Roche Holding AG ($ROP)

[Operator Instructions] One last remark, if you would like to follow the presented slides on your end as well, please feel free to go to Work.com investors to download the presentation. At this time, it's our pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.

Thanks, Henrik. And could I have the agenda slide, please. So welcome to first IR event in 2026, focusing on the Phase III ENHANCE 1 and 2 results for fenebrutinib in RMS, which just got presented yesterday at AAN in Chicago. Today's call is scheduled for 60 minutes, and we will have our Rush team dialing in from Chicago. Let me quickly take you through today's agenda. We have 2 speakers with us. Following my opening, the first speaker for today will be Alexandra Goodyear. She is an MD and our life cycle leader for at Alexandra will provide a quick introduction to fenebrutinib and this molecule truly differentiates from other BTKs who have been in late-stage development for MS. She will also highlight again the positive Phase III [indiscernible] results for fenebrutinib and PPMS, which have been presented earlier this year at [indiscernible]. Our second speaker for today will be then [indiscernible]. [indiscernible] is an MD and PhD CPC, a Medical Director of [indiscernible] [indiscernible] program and associate professor and staff neurologist at the division of neurology at the at St. Michaels Hospital at the University of Toronto and the scientist at the Kenan Research Center of the La Cache Knowledge Institute. She is the lead offer for Enhance 1 and 2 and has been sitting on the study's steering committee. [indiscernible] will take us again for the positive Phase III enhance 1 and 2 results for fenebrutinib and RMS, which we presented yesterday at AAN. Afterwards, we will have a Q&A session. In addition to our 2 speakers, we will be joined for the Q&A session by Hideki Garen. Senior Vice President and our Global Head of Product Development for Neurology; and by [indiscernible] Gateway, our Executive Vice President and Head of Product Development and our Chief Medical Officer. And with that, over to you, Alexandra.

Thank you very much. I will take us through an overview of fenebrutinib's development program. Net slide. With the positive Phase III study data in RMS and primary aggressive MS, fenebrutinib has the potential for both first and best-in-class. And fenebrutinib has the potential to be acting on B cells and macrophages in the periphery as well as B cells and microglia within the central nervous system. And with this ability. We're hoping that fenebrutinib as seen in the Phase III that Dr. Erb will take us through is decreasing relapsing biology as well as progressive biology. And these 2 together are leading to overall decrease in disability accumulation. And with this, fenebrutinib has the potential to be the first and link high-efficacy oral treatment for both RMS and PPMS. And with this has the opportunity to increase high efficacy treatments for patients as well as expand the Roche MS [indiscernible] footprint. On the right-hand side, you see the fenebrutinib development program, where we have now had 4 positive trials in MS, including the Phase II RMS trial, the [indiscernible] MS trial and the 2 newly identical relapsing MS trials. Fenebrutinib has been studied in a large number of patients across the entire development program and data will be submitted for a filing midyear. Next slide. Here is the primary progressive MS data that Bruno alluded to that was presented earlier this year. On the left-hand side, we're looking at the Kaplan-Meier curve for a disability progression that was analyzed by the composite endpoint of CCDP Here, you can see that the treatment curves separate already at week 24, fenebrutinib being the blue line on the pad. And that separation of curves is maintained throughout the study duration. And with this, fenebrutinib achieved non-berry versus orolizumab in the only head-to-head trial of any antitherapy versus ocrelizumab. And on the right-hand side, you can see the breakdown in the composite disability progression endpoint. So the makeup was EDSS, Time 25 Walk and [indiscernible]. You can see that the most profound treatment effect was seen with [indiscernible] test, which is an upper end mobility test, very important formations for them to be able to maintain independence throughout their lives. Second, the -- followed by the effect on ESS and then Time 25 Foot walk. Notably in a post pug analysis that looked at the same composite endpoint that was used in [indiscernible], which was a contemporary [indiscernible] Phase III study of ocrelizumab versus placebo, which used the endpoint of EDSS and [indiscernible] test. When we look at that endpoint in the [indiscernible] study, we saw a 22% reduction versus [indiscernible]. Next slide. This differentiated data that we have been showing, we think is really stems from a unique structure and binding mechanism of fenebrutinib. On the left-hand side, we show the chemical structures of fenebrutinib as well as some of the other BTK inhibitors being explored in late-stage development for MS. And you can see that fenebrutinib's structure is very weak. We've highlighted portions that get into both the H2 and H3 pockets of the burgers in [indiscernible] kinase and allow it to buy noncovalently and very selectively. If we -- on the right-hand side, we see that we were able to achieve the selectivity that we were aiming for when designing this molecule. What you're looking at on the right-hand side is a panel of very similar kinases to BTK. BTK is the first row right at the top. We can see that fenebrutinib binds to BTK and a low concentration. And then if you -- and then really no other off target kinases until you get to very high concentrations. This compares very favorably to -- compared to some of the other covalent inhibitors, which we can see are hitting multiple kinases. So we're hoping with this that this helps improve the long-term safety outcomes with fenebrutinib. Next slide. On this fenebrutinib has high systemic exposure as well as CNS penetration. On the left-hand side, we're looking at pre plasma concentration curves and fenebrutinib being the red line at the top, you see achieves much higher concentrations over the whole 24-hour dosing period. And this really reflects the different strategies of having a noncovalent drug versus covalent drugs and then optimizing the noncovalent drug to have high exposure. And this is important so -- because the free plasma action is the part that is able to cross the blood/barrier in order to bind with myopia and the selling the central arises. And on the right-hand side, we are showing the data that fenebrutinib is able to achieve that. Forward looking at on that side is a human CSF concentrations of these drugs, fenebrutinib being the blue bar all the way on the left. Each drug has its own IC90, the concentration needed to inhibit 90% of the target. And we can see that fenebrutinib is able to cross the blood/brain barrier and be in concentrations within the CSF well above the IC90, which is really differentiated compared to the other BTK inhibitors as shown here. Next slide. I think that brings us to doctor who's the presentation of our Phase III data in RMS. Dr. Ho.

