My name is Marek, and I'm the technical operator for today's call. Kindly note that the webinar is being recorded. I would like to inform you that all participants are in listen-only mode during the call. After the presentation, there will be a question-and-answer session. You're invited to send in questions for this throughout the entire session using the Q&A functionality of Zoom. In addition to that, you may also raise your virtual hand to address your questions verbally.
For participants joining via phone, to raise your hand, use star nine on your phone's dial pad. When you then get selected to ask your questions, please follow the instructions from the phone and press star six to unmute yourself. One last remark: if you would like to follow the presented slides on the internet as well, please feel free to go to roche.com/investors to download the presentation. At this time, it's my pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.
Thanks, Henrik. Could I have the first slide, please? So welcome to our first IR event in 2026, focusing on the phase III FENtrepid results for fenebrutinib and PPMS, which just got presented last Saturday at ACTRIMS. Today's call is scheduled for 60 minutes. However, in case we would need a bit more time, we can go over just to make sure that we can take all your questions. Let me quickly take you now through today's agenda. I will start today by providing a quick one-slide wrap-up on our Ocrevus franchise before we will dive into our MS pipeline and the latest exciting data presented at ACTRIMS. Following my introductory remark, the first speaker will be Hideki Garren, Senior Vice President and our Global Head of Product Development for Neurology.
Hideki will provide an MS pipeline update focusing on fenebrutinib and how this molecule differentiates from other BTKs in late-stage development. He will also provide a summary on the phase II RMS data for fenebrutinib, which have been very consistent with the phase III FENhance 2 data, which we plan to present at an upcoming conference once we have FENhance 1 results in-house.
Hideki will finish his presentation with highlighting also our early-stage clinical pipeline in multiple sclerosis, where we explore new drug modalities and new drug targets. Our second speaker for today will be Dr. Amit Bar-Or. Amit is an MD, FRCPC, Director of the Center for Neuroinflammation and Experimental Therapeutics, and Chief of the Multiple Sclerosis Division of the Department of Neurology, Perelman Center for Advanced Medicine at the University of Pennsylvania.
He's a member of the FENtrepid Study Steering Committee, and he's the lead author and presented the data last Saturday at ACTRIMS. Dr. Bar-Or will take us again through the phase III FENtrepid results for fenebrutinib and PPMS. Afterwards, we will have a Q&A session. In addition to our two speakers, we will be joined for the Q&A session by Alexandra Goodyear. She's an MD and the lifecycle leader for fenebrutinib within the Global Product Strategy Team for Neuroscience.
Could I have the next slide, please? So before we get started, I just wanted to quickly summarize the latest information provided on our Ocrevus franchise. I thought this makes sense, as with fenebrutinib, we are now really excited that we potentially will have another medicine available for multiple sclerosis patients following Ocrevus, which was the first ever CD20 launched back in 2017 and which revolutionized the MS treatment paradigm.
As you can see on the left side, Ocrevus remains the number one new-to-brand medicine with 450,000 patients being currently treated. It's important to keep in mind that Ocrevus is the first and only twice-yearly anti-CD20 approved for both RMS and PPMS and is available for IV and subcutaneous administration. When Ocrevus was launched in 2017, it redefined the treatment paradigm by establishing high-efficacy B-cell depletion as a foundational standard throughout multiple sclerosis.
One additional comment here: as Ocrevus is the only approved CD20 antibody in PPMS, and since the phase III FENhance trial compared fenebrutinib with Ocrevus, this is really the only clinical data set generated directly comparing a BTK with a CD20 antibody and therefore really delivers unique insights on how these two different mechanisms of action compare to each other and might get positioned in an evolving future treatment paradigm.
I'm sure we'll touch on this later in the Q&A session. On the right side of the slide, I quickly wanted to summarize the latest developments for our Ocrevus franchise. As you know, at year-end 2025, we had more than 17,500 patients on Ocrevus Zunovo, and we saw a clear acceleration in the uptake in Q4, something we had been waiting for since we got the J-code in April last year. As you know, Ocrevus Zunovo expands use via a 10-minute subcutaneous injection, which is a more convenient delivery option for patients and practices. We have previously communicated that we see Ocrevus Zunovo as a CHF 2 billion incremental sales opportunity by 2029. But of course, there will be more than CHF 2 billion in Ocrevus Zunovo peak sales, as there will be also switching from IV to subcutaneous occurring.
What really excites us about the momentum we have seen now in Q4 is that more than 50% of the total global growth was driven by Ocrevus Zunovo and that more than 60% of the subcutaneous volume is coming from community practices, with around 50% of subcutaneous starts being new-to-brand. That's exactly what we had hoped for: to see an increased demand outside of the larger IV treatment centers where Ocrevus is well established as the leading medicine.
And now looking one step ahead in terms of future development steps for Ocrevus, we are now working on a high-concentration formulation for Ocrevus, which would significantly reduce the current injection volume of 23 mL so that it can be combined with an innovative on-body injector. This on-body injector is currently tested in a type of PKPD bridging study and should allow for home administration and potentially even for self-administration twice yearly.
We expect to launch this Ocrevus high-concentration formulation with the on-body injector in 2028. With that, I'm at the end of my opening remarks. On our exciting emerging MS pipeline, you will hear more from Hideki and Amit. And with that, I hand over to Hideki. Please.
Thanks very much, Bruno. As Bruno mentioned, I'll go over our really exciting neurology pipeline globally or as a whole, and then I'll talk a little bit about fenebrutinib. If you can go to the next slide. As you can see, this is our pipeline, which is really exciting in terms of the breadth and depth of the portfolio, which spans not just MS, neuromyelitis generally, neuromuscular diseases, and neurodegeneration.
