system. So it was very exciting for all of us in the MS Center to have some of our patients who were just doing terrible, who went on the nasal foralamab and then were doing better. So I'll turn it over to the next slide. And we'll turn It over to Dr. Chitnis, who was in charge of our expanded access trial. I'll say one word before Dr.Chitnis starts. We didn't know whether this would work or not, but I had a patient that was doing very bad, even though they were on ocrelizumab. We got permission from the FDA to give nasal foralamab. We treated the patient. And after three months, Dr. Singel comes running up to my lab. Oh, my God, Howard, you're not going to believe this. Complete decrease of microglial activation. Then under Dr. Chitnis' leadership, we went into an expanded access trial. she'll tell you about it, where we treated a number of patients and saw very positive effects. And then the big question is, can we replicate that in a blinded multi-center trial? And that's what we found in this trial. So I'm going to turn it over to Dr. Chitnis, and she'll talk to you about the expanded access trial. Great. Well, thank you, Howard, and welcome to everyone who is viewing this or participating. so I will echo Howard's words and just say that non-active secondary progressive multiple sclerosis is one of our major unmet needs we have no treatments for this form of disease patients continue to have progression disability worsening and it's a really difficult thing to see as a as a physician taking care of these individuals and so I was very excited when Howard showed me the animal data from his laboratory showing that this anti-CD3 molecule, when given intranasally, does induce regulatory cells that go into the brain and dampen microglial activation. And so this has been shown on multiple mouse studies. And, you know, now our job was to think about how can we translate this into humans. Before we started the expanded access study, we did do a phase one study, which we will refer to throughout this presentation. And we tested three doses in that study. So a 10, a 50, and a 250 microgram dose. And from that phase one study, because of the results in the 50 microgram dos, the middle dose, we decided to start dosing patients with the 50-microgram dose in an expanded access program. So as Howard mentioned, there was a, you know, a very difficult patient who was just having a very difficult time progressing and really wanted to try anything that we thought was promising. So, we discussed starting intranasal feralumab, and he was our first patient in this program. Next slide. So, in this program, we started with our firstpatient. He demonstrated improvement. In fact, clinically, he started to stabilize and was no longer worsening. Within three months, six months, he continued to show this pattern, and that continued on for at least one to two years, and then he had to stop drug for other reasons. However, we were able to enroll additional patients, and we have dosed now 10 patients in this expanded access program, which who are reported in this publication in a journal called Neurology, Neuroimmunology, and Neuroinflammation. It's one of the top-ranked journals in neuroimmunologie and multiple sclerosis research. So we reported in these 10 patients. So first of all, the drug was very safe. There were no toxicities, there was no treatment-related adverse events observed, and no anti-drug antibodies detected in the serum. The second thing that we observed, and I'm going to go to the box at the bottom, is what we call the EDSS, or the Expanded Disability Status Scale, that's stabilized in all of our patients after six months of treatment. Now that is a win, actually, for progressive multiple sclerosis, because typically this EDSC, or disability score, continues to worsen. And some of our patience, after 12 months of treatment. So three out of four patients actually improved their EDSS score. And we measured this very carefully. We have a large MS center. We've been studying MS for over 25, 30 years. And, you know, we measured those very carefully on an anecdotal basis. Patients also reported just they were feeling better, doing better, able to do more in their everyday lives and jobs. So that validated our findings in the EDSS scoring. We also found that fatigue improved in 7 out of 10 patients after 6 months of treatment. And this was quite substantial improvement. We measure fatigue using a scale called the MFIS, or Modified Fatigue Impact Scale. And, this is a 21-question questionnaire, there are subscales to this MFIS questionnaire, and we were able to find that there was an improvement or reduction in fatigue in 7 out of 10 of these patients by at least a score of 4. Some of these patience improved by scores of 15 to even 20, but on average the reduction was at least four to six. The change in fatigue or the MFIS score by at least four has been determined to be clinically meaningful. Several publications speak to this, including