Thank you, Alexandra. So I will now with that back from you through the very recently reported results from fenebrutinib ENHANCE 1 and 2 nearly intial Phase III clinical trials evaluating the efficacy and safety of fenebrutinib and comparison to active imperative in 3M. Next slide. So Alexandra has already very nicely outlined this, but BTK inhibitors are of very high interest in the MS field because we know that BTK signaling is crucial to activation of both B cells and myeloid cells in the periphery and the central nervous system. And so we know that inhibiting BTK has the potential to address both relapsing and progressive disease biologies across the entire MS disease spectrum. As you've already heard, fenebrutinib is a BTK inhibitor that was uniquely purposefully designed. It is CMS penetrant, which is very important because we're talking about modulating both relapsing and progressive disease biology. We want to ensure that a drug that is active in the periphery can easily get into the central nervous system, which I ever do clear lead to. It's noncovalent, it's highly selective and importantly has an optimized PK profile, which is likely in large part of the reason we see a clear effect of fenebrutinib on relapsing disease biology that I'll tell you about in a second. Already in a Phase II clinical trial, the [indiscernible] study. Fenebrutinib demonstrated their complete suppression of disease activity in people with relapsing MS. And as you've heard, in the Phase III [indiscernible] study that evaluated fenebrutinib versus [indiscernible] and people with higher PS. Fenebrutinib demonstrated efficacy and that it was non-inferior in reducing the risk of composite and firm [indiscernible] progression. And in the post-talk analysis that Alexandra, where there was a modified composite endpoint, fenebrutinib demonstrated superiority and is postal analysis in comparison to [indiscernible]. Today, right now, we'll be focusing on the family as 1 and 2 trial results and the objective of these 2 trials was to evaluate the efficacy and safety of fenebrutinib in comparison to tariffing and people with relapsing MS. Next slide. So this was the study design of Fannyance-12, which were 2 largely identical Phase III multicenter randomized trials. As you can see, the inclusion criteria of our typical for what we usually see and contemporary relapsing MS clinical trials. People with relapsing MS were randomized in a 1:1 ratio to either fenebrutinib at 200 grams twice daily or the active comparator of [indiscernible] at 14 milligrams once daily, which is a very commonly used first-line world disease [indiscernible] treatment and relapsing MS. And at the end of the saying, they were given the option to continue with the open-label extension period. The trial went for a minimum of 96 weeks for each participant because it was an event-driven trial. And as you can see, study visits were done periodically as expected with both contemporary relapsing MS trials, and there were MRIs performed as well and of course, safety was evaluated for the duration of the study. Next slide. So the finer end point as expected because these were trials looking at relapsing MS was the annualized relapse rate. For key secondary endpoints, the key clinical disability progression endpoint, again, comps confirmed disability progression was used. And so this is an endpoint that consists of either BSS progression, which is the typical global neurological disability scale that we use in really every [indiscernible] trial. However, a participant was deemed to have [indiscernible] progression in either or the EESS test, which is a test, [indiscernible] or [indiscernible], which is a semiquantitative measure that measures ambulatory speed. In addition, key MRI endpoints were evaluated as well, which included T1 [indiscernible] enhancing lesions and the development of new or large T2 lesions. I wanted to note as well that as of any clinical trial, there was a statistical hierarchy and each of the endpoints that we discussed, it was prespecified that is [indiscernible] will Bruno [indiscernible] evaluated in each individual that enhance clinical trials. Separately, however, there was planned prespecified pools analysis of the disability, the composite confirmed disability progression end point and this is relevant when we discuss what was observed with respect to these secondary clinical end points. Next slide. So when we look at baseline characteristics across [indiscernible] 1 and 2, as you can see, clinical characteristics were quite well matched between treatment arms across the 2 [indiscernible] studies. And also just wanted to know when you look at the denim in MS diagnosis, and I'm just going to draw your attention to the fourth row down, and I know it's a very busy table, but it's very clear that this was a really early group of people with relapsing MS because the median time since diagnosis was 1 year. So really, a lot of these participants for early diagnosis. And similarly, when you look at the proportion of people who have previously been on disease modifying treatment, which is [indiscernible], as you can see, only about 15% to 20% of participants were previously treated. So the majority of these participants were within in Europe diagnosis as well as treatment naive. And so these points just illustrate that this was a very early population of people with relapsing MS. Next slide. So when the primary end point was evaluated, as you can see, fenebrutinib very clearly substantially reduced the annualized [indiscernible] rate versus teriflunomide in both [indiscernible] 1 and 2, and it was a substantial reduction. And as you can see, the reduction -- the relative production was 51% and 58% in FENhance 1 and 2, respectively. Next slide. When you look at Denver subgroups, as you can see, generally, the treatment effect was consistent across different so [indiscernible]. However, in people who were younger and had a lower time since symptom onset as well as the those who had [indiscernible] enhancing nations and those who have less disability, it seems that the treatment effect was accentuated. So overall, it seems that the treatment effect is consistent, but not really surprisingly and those who are earlier aligning the disease course, the treatment [indiscernible] to be accepted. Next slide. Moving on when key secondary MRI end points were evaluated as with T1 gadolinium-enhancing fenebrutinib very clearly decreased T1 gas lesions versus teriflunomide at 70% as well as 77% in FENhance 1 and 2, respectively. Not surprisingly, when you were in large 2 regions were evaluated as well as you can see fenebrutinib clearly reduce the formation of or enlarging T2 lesions in comparison to teriflunomide by 76% and 82% in FENhance 1 and 2, respectively. Next slide. Now when [indiscernible] disability endpoint was [indiscernible] in each individual trial, as you can see, although there was a consistent trend towards