I'll highlight a couple of things here. First of all, as you will hear in great detail, for fenebrutinib, we've achieved significance in PPMS as well as positive readout in the first RMS study. We also had a positive readout with Enspryng, which is an IL-6 receptor monoclonal antibody in MOG-AD. Furthermore, we announced Elevidys three-year data, which is the gene therapy for Duchenne's muscular dystrophy and the sustained effectiveness seen there.
And then lastly, we've advanced to phase III two molecules: prasinezumab for Parkinson's disease and trontinemab for Alzheimer's disease, which is our Brain Shuttle-tagged antibody against A- beta. So if you go ahead to the next slide, please. Focusing on our MS portfolio, as you can see, there is a huge unmet medical need in multiple sclerosis. About 30% of patients remain on oral or low-efficacy treatments. 30% of patients continue to progress. It really, therefore, underlines the need for new treatments which address both the relapsing and progressive biology.
And that's described on the right-hand part of this slide, where there's more of a biological definition of multiple sclerosis, with both relapsing biology as well as progressive biology, the progression which underlines the whole course of MS from the very beginning. With our leading portfolio in MS, we're well positioned to provide treatments, potential treatments for options across the spectrum of disease, from relapsing to progressive biology. You'll hear a lot more about fenebrutinib in a minute, which we think is one of the first that can address that.
If you can go ahead to the next slide, please. Underlying all this is our strategy within multiple sclerosis, which is our ambition to cure MS with our vision to stop, reverse, and prevent multiple sclerosis, with capabilities underlying that, with development excellence, biomarkers, with our unique Dia collaboration, and as well as target discovery with our two REDs, two research houses, pRED and gRED, that provides the pipeline to fulfill this strategy. Go ahead to the next slide, please. So a little bit about fenebrutinib before I hand it over to Amit.
It has potential for first-in-class and best-in-class in both RMS and PPMS. We'll go into detail in terms of the detailed data for FENtrepid, which is our PPMS study, as well as we've announced the FENhance 2, which was our first relapsing MS study to read out, which showed substantial efficacy. Now, BTK is a molecule BTK inhibitor is a molecule that can address both relapsing and progressive biology, the relapsing biology driven by acute inflammation in B cells, the progressive biology driven by macrophages and microglia.
And the reason that's important is that this can address disability accumulation in addition to the relapsing biology. So this BTK inhibitor dual mechanism action really has potential to impact both relapsing and progressive disease. And as mentioned, the readouts for FENtrepid, we'll go into details, FENhance 2. We had a positive readout and FENhance 1. We will have a readout in Q1 of this year. I'll go ahead to the next slide. Fenebrutinib was designed as a best-in-class molecule. It's the only non-covalent BTK inhibitor in MS, and it's highly selective. The selectivity is shown in the right panel.
Therefore, it really has a unique opportunity for both benefit and to reduce risk in this patient population. If you go to the next slide, please. Fenebrutinib has an optimized pharmacokinetic profile. It's shown in this slide compared to the other BTK inhibitors in development. And it also has a very high CNS penetration, as shown in the right slide. And it's the only BTK inhibitor that reaches near maximal inhibition of B cells and microglia in the CNS. Finally, next slide, please. I'll just remind you of our FENhance, the FENopta phase II study that read out.
Because of this readout, we're very confident of the positive results for FENhance 1, the study that remains to be read out in Q1. As you can see in the left-hand panel, we had a reduction in relapse rates to the point where there's approximately one relapse every 17 years. And we also have near complete suppression of Gd lesions, as shown in the right-hand slide, acute inflammatory lesions. So this is why we're very confident in the FENhance 1 readout.
The results we've seen in FENhance 2 are consistent with what we saw in the phase II FENopta study. So one more slide, please. That's our fenebrutinib molecule. We also have molecules in development which are very exciting and can add to the patient options for multiple sclerosis treatment, including our brain shuttle CD20 on the left-hand side in phase I. We have a CAR-T against CD19 and CD20, also in phase I. And then finally, on the right-hand side, we have a MAGL inhibitor in phase II in combination with Ocrevus. So we're really excited about our portfolio and options for multiple sclerosis patients. So with that, let me hand it over to Amit.
Thank you, Hideki. So this is the same slide deck that I had the privilege to present at the ACTRIMS meeting on Saturday on behalf of all the participants, the investigators, as well as our colleagues at Roche, Nilesh Mehta. And you can see the title slide here. So this will be the phase III data of fenebrutinib versus ocrelizumab in PPMS. This is the FENtrepid study. And just the disclosures briefly. I won't belabor the introduction. Hideki did a terrific job.
I'll just highlight perhaps the third bullet, that there really is tremendous excitement in the field about the prospect that a single agent may impact both the relapsing disease biology in a meaningful way as well as the non-relapsing progressive disease. And here, of course, we're focusing on primary progressive MS, which has been the toughest nut for us to crack in our field. FENtrepid is a phase III multicenter randomized clinical trial. You can see on the left that it recruited individuals 18-65, noting that 65, by the way, is higher than other trials in progressive MS, whether secondary or primary, an EDSS range of 3-6.5, and of course, a diagnosis of primary progressive MS.
Individuals were then randomized 1:1 in a double dummy parallel group double-blind trial, either to fenebrutinib at 200 mg by mouth twice a day or the ocrelizumab standard clinical dosing, followed by an open-label period. This just shows you some of the readouts over time. It's noteworthy that while this was an event-driven study designed as such, each individual had to have at least a 120-week treatment period before the trial was reaching its conclusion. The slide here points out to the primary endpoint.
This is a composite of confirmed disability progression at 12 weeks. And so, of course, in our field, we want to make sure that we look at changes in neurological status to assess disability developing over time and confirming that it is indeed likely to be related to progressive disease as opposed to relapsing disease by having a confirmation of that worsening at 12 weeks. This is a composite which allows people to meet their primary endpoint in one of three different ways, either achieving confirmed disability progression on EDSS, the standard increment in EDSS of 1 point or more if your baseline EDSS is less than 5.5, or 0.5 increase in the EDSS if your EDSS at baseline is greater than 5.5.