Rooney et al. published in a multiple sclerosis journal. So we did see a meaningful improvement in fatigue. And then the last point, you know, is the question around why is this happening? How did we improve? Or how did we see reduction in these two major disability scores, this could be explained in large part by what was seen on the TSPO PET. And I will turn it over in the next slide or two to Tarun to discuss the TSTO PET results. But just the bottom line was that 8 out of 10 patients showed reduced inflammation or neuroinflammation after three months of treatment. And this is inflammation in the brain associated with microglial or activated microglia, which have been associated with progressive forms of MS. And this has been the really difficult thing to treat in multiple sclerosis, is the neuroinflammation that's trapped behind the blood-brain barrier. And we found that there was a reduction in this type of inflammation. Next slide. All right. So, as Dr. Chitnis mentioned, in the expanded access program, we saw a significant reduction in the PET imaging signal using F18PBRO6, which is a radiopharmaceutical that targets a molecule called TSPO, which has been shown to represent the innate immune activation in the brain, which is the compartmentalized immune activation behind the closed blood-brain barrier. This immune activation is not readily visible on conventional MRIs. And that is why there is this need for this technique of TSPO PET. And as you can see here in panels A and B, these are maps of abnormal voxels in individual patients using a Z-score approach where an individual patient scan is compared to a group of healthy people. And on a voxel by voxEL, a voXEL is basically a volumetric pixel, we map out the extent of abnormality. And the brightness of the color represents the extent of abnormal signal that we see there. So in both panels A and B, you can see in the top row, which are different views of the brain, there is a lot of red, which means there were a lot abnormal walk cells in these patients. And after treatment with 50 microgram of nasal feralumab for three months, in the second row in both these panels, panels A and B, you see a reduction in all that red signal. And that kept on progressively decreasing in the last row in panels A & B at six months following treatment with 50 microgram of nasal foralumab, where you see that this red signal is significantly decreased. And when we analyzed all available patients in the expanded access program in panels C and D, you can see a statistically significant difference after treatment with 50-microgram nasal feralumab in the expanded access program. Next slide. Tarun, if I may interrupt just for one second, just to go back. Just to be clear for the audience, panels A and B are two different human beings, two different patients who have SPMS, and the three different images you see across each row are different cross-sections of their brain. And as Tarun made clear, if you see less light, it means less neuroinflammation as you go down each row. Yes, that's correct. Sorry for the interruption, Tarun. No worries. Yeah. Next slide. Sorry, back to Robert. Yeah, the other big question, if the nasal for allumab works, and we know in the laboratory It works by inducing regulatory T-cells and modulating immune function. We can take these cells out of the animals and study them, et cetera, et cetera. But the big question was, could we show a change in immune function in people treated with the nasal foralamab? And that's a big challenge and not something that's easily accomplished. Many people are trying to modulate the immune function with various treatments and it isn't easy to see it. But we saw a really a very clear and dramatic effect on the immune cells, immune function. This is work we did, work that Dr. Chitnis did. And the total picture is very complex. I'd love to show you all the different immune cells that changed. But let me highlight three things. Number one, we increased regulatory T cells. And this is the central mechanism by this works. So this proves the theory works and we could see it in people in terms of the enhancement of regulatory T cells. And when I told it to Dr. Sakaguchi, he loved this because he was trying to figure out a way to induce regulatory T-cells. The other thing, number two, is that there's a decrease in cytotoxic T cells. Cytotoxin T cells are the cells that cause damage in the nervous system. And the nasal foralamab not only decreased regulatory T cells, but it decreased cytotaxic T cells and then the final point. We did spinal taps on these patients. You can't take brains out but we did spinal tabs and did very careful analysis and we saw a decrease of inflammation in the spinal fluid of the patients that we treated. It was really remarkable. And something else that doesn't say it here, we not only found decreased inflammation, but there's some good proteins, proteins that help nerve cells grow like BDNF or whatever, and those went