favoring fenebrutinib in [FENhance 1 and 2, the confidence in oral still slightly over last one. However, when the pooled CCEP endpoint was evaluated across both FENhance 1 and 2, as you can see, the confidence interval did not over 1 and is favored fenebrutinib. Similarly in that [indiscernible] CCDP analysis, which included only EBSS and [indiscernible] test, and just as a reminder, as [indiscernible] said, this was the point that was actually recently used in the [indiscernible] trial. As you can see, you see similar trends. Consistently, there is a trend favoring fenebrutinib with this modified CCDP on quite as well. And then when you look at the pooled analysis, you can see that there is a clear treatment effect with the confident [indiscernible]. Next slide. Moving on. When you look at the treatment effect of the individual components of the CCDP measure, so this composite measure, as you can see, first, the greatest number of events was related to changes in [indiscernible]. However, when you look at the treatment effect of individual components of the CCDP score, it really was the 9-hole peg test that seemed to have the strongest treatment effect of fenebrutinib versus [indiscernible]. So this is interesting and probably informative about the CCDP measure because a sense treatment effect is greatest with the 9-page test, but the most frequent events that were observed were with the [indiscernible]. Next slide. Moving on to safety. When you look at the overall safety profiles, these were generally comparable panini and fenebrutinib [indiscernible] with rates of any adverse events as well as serious adverse events and adverse events leading to withdrawal for treatment. However, there was an imbalance in fatal adverse events with 7 fatalities observed in fenebrutinib treated participants and a single [indiscernible] treated participants. However, looking break down and take a look at each of these individual fatalities, and we'll do that on the next slide, it's reassuring because there was no clustering of pauses that seem to suggest that there is some signal related to fatalities in fenebrutinib, and we'll work out that in detail on the next slide. Also wanted to highlight, obviously, with any immunomodulatory treatment, there is some concern about infections and you go to the serious infections, and it was reassuring has FENhance 1 and 2, a proportion of people who've had any infection was similar between treatment arms. And importantly, the proportion of people who had any serious infections was similar across treatment arms between fenebrutinib and teriflunomide, which was [indiscernible] to see. Getting that to the fatalities. This is a table that Sunrises all of the fatalities seen across the FENhance 1 and 2 clinical trials. So the first 7 cases are fatalities of participants who were on fenebrutinib and that final pace listed here is the fatality that was observed in a participant was on [indiscernible]. So a couple of things. First of all, it's reassuring that there is no clear clustering of events that's related to something that potentially could be related to our mechanism of action that you know of fenebrutinib, which is a BTK inhibitor. And of the 7 fatalities that were served on fenebrutinib treatment participants, most of them were considered to be not relevant to timber, but 2 of the pieces were deemed to be likely relevant to fenebrutinib. And these were the 2 infectious cases, which included our participant who had pneumonia as well as the participant who had [indiscernible]. However, with both of these infectious cases, it's important to note that there were complicated other contributing factors. With the case of pneumonia, the family actually declined hospitalization despite the physician recommending this. And with the [indiscernible] case, probably some people may not be familiar with the this bug, but this is a bug that is endemic to some regions in Latin America often related to [indiscernible] exposure, which was the case in this particular participant. And this is a bug that can actually cause even in immunocompetent individuals [indiscernible]. As you can see with the other fatalities that were served in the fenebrutinib treatment arm, there was adhesive intestinal ischemia, a case of hemorrhagic stroke, a case of death, a case of suicide, [indiscernible] a case and other [indiscernible]. So overall, these other debts were not considered to be relevant by the study [indiscernible] to fenebrutinib. And generally, it seems that when you look at these individual cases, it's reassuring that there is no clustering during new events that raise in replaced might be related directly to fenebrutinib. Next slide. Liver Safety, as you know, is a signal that we need to pay attention to with BTK inhibitors because a number of BTK inhibitors have shown that they can cause liver enzyme elevations. So while we look at this FENhance 1 and 2, as you can see with any liver enzyme elevations, 3x on a the upper limit of normal, the proportion of individuals that have this lose or across treatment arms and was in keeping what has been seen with other BTK inhibitors that have been evaluated in Phase III clinical trials. Of note, there was only a single [indiscernible] case in a fenebrutinib treated participant as informed by the hepatic adjudication coma. And there was also a single high [indiscernible] case in the [indiscernible] arm that was confirmed by the hepatic adjudication committee. And it's important to note that with all of these liberations, these were all the [indiscernible]. Next slide. So to conclude the results of FENhance 1 and 2 demonstrate that fenebrutinib is clearly superior to teralunamine in significantly reducing relapses as well as disease activity on MRI, demonstrating that there is likely a substantial impact of fenebrutinib on relapsing disease biology in MS. With respect to the disability metrics, there was a consistent track favorites fenebrutinib over [indiscernible], which, together, when you keep in mind the results of entrapped, suggests that fenebrutinib has also an impact on progressive disease biology in MS. For safety, the rates of adverse events were comparable, including [indiscernible] level elevations as well as infections. There was an imbalance observed in is, but we've gone over each of these in detail. And overall, it seems to be reassuring that, again, there is no clustering causes of fatalities that seem to be relevant to the known mechanism of action of improve. So keeping together these results demonstrate that fenebrutinib is the first BTK inhibitor to show clear efficacy on relapsing disease biology versus an active comparator. And again, when we bring into this, the results that we've seen with [indiscernible], fenebrutinib is the first and only world treatment option to demonstrate efficacy across the entire MS disease [indiscernible]. Thank you very much. And I will just hand that over to Bruno.