But you can also reach the primary endpoint if you have a 20% or higher increase from baseline in the Timed 25-Foot Walk, as well as the 20% or more increase from baseline in the Nine-Hole Peg Test. This was designed as a non-inferiority study, as shown on the right. The FDA has two approved methods, the synthesis method and the fixed margin method. The synthesis method is the one that was used here, but it's noteworthy that the same outcome was achieved also with the fixed margin analysis for non-inferiority. The baseline characteristics are shown here and essentially quite well-balanced groups. You can see at the top in terms of age and sex, very similar across groups. The age indeed is just under 50.
In terms of time from symptom onset and from PPMS diagnosis, just between nine to 10 years from the symptom onset and just under five years from the diagnosis, so well-established primary progressive MS population, approximately 25%, a quarter to a fifth of individuals, had some prior disease-modifying therapy use. Importantly, as shown here with respect to the Gd lesions just above, is that you have a very low level compared to what we've seen in other trials of 10%-11% of presence of focal inflammatory lesions as assessed by the enhancement with gadolinium at study entry. Just to compare to the ORATORIO study of ocrelizumab versus placebo in PPMS, essentially double, if not a little bit more than double, seen at the study entry.
So this really is a population of primary progressive MS patients with a well-established progressive disease biology and little, actually, of the focal inflammatory disease that we think of as relapse biology. At the bottom now highlighted are the different components of the composite CDP. You can see that they're very well-balanced across groups, which is important in terms of subsequent analyses. This is the primary endpoint. So fenebrutinib indeed achieved non-inferiority relative to ocrelizumab using the composite confirmed disability progression. What you can see on the left-hand side is that the curves are together initially, but they separate at 24 weeks. They continue to remain separated throughout the remainder of the study. This achieved non-inferiority by the synthesis test statistic, as noted.
It's also noteworthy that nominally, from the time of separation and throughout, those individuals on fenebrutinib did a little bit better than those on ocrelizumab. That results in a 12% risk reduction of confirmed disability progression. This is an exciting observation for us, given that the ocrelizumab, of course, is the only currently approved treatment for primary progressive MS. I must say that many of us in the field felt that this was a pretty brave study to do, pitting fenebrutinib as a BTK inhibitor against ocrelizumab. It's a very exciting primary outcome measure. Now, it's interesting to reflect on how the different components of the composite CDP primary outcome measure contributed to people reaching the primary outcome. What you'll see on the right-hand side is that, in fact, the greatest contributor to achieving the CDP12 was the Timed 25-Foot Walk.
The second contributor was the EDSS, and the third was the Nine-Hole Peg Test. Yet when you look at the relative contribution of each of these to actually establishing the non-inferiority between fenebrutinib and ocrelizumab, the Timed 25-Foot Walk was not particularly helpful. It was really the Nine-Hole Peg Test and the CDP12 that the non-inferiority was established by primarily. And it's interesting to reflect that in the ORATORIO-HAND study, the ORATORIO-HAND study, which was another PPMS population looking at ocrelizumab versus placebo in individuals who, in many cases, were already experiencing a lot of difficulty with their gait, perhaps were in wheelchairs, but the recognition that they too may benefit from an intervention. And the decision there was to have a two-part composite that did not include the Timed 25-Foot Walk, but included the CDP12 for the EDSS and the Nine-Hole Peg Test.
That study was a positive study. If you applied the same two-part composite to the FENtrepid data, you would, in fact, achieve a hazard ratio of 0.78 without crossing unity. That would have been a 22% risk reduction of fenebrutinib as a superior agent to ocrelizumab. It's interesting to reflect on that. I can tell you, as an aside, that our field is learning from every clinical trial and learning that it's very important for us to think of how to ideally adjust and match our outcome measures to the population that enters the study. Moving on now to the question of how different subgroups behaved with respect to the primary outcome.
What you can see here is that pretty much all, with the exception of one point estimate, are left of unity, meaning favoring fenebrutinib over ocrelizumab. And this is true whether you look at age, whether you look at baseline disability by the EDSS. And very importantly, when you consider those who did or did not have gadolinium-enhancing lesions, again, as a measure of focal inflammatory disease, it is, in fact, the case that the group that did not have focal inflammatory disease had the best point estimate with respect to the comparison between fenebrutinib and ocrelizumab.
And again, as a side note, in studies of progressive MS where there is some presence of focal inflammatory disease that we think biologically represents relapse biology under the surface, when you have a benefit of your drug, it is sometimes difficult to interpret or to attribute that benefit to an impact on actual non-relapsing progressive disease versus an impact on the relapsing disease biology that is now, we know, present even in people who clinically have a phenotype of primary progressive MS. So this really is a cohort with little Gd lesions to start with and an effect that is present very clearly in those who do not have the Gd lesions. And the other at the bottom is, you can see, baseline B cell count. People may ask, what happens if you consider this treatment in people who come off of an anti-CD20, such as Ocrevus?
You can see here that if you consider individuals at entry with less than 10 B cells per microliter, which is pretty low and likely reflects people who have been or had been on anti-CD20, that they too benefit from this intervention, even compared to ocrelizumab. What about the safety profile? So overall, at the top, you can see that there is no imbalance in terms of any adverse events. And there was no imbalance in terms of serious adverse events. There were, however, more fatal events in the fenebrutinib arm, 7 individuals, compared to 1 in the ocrelizumab arm. And as far as adverse events leading to withdrawal from treatment, approximately 14% in the fenebrutinib arm compared to 5% in the ocrelizumab arm, the great majority of those withdrawals were based on protocol-mandated discontinuation and withdrawal because of liver enzyme elevations.
