AB Science S.A. (AB.PA) Earnings Call Transcript & Summary

Good day, and welcome to the KOL call on masitinib in multiple sclerosis, boosted by AB Science. Today's conference is being recorded. At this time, I would like to turn the conference over to Alain Moussy. Please go ahead.

Welcome to our web conference led by AB Science to present masitinib results in primary progressive and non-active secondary progressive multiple sclerosis. My name is Alain Moussy. I'm the CEO of AB science, and I will have the pleasure to lead this web call with my distinguished associates and KOL and MS and also colleagues in AB Science. We move -- let me present you the agenda. So the agenda is structured around 4 points. We'll briefly introduce the participants. We will review the landscape in multiple sclerosis and in particular, in progressive forms. And we will give, of course, the results of masitinib in the stage Phase IIb/III studies, and we'll answer your questions. Next slide, the participants. So with me, the KOL experts and distinguished experts, I'll briefly introduced them. There is Dr. Patrick Vermersch, who is Professor of Neurology at Lille University in France, Dr. Bob Fox, with staff neurologists at the Mellon Center at Levlane Clinic; and Dr. Ken Mapal, who's Professor of NOI at Charite University in Berlin. From AB Science with me, there is Olivier Hermine with our Chairman of Centric Committee and distinguished member of the Academy of Science in Paris; Laurent Guy, Chief financial officer and myself. Patrick is with me, if you want to briefly introduce yourself before you present the data.

Okay. So I am Patrick Vermersch, professor of Neurology, involved in biology, but also in neurology for maybe more than 3 decades now. Also board member of the prestigious European [indiscernible] foundations. I published many papers in biology in Alzheimer's disease during the first period. And then many many papers in MS with some impact on new drugs, new targets, holistic markers in MS and neuroimmunology and maybe member in steering committee, advisory board of most of the new drugs we have today in MS. And also quite a good involvement during the last year for masitinib with our first proof-of-concept and maybe the PI of the study, we will present today. So maybe briefly to introduce what is MS? Concerning first the clinical phenotypes of MS, mainly 2 types of MS. There is a continuum between the two forms, but at onset, most of the patients will have the so-called relapsing-remitting form, about 85%. At the opposite, some patients had no relapse, but progressed from the onset the primary progressive MS form is around 15%. The key point is after maybe 5 years, 10 years or 15 years, most of the patients, which switch from the relapsing-remitting form to the secondary progressive form. Some of the secondary progressive form are active, but most of them are nonactive. So globally, we consider that about 50% of the MS patients are in the progressive form. Most of them, non-active, secondary progressive and primary progressive form. So maybe let me show you some key points to distinguish progressive and relapsing forms of MS. They are distinct, even there is a continuum. And these key distinguishers may explain why we have many therapies, targeting the peripheral adaptive immune system, so mainly T and B cells. Definitely very effective in most of the case in relapsing-remitting MS form, but unfortunately, have failed or our inconclusive results in PPMs and non-active SPMS because there are many distinctions. Maybe we know that there is some contrasting results between time to disability progression and the relapse rate, frequency of severity. Most of the patients at the progressive form have no or very few active plaques. The inflammation is trapped or compartmentalized within the CLF in the progressive form. Typically, MS is much more a spinal cord disease. We have less peripheral immune cell activation in the progressive form and maybe is probably the key point to highlight is that in the progressive form, there is a strong involvement of the innate immune system. So also, we have some major point to discuss about this innate immunity involved in the progressive form of MS. Contrasting, we know in the relapsing form with the involvement of T and B cells. In the progressive forms, we have involvement of other types, I'll say, also immune cells, of course, but for example, master cells or microglia. We accumulate during the last year, many data from basic research, research, telling us that innate immune system made a major role in the progressive form of MS. We know that progressive form predominantly driven by self-perpetrating innate immune-related inflammation that become contained into the CNS. Of course, we know that mass sales, but probably more microglia are types typically of the innate immune sets present in the CNS, strongly associated with the pathophysiology of the progressive form of MS. And definitely, we need to target this innate immunity to control what happened into the progressive form of MS. So we need to target mast cells and also activated microphages microglia to control the disability progression in Progressive MS. On the next slide, maybe I will not go into the details, but on this simple slide, we show the involvement of such cells, showing, for example, the activated microglia on the left part of the slide, you saw in brown, the active microglia in the typical PPMS patients. We know there is also not only activated microglia, but we see hypertrophic astrocytes form at the rim of the chronic active MS form, the so-called slowly evolving lesions, which are the drivers of the progression in the secondary progressive form of MS. Surprisingly also, we are able to detect in almost all the progressive form the master cells and the master cells in the progressive forms are able to release enzymes, leading to demolition and disruption of oligodendrocytes and neurons and as you know, oligodendrocytes synthesize the main into the CNS. So definitely, we have strong data suggesting the involvement of the innate immune sales and contribution to the neuro degeneration we have in MS.

Thank you, Patrick. And the next slide will be presented by Olivier Hermine.

Hello, everybody. So as it has been nicely presented by Patrick Vermersch, microglia and mast cells may play a critical role in the physiopathology of multiple sclerosis. So we have designed drugs, which is able to block the activity of macroglia and mast cells, and the name of the drug is masitinib and why masitinib is working to block mast cell activation and microglia activation is because these drugs block several kinases, including the KIT, LIN and SIN, which are very critical for the migration, for the activation and eventually for the survival of mast cell. So if we do block this free kinases, which is the case with masitinib with a low concentration, we may block the mast cell activation. In addition, masitinib by blocking the MCSF receptor 1 and blocking also LIN and SIN may block the macrophage microglia activation. So these 2 activity of the masitinib explain why we do block mast cell and microglia. In addition, masitinib can be taken orally, which is a very simple way to administer the drugs. And also, these drugs may cause the [indiscernible] blood barrier, which explains why it may block mast cell and microglia in the brain in the MS.