Thanks for the presentation. And with that, I think we open the Q&A. The first questions go to Luisa Hector from Berenberg. Luisa?

Great. Thank you, Bruno, and thank you very much for the call. I would love to hear Dr. Oh Just in terms of now that we've got all of the data in but who are the patients that you feel should be on fenebrutinib, where you're positioning it both in the relapsing and the progressive group.

Sure. So I think FENhance 1 and 2 has [indiscernible] very clearly demonstrate that even in very, very early, active elastin MS patients, this is a drug that has a very profound effect on clinical and MRI measures of relapsing disease activity. In fact, the effect that we see is akin to our currently available highest efficacy therapies. So definitely, the nature of that is suitable in early relapsing MS, which was the trial population in FENhance 1 and 2. However, based on what we see in fenebrutinib, it's also clear that it is not inferior and there's good suggestion that based on what we know about the drug and the mechanism of action and the fact that it gets into the central nervous system and the magnitude of benefit that was seen in fenebrutinib, this is a drug that is at least not interior, maybe even better than our only available agent in PPMS. So taking together all of this and the fact that in the field as clinicians, when we think about relapsing MS, we know that both relapsing and progressive disease biologies are play across the spectrum of the disease, which includes PPMS, but also many different stages, if you will, of relapsing MS. So this is to say that based on what we see across the entire fenebrutinib clinical development program as well as what we, as physicians and scientists are thinking in the field right now about, it seems that this is a drug that is likely will be useful across the entire spectrum of MS. Even people with relapsing MS who are clearly having progressive components of disease because of what we see in [indiscernible].

Luisa, does it answer your question or you have a follow-on question?

Yes. Can I then ask do you see yourself choosing whether to start a patient on fenebrutinib or [indiscernible]? Or is there a sort of sequencing that seems obvious to you now the data in hand?

So treatment decisions are always pretty individual, but in certain people -- so there's always medical preference of that patients have for mode of administration and frequency of therapy. However, in the end, as with those pieces, it all depends on the individual patient. But the benefit that [indiscernible] we have over a drug biopolisumab, which is a very commonly used drug, as you know, in the MS field is that it may have a clearer effect on progressive disease biology. So although with the pure relapsing component of disease, I think we would use both drugs in a similar fashion. If there is a relapsing MS patient that clearly has evidence of progressive disease, which we see in the majority of people with relapsing MS, even in the earlier stages of disease, it may make sense to use a drug like fenebrutinib because we know that it had an effect on relapsing as well as progressive disease biologies.

Very good. Next question go to James Gordon from Barclays.

James Gordon from Barclays. A couple of questions, please. First question was assuming Funny does get approved for RMS and PMS, how do you think the label might capture any potential liver infection or suicide profile of the drug? And how would that impact uptake? Are there what sort of the precedents for the drugs, which you could think about, which had similar profiles in any of these attributes and how did that impact uptake? And maybe just squeezing in 1 other one. I've been asked by some people like in terms of suicides, could there be a mechanistic explanation? Or do you think it would be noise? How to think about that, please?

Maybe I'll start just high level on the label, you might expect this, but it's too early to comment. In fact, we're -- as you know, when we're submitting the entire data package as a composite package to the FDA by midyear, and we'll go through the process thereafter. So it's too early to speculate on the label, I don't mind not say. But first, with the other aspects, I'll turn to our Juan or others.

Bruno, could you mind repeating some of the key aspects there. It was a bit hard to hear here on what aspects you might want Dr. Oh myself to elaborate on.

James, can you, sorry.

I'm assuming you can still hear me.

can hear you, yes.

I've been asked about a couple of attributes. So 1 was about the liver profile, one was about a potential increased risk of infection and then whether it's connected or not, but in terms of suicide profiles. So there are other MS drugs that also have some of these things. So if some of those were -- we'll see if they are some of those were reflects on the label, how would that impact how a doctor might go about using a which has both volunteer liver infection or suicide?

So perhaps Dr. Oh, you'd like to start on how we would use the drug and how does that impact using ratio?