We'll now look in more detail at the reported fatalities. So I'm going to go through each one of these individually. I think it's important. You can see at the top, the first individual is someone who succumbed, sadly, to COVID-19 and very unfortunately was non-vaccinated to SARS-CoV-2. This was a young 37-year-old woman with a moderate EDSS, 51 days into the study, so very soon after entering the study. The second person, also very unfortunate, insulin pump failure and diabetic ketoacidosis, which resulted in them passing away well into the study. One individual on fenebrutinib with a myocardial infarction. There were no other identified risk factors in that individual or in the family history. A sudden death in an individual who had a preexisting cardiac arrhythmia. There was one completed suicide in the fenebrutinib arm. This was really a very short treatment duration, 15 days into the trial.
Very hard to attribute that to the drug. There was a suspected suicide in someone who did have a history both of generalized anxiety and insomnia, one pulmonary embolism in the fene group, and an individual with known chronic cardiac failure and hypertension. And then the individual with a fatal outcome in the ocrelizumab arm was someone who died of lung cancer metastases with known background tobacco use. So there's an imbalance here. For what it's worth, the investigators assessed all of the fene-associated fatalities as unrelated to the study drug, so not related to fenebrutinib. One always looks for patterns. One tries to understand whether there's anything here that jumps out as a pattern. I would comment that these are all deaths that one can see, certainly in the normal, but certainly in the MS population as well.
There's no obvious pattern here either in terms of the cause or in terms of the timing. There's just a little lag here as I click on the slides. Let's talk a little bit about the liver enzymes. So you can see with fenebrutinib that there was a higher frequency of liver enzyme elevations as assessed by the fold rise above upper limit normal of the ALT. That is included in the lower elevations, although those are ones that we're not as concerned about. We're more interested in the ones that are particularly high elevations and particularly those that may meet Hy's Law criteria. You can see that above 20-fold upper limit normal, 0.6% of individuals on the fenebrutinib arm experienced that compared to 0.2% in the ocrelizumab arm. So small difference, very low percentages, but small difference.
Then where you had the upper limit normal above 3% as well as bilirubin elevations, this is what meets the Hy's Law, at least biochemically. There were no actual confirmed Hy's Law cases, as you can see at the bottom, in either arm. Biochemical Hy's Law, which was seen in two patients on fenebrutinib and one in ocrelizumab, are defined as individuals who reach these lab test elevations but actually have very plausible other reasons for developing this, as was indeed the case here. And importantly, the ALT elevations attributable to fenebrutinib essentially occurred during the first 22 weeks of treatment. And all of the cases resolved. This relates to BTKI-related adverse events, ones of special interest. And they were pretty comparable overall between the treatment arms. From the standpoint of infection looked at at the top, there were no differences in all infections and infestations.
And when serious infections and infestations were considered, if anything, a slightly higher proportion in the ocrelizumab arm compared to the fenebrutinib arm. A known potential risk, especially with the early BTK inhibitors, is bleeding. And while bruising occurred at a higher frequency in the fena arm compared to ocrelizumab, these were essentially all mild. There were no serious hemorrhage imbalances between the two groups. And as far as neoplasms, again, no particular imbalance in terms of malignancies. And then non-melanoma skin cancers, perhaps a very small signal, as shown there at the bottom.
The conclusions that we have from the FENtrepid trial is that it achieved its primary outcome of non-inferiority to ocrelizumab in reducing disability progression based on the composite and, in fact, had a numerically favorable outcome starting all the way through from week 24 to the end of the study, including, importantly, those who did not have, the majority of patients who did not have gadolinium-positive lesions at baseline and, again, of interest, the strongest treatment effect observed on the Nine-Hole Peg Test. The rates of the AEs and the SEs were comparable, including infection. There was a higher incidence of liver enzyme elevations and then an imbalance in the fatal adverse events in fenebrutinib compared to ocrelizumab. Emerging data, as you've heard, will hopefully provide us insights in terms of preventing disability accumulation by targeting both the relapsing and the progressive biologies of MS.
And I will essentially stop here, making the point, I think, and in my mind as well, that we very much hope to see fenebrutinib emerging as the first oral and second-ever therapy to demonstrate efficacy, as shown in FENtrepid, not just in PPMS as a CNS-penetrant and highly selective BTK inhibitor, but perhaps also in the relapsing-remitting spectrum as predicted by the phase II study, the FENopta study that Hideki commented on, and as emerging, at least, in the FENhance 2. And we're looking forward to the FENhance 1 results. So again, I'll stop here. You'll be hearing more in the future. And just to acknowledge again all of the participants, the site investigators, the members of the steering committee, and colleagues from Roche and Genentech. And I think we'll open it up to questions.
Yes. Thanks, Amit, with that, we will start the Q&A. The first questions go to Sachin Jain from Bank of America. Sachin, please.
Hi there. Thanks for taking my questions. A few, please. If I could just kick off with a general one for Dr. Bar-Or, just based on this data, what percentage of PPMS patients would you use this in relative to CD20 and why, and just your perspective as a clinician on the liver risk that's seen in this study? And then two, I guess, specifically for the Roche folks. What's your visibility on liver enzyme elevation in the second RMS study, FENhance 1? Just are you able to comment relative to the commentary?
I think, Bruno, you put out this morning that FENhance 2 liver enzyme elevation was in line with placebo. And then on the PPMS data, the presentation refers to resolution of liver enzyme elevation, but I think that's only greater than 5x . So I assume that means that liver enzyme elevations greater than 3x or 3-5x times didn't all resolve. So any color on that and why that's not a concern? Thank you.