So because of this [indiscernible] in the progressive forms of MS and because of the mechanism of action of masitinib targeting both mast cell and microglia, we at [indiscernible] have decided to position masitinib to treat or try to treat patients with progressive forms of MS, both so primary and non-active secondary, which recognize is a difficult-to-treat population. And we know -- I'm not going to, of course, describe the -- primarily the non-active secondary progressive, but just in secondary progressive, it's very important for our audience because not everybody is an expert in MS to understand that there are 2 sub-forms of secondary processes, the so-called active and inactive forms, and the nonactive can be defined in two ways clinically or radiologically here in our studies. We have taken nonactive define clinically, meaning that there is no progression -- there is progression, sorry, without any relapse in the last 2 years, but there was no imaging, I would say, to define this nonactive. And we know from the literature that the primary progressive form represents 15% of the patients, but the non-active secondary progressive is a huge population of roughly 30%, 35%. In terms of unmet medical need, this is huge. And to better understand our huge [indiscernible], we have put the full landscape of multiple sclerosis including the relapsing-remitting forms, and we know that there are 15 drugs -- 15 to 16 drugs, which are registered in relapsing-remitting or in active forms of secondary progressive MS. And ranging -- some as old as 1993 for the interferon stimulator. And the most recent one last year, but only 2 are registered actually in progressive forms, there is OCREVUS registered in 2017, targeting in 2020 and most recently, siponimod had the positive study in secondary progressive form, both active and inactive, but where the [indiscernible] showed actually activity in active progressive. So it's a huge unmet medical need for 50% of the patients with very limited drug registered at this time and the last one very recently. Then we move back to the science with Olivier.

So to demonstrate and to have some kind of preclinical model, we used the classical model of immunized -- autoimmune encephalopathy, which mimic in some way, the multiple sclerosis. So in this model, and you can see on the right curve, you see the deterioration of the mice after immunization by Myelin. And when we treat this mice with masitinib and by blocking mast cell and microglia activation, you can see that as a low dose of masitinib, no effect was seen or very little effect with dark curve, but when you look at the green curve, you can see when we increase the dose of masitinib as a dose which is reachable in vivo ni mice but also in human, you see a dramatic decrease of activity of the disease and show it clearly in the clinical model of MS, that masitinib might be a good drug to treat this mice. So based on the data we moved through the clinical study.