So Liver at time monitoring is something that most immunologists are very familiar with. And with probably almost all of our existing drugs, there's different schedules that we use for with enzyme monitoring. And even going back to the days of the old [indiscernible] beta agents, this is something that we're [indiscernible]. The liver monitor -- liver enzyme monitoring protocol and then enhance 1 was every 2 weeks after initiation of study drug. And it seems like with all of the pieces that were observed is really within 20 weeks that we may see liver enzyme elevation. So overall, I mean, I'm not sure exactly what the label will say and obviously, these discussions what we had in the next little while. But is probably expected that there will be a requirement for liver enzyme monitoring somewhat frequently, but this will be time limited. So as a clinician, it's -- you don't ever want to be doing some sort of intense monitoring forever. And every 2 weeks, it is relatively frequent. However, I think this goal will be very manageable in clinical practice because it's time limited. And again, this issue of liver enzyme monitoring is something that we do with almost all of our current MS therapies, so something that is pretty familiar and that many MS [indiscernible] are quite accustomed to. With respect to the question about infection, I think the results from the [indiscernible] Fenner clinical development program are actually quite reassuring. In FENhance 1 and 2, when you look any infections and particularly any serious infections, there really be wasn't a difference between fenebrutinib and [indiscernible], which is reassuring. But obviously, this will continue to be lined in the open-label extension. Finally, with respect to the cases of suicide that Mercer, many of these cases did have some founding factors. But obviously, this is something that we will need to make attention to. There have been precedents for this with respect to MS disease borderline treatment. Again, back in the days of the interferon beta agents. Beta [indiscernible] actually did have a signal for this. And so this is something that obviously clinicians will have to keep in mind and probably will have to have some calcium with patients with were in. I think we also need to keep in mind that with these cases that were observed, there isn't really a biologically plausible mechanism by which fenebrutinib or BTK inhibitors in general might do this. And so really need to delve deeper into the cases and to continue to mine to understand this, but also need to keep in mind that in MS depression is very, very common and seen in 50% to 80% of people even at the very beginning of the disease. So there are a number of complicating factors here that may get unclear really if this is related to fenebrutinib. And then there's other reassuring pieces of data that [indiscernible] fenebrutinib has been studied in other autoimmune conditions, and they are really was not any suicide signal that was observed. And in the Phase II [indiscernible] trial as well, which is obviously a smaller study. There really weren't any cases observed. So this is something that we need to continue to monitor and offtake lightly. However, it's really not clear whether these cases were really related to fenebrutinib.

If I could just jump in, just to say that for Roche and [indiscernible], patient safety is extremely important. It's the #1 concern we have. And of course, we want to work with regulators to make sure that they are safe while getting the truck patients who is possible. We do want to have that in these 2 studies and the PPNR study as well, patients with suicides were not excluded as part of the study. And as Dr. Oh mentioned, and other studies offside of fenebrutinib, we have over 60 patients where [indiscernible] was not seen.

James, did this answer your questions on the potential safety profile and how you would manage it in practice?

That's great.

Next questions go to Alex Ebeling from UBS.

Two, please. First on liver enzyme elevations. So here there were lower in the FENhance 1 and 2 studies relative to the FENhance 1 and 2 [indiscernible] study. I'm wondering what you believe is the reason behind this? Do you think it's related to the age of the patients enrolled or anything else? And second question on 1 of the deaths. I was just wondering if you could provide any more color on the fatality from neurotics at I mean the slides state that the pathogen and you said that it can cause serious infection even in immunocompetent patient, but the death was related to fenebrutinib. So what gives you confidence it's not a signal of excessive immunosuppression?

Sure. So I'll address the [indiscernible] issue. So I think it's always difficult in study settings to know definitively what is related to a study driver or not. And because of what we know about the mechanism of action of BTK inhibitors, they are an immunomodulatory agents. And this is the case for all MS disease modifying treatments because you need to modulate the immune system to show an effect in this disease. If there is an adverse event that plausibly is related to the mechanism of action of a drug, this is when it's deemed by the study site investigator usually that it is likely relevant. And so it's not surprising that the fatalities that were related to infection [indiscernible] exactly what we know about the mechanism of action of the drug was deemed to be likely related to fenebrutinib. And of course, there's a lot of rationale behind why this would be the case. With [indiscernible], we talked about how it's endemic and it can even in immunocompetent post cause serious infections. I think that's one piece of information that's reassuring that fenebrutinib is not a drug that causes substantial immunosuppression so that you'll see these somewhat [indiscernible] infections. However, I think it's reassuring that there aren't other opportunistic infections that have propped up in this pretty large clinical development program. In addition, I think we need to keep in mind also when you look at the totality of infections, in particularly, serious infections across the fenebrutinib clinical development program, which also included older patients with PPMS, there really wasn't a different scene with respect to serious infections. So although it's a rare infection and potentially can be related, when you look at the totality of the [indiscernible] observed with respect to infections, which is obviously the adverse event that we tend to pay most mentioned to, it doesn't seem like there is some signal for severe immuno compromisation as well as opportunistic infections.