A good number of questions. All excellent. Maybe I'll jump in to start. I think that imagining the approval of fenebrutinib for primary progressive MS, I would frankly have no reason to think of it as a treatment that couldn't be applied to anybody with a correct diagnosis of PPMS. I think the issue of liver enzymes, which we'll talk more about, we're all trying very hard to figure out who the very few individuals are who may be at risk for serious liver outcomes. And of course, if we could identify them and exclude them, and that at the time would be the only population I would think should be excluded if we could. But otherwise, really, no particular reason.
Whether they do have focal inflammatory disease based on GAD lesions or new enlarging T2 lesions or not, I think that this would be an agent that would be certainly up for discussion across the broad population of PPMS. The liver enzyme abnormality, of course, an imbalance between fenebrutinib and ocrelizumab, and across all the fold elevations of the ALT, again, as I alluded to, we are less concerned about the lower range. And what we've seen, in fact, if you consider the HERCULES trial program looking at the non-relapsing SPMS versus the GEMINI program in relapsing MS, there also was a difference there in terms of elevations in the lower range. And it's not surprising to see elevations in the older patient population, as, of course, was true for HERCULES versus the GEMINI populations.
In this case, we're dealing with a population with the entry criteria of up to the age of 65, which is higher than the HERCULES entry criteria of up to 55. So I think we're looking forward to seeing these type of subgroup analyses. We haven't seen them, I think, yet from either company, but these are being worked on. And I suspect that what we're going to see is that age is the likely explanation for the imbalance in the lower range, which, again, we are less concerned about than the upper range.
Thanks, Amit. To jump in on the questions about the RMS studies and the liver enzyme elevations we've been seeing there, the comment was correct that in FENhance 2, the liver enzyme elevations are much more similar to what was seen with GEMINI and also very similar to what was seen in Evobrutinib . FENhance 1 is, of course, still blinded, so we can't comment on that. What we can say is overall, in the blinded population, that there's no reason to expect alternative data coming out of that study.
I think, Sachin, you had one more question, which was on the resolution of the elevated liver enzyme levels and the range of three to five.
Yeah. The slide sort of denotes that the resolution refers to above five. So just obviously to try to answer your question.
Very happy to respond to that. We have seen 100% resolution of liver enzyme elevations across the program, no matter the level.
Thank you.
Okay. All questions answered, Sachin?
Yeah. Perfect. I'll get back in, Keith. Thanks, Bruno.
Yep. And then we move on. The next questions go to Graham Parry from Citi. Graham, please.
Great. Thanks for taking my questions. Just to follow up on liver enzyme elevation, actually, you commented that liver enzyme elevation is similar to GEMINI and to studies on a cross-trial comparison and Ocrevus in FENhance 2. Could you just comment there on the high levels of elevation and how they compare when you're looking at a cross-trial, that they look more like GEMINI? Should we think about this as being a very different patient population to FENtrepid?
And then secondly, I asked on the full year 25 call how important confirmed disability progression versus annualized relapse rate might be for differentiating fenebrutinib. And the question was answered saying that annualized relapse rate was a very good endpoint. I just wanted to clarify what Roche sees as the differentiating feature or unmet need that fenebrutinib is addressing, or is it more just that it's an oral dosing option for patients? Thank you.
Would you like me to quickly address the liver enzyme question, then we can hand it to Amit for the clinical one?
Yes.
Perfect. Regarding the high elevations, those are also lower in the RMS population.
And just to clarify the question, are you asking about annualized relapse rate in the context of FENtrepid?
As we drill down to what the differentiating feature of the product would be, does Roche see that as being the annualized relapse rate reduction in RMS, or is it confirmed disability progression? Because as a brain-penetrant molecule, then there's a potential here, and we obviously haven't seen the data, that you could get a CDP benefit. So the question is, what makes this different to Ocrevus other than just it being an oral dosing option?
Well, I would say, first of all, that what we learned from both evobrutinib and tolebrutinib is that they are at best modestly effective against relapsing disease. And any profile that they might have, and this would be the case not for evobrutinib, which is not CNS-penetrant, but for tolebrutinib and HERCULES and GEMINI programs, showing what I think is an impact on CNS-compartmentalized inflammation, but with a profile that would be viewed as rather modestly effective, certainly not superior to teriflunomide, which we think of as a modestly effective agent. Fenebrutinib, based on the FENopta and the first of the two phase III FENhance trials, I predict is going to be highly effective against relapsed disease. And that's great because one of the questions there are people over time who are not going to tolerate anti-CD20.
There are people who may not want to or may not have access to infusions or not like injections. And so I think there'll be a lot of uptake for an agent as an oral agent that could impact importantly both the relapsing and the non-relapsing disease components. And as the community was thinking about tolebrutinib and whether it would be approved, one of the things we kind of struggle with is if you have somebody who's on a high-efficacy therapy but progressing - so the biology of progression is there - what happens if you stop that high-efficacy therapy against relapses and start one that is at best modestly effective?
And that would be a concern. And not everybody would be comfortable doing that, especially for patients who had evidence of a lot of focal inflammatory or relapse disease activity prior to going on the high-efficacy therapy. To me, fenebrutinib is an agent that I would be delighted to think of as having a similar profile, if you like, on both relapsing and progressive disease, but as an important alternative or as a first in PPMS.
And if I can just add, fenebrutinib is really the first and only oral high-efficacy potential treatments for both PPMS and RMS. And FEN, along with Ocrevus IV, Ocrevus sub-Q, has the potential to offer a leading portfolio for patients and choice for patients of high-efficacy treatments.
Great. Thank you.
Graham, any additional questions?
No, that's great. Thank you.
Okay. Then we go on. Next questions go to Luisa Hector from Berenberg. Luisa, please.