up. So the immunologic findings totally validate what we saw clinically in biped imaging. And in other data, we looked at these changes in the blood and looked at the changes in the spinal fluid, and Tarun was able to correlate the changes in the spinal food and blood with what he saw in PET imaging. So it puts it all together in a beautiful way. And this also now provides us with a way to measure immune function in all the other patients and diseases that we hope to use a nasal Feralimab. And this opened the way then for our double-blind study. We had all this positive result. We wrote up our paper. It got published. But this is open label, and it's very clear you have to prove, even though it was very strong, you have to prove in a double- blind way that this is real. And this led to the INFORM-MS trial that Tiziana set up, Tanuja is the principal investigator of, and involved, I think, eight centers. And we can show you that and how it validated and confirmed the expanded access program. Next slide. Great. So I'll take it from here. So as Howard alluded to, our next step was to set up this Phase IIa study. This is a placebo-controlled double-blind trial of intranasal feralumab, multicenter, and non-active secondary progressive MS. Next slide? And so the study design is shown here, and we, in total, screened 67 patients. 48 were randomized to three arms, 18 were randomized placebo, 19 to feralumab, 50 micrograms dose, and 11 to the 100 microgram dose. We, you know, it has been a bit challenging to enroll or was challenging to enroll non-active SPMS patients and especially in the time frame that we had allotted ourselves. So we did choose to limit the number of patients enrolled in the 100 microgram arm and focus on enrolling in the 50 microgram arm since that's where we had the most data, successful data in our expanded access program on 10 and now 14 patients, as well as our phase one study, which demonstrated that this was the best dose immunologically. So, we had a number of different readouts. Safety was assessed in all of our patients. We had PET scanning done in all the patients at one site. And so, you know, you can see that most of the patients completed their PET scan pair. However, there were a few patients for various reasons or manufacturing technical issues, could not complete the pair of PET scans. However, the majority, the vast majority did. We also captured fatigue scores or MFIS scores in almost all patients except for one, and also our EDSS or disability scores in all patients. And there were many other secondary tertiary outcome measures that were also included, but these were really the four main outcomes that we were focused on. So, safety. And just so that people understand, a PET scan pair means a PET scan of the patient before they receive for allumab, we call that baseline, and a PET scan at 12 weeks after 12 weeks of treatment of for alliumab. That's what a PET scan pairs. Perfect. And also to also confirm that this was a three-month study. So we powered it, we based it on the expanded access results where we had seen results within three months on the PET scan in particular. And so we based this trial design on our expanded access program. And you can imagine three months is a very limited amount of time to show a difference. However, we did. So next slide. So the major top line results, Tarun will go into the PET scan results in much more detail, but on this TSPO PET, which measures microglial activation, there was a significant reduction in the TSPOPET signal in the 50 microgram arm, which was sufficiently powered to show a difference. In the exploratory arm, the 100 micrograms, we had only 11 patients compared to the 18 or 19 in the other arms, and so we did not see a significant difference. And we also thought that, you know, this might be partially due to the limited number of patients, but possibly also due tothe fact that the 50 microgram dose had, in many studies, shown to be the better dose and has that sweet spot of immune modulatory effects. And just sort of speaking to the immunology of this, you want to give enough of a boost to the regulatory cells, too much of a signal or boost could also induce cell death. So we don't want to do that. And that could be a potential reason why the 50 microgram dose was really the sweet spot. We also noted a clinically meaningful difference in fatigue or the mfis score of delta 6.17 in the 50 microgram arm and delta 7.18 in the 100 microgramarm and so this was a within paired analysis so within each dose group we looked at the difference between baseline and 12 weeks and showed this reduction in fatigue scores. It was not an ANCOVA analysis across the entire three cohorts, however, just within group analysis. We were not sufficiently powered to look at an ANCoVA type of analysis that would have required several hundred patients per arm. But despite that fact, even within these small numbers, we showed a significant reduction in the fatigue scores, which mimicked what we showed in our expanded access program with a mean difference of about six to seven reduction in the MFIS scoring. Sort of as a background, you know, as well, fatigue is a major unmet need in progressive or in multiple sclerosis in general, and it's particularly prevalent in progressive multiple scлерosis. And there is much more evidence now indicating that fatigue, in fact, is both a precursor of progression and shares a lot of the same immune mechanisms, including activated microglia. So, the last point that I'll bring up was that the study drug at both doses was safe and well-tolerated. There were no drug-related SAEs, and patients did very well, and there were no discontinuations due to SAEs or AEs in this trial. So I think that is really the summary, top-line results, and of course, there's much more analysis to be done on some of our tertiary outcome measures, including the immunology. Next slide. Turn it over to Dr. Singhal. Yeah, thanks, Dr. Chetnis. So as Dr. chetnis mentioned, in the INFORM-MS study, neuroinflammation was statistically significantly reduced. When we looked at all patients with the analyzable scans, which was NO40, and COVA analysis, which takes into account all the three groups together, the F18PBR06 TSPO PET demonstrated a significant reduction in globally normalized white matter signal measured by this index called SUVR, or standardized uptake value ratio, with a p-value that was lower than 0.05. it was 0.0168 after 12 weeks of treatment with 50 microgram of nasophralumab as compared to the placebo. And that result was statistically significant. And you can see below in the two panels, one labeled as nasophuralumab and the other labeled as placebo, these are two different patients. These are examples of those same z-score maps that had shown a statistically significant reduction in the EA or the expanded access program. And these are represented here with the similar color scale, where red represents more abnormal voxels in a given patient. And you can see on the left-hand side in the nasal for allumab panel, before treatment, there was all these areas of red, which means that there was high amount of innate immune activation or inflammation in this particular individual. And after treatment with 50 microgram of nasal feralumab, you can see that we replicated our results that we saw at our center with the reduction in the inflammation after treatment with nasal feralamab 50 microgram dose. On the other hand, this is a patient on the right side, which was treated with placebo, had this abnormal signal at baseline. And after treatment mit placebo for 12 weeks, there was an increase in this signal. So after controlling for other variables, when we look at patients that we had in our EA program, and we compare it with our data in the phase two, we replicated the finding of reduced microglial activation after treatment with feralumab. And in fact, the findings were enhanced by this placebo comparison, where we had this evidence of increase in placebo arm after adjusting for the other covariates. And that was statistically significantly different or better outcomes with the nasal feralomab treatment as compared to placebo. So this is a great replication of our findings in the Expanded Access Program on this phase two in a double-blind, randomized placebo-controlled study. Next slide. Dr. Chitnis. Yes. So this has now a close-up of the fatigue scores. So this the MFIS total score. And just as a quick reminder, this is 21-point questionnaire that the patients answer. And you can see in the 50-microgram dose, there was a reduction by 6.17 in the fatigue score. In the 100-micogram dose, a reduction of 7.18. Both were statistically significant within their own group. However, in the placebo group, there were no significant changes, as you can see by this p-value of 0.4, which is almost a coin toss and a really minimal reduction. so you know what it what does this mean and what does a change in six or seven points on this fatigue scale what does it actually mean so the publication on the right is the one that i was referring to showing that a reduction of at least four points on the fatigue scale is clinically meaningful and so they compared this to quality of life measures they compared those to other outcomes in patients and found that this change in four is clinically meaningful so these results surpass that and this also anecdotally I can also recount that patients in the expanded access program had a similar reduction on fatigue scores and they would tell me things like I feel so much better I can get on with my day and do things that I couldn't do before I can work for hours longer than I used to work, and it really does translate. So, you know, we think that we see replication of our open-label study. We see reduction in fatigue here, and this, you know…is clinically meaningful. Next slide. And I'll talk to this. So sorry for the duplication here, but we just wanted to make sure everybody got the message. So, the message is in the phase two placebo-controlled double-blind study, the drug in our hands, we observed that it was safe at both doses. We believe this is the first non-invasive anti-CD3 therapy that has been shown to be safe and well-tolerated. And by non-invasive, we mean you don't have to take it IV, you can inhale it nasally. Our primary endpoint, so that's the endpoint that you say to the FDA you're going to meet, was a reduction in microglial activation as measured by PET. We met that endpoint at 50 microgram dose, which was the dose that you've heard was the dose we have the most experience with, and then immunologically, we had the highest expectation or hope for. And the p-value is 0.0168. So just to remind you, a p- value of p.05 or less means that you have, there's a 95% likelihood it's not random. That is, there is a real effect here. So we had a very good p-Value. And then lastly, fatigue was a secondary endpoint. And as Dr. Chittins pointed out, we didn't power the study, meaning we didn t enroll, and we didn't intend to enroll, enough patients to have statistical significance of the secondary endpoints. We've needed 10 times as many patients. But nonetheless, within the arms, we actually saw that fatigue was improved meaningfully, according to the paper that Dr. Chitnes presented, meaningfully from the beginning of treatment duration to the end of treatment duration. So we are thrilled with the data. Next slide, please. SPMS is not the only thing that we have going on in the clinic. We also have a phase two trial in a disease called multiple system atrophy. That data will read out in the next three to four months. We have a study in Alzheimer's. It's a double-blind placebo-controlled study. And that trial is fully enrolled. We're waiting for the patients to receive their final dose. and we expect top-line data in that study in Q1 of 27, so three to four months away, five months away. Very short period of time. And then finally, we were accepted into a very prestigious program called ALS MyMatch. It's a consortium of the Centers of ALS Clinical Excellence in the United States. There are only two companies in the program, of which we are one. We dosed our first patients in that study just a few months ago, and we expect that trial will read out in 2027 for sure. So, if I could go to that, and мы have ongoing programs that are expanded access or open label extension for the patients who are in the SPMS trial. Next slide. I just wanted to leave you, before we go to questions, with two slides. I don't want to deal, Dr. Singhal's thunder here, but we have seen the same trend in reduction in microglial activation as measured by TSPO PET in Alzheimer's. These are images of a patient's brain, three different cross-sections, but if you look at the top row, it's just three different cross sections of a patient's brain, and if you compare the top row and the bottom row, you can just visually look and see there's a reduction in neuroinflammation as measured by PET. That's in Alzheimer's, so more to come on that in three months or so. Next slide. And in multiple system atrophy, which is a terrible disease, which has no approved therapy and is fatal. Again, we have data in inpatients now where after three or six months on faradumab, there's a significant reduction in neuroinflammation. And again, we'll be presenting more data on that in the next six months or so. But the take-home message is the mechanism of neuroinflammation is common across many neurodisorders, and we are seeing a reduction in neuroinflammulation with nasopharyngeal. Next slide, please. So, I think I'll open it up to questions, and Drs. Weiner, Chitnis, and Singel will be answering the questions, so fire away please. Thank you. To ask a question, you will need to press star 1 and 1 on your telephone and wait for your name to be announced. To answer your question, please press star one and one again. We will now take the first question from the line of Tom Schroeder from BTIG, please go ahead. Good afternoon. Good morning. Thank you. Very helpful. It's new stuff for all of us. We appreciate the detail. I guess the question is really for Dr. Sinkhal, but I'm glad to have all the input. The only wrinkle to this trial, you know, the fatigue data is unrelentingly positive at both doses and the TSPO data doesn't follow in the high dose. I'm curious, how noisy is the TSPO imaging? It's a complicated scan. And did the patients that got clinical benefit but didn't seem to show a good scan, were their cytokine markers also less impressive? How does everything correlate? And then the follow-up to that is, when would you expect to present patient-level data? Did most patients see something in TSPO? How small a change can you see? I'm kind of looking for a little bit of intuitive background to your technique because we all know a little bit about it, but I don't think any of us really understand how much detail you can glean. So any detail, and as I say, any other, the experts, I'm glad to get your input. Thanks. yeah so i think the key reason from a pet imaging perspective for the 100 microgram result is the sample size so you know pet imaging is a very sophisticated and sensitive technique and has to be evaluated in a very careful and informed manner and we have been studying this f18 pbro6 pet for over 10 years now across diseases and came up with these approaches over the years And in the Expanded Access Program, for example, we used the Z-score approach and we have done the global normalization approach before. So overall, I think for the 100 microgram, the reason is in the lower sample size. And obviously, there is going to be more analyses, including cytokines and other markers with Dr. Chittins and Dr. Weiner, which will provide more insight into it. Overall, I think we are replicating the results of the reduction in microglial activation as compared to the placebo, which we saw in the EA program. And when we look at our MGALP scores, for example, at our center, they're exactly the same. It's like it's very profound replication when you take care of a lot of other variabilities in terms of centers, et cetera. And the vast majority of patients, for example, at our center, they showed a reduction on treatment, and on placebo, they show an increase. So, you know, PET imaging is known to have noise, but we do appropriate normalizations, and that has been, you know, a big challenge in the field, how to normalize the data. And that is why it requires all this experience to find out what are the determinants of that type of noise. And that's our current assessment of that data set. Yeah, this is Dr. Weiner. Let me say something. You mentioned that between the 50 and the 100, the higher the dose in general when you do this, the less it tends to work. and I think that the difference between the 50 and 100, we didn't have enough for the PET scan to know whether it works or not. We know the 50 works very well. We have very good immunology on the 50, and we now are going to be able to look at the immunology on the 100 as well. It may be that the fatigue is more sensitive. It's a more global measure of the MS patient because it's a symptom. So I think that we can't say anything about it, but it all fits with what we've seen in terms of higher doses may not be as well tolerated. And we will be reporting on immunology comparing the 50 and the 100. But this was exploratory. And мы chose the 50 for this study and all our studies because that seems to be the right dose. So we'll see what comes out, but I wouldn't say that it's not consistent. I think it's that the fatigue may be more sensitive to changes that are going on. Maybe I'll just add one point to all of this. So fatigue is a very specific symptom that relates to your awake network. So not all of your brain is involved in the mechanisms of fatigue. and in studies that Dr. Singhal has published previously, there are certain areas of the brain on microbial PET that are particularly associated with fatigue. So the substantia nigra that's also involved in Parkinson's and the hippocampus are some of the areas. So there is a fatigue network in the brain and that is affected in MS. It's not all areas ofthe brain, so it may be just where you know, the lesions happen to be, and that's why fatigue was more sensitive. And on TSPO-METPET, we're measuring inflammation in the entire brain. If there was a subscore that eventually, you know,, might be done, then there might be better correlation with the actual fatigue network. Just to follow up, do you think we would see data sort of at that level of image analysis from this trial, or is that something for the future? I'll let Dr. Singhal answer that. I mean, I think eventually it could be done, but it's just a matter of time. No, we'll be analyzing data more and more. There's no question about it. You know, it's a very rich data set, and we'll be looking at it. So this is Dr. Weiner. Just, just, oh, sorry, Howard, go ahead. Yeah. We'll look at the 100. We probably are not going to be doing, you know, large number of patients comparing the 100 to the 50 to see whether it links exactly with that. We all have immunology data and some PET scan data on these small number of patients on the 100, but we have enormous data on the 50, etc. Ivor, you were going to say something? I was going to stay tuned for additional data. Remember, this top-line data is hot off the press. It's literally a week old or maybe slightly older than that, but it's not old. We're burning the midnight oil to crunch this data. All right, great. Thanks for all the thought. Thank you. We will now take our next question from the line of Elmer Piros from Lucid. Please go ahead. Yes, good afternoon, good morning. Just to come back to the two doses, if we assume that the 100-microgram dose is over the top, and as you surmise, would it be also possible that the fatigue scores, because we have a limited number of