Thanks, Dr. I'm happy to take the question on on PPMS liver enzyme data versus RMS. And you are correct that there is a big difference in gauge of the populations that we studied in the RMS study versus the PPMS study. In the RMS population, the average age was approximately 35%, 36% versus in the primary progressive MS trialing, which we enroll patients up to age 65, and the average age was 49. So you're correct that age does play a factor. And also it is a signifier of also the increased comorbidities that you see in the PPMS population and polypharmacy that you see in the PPMS population -- and older population. So it's probably those 3 things together gaming comorbidities and comments that are really contributing to that. So we found that surprising to see that difference between the RMS and PPMS populations.

Alex, did we answer all your questions?

Yes. Great.

Let's move on. Next question go to Sachin Jain from Bank of America.

A couple more on safety from the of side and then 1 for Dr. Oh. So maybe if you could just provide any color on your FDA interactions around safety. As you can tell from the corn investor is clearly worried by the safety profile and approvability. Just wonder how you would frame your dialogue with the regulator, I'm assuming, on going around the safety issues that have come up? And then the second question is, as we think about what questions the FDA may ask on a potential outcome, just wondering what additional work you can do prior to submission to address what questions you think they may ask on suicide and infection would you present in that data? Because obviously, we've only got limited information on the infection and suicide allergy so far? And then how you're thinking about post-marketing commitments as you put the package together. So those are the questions for Rosh folks. And just 1 simple 1 for Dr. Oh. The PPMS at will be unique to fene within the BTKs. To what extent does that data influence your potential adoption in RMS?

Would you like to start?

Sure. So in the MS field as clinicians, we're recognizing more and more that the current classifications that we have of MS are not adequate nowadays just because when we designate someone, we often simultaneously very early on in disease clinical and when you have the tools imaging evidence of progressive disease biology. And then in progressive MS that PPMS is considered to be probably the most purely progressive form of MS, we often see evidence of relapsing disease biology as well. So because of this, we know that MS is a disease continuum. And having the totality of the data available for fenebrutinib where it really has gone from really early relapsing MS all the way to the most purely progressive form of MS, which is PPMS and to demonstrate a clear effect across that spectrum. That is what gives us reassurance that this is a drop that probably will be beneficial from the beginning to kind of the very later progressive stages of disease. So from kind of a clinical standpoint, it gives us reassurance that individuals will likely benefit from fenebrutinib probably for different reasons across the entire spectrum of disease. The issue though, of course, is that, in the real world, usually medications are approved for specific indications. And so when you have an indication both for PPMS as well as relapsing forms of MS and within relapsing forms of as clinicians tend to be pretty liberal with what we designate as relapsing forms of that because, again, we know that relapsing disease biology happens across the spectrum as is progressive disease biology. This just gives us flexibility to use the drug, again, pretty literally across the spectrum about us.

Thanks, Dr. Oh. And we appreciate the interest in how things are going with the FDA. Of course, we are evolving at the typical processes for interactions with the FDA and health authorities, we are very early in that process. As we've shared previously, we did share in the top line data with the FDA right away following our data readouts. And currently, we are in the process of putting together our filing dossier. So we're in contact, but it is early to comment on that before we are in formal in the final process. Liva, is there anything you would like to add to that?

Sachin, did this help?

I guess the second question was just what additional work do you plan on doing around the sociality infection? And would you present that at some point?

Thank you. We, of course, have an ongoing open-label extension study in which we are following the patients from the original Phase II [indiscernible] study as well as the relapsing studies and the primary progressive study, we are rolling all of those patients in an open-label extension study. including patients that were originally on the active comparator and have now switched to fenebrutinib. So we think that will be very enlightening on confirming or repeating the signals that we're seeing in the double line treatment period. Whether or not we need to do post-approval commitment studies, there will be something determined in filing, that would, of course, be very typical for MS drugs. Most if not all of them have a post-approval commitment side. What those will be will come out in -- during the filing process.

Let's move on. And the next question going to Peter Verdult from BNP Pariba.

Peter Verdult here from BNP. Two questions. So Alexandra or live. I know your focus right now on the filings, but if you allow me just to look ahead, is there any future clinical development that you want to do with Fannie in SPMS within MS or any indications beyond MS? That's question 1. And then Dr. Oh forgive me. So just returning to the first question, but pushing you for maybe a little bit of numbers. But assuming fenebrutinib is approved end of the year, can you give us some ballpark numbers in regards omitting MS and PPMS in terms of what proportion of new or current patients would you consider starting on Fanny or switching? If I could push you with some numbers, that would be appreciated.

I'm happy to start talking about the future fenebrutinib development began. We are exploring different opportunities because of [indiscernible] and kinase is an excellent target for many autoimmune diseases. So we are exploring where that could fit well with the Roche portfolio. Within MS specifically, we at Roche feel very much like Dr. Oh. MS is one disease, and there is relapsing and progressive biology in all patients starting from very beginning. So medically and clinically, we think we have the data necessary already to really guide physicians on use of fenebrutinib in clinic. So at the moment, there is no plans for SPMS study.

I can add with that. I think Dr. Oh ,and also said this very well. certainly, there may be additional studies that we would do. For example, the [indiscernible] there have been conversations about [indiscernible] we're buying understanding of the difference between the inflammatory component and the progressive components. So there may be other things we can do to fully elaborate that and the mechanisms that are happening and that may help inform in practice, the conversation about which -- whether to use fenebrutinib, for example. But from the same point of additional states in subtypes, fully agree that we don't think that will be indicated.