There we go. Thank you, Bruno. Thank you for the call. So for Dr. Bar-Or, I wanted to check, did Ocrevus perform as you would have expected, and what proportion of your primary progressive patients are being treated with Ocrevus today? And if not, why not? And maybe to just understand some of the wording. So you have the primary endpoint, the three-part composite. I know in the press release, you talked about a reduction in disability progression. Can that be claimed, and is there anything you can claim on the two-part composite endpoint where you showed it versus Ocrevus and the outcome there? Can you sort of drill down and make any claims where the data looks more favorable? Thank you.
Maybe I'll start at the end. So I don't think one can make formal claims about that, given the predefined statistical plan for non-inferiority. That said, the data is the data. And we always want to see the data. And you see the point estimates how the curves separate. If the curves were separate at the beginning, which sometimes happens, then maybe an imbalance in patients coming into the study, and it's very difficult to interpret. But they separated at week 24, not before, and then they remained separated, with fenebrutinib consistently having a favorable impact relative to the ocrelizumab. And to me, that is something that is noteworthy. We are interested to see what will happen, of course, in the FENhance trials as well.
With respect to the question of, "Did I see what is expected?" I wasn't sure initially whether you were referring to within the clinical trial or sort of in practice. And I'll start with practice first. Of course, in the clinical trial, the very fair assumption is that it's behaving in PPMS as it was shown to do so in the ORATORIO study. So modest but important impact on limiting progression of disability in individuals with primary progressive MS. Our clinic, which follows approximately 6,000 individuals with MS - so that's a fairly large clinic, one of the larger ones in the U.S. - we have over 3,000 people on anti-CD20, the majority of whom at the moment are on Ocrelizumab. I'm always very reluctant to say, "In clinical practice, I see an effect." People do get worse.
But I think that the population that we've followed on Ocrevus with PPMS generally recognizes that they are on the best available, the only available treatment. And that too is reassuring, being proactive about their care. Again, very difficult to gauge when people are getting worse, whether they would have gotten worse even more so without the treatment. But of course, that's what the clinical trials are for. So did that answer the questions, or were you also asking in the context of the trial?
Can you still hear me?
Yes.
Yes. Yes. And also within the trial, so the performance of Ocrevus within the trial was as good as possible?
I mean, it's close, nominally not as good as fenebrutinib, right? But one can't comment about how much it did other than relative to fenebrutinib.
Okay. Thank you very much.
Sure.
Okay. Then the next questions go to Michael Leuchten from Jefferies. Michael, please.
Thank you, Bruno. A few questions for Dr. Bar-Or, please. One, just going back to the shape of the curves. If this is a composite of the disability measurements, it's good to see the curve separating early, but why wouldn't it separate further given it's a composite, not a single estimate? Just your views on that, please. And then the question on, "How do we get so many ALT above 3 times if there was monitoring in place?"
Just trying to understand how those patients sort of weren't detected earlier. Does it just happen too quickly to catch them? Just sort of wondering about the timing around those. And then lastly, I think this is for the Roche team. Can you explain to us who determines whether Hy's Law cases are a Hy's Law case? Is that the way you'd look at the data? Is it a regulator? Who makes a call whether the comorbidities, if I can call it that, make it a non-Hy’s Law case?
So maybe I'll start with respect to the composite. So if you hit one of the three, then you've hit your endpoint, and you're not contributing to further. So if you hit by one of them, the fact that you hit subsequent and that's an interesting analysis that one would want to do. When you look at these reverse Kaplan-Meier curves, you always have to be cautious about what you see towards the end, just because if you look across the bottom, there are fewer and fewer and eventually really, really few people contributing to the comparison. So if there were an opportunity to help people avoid the progression of disability on multiple counts over time, that's an interesting question.
To me, what we've learned as a community from the trials—and we had a very detailed discussion about this on Saturday at ACTRIMS—the question, again, of how to best choose the outcome measures with respect to these individual measures or different combinations of composite to match the population. So it kind of makes sense on the one hand that if people can't walk, there's no point in using a walking measure. Here, apparently, people also had difficulty with that test discriminating the two.
And there are potentially good reasons. A Timed 25-Foot Walk, for instance, can change quite a bit. If you are not as bad as you were, you may, or if you get worse, for instance, you may then need an ankle-foot orthosis that you didn't need before. And now, with the ankle-foot orthosis, you might actually walk faster than you did before. So that can contribute to noise in the assessments. And of course, when you have a more noisy measure, it becomes much more difficult statistically to see it separate, even if there's a potential separation or comment on non-inferiority there.
I'm happy to take the part of the question regarding liver. Amit, if that works out for you?
Sure. Yeah. It's fine.
Absolutely. So there was a question about the percentage of greater than 3x the upper limit of normal and how are we catching those. It's important to recognize that the every-two-week testing was actually introduced quite late into the program. So for the liver enzyme elevation data that we're looking at, approximately, I would say, the vast majority of that was captured with monthly testing with which we started the program. After we introduced every-two-week monitoring, we prevented any further Hy's Law cases as well as any high elevations. The goal of liver enzyme testing is to prevent severe liver enzyme elevations, not to prevent the lower ones because, of course, around 3x, 3-5x the upper limit of normal can occur due to many things in life: infections, something you eat, how you're working out.
So we are following the liver enzyme elevations in order to prevent the high ones. And we saw that with the introduction of every-two-week testing, we have brought down the elevations seen so that you are making sure that you're keeping patients safe while they're on therapy. And then the second part of that question was, "Who is determining what is considered a Hy's Law event?" And thank you for that question. We do have an independent adjudication committee for Hy's Law events.
Thank you.
Very good. Next one in the row is Colin White from UBS.