patients in this dose group, and since they are subjective, that they are less reliable or less quantifiable per se. And the issue is with the fatigue scores as opposed to the lower activity on microglial activation. That would be my first question. So I can start to answer that question. So you're really asking, is the fatigue score a reliable score and can we trust it? So I would say yes, we saw a significant reduction within ARM at both the 50 and the 100 microgram dose in a randomized trial, multi-center. So this is blinded, randomized, multiple centers involved, and we saw significant reduction. So I do think that we can trust that result, and it is very consistent with our results from the expanded access program. So we saw, in fact, a six to seven point reduction in the fatigue score in the expanded access program. So we're showing replicability and consistency now across two, you know, of the two studies. Thank you, Dr. Chitnis. Maybe the next question would be, have you been able to observe a patient level correlation between the magnitude of microglia reduction and fatigue improvement? So that analysis is ongoing. You know, that's a much larger analysis. And as Dr. Chittin has mentioned, we have to look at the sub regions of the brain rather than, you know, like white matter, for example, that we have focused on and reported. So that analysis is ongoing, and we are also interested in learning about that. And the last question would be about the future. How would you design a potentially pivotal trial? What sort of measures? No one really expected EDSS to change after three months, but would you start focusing on that type of measurement in a longer, maybe a one-year, one- to two-year trial? So I can start to answer that question. So, you know, I think for a phase 2b or phase 3 trial, of course, we need a clinical outcome measure that's clinically meaningful. And there is a strong rationale for focusing on MFIS or the fatigue score as the pivotal measure. Another contender, of course, is the EDSS, the ETSS score. And so one could measure these in several ways. So the fatigue score, we've seen a significant reduction, at least four points or more in the 50 and the 100 microgram dose. So it could be anchored on that change in a larger study. Another contendo is both stability as well as potentially improvement on EDSSS. And so in our expanded access program, we saw stabilization of the EDSS score in all of the patients over six months and an improvement in three patients out of 10 at the 12-month mark. So there is also potential for using the ETSS either stabilization and improvement or one or the other. And I think this is going to determine the sample size for the study. So, you know, there's strong data for one or more of those outcomes. This is Dr. Winer. You can also measure confirmed disease progression is another outcome measure because over time these people get worse and the EDSS might get worse in some but not in others. So another outcome measures confirmed disease regression, but we have to look at everything in numbers, etc. And Elmer, if I may just add one more or a couple more points. We will be working with the FDA and having an end of phase two meeting to answer exactly that question as we develop a protocol for a pivotal trial. But I think the take-home message is the data here support advancement to a pivotal, acceptable, approvable trial. That's point number one. We will be having a phase two meeting with the FDA. And point three, when Dr. Chitnis says stabilization or improvement in EDSS, I hope the audience remembers that that's a spectacular result that we saw from the expanded access program. And if you compare it with drugs that have not been approved, for example, Sanofi's tolobrutinib drug was not approved by the FDA in December of 2025 for liver toxicity exceeding the benefit of the drug. In that trial, patients in the treatment arm of the drug, their EDSS score was declining. It wasn't stabilized. It wasn't improving. So you're putting it in context. This data is spectacular all in, including the EDA data. Thank you. Thank you very much, Albert. Thank you. There are no further questions on the phone at this time. I would like to hand over for webcast questions now. So, a question has come in. Do you anticipate use of feralumab in combination with other disease-modifying therapies, such as ocreluzumab, in individuals with SPMS or other forms of MS? And I will answer part of that question, and I'll turn it over, I think, to Dr. Weiner, but the simple answer is yes, we do anticipate using feralumab in combination with other disease-modifying therapies. So, for example, we have announced that we are going to be initiating a trial in Saudi Arabia at KMARC, at their medical research center, And that trial will be a combination trial of feralumab and ocrelizumab in relapsing remitting patients who aren't responding well to CD20 or ocreluzumab is CD20 therapy alone. And Howard, maybe you can