I can answer the kind of all our numbers for treatment cases. So these are really, really all part numbers. But when it comes to choice of treatment when a patient is treatment naive, so newly diagnosed, I think very clearly, the field is evolving to start with high-efficacy treatment in almost everybody with a new diagnosis of relapsing MS from the beginning. And what we currently have now that is probably the most widely used treatment in general are the anti-CD20 agents, and there's a number of them. But fenebrutinib would very early be a choice that patients would make from amongst these high efficacy treatments against relapsing disease biology. And that choice is often made by patients to be honest, just because people have very like strong preferences about mode of administration and how frequently they need to get therapy. Some people just really want to be on oral therapies and don't want to think about having to go into an infusion center and needles and all of this. And then some people like the from just having to go somewhere once every 6 months and not having to [indiscernible]. So probably in a decent proportion of newly diagnosed people with MS, fenebrutinib would be a very good drug because it has high [indiscernible] MS relapsing disease and we have excellent evidence in the field demonstrating how important it is for most people from the very beginning of the disease to start treatment with high efficacy against relapsing disease activity, which tends to be the dominant driver of disease in very, very early stages. I wanted to add to that, though. In people who, even from the beginning of disease, clearly have evidence of some progressive components of disease, fenebrutinib will then be the treatment of choice because you have the benefit of having the agent that has very high efficacy against relapsing disease, but also has an effect on progressive disease mechanisms, particularly when we take into account what we know about the drug, which is that is it easily gets into the central nervous system. And what we know from the [indiscernible] trial, where it was non-inferior to oprolizumab, but there is a clear suggestion that there was a benefit on these progressive disease processes in the [indiscernible] trial. With respect to agents who are switching, reasons where in will vary quite a bit. But again, given what we are understanding in the field that current thing we have any people on high efficacy treatments, and they demonstrate clear, but it is a slow progression over time. Fenebrutinib would probably be the first treatment option in that set. So for treatment sequencing because we're reassured that it is very potent against relapsing disease activity, but again, has that benefit of targeting progressive disease mechanisms that many of our current therapies cannot really do in a meaningful way. So ballpark figures, I'd say in treatment naive probably 30% to 50% of people would consider starting on a drug like fenebrutinib so long as the safety profile is similar to what we used with the current high-efficacy treatment options. And that in many switch is, obviously, not necessarily switches related to family planning or tolerability, things like that, but many switches can be related to efficacy. In fact, I'd say probably 50% to 60% of switches tend to be related to efficacy. This would be a very natural probably 1 of the top choices. So I would say over 50% of people in a first switch setting would probably consider a drug like fenebrutinib given what we've seen with the clinical trial data as well as what we know about medicine.

Sorry, I mentioned you got a lot of ballpark numbers here for your model, Peter. Any additional questions or...

Well, I could try my luck and say do it again through PPMS, but I will be cheeky. So I'll refrain and let the next person ask that question or do something else.

Okay. Very good. Let's move on. Next question will go to James Quigley from Goldman Sachs.

I've got a couple of follow-ups as well here. So on the suicides, I mean you've been pretty clear, you don't think there is a biologic rationale for BTK and driving potential suicide ideation, but did you take any measurements of mood changes or changes in depression levels as part of the adverse events monitoring for FENhance of [indiscernible]? Did that data give you any more confidence that there is no or very low suicidality risk? And the second question for Dr. Oh, how do you compare the disability progression data across trials? Obviously, taking into account the limitation of cross-trial comparison, but in the Kesimpta trials versus Aubagio, there was a 34% benefit in CDP EDSS score of fenebrutinib, but when we look at the CDP EDSS, the benefit was around 19% to 23% and across both the trials and then also in PPMS, the numerically higher reduction versus [indiscernible] as you said. So how do you extrapolate these data through to the MS population -- the RMS population when you're thinking about disease and disability progression?

I will start with the question about mood in the trials. As was stated earlier, we did not have this previewed as there had not been any signal of depression or suicidality in our early phases of studies. So the Phase III study was not set up in order to evaluate mood. There was -- we did not have a mood scale there. Going forward, there was a question earlier about whether or not we would be doing future studies to evaluate this. If we were to do so, perhaps including a mood scale to be able to evaluate depression and evaluate whether it gets worse would be something that we would consider. That is not being planned now, but throughout our filing processes if such a study came forward, including an mood scale would be very appropriate. We did have the CSSRS scale as is recommended by the FDA for any neuro treatment that's in development. And there, there we saw -- it's not a depression scale. We thus to a silo animation to evaluate that. And in the CSSRS scale, we did not see any clear trend in suicidal ideation. So you would kind of think mechanistically that if there was -- if there was a biologic reason for this, that you would see patients reverse in an ideation, confusion versus behavior. And this we didn't see. We have these rare events, but we don't have a clear signal on suicidal ideation. So to us, this shows that there are gaps. And so perhaps we would include, as you suggest, we have some indicators in major studies, but we don't have that data today.