Hi. Thanks for taking my question. It's Colin White from UBS here. Two questions from me, please. The first is on the positioning of fenebrutinib in the treatment of PPMS and RMS given unexpected REMS similar to what we've seen in the clinical studies in the requirements for liver monitoring. Firstly, in PPMS, does this position it in patients that are maybe not doing well on an anti-CD20, or does it position it in a broader population? Similarly, in RMS, with those liver monitoring requirements, does it position it ahead of anti-CD20 as a similar first treatment option with anti-CD20s or perhaps afterwards?
The second question I have is, looking ahead to the RMS data that will be presented and thinking about the benchmarks for relapse rate and lesion reductions versus Ocrevus, is something like an anti-CD20, like Briumvi ULTIMATE trial where we saw a 50% reduction in relapse rate versus Ocrevus and greater than 90% reduction in lesions? Is that are these appropriate benchmarks, or should we be thinking about it differently than that as we head towards the data? Thank you.
Maybe I'll start, and Alexandra, you can perhaps follow. So at the moment, I'm optimistic that fenebrutinib will have an indication in primary progressive MS and relapsing MS. Of course, we need to confirm that with a FENhance 1. I think that an important point raised by Hideki in his introduction is that we really think differently now about the biology that we're trying to target. And while the regulatory agencies are still going to require to call it something that is sort of in the clinical spectrum and as an aside, the same international committee that's charged with the new diagnostic criteria that have come out, as you probably know, recently is now charged with revisiting the clinical course descriptors.
We will probably one day get rid of SPMS as an entity because this notion that people start with relapsing biology and then one magical day transition into secondary progressive MS is now understood to be simply incorrect biologically, that both relapsing biology and non-relapsing progressive biology occur in an individual patient at the same time across probably decades of their experience.
We now have direct measures that capture at least some of the presence of progressive disease biology as early as you diagnose patients. Even in ones who are referred to as radiologically isolated syndrome, they had an incidental finding of lesions that turn out to be consistent with MS and further testing that confirms MS without having had a symptom. That, of course, is not necessarily going to be relevant for the here and now, but not that distant future.
The point is that as a clinician and an academic clinician, there is presence of progressive disease biology even in people who clinically you'd call relapsing remitting or relapsing MS. And if I have an agent that I believe works on both of these biologies, I'd be excited to start it. And of course, if it's considered to be well-tolerated, which this agent really is, the safety monitoring, I think, if we can mitigate, I would be very comfortable offering this treatment for anybody in the MS spectrum in whom I think there is both some element of relapsing disease and progressive disease biology.
So that's really just to kind of share with you some of the evolution and sort of the conceptual framework of MS by the community. And we need to help the regulators sort of catch up with that. Once these are approved, I think that there will be a pretty substantial uptake as people recognize the potential benefit on these two biologies across a very broad spectrum of patients.
Colin. The follow-up question was on expected RMS data.
Yeah. It was on benchmarks, appropriate benchmarks to think about in terms of relapse rate and in terms of lesion reductions, percent reductions versus Ocrevus. What should we expect?
As Hideki started off with and then Amit commented on, of course, we can't share the totality of the FENhance 2 data yet, but we're very happy to see that it's very consistent with the FENopta data. So if you play that forward, then we could anticipate a really profound reduction in both ARR and Gd+ lesions.
Very clear. Thank you.
Very good. Then we move on. Next questions go to James Quigley from Goldman Sachs. James, please.
you very much for taking my questions. I have two for Dr. Bar-Or, please. So firstly, from a monitoring perspective, with some of the current oral therapies, including Aubagio, they already have a liver monitoring requirement. So typically, how long would you monitor with other therapies? And how burdensome would you characterize every-two-week monitoring for 20 weeks or so? And is there anything in the data to suggest that patients could stop monitoring after a certain period of time? So if there's nothing, very limited increases after 10 weeks, is there a chance you could stop those early?
And the second question, and again, maybe asking you to somewhat speculate here, but we've seen two covalent BTK inhibitors not show any benefit in annualized relapse rate in RMS, and one non-covalent BTK show a benefit in both PPMS and one RMS trial. Again, we need to see the rest of the data for FENhance 1. Hideki showed some data on plasma availability and greater inhibition in the CNS. Given what we've seen so far in the clinic, how convincing do you think it is that non-covalent BTK inhibitors could have greater efficacy than the covalent binders, or is it more down to dosing and therapeutic window of each asset? Thank you.
Sure. So with respect to the liver enzymes, depending on the totality of the data with fenebrutinib once the FENhance 1 and 2 come out, if it's basically consistent with what we've seen up to now, I would be comfortable with the requirement of biweekly testing for the first period and then going on to the same frequency that we do with other agents. Keep in mind that neurologists are actually pretty familiar with monitoring for liver enzymes. We deal with medications for epilepsy, for headache over the years, etc. So this is not new to us, including in the MS field, of course, as you pointed out with Ocrevus. This would be an increased burden initially compared to what we do, no question.
But I think that the prospects, if borne out, of what this treatment has to offer for an upfront increased intensity of monitoring would be embraced by most patients and clinicians. I do think that we will look to Roche Nilesh Mehta to sort of help us with that, right? I think that's going to be important. I suspect the regulatory agencies will want to see something in place that they will feel confident will keep people safe as well. The very interesting question about whether it is indeed the reversibility, the non-covalent reversibility of fenebrutinib that contributes to the differences, I think first that the data to date already suggests to me quite strongly that fenebrutinib is different from tolebrutinib, evobrutinib in the context of the impact on relapsing disease biology.
The extensive work that I understand went into the choice of dose regimen for fenebrutinib included a very comprehensive assessment of how a non-covalent reversible binder may differ from the covalent irreversible. And one of the important points is that you're less concerned about perhaps the Cmax of your therapeutic and more about the area under the curve. And it's very interesting to speculate that an area under the curve that is more comprehensive may, in fact, result in different biological responses that could have relevance to disease biology.