[indiscernible] got to the Slide 14. This is the clinical program -- clinical development plans of masitinib in MS. We started with a proof-of-concept with limited number of patients, 35 patients, where we try to detect the signal. And then -- and we'll go back to this data very quickly with Patrick. And then, of course, the highlight of this call is to present you the new data that we just received in this study called 7002 with 656 patients. So as just discussed by [indiscernible], no, we had the opportunity to publish the first paper in 2020 call a proof-of-concept study. However, we are positively surprised to see maybe the effect of masitinib in the population, even a small population. However, we are able to show an improvement is called MSFS score. It's composite score of disability in MS validated score. You see the positive impact with masitinib more than 103% comparing with baseline and compared with a deterioration or worsening of the MS core with placebo, minus 60% from baseline, only a 12 -- almost 12, so quite impressive results. Encouraging results observed as early as month 3 and sustain over time 2 months '18. Quite also interestingly, similar trends seen in PPMS and non-active SPMS sick populations, the safety was overall acceptable, and of course, because the study achieved its objective with quite a limited sample population, maybe warranting further evaluation of masitinib in progressive MS. This first proof-of-concept study was published in BMC neurology, a small population, so in BMC Neurology. So maybe, of course, it makes sense to switch as soon as possible to this Phase IIb/III design. Of course, it takes time, but it's a very complex population, as you know, to have this study, of course, double-blind, placebo-controlled, 2 parallel groups, 2 doses tested in [indiscernible] with its own placebo groups so masitinib 4.5 milligram per kilo day versus placebo, 300 patients, randomized 2:1. Another study masitinib titration up to 6 milligram per kilo versus also its own placebo, also 2:1. And this [indiscernible] was introduced later in the study to replace through an amendment, a fixed starting dose of 6 milligrams to improve the tolerability of the safety. And also, of course, its own placebo control arm. So therefore, statistically studies is treated as 2 independent sub-study and there a common study in [indiscernible], with alpha controls that 5% for each dose as usual. However, because of a selling function for the interim analysis was bad and [indiscernible], so the residual alpha risk for the final analysis was 0.0296 after this analysis. As usual, the main inclusion criteria, also, of course known by the -- recognized by the authorities for both primary MS -- progressive MS and non-active progressive MS. The criteria was no relapse, [indiscernible] by EDSS preparation. So we need to see in the document that really the patient progress during the last 2 years before inclusions, and we consider an increase in the assets at least by 1 point and must be, of course, some other criteria, [indiscernible] from 2 to 6 included of baseline and large populations concerning the edge from 18 to 75 years for that. So maybe the design of this study, the specified primary endpoint also recognized by the authorities. It's about EDSS, which is a score used in everywhere in the world in MS was the change from baseline in absolute EDSS value average over the 2 year study. What was considered? It's a very important point to consider. It was a mean of all changes from baseline EDSS, mustered at 8 time points for each patient every 12 weeks from week 12 to the end of the study, week 96. The statistician discussed the point that it was calculated with the GEE model, generalized estimating questions, which is validated way to analyze its data to -- for repeated measurements, adjust for correlation across variables and across time and give a true treatment effect over the 2 year study. The primary analysis is not as many study as a onetime Ancova test at the end at week 96. Interestingly also to reinforce this data with the EDSS. It was also a pre specified transitivity analysis. Change from baseline in ordinal EDSS score average over also the 2-year study. It was also to reinforce the clinical relevance of the data we have. So instead of the change in the absolute EDSS because EDSS is not a linear change. So ordinal EDSS change is very important to consider, plus 1, 0 or minus 1. Minus 1 is worsening in EDSS. Plus 1 is improvement in EDSS and 0 if EDSS remains stable over time. So this ordinal model allows us to take into account the fact that the magnitude of the EDSS necessary to define improvement of worsening over time depends on the EDSS score itself, which is not linear one. So the evaluation is the mean of all ordinal EDSS changes from baseline, [indiscernible] also at 8-time points for each patient every 12 weeks from week 12 to week 96. And also, the analysis is calculated with the GE model. So also, it makes sense that we need to have also time to first EDSS progression as we know, and we have in the common literature in MS and also interesting time to confirm EDSS progression. We are also pre specified for the sensitivity analysis. Of course, we consider the absolute churn in EDSS, the ordinary arginine's because, of course, the study was not powered to detect an effect on these endpoints. We need for that to have maybe 9,000 or maybe almost 1,000 patients or more to detect something using EDSS because EDSS is not really very sensitive to change. It's some limitation of the EDSS. So the study was not designed and powered to detect such an effect on the confirmed EDSS progression [indiscernible] the expected percent of events at week 96 based on the literature is something like between 20% to 30% for EDS progression and between 10% to 20% for the confirmed EDSS progression after 3 months. So even quite significant, you see a number of patients involved. This study enrolled 300 patients per dose tested, meaning that the expected number of progression was between a 60 to 90 events and the number of confirmed progression was between 30 to 60, so quite a relatively limited number of events. And as discussed earlier, we need to detect something with the EDSS progression more than 1,000 patients there. Of course, as you see, the disposition of patients, the study comprised 2 independent subsidies, testing 2 distinct dose regimens analysis have perform. You see the first on the left dosing masitinib 4.5 milligram per kilo versus matching placebo. You see the number. The ITT [indiscernible] of the modified ITT population with the only 1 patient not really take the drug. So every patient taking at least one drug was, of course, included in the modified ITT population and also for the safety population. In the middle, you see the dosing in masitinib 4.5 to 6 titration study versus also matching placebo. You saw [indiscernible] the same population. Maybe a detail concerning the dosing masitinib 6-point milligram per kilo versus placebo. It was a small population. However, there is a decision to stop early the study by the sponsor field and replace with masitinib 4.5 to 6 into the titration population. As a result, group 4.5 milligram and group titration up to 6.0 milligram per kilo were not conducted at the same time, not in the same centers. Maybe what was baseline characteristic of the masitinib 4.5 milligram kilo per day. Maybe roughly well balanced between masitinib and placebo is the 200 is a masitinib group, 101 is a placebo. Maybe the 6 ratio was relatively equivalent for both groups. We see the age also maybe a little bit less than 50 years old. As usual, we have in this progressive population. So really representative of the population we have in our clinics in routine. You see also the duration of first MS symptom to randomization, maybe roughly 14 or 13 years. Also maybe for some it's, of course, early SPMS population. You see the EDSS score relatively disabling population. You see the mean EDSS roughly 5.2 the medium, 4.5. However, if you look at the distribution of EDSS baseline at the bottom of the table, you see roughly 50% of the patients with EDSS score 6 even the major is 5.5. However, you see quite a disabling population because we need, of course, in this progressive MS population, we have -- most of the patients are in this range of EDSS disability. Maybe let me show now the primary analysis at 4.5 milligrams on this slide. As you can see, I will go into the details, but the study met its primary analysis, demonstrating a statistically significant reduction in disability progression on EDSS, you see the p-value. If you look in details the curves we have, in blue the masitinib one, in red the placebo one. You see roughly with the masitinib, maybe roughly a small improvement in disability during the first period and route after [indiscernible]. You see the curve, maybe a very slight increase in the mean EDSS. In red, you see definitely an increase in EDSS. And if you look into the details, you see for most of the time point, you see, interestingly, there is very only a small overlap, if you consider the confidence interval, which is, of course, interesting. On the bottom of the slide, you see the primary analysis, it's important to consider. It was the mean of absolute changes from baseline EDSS measure at 8 time points every 12 weeks up to week 19. 96 [indiscernible], maybe almost that means no change in the masitinib group and maybe an increase in the placebo group, you see the means difference reaching a significant peak value. Now if you look into the details, the subgroup of patients, even the study was not powered to show an impact in the 2 different populations. However, you see roughly the consistency of the data we have in both population, PPMS and non-active SPMS. You see also the difference concerning the means. There is a difference between the 2 groups, interestingly, for both group of patients, which is, of course, great. And now interestingly also discuss about the ordinal EDSS, again, in the 4.5 milligram. For both groups of patients masitinib on placebo, remember, it was plus 1 improvement, minus 1 worsening. So interestingly, it shows a global view what happens in the -- in patients treated with masitinib. And this method allows us to give you an old ratio showing definitely a significant 39% increased probability with masitinib of having either more disease improvement or a few years disease progressions. And maybe you see the out ratio, 0.61. It is significant as you see the peak value, the equivalent, of course, is significant, 49% increased probability, which is definitely quite impressive in this disabled population. No more classically, I would like to say, to show you the couple of major curves concerning first. On the left, the pre-statistical analysis on EDSS [indiscernible] analysis of time to first EDSS progression plus 1 point. You see the [indiscernible] ratio interestingly, 0.58, which is significant. You see the p-value [ 0.0342 ], it is significant difference between placebo and masitinib. Of course, if you look now on the right of time to confirm 3 months EDSS progression, we have a smaller number of events, as we discussed earlier. However, if you look at the curves and see, if you look also the other ratio, there is not a strong difference. You see it was significant reduction for the risk of first visibility progression and for the reduction of the risk of confirmed disability progression, it is 37%, which is interesting, not significant, of course, because it was a small population and a relatively small number of events. What is also very clinically relevant for both neurologists but also, of course, for patients, is time to reach are a proxy of time to [indiscernible] is time to EDSS 7.0. If you look again on the left, the analysis of time to first EDSS score of 7.0. You see the reduction of this risk significant 98% reduction of the risk of reaching EDSS score 70 over time during the time period of 96 weeks. On the right, quite impressive also even it's, of course, a small number of patients. However, we have a 100% reduction of the risk of reaching EDSS score of 7 points over time of confirmed progress, which is, of course, very important for patients.