And I can address the comparing disability progression across the clinical trials. Well, we're always tie in school to never compare best clinical trials. And particularly with disability of impression, it's tough because there really is a period effect related to clinical trials these days. When you looked simply at relapse rates in the placebo arms of relapsing MS clinical trials in the past 2 decades, you see a dramatic decline over time. And this is directly related to the fact that our diagnostic criteria continues to evolve over time, more widespread availability of MRI and kind of [indiscernible] an MRI criteria required to come to a disease of MS. So Overall, this has really resulted in the face of MS being completely different from what it was actually 2 decades ago. And so what we know is that we're in clinical trials, we're proving mild and -- milder and milder population of MS. And this is reflected in the baseline characteristics of the FENhance clinical trials where generally, the average age is similar. But clearly, people have less disability and are really within a year of MS diagnosis in these clinical trials. So already, you have a milder MS population. And so with that, it becomes harder to detect disability progression when people are still early in their disease course. And so this is why it's called taking care disability progression, which is the harder measure by far in comparison to the clinical measure [indiscernible]. It's very challenging to compare that across clinical trials. I also wanted to note that in contemporary clinical trials, we do see this issue of problems detecting differences in disability progression, even though we know clearly, these are drugs that have a profound effect on relapses and therefore, should also have effect on disability progression. Take, for example, the plituxima Phase III clinical trials, which were the [indiscernible] anti-CD20 clinical trials, where very clearly, there was an effect, a profound effect on BLS disease activity clinically. But you don't see that corresponding effect on disability progression, and this is similar to this temporary to the study population of fenebrutinib. So all this to say, I think it's really acknowledging to look at numbers and try to compare across clinical trials because of this evolution of Mike the mild or use case population. And so would be a disservice to draw conclusions based on just that magnitude of that disability progression, which is already a very challenging measure.

And I just want to add, I guess, probably agree about crosstalk compares have had lots of palaces. It's important to note [indiscernible in study we compare. So we've been the relapsing MS compared to [indiscernible], which has already shown a demoing benefit of 30% of the in the past and our divides competitors ales where we have shown 24% visibility improvement credit foreseeable. It's already in our studies, we have raised the bar in terms of measuring slow progression.

Very good. Okay James, to answer all your questions?

Yes.

Next question is go to Stephen Scala from Cameron Stephen.

Congratulations on the data. I do have 2 questions, but they are both on safety. So first, Dr. Oh, I'm just curious, have you ever seen a trial in neurology with such a significant adverse SKU in deaths and have it just be a random finding and that, that drug was ultimately approved despite that finding? And then the second question, perhaps to the Roche folks, was the liver monitoring instituted while the trial was already underway? And if yes, how many liver enzyme elevations were observed before that implementation and how many were after that liver function monitoring implementation?

I can start with that right away. You're very [indiscernible] in remembering that this was implemented during the clinical trial process. We started all 3 of the Phase III studies with monthly monitoring. And at the time that we implemented the change to every 2-week monitoring, we had well recruited in the study and we're over 50% recruited. The PPMS trial was probably over 70% recruited at that time so that the data that we're looking at in terms of liver enzymes is predominantly collected with the monthly monitoring. Once we implemented the every 2-week monitoring, we did see a shift in detecting the liver elevations earlier. So we -- which also gives us the reassurance that our our every 2-week monitoring is working. After we implemented the every 2-week monitoring, we did not see any further high elevations. And of course, the single-line locate occurred while on the monitoring in place.

I can address the question about deaths. So I don't know all the numbers by heart. But in recent memory, I don't think I have seen an MS Phase III clinical ride with this significant imbalance, this magnitude of an imbalance in deaths. However, I think these rare, but serious events, by chance, can result in these imbalances that we see. And so this why it is so important to tear each and every single pace to see if there is some possible mechanism that may be relevant to fenebrutinib. And as you saw from the FENhance data as well as the [indiscernible] data, there really isn't any sort of clustering of events. It is a little bit odd that there is this just based on sheer numbers alone and imbalance. But I think the most responsible thing to do is to tease apart every single case. And overall, there didn't seem to be that is relevant to what we know about the mechanism of TK inhibitor. So obviously, this will need to continue to be evaluated, but the short answer is no, I have not seen and any recent Phase III trial with the similar magnitude of deaths.

Then we go to the final questions. Finanl questions go to [indiscernible].

A question on the subgroup analysis. Do you have any idea of why prior [indiscernible] use could be beneficial for fenebrutinib treatment? And could this data be informative for the real-world sequencing of therapies, which indeed will be a bit contradicting to your prior comments that fenebrutinib would be ideal for naive patients?

Perhaps I can just comment before handing this to Dr. Oh, that, of course, the -- as Dr. Oh described in in the baseline characteristics, patients previously treated with DMTs was a very small proportion. And because of that, we have to be cautious when making inferences there that their confidence in the rules around that group are large. So just reminding us that that's actually a small data set, which we were not powered to make conclusions that Dr. Oh, any further comments?

No. I mean I think it was really only 15% of the entire setting population that contributed to that. So I completely agree. I think we just need to be cautious about which other analyses are more meaningful. There is just based on first.

Excellent. I think with that, we are at the end of our call. I would like to thank again all of our speakers for their time and their efforts exploring new treatment options for MS patients. Let me also thank the our team members who worked on the slides and prepared the event to call out here, Alex Mora and [indiscernible] Karl and also [indiscernible] Lloyd for event organization. I hope event was helpful providing a timely update of our MS franchise. If there are any remaining questions, please reach out to the Roche IR team. We will be happy to help. And otherwise, we bet meet again soon at our Q1 results call tomorrow or on 1 of the roadshows on Friday. With that, we'll close the call. Have a good evening. Have a good day. Bye-bye.