comment further. Yeah, it's now known that there's two components to MS. There's the inflammatory component and the progressive immune component. And Steve Hauser, who heads the Weill Institute at UCSF and was the developer of anti-CD20, he visited here last week. And he was very excited by the data. And he says, Howard, you have to use this in combination. This needs to be given with anti- CD20 because it attacks a different part of MS. so I was very encouraged to hear that it's something that Dr. Chitnis has said we're now going to be doing those combination therapies so I would predict in the future that people will be put on you know combination therapy is used throughout medicine will be put on an anti-inflammatory drug like Ocrevus or anti-CD20 and will also then be put on a nasofaralumab, and the safety profile of nasofaramab would go very well. So, I think the answer to the question is yes, we will be trying combination therapy. So, another question has come in. In the INFORM-MS study, which is the Phase II placebo-controlled double-blind study. Are your patients on prior disease-modifying therapies? If so, was there a wash-off period, and how long was the wash-out period before onboarding for Alumab? So, I can answer that question. So, yes, the majority of our patients were on prior disease- modifying therapies, and they were not doing well, and that's why they wanted to enter this trial, of course, with their collaboration with their neurologist. And so, some of these patients were on anti-CD20 antibodies like ocrelizumab or ocrevus. Others were on other treatments. And there were standardized washout periods prior to starting in the feralumab trial. So, typically, it's six months for the anti- CD20 antibodies and one to two months for the oral medications and other drugs. And this is fairly standard across MS trials. And just to add to that, the FDA is heavily involved in telling us what the washout period is. So, that's all part of the protocol. Another question has come in, says, will Thoralimab be a treatment for PIRA? And I think we've sort of pseudo-answered this in the Saudi Arabia question, but Tanuja, maybe you can comment a little further. Yes. So, we know from the pivotal Ocrevus or Ocrelizumab trials that PIRA occurs in somewhere in the range of 30% at least of patients over at least a two-year period, more frequently when you go to five years. So, pura or progression-independent relapses is a very important question in patients who are even treated with some of the strongest therapies that we have that shut off relapsus. So pura, or progression, does continue to occur. This is due to neuroinflammation that is in the brain, trapped behind the blood-brain barrier that the anti-CD20 antibodies can't get to. And so, you know, we strongly believe that feralumab will shut down that type of inflammation and stop progression independent of relapses or PIRA in patients who are on anti-CT20s or on no other treatments or on other therapies as well. Terrific. I think there's perhaps one more question coming in. The question says, beyond fatigue, did you observe any positive trends in disability, progression, cognition, walking performance, or other functional endpoints as in the EA program? I think the question means, in the INFORM MS trial, did we see any of those endpoints similar to the ones we saw in EA? All right. So, I mean, that's a fair question. However, just remember the INFORM-MS Phase 2A trial was a three-month study, whereas in the EA Expanded Access Program, our first time point that we focused on was six months, and then another was at 12 months. So it's really not quite a fair comparison. That being said, the EDSS score did not change in the INFорM-Ms phase 2a trial again at three months and we're analyzing all the the rest of the outcome measures but we did not see significant changes at least in in the results that we've analyzed so far but we would not really expect to because it's it's a very short study three months and it's quite remarkable that we saw a reduction in both the TSPO PET as well as fatigue scores at three months. Most drugs take, you know, many, many months, half a year or a year to take on their full effect. Thank you. We just have maybe a minute left. So, I would like to wrap up by saying thank you to our key opinion leaders. I would like to make a statement, which is, I'll ask, is it fair for me to summarize the results of the of the inform ms phase two placebo control double blind trial as positive results that would support advancing to a pivotal approvable trial do each of you agree with that statement yes yes yeah i agree 100 no question all right again we're um for the listeners thank you so much for listening we really appreciate it to our key opinion leaders we greatly appreciate you taking your time doing this. If anyone has questions, you can follow up with us directly after this webinar. Thank you so much for all attending. We really appreciate it. Thank You very much.