Thank you, Patrick, for commenting presenting these results. So we try here on Slide 26, to give a comparison of these results, with the results obtained in the similar population, primary or secondary progressive. So as we already said, there is previous ocrelizumab and siponimod with some positive data here, obtained with a greater number of patients. Ocrelizumab study was 732 patients, and siponimod, 1,651, 600 in active forms of summary progressive and 1,000 is nonactive. And there is also [indiscernible] to 255 patients recruited in the same population in this study with masitinib. Now if we take the, as Patrick said, the classic measure, which is a time to confirm the ability progression. So we see the masitinib data at 4.5 milligram with [indiscernible] ratio of 0.63, so the reduction of 37%, nonsignificant, to be compared with the data of the other studies, which are significant for those studies, but our comes with a [indiscernible] ratio, which is higher, so a reduction in probability of progression, which is lower, 24% and 21%. So this 37%, although not significant, compare far favorable. The ordinal change, which is another way to look at it and it takes into consideration not only worsening but also improvement because some patients could improve with the brand is consistent at 39%. And the average of change in EDSS over the 2-year period could be compared with the Biotin study, which actually used the set of Ancova at 9 months, not really an average, but we could actually estimate the average by taking the different time points. So it's an estimate from us. It's not actually published in the publications, but what is interesting is that when you do this average, you more or less find the same difference of average change between the treatment and the control. I said that the Biotin data was opened over a 9 months period and the [indiscernible] of masitinib 2 years per. So all in all, the data compare favorably with previous data. And we'll continue with the safety now and Patrick.

Of course, it makes sense. You have the data concerning the efficacy. The other way, of course, is a clear look concerning the safety. I'm not going to the details because probably we'll discuss later, we have a large amounts of data accumulating now for many years using masitinib in humans. And what we can say is that the safety in this study was consistent with the known -- well-known profile of masitinib. If you look at some common treatment-emergent [indiscernible], we have some GI like nausea or diarrhea, also some cutaneous adverse events, some rash and [indiscernible]. We have also a couple of patients with very few adverse events in the hematological analysis. On the table, you see only the most frequent severe, i.e., with the difference between masitinib and placebo, at least 1%. So quite a stringent difference. And if you look, we have only a couple of patients in masitinib, but of course, also in the placebo group. If you look into the details of safety issues of main interests, for example, we have a couple of patients with lymphopenia, which is mild to moderate. There is no very strong or severe lymphopenia. There is a couple of patients also with neutropenia, but also consider as not very severe. We have also some lever enzyme increase. And also in the bottom, you have 2 patients with a rash, significant rash, considered as severe by the investigator. So roughly, maybe reassuring data about the safety in this study. So maybe briefly because we'll not go into the details, but concerning the -- another starting with the masitinib 6 milligram bark concerning the primary analysis. As discussed earlier, there is no significant treatment effect on EDSS observed for this high-dose masitinib. However, if we look into the details of the data we have, numerically, maybe masitinib 6.5 milligram titration was comparable with the data we have with masitinib 4.5 milligrams. What was very strange is that the placebo comparator for the 6.0 milligram titration showed an abnormal improvement in EDSS changes. We have a couple of patients who got out layers data-driven by PPM subgroups. So it was very difficult to interpret and to compare this unexpected improvement in the placebo group with the patient we did with masitinib 6.5. So we cannot conclude what is really the impact of the 6.0 milligram. So considering both aspects and the positive benefits with balance with 4.5 milligram per kilo per day, the 6.0 milligram titration ship will no longer be pursued in EDSS. Then we would like to present the next steps that we in fit in the coming months. We intend, of course, to present detailed study results at 1 or major -- or more major sense conference in the next 6 months, provided, [indiscernible] they not canceled by an expected health situation you now. And publications, of course, we have to publish, and we want to publish this data, obviously. Regulatory-wise, we will consult as soon as possible with FDA through EOP 2 meeting and with the [indiscernible] advice to discuss the appropriate pathway forward with this data. And the 2 questions you ask is the possibility to file based on study -- on the single pivotal study, we know the difficulty of this exercise, but still given the unmet medical need, it is worth asking the questions. And in case the single pivotal study is not enough, of course, we will discuss the design of the confirmatory study to be started as soon as possible. Then in terms of intellectual property, which is important for the analysts and for us as well, we remind that we have actually already a pattern that protects the use of masitinib in MS until 2031, but we also filed a new patent with this data that we expect to be granted and that would protect the franchise until 2040. With that, we gave you the highlights of the program and the most recent data, and it's time to give, I would say, the opportunity for our distinguished experts to give their opinion freely and starting with static and then with Bob and [indiscernible]. That's okay. I'm very happy to open the discussion. Of course, as you just see, the clinical data are extremely encouraging. And of course, in Europe for progressive MS patients. Maybe my -- the first point of the discussion will be, of course, to come back to the very high unmet medical need for people with PPMS and non-active SPMS, even we discussed earlier, maybe the data we have with ocrelizumab and also with siponimod, but as you probably know, the positive results we have with such a drug are mainly driven with patients with some degree of activity, clinically or radiologically. And these drugs target beyond T cells. So target the adaptative immune system. And we know if you use these drugs targeting adaptative immunity. Maybe you observed this strategy has failed or had inconclusive results in PPMS on non-active SPMS or very severe safety issues. So definitely, the clinical data supported by the mechanism of action of masitinib. We need to use drugs targeting the net immune system. We accumulate so many data in MS showing that for Progressive MS, we need to target not the peripheral adaptative immunity, but to target the innate immune-related inflammation, which is the main driver of disability progression. And what is fantastic to my point of view that is the first time, it's a clear demonstration that not targeting lymphocytes, we have a positive results targeting innate-related inflammation. So of course, it's -- what is interesting. Of course, many companies try also to target other parts of immunity, but masitinib is the first drug targeting mast cells and microglia. So definitely a distinctive and relevant mechanism of actions. So the results are very promising. First, why? Because even using EDSS, which is not a sensitive scale to detect something. However, we're using DSS, we have masitinib significantly devised delays disability progression, [indiscernible] is average change in EDSS, but also absolute value of ordinal change. Probability of having either or more disease improvements or few year disease progression is significantly increased by 39% with masitinib. Time to first progression significantly delayed by 42% and time to confirm progression is delayed by 37%. Interestingly, of course, in this relatively sometimes all population, the safety profile appears acceptable in these targeted indications. And masitinib compares favorably vis-à-vis drug like OCREVUS, [indiscernible] or missense and also [indiscernible] Biotin.

Thank you, Patrick. And now we are pleased to give the opportunity for folks to give us his opinion, but feel free to introduce yourself and say your opinion.

Sure. My name is Bob Fox. I'm a staff neurologist at the Cleveland clinic here in Cleveland, Ohio. I've been involved in MS Clinical Care and clinical Research for about 20 years now. Involved in many clinical trials in the development of MS Phase I to Phase IV clinical trials, advanced imaging measures to study MS. So this trial is very exciting. And next slide, if we could. What is exciting to me, similar to what Patrick shared, is, first and foremost, the high unmet need for having a treatment in primary progressive and non-active secondary progressive MS. So this accounts for about half of our patients with MS, and we really have virtually no treatment options for them at this time. All of our current treatments clearly work on the active inflammation that infiltrative inflammation lymphocytes activated in the periphery, the B and the T cell lymphocytes infiltrating into the brain and the spinal cord to cause injury through their inflammatory cascade. This drug was targeting a very different type of MS at different stage or manifestation, and that is the later stages when that infiltrative inflammation subsides. And settles down and becomes much less prominent. And what it is replaced by is the innate immune system that immune system that lives within the brain, not infiltrates into the brain, but lives within the brain microglia, astrocytes, mast cells, things like that, that are thought to have a compartmentalized inflammation. And there are some other mechanisms of progressives and whether this drug works on them is a little less clear and will require a bit more work, but what is clear is that there is activity on the innate immune system and the innate immune system is thought to be involved in progressive MS both primary progressive and noninflammatory secondary progressive MS. So what really excites me about this drug is that it works on a different manifestation, a different pathophysiology than we've seen any other drug work on in multiple sclerosis. And then turning to the results. The results are very exciting. There's a significant delay in EDSS progression. So that is exciting to see. We see very compelling differences in the progression rate of EDSS, as we saw in those curves earlier, also the time to EDSS 7, which is an important marker of lack of ambulation, inability to walk more than a couple of steps. So that is a marker of a very relevant benefit when we think about treatment trials and the clinical relevance of our measures to MS. The treatment effect was seen across the 2 different disease phenotypes, both primary progressive and the noninflammatory secondary progressive MS had fairly similar response, which is encouraging. So this was not driven by just 1 subset of the patients, but looks to be similar and consistent across the two. And then finally, the safety profile, a very important aspect when we're thinking of treating patients, safety profile appears to be quite acceptable. These patients can be quite brittle. These patients in the later stage of MS can be susceptible to a variety of complications, increased risk of infectious complications from their decreased mobility, respiratory infections and bladder infections and things like that. And we really saw quite an acceptable safety profile out of this drug. So I think for those 3 reasons, it's really hitting an unmet medical need. The form of MS that doesn't have active or infiltrative inflammation, the mechanism of action aligns to that. It's not addressing the infiltrative inflammation, but instead is looking at the innate immune system and possibly other mechanisms. And the delay in progression of disability was quite compelling with some very clinically relevant outcomes with a strong safety profile. So I'll stop there.

Thank you, Dr. [indiscernible]. So now I give it to Dr. Freeman Paul to introduce himself and his opinion.

Yes. Thank you very much. So I'm freedom Paul. I'm a neurologist here at [indiscernible] University Medicine, Berlin and Berlin, Germany. I've been into MS current research now for more than 15 years. And I'm Head of the Charitas MS center and of the neuroimmunology outpatient clinic, on our campus in Berlin Bu with more than 2,000 patients with MS and other new inflammatory disorders. And what I find particularly appealing about this study and the results is -- I mean, most of, let's say, the outstanding findings have been presented by my colleagues, but what I would like to add to that is that the efficacy is convincing, particularly in a population with advanced disease. This is something very important to me. Patrick Vermersch mentioned the mean median EDSS of above 5. This means patients with a longer disease duration with significant disability do benefit from this intervention and this is something that is unique to the study. First of all, there's another very unique point. This is the mode of action that is new to the field of MS therapy, as was mentioned by my colleagues. And the third point is that there is a very good safety profile. And also comparing masitinib to the other very few drugs, by the way, that are now in the field to treat progressive MS. The data are also very, very convincing in comparison to the other compounds that have been mentioned, biotin and ocrelizumab and siponimod. So to sum this up, I think there still is a high unmet need to devise a treatment options for patients with progressive MS. There are still very few options, particularly in patients as was investigated here with no relapses. That means with progressive disease, both SPMS without relapses and [indiscernible] SPMS, where the new regenerative component of the disease, so to speak, and the inflammation behind the blood-brain barrier. Patrick mentioned the compartmentalized inflammation seems to be paramount to the disease process, driving progressive disease. So this is something unique to the field, and that's why I think that it deserves to be investigated further.

Thank you very much, Dr. Paul. So it is time now to go to the last part of this agenda, which is to open or respond to the questions of the PIC. You have to wait to answer questions. You can do it using your phone or you can write them, and we will take them.

[Operator Instructions] And we'll take our first question from Keay Nakae from Chardan.

Yes. Thank you for this very informative presentation. Question for the doctors. Why haven't we seen more efforts to address the non-active patient population, especially by these companies that already have a stake in the MS disease space by treating those with the active infiltration while they may need a different drug, why haven't they been more aggressive with this unmet need group of patients too?

Yes. I'm happy to take that. What we -- we have only recently appreciated the differences in pathophysiology between relapsing MS relapsing forms of MS, that being clinically isolated syndrome, relapse and remitting MS and active secondary progressive MS in the last 5 years or so, indeed, the U.S. FDA only approved a drug differentiating active secondary progressive Ms from non-active secondary progressive MS last year. So it's a more recent appreciation within the field, One. Two, people tend to -- when they have a hammer, they start looking for a lot of different nails to hit. And because they had effective drugs in for the inflammatory aspects of MS, they just kind of naturally turn to Progressive MS and figured it's probably close enough and similar enough, but they had very disappointing results. Where they were able to hedge their bets, like, for example, OCREVUS and primary progressive MS, they purposely enrolled patients who were younger and shorter disease duration. So we're more likely to have active inflammation. And indeed, a subset analysis found that those with active inflammation were much, much more likely to respond to OCREVUS in the primary progressive trial than those who didn't. So I think it's a growing maturation within the field. And then third, we haven't really known exactly what the pathophysiology of progressive MS is. There's right now quite a few grant requests out from different organizations, including the progressive MS Alliance, asking for people to try to figure out what the pathophysiology of progressive MS is, are we sure the innate immune system is a part of it? Well, we know pathology shows that the immune system is involved, but is it a cause? Or is it a downstream effect like anything else on pathology, you don't really know, but when you use a drug that interferes with that and you show benefit, that gives empiric evidence that the innate immune system is indeed actively involved in the progression of the disease. So it's a little bit backing into it. And did this company take a bit of a risk going there? Sure, but I think the results show that, that risk paid off.

A second question company does another phase to.

We can barely hear you.

Okay. Can you hear me better now?

We can hear you. Yes, we can hear you.

Okay. So going forward, if the company is to do another Phase III there was a slight difference in the progression of the patients with the nonactive seeming to have a an improvement in symptoms before they began to progress but the placebo group obviously didn't progress at the same way as well. But would you recommend separating out be nonactive from the other group evaluated as a way to possibly increase the probability of success in a confirmatory study?

Okay. It was difficult to understand your question. Sorry to ask you to repeat slowly.

Sure. I'll repeat. When you showed the slide between the non and offer and the other group of valuations the progression of disease was slightly different, although unclear if those differences are meaningful enough so that if you go into another study, should you should you do a separate study for each group of patients?

Maybe first point, as you can see on the table, that is maybe relatively similar difference between the PPMS group and the non-active SPMS group, as you see, the difference between -- the difference are relatively similar. Maybe it's encouraging because we think that the pathophysiology of both groups are relatively similar, independent to the activity. So maybe it's not surprising for me that there is quite similar results there is minor change, I would like to say, of course. But as you know, the EDSS is not really a service to change. So I think clinically relevant, such a difference. Comforting, of course, by the ordinal change. However, I think it's encouraging. It's not surprising to see similar behavior of both population, I would like to say. Okay, from the sponsor perspective, this Slide 22 convince us to treat both populations. If we had to do a second study, we will do it in the 2 subpopulations. But it was 1 of the questions that we had in mind, whether if any positive data we had, it would be driven let's say, by secondary positive in active rather than primary positive or the opposite. Here, we have the answer. Both populations are actually treatable by masitinib and the data looks very consistent.

Ed, we don't have many trials that have enrolled both PP and SP, but where we have, they have also seen that the primary progressive patients progress a little bit faster than the secondary progressive MS patients. So this has been seen before. I don't think it necessarily requires doing separate trials, but it does require that recognize those different progression rates and include that in a sample size estimation. And then, of course, regulators will have an opinion about whether they can both be combined together, and how much power is needed to do a subgroup analysis?

And maybe I would like to add a major point that recently, a presentation and a paper in 2014, consider to pull together the progressive form of MS and to differentiate into this population of programs patients with activity and patients with no activity. I think it's a main criteria. When we have a patient with a progression, we need to consider either active or nonactive. And definitely, it's here the targeted population in the non-active progressive patients.

I agree with Patrick, along the lines of the new [indiscernible] ball criteria, it makes sense to combine these cohorts into one study, of course, taking statistical deliberations into consideration. I would like to emphasize another point in this regard. Patients were eligible in the absence of relapse activity prior to enrollment but were -- had to have disability progression as displayed by the EDSS. And this is something very important because this sets this study apart from, for example, the ocrelizumab trial where a progression -- a documented progression prior to enrollment was not a prerequisite. It was not an inclusion criterion. And this means that this trial successfully recruited active, not in terms of relapses and rate graphic activity, but active disease in terms of clinical progression prior to enrollment. And this is something very, very important also for the design of further trials.

Two more questions, if I may. One, in terms of enrolling, either the product progressive or the nonactive, it is one or are both more difficult than those would be infiltrating active form with users?

Sorry, I couldn't hear the audio. The connection was too bad.

Yes. I'll repeat, sorry. How difficult is it to enroll patients with the nonactive form of the disease?

Guess it's actually quite easy because we really don't have effective therapies for them. We don't have many trials that are enrolling patients in that stage of the disease. And so really, it's a big unmet need, and it makes it much easier to enroll into trials. In contrast, relapse or remitting MS, we have many, many, many therapies for that. And so enrolling patients into those trials tend to be much more challenging because we have good treatment options for them. So personally, I don't see it as a large hurdle. I'll throw it to Patrick for other thoughts.

Okay. Yes, maybe it's not very easy to recruit because there is no standard of drugs for this non-active population, so very easy even versus placebo because indeed, as discussed by Bob, we saw unmet needs, very easy to recruit even versus a placebo.

Okay. One follow-up question, if I may, and that's related to using EDSS, appreciating the DoD linear measurements here, the overall sensitivity that you use, do you think that, that will be a part of a future clinical trial that you might use you might -- the company might do as well?

Maybe first, that's true. That it's an issue. To use DSS because indeed, EDSS is not so sensitive to change. And during a 2 or 3 years period, we have quite a relatively small percentage of patients will really confirm EDSS change. However, maybe the authorities until now as always towards the EDSS. We try to have some other metrics, other parameters, but usually in secondary or tertiary endpoints, but not in the -- as a primary endpoint. And even in the near future, definitely, we need to consider the EDSS, but I discussed by Bob, the key point was how to select patients. And here in this study, definitely before inclusion, we have -- we need to have data telling us that really patients have progressed during the last year or during the last 2 years, which was the key point. The inclusion criteria are indeed a critical point for a clinical study in progressive MS.

We have other questions. We have other questions.

We'll take our next question from Sean Lee from H.C. Wainwright. Please go ahead.

This is Sean. I just had one on the 6-milligram per program cohort is the placebo arm that showed an improvement in EDSS scores. I was just wondering, maybe Dr. Fox, if someone ask could clarify, whether this is a common occurrence in the study trial or if you've seen before? What are your thoughts on the causes of this? And perhaps what strategies could be taken in the next study to mitigate this effect?

Yes. So we do sometimes see improvement in EDSS. Sometimes patients are actually getting better. Sometimes, it's part of the variability and limited reproducibility of the EDSS scale. It is a categorical by definition scale and the way 1 neurologist interprets that scale may be a little bit different from another or even the same neurologist from 1 day to another day. Seeing those changes, we do see from time to time. One of the challenges is that this was a modestly sized trial. It wasn't the 1,500 subject trial that we see in fully powered, fully vetted Phase III trials. And so there can be some noise and unexpected changes in a limited size group. So it is a little disappointing that, that is what happened. We are stuck with what is reported by the investigators in the group. I think the main solution is the larger numbers where that variability smooths out over time. There are additional ways to standardize the EDSS, how it's collected and how it's reviewed and verified. And so that is another way to help improve the veracity of the data that comes out.

Your next question from Brian Bakken from Barclays.

Apologies if this is address earlier. Can you help me understand why used EDSS as a primary endpoint and not BDP? Just trying to see how much I should read into the non-statistically significant 37% when comparing to ACREVUS?

Maybe not sure to fully understand your question. You ask why we use the EDSS as the primary end point. Because I think it's common in MS. Of course, in the relapsing-remitting MS, we consider the relapse rate but here, of course, there is only a few or even no relapse in such population. So for disability, it's the main point, of course, for these progressive patients. And the way -- the only way I would like to say consider by neurologists, but also much more by the authorities is to use the EDSS. Of course, there is many limitations for the EDSS, not really sensitive to change. You see in the presentation, we have quite relatively small number of events, even in the placebo group. So to show, of course, a significant difference between an active group and a placebo group. We did really to have a very effective drug. And here, we have significant data with masitinib, even if the EDSS is not changed to change, which is very encouraging for us because if we have other metrics to measure disability, probably we have a greater impact with masitinib. But maybe the main point is that the authorities ask to show data using EDSS and also its worldwide use by all the neurologist in the world.

From the sponsor perspective and regimentary discussion, EDSS is a gold standard and very difficult to do something else. However, there are different ways to calculate the change in EDSS. And here, in this study, we provided ready 4 or 5. The classic one is the time to confirm progression 3 months or 6 months, but which requires a very large population to obtain any significant data. And you can see in our study that with 300 patients, the time to control a EDSS cannot be significant, although the OR ratio is very good, actually, as compared to other studies positive. And the time to first progression is not really recognized. Although here, it's a progressive forms of MS. So it's not relapsing-remitting. And so maybe the first possession is already makes maybe more sense than in relapsing-remitting forms, but still. And this is why we came with 2 different approaches to calculate the evolution of the EDSS, one which takes into consideration the magnitude of the change in absolute value, the change in EDSS, but the very important point is that we don't measure it at a fixed time point at week 96 bearing the risk of the discontinued patients and everything, but we measure it 8 highs every 12 weeks around the period with the GE test that completely de-correlate everything which is correlated and the time, the retention of the variable, the -- any correlation is adjusted. And it really gives the true effect. So the GE is conservative, so to speak, in terms of calculating. And this is more or less never been done before, and it will be an interesting discussion with the authority. And then the ordinal change has already been done. We have not been the only 1 to provide this data in the studies. Usually, when it's given is given as a secondary analysis, not as a primary analysis, but still, it's not new. It has been already provided in other studies. We can refer to those studies. But -- and this is an advantage because you can [indiscernible] virtual probability, which is well understood by the physicians, by the patients. And here, we have a 39% probability -- increased probability with masitinib to have either more improvement because it exists or show worsening. So the way you calculate it is important. Here, we provide the 4. The good news is that it's completely consistent, but there are not enough patients for the time to confirm EDSS. With that, we have a package, and I think it's -- it will be an interesting discussion with the authorities.

[Operator Instructions] So we have no further questions on the phone at this time.

We can take some questions in writing. So the first question I have received is there since medicine is developed in several indications in neurology. Do you see a link between multiple sclerosis progressive forms, [indiscernible], multiple sclerosis and Alzheimer's disease? For this question, which is very important. Definitely, is also a neurodegenerative disease from the onset. And of course, this neurodegeneration is very important in the progressive phase. However, it's also related to inflammation. But what is interesting is accumulate data, not only in the next but also in ILS, for example. And we know that others science provides many interesting data, not only in MS, but in other neurodegenerative disease because inflammation at partially or importantly, is also important in many neurodegenerative disease. So of course, it's very good news for MS patients that we have also maybe promising data in disease like ILS, for example. ILS is also maybe a spinal cord disease, neurodegenerative is spinal cord mainly and also maybe it's great to have both studies ILS and MS because MS is also neurodegenerative disease. And we know the involvement in many neurodegenerative disease, the role of microglia, the role of mast sales also. So all the data go in the same way.

I, you want -- yes, I may add something. I think it's a very interesting question. And recently, our data and others suggest strongly that all of this knowledge in active disease may involve in innate immunity, which is quite difficult to assess sometimes, as we discussed before, if it is a cause of the consequences, we have developed several mice models of ILS, of Alzheimer and of MS. And in all of these models, when we do remove mast sell or when we do block mast cells and microglia by kinase inhibitors, we present how we slow down the progression of this disease and what we strongly believe today is that all of this immune innate cells may play a role in the physiopathology of most of the degenerative disease, regardless, the primary event of the disease might be a neuronal defect. It might be some protein aggregation, it might be some immune aggression by the adaptative immune cell, but at the end of the day, all of these aggressions may send some signaling to microglia and mast cells to and use and the activity, which in turn, may destroy the synapsis or the neurons or activate the microglia with the same consequences. So I think all of this neurodegenerative disease may have a common physiopathology, which is linked to the activation of a innate immunity. And we have a strong data in mice. And now in new months, we do see the same kind of results.

Thank you. We'll take the last question?

Yes, one last question. What makes masitinib different from all other kinase inhibitors out there, and we know that there are some other kind of inhibitor developed in MS?

Of course, yes, now because we accumulate data suggesting a PE role of microglia in MS. Maybe other companies already try to target microglia. We have some previous data suggesting to inhibit the Bruton Tyrosin kinase, for example, may also be beneficial for the patients. Myer Company, Sanofi, also try to accumulate some data suggesting it could be good for the patients. However, with such a drug by Merck or Sanofi already published and presented a Phase II. They also control the proliferation of B-cells. And so they don't demonstrate a unique role of a drug on microglia. And we have only masitinib doing that. So maybe the first time, the first drug targeting only mast cell and microglia with positive results. Now, however, it's a good symbol to look at the data accumulated by the other companies like Merck and Sanofi telling us that, of course, it's a very promising and encouraging target for many neurodegenerative disease, including MS.

[indiscernible], any insight on this new TKI.

No. I think you have said all, let's say, relevant details.

Okay. Well, time maybe to close this web call, I would like to thank all participants and the audience for sharing this time with us. We hope we addressed most of your questions. More will come, of course, to the CEFIC conferences and publications, and we'll put this presentation and [indiscernible] already on our website, if you want to go back to it to review it. Thank you, again, for your time. And we hope to have the pleasure to have other news in other disease. Have a good day or good evening.

Thank you very much. Bye-bye.

This concludes today's call. Thank you for your participation. You may now disconnect.