And an important insight, at least already from FENopta, is it looks as though there is some degree of B-cell depletion with fenebrutinib, which is not seen or at least has not been reported in the same way with tolebrutinib and evobrutinib. That may be important because it may, again, underscore biological differences between the agents that would confer to fenebrutinib a much higher efficacy on relapsing disease activity than the others out there that we've heard about to date.
Yeah. And just on top of that, fenebrutinib is a unique BTK inhibitor. It not only is non-covalent and reversible, it's very high potency, very high selectivity. And what's important to keep in mind is the optimal PK profile that was shown in that slide that I showed earlier. So optimal PK could contribute to the efficacy as well.
That's really what I was referring to as the area under the curve in terms of exposure, for sure. Yeah.
I was going to comment on what is Roche doing to contribute to identifying patients at risk and also how are we thinking about reducing burden for patients and physicians. And I think in this space, we're very lucky that MS and neuroimmunology is considered an end-to-end disease area in Roche. So we really can draw from the support of the entire organization. And so as we're getting this data out of the phase IIIs, we are able to loop that back with our translational medicine colleagues, with our early research colleagues, and of course, now with our growing AI and machine learning capabilities so that if anyone was going to be able to identify a predictive measure to predict patients that are at risk, we have a good shot at being able to do that.
Then on the other side of the commercialization engine, we are really focused on what we can do to reduce burden for both patients and physicians. We are actively working through that. Of course, throughout the filing process and as we have dialogue with the FDA, we will determine what is necessary. We are very committed to bringing fenebrutinib to patients in a way that is easy and non-burdensome to them.
Very good. With that, we move on. Next one in the queue is James Gordon from Barclays. James, please.
Hello. Can you hear me now?
Yes, we can hear you now.
Thank you. James Gordon from Barclays, couple of questions, please. First one was on PPMS. So have you had a chance to discuss this data with FDA, particularly with relation to the agent's liver profile and in terms of how different this is seen as being versus tolebrutinib, which obviously got a CRL due to the liver profile? Because the key investor question I've had today is, how confident are you that this isn't going to be seen as the same given the response on the liver profiles? So if you could talk about that, please.
And the second question was just on timing. So I think that the second RMS trial, we're going to get to mid-H1. So could it theoretically be possible that we would get data from the two RMS trials, both at AAN in late April or 18th or 22nd of April? Or is that a bit ambitious? We might have to wait until later this year to understand what this really looks like in RMS.
I'm happy to address both of those if that's okay. Perfect. Regarding the path to approval and especially how is Roche thinking about that in light of the tolebrutinib CRL, we think that the CRL was written very clearly and transparently and really elaborated on the FDA's view on benefit-risk and what's necessary to achieve. And happily, that's very much in line with Roche's thinking as well. So it has to do with benefit, then risk, and then, of course, risk mitigation measures. So with that, we have shared all of our data with the FDA. We are in dialogue with them. And based on both benefit, risk, and what we think we can do for risk mitigation, we do think we have a path to approval.
Specifically in terms of mitigation measures, the most important being what we talked about before, that going from monthly monitoring to every-two-week monitoring, we've been able to prevent high elevations and any further Hy's Law. Although in the CRL, they discuss the weekly monitoring for tolebrutinib being not adequate to capture high elevations, for fenebrutinib, we have not seen that. We think we have a different molecule. We have. The FDA thus far seems to be appreciating that as such.
Thank you.
Regarding timing, you are correct. We are looking to see data kind of mid-H1, end of Q1. So if everything goes well, we would be very excited to see that data at AAN.
Thank you.
Very good. And we move on. And next one is Steve Scala from Cowen. Steve.
Thank you very much. A few questions. First, for Dr. Bar-Or, will you switch any CD20 patients to fenebrutinib in RMS based on the data to date? Secondly, for the Roche folks, when modeling fenebrutinib in the commercial market, do you assume there will be other BTK competitors on the market, or will fenebrutinib be alone? And curious, where are the majority of the patients or opportunity, I should say? Is it in the US or OUS? And then the last question, you mentioned the numerical trend favoring fenebrutinib over Ocrevus, but did Roche actually test for superiority to Ocrevus after testing for non-inferiority, and did it indeed fail superiority? Thank you.
Can maybe I'll start? Oh, good.
Yeah. Perfect.
Is that okay? So I think the first question was, would I switch people, and if so, who, who are on Ocrevus for relapsing MS to fenebrutinib? So first, for individuals who are having issues with anti-CD20, which again is overall very well tolerated and people do very well from that perspective on Ocrevus, but nonetheless, there are some who will have difficulty with it. There are some who will develop some infections, more frequent infections, run-of-the-mill ones, but more than they were used to. And then there will be some who will have their IgG levels go down to levels that are quite reduced and even below lower-limit normal. And we know that there's a small increased risk of more serious infections.
So anybody who needs to come off or a consideration of coming off Ocrevus, I would be comfortable switching to fenebrutinib, again, assuming that it will emerge as having the high efficacy on relapsing disease that we're hoping it will. The question of whether I would switch someone who's doing well on Ocrevus. And here, I think, again, it depends on how much one leans on the FENtrepid data suggesting that fenebrutinib may actually be a little bit better than Ocrevus. And I think while, again, statistically, one cannot say that formally, recognizing that the Timed 25-Foot
Walk really did not help here. It kind of hurt, in a sense, that those who did have an opportunity to contribute did so with the Nine-Hole Peg Test and the EDSS. And of course, this would be viewed as post-hoc and sort of cherry-picking, and we want to avoid that. But if faced with a situation in the clinic where somebody is concerned about progressing in the face of Ocrevus, and we do have more and more people with relapsing MS who run Ocrevus for relapsing MS but nonetheless have emerging progression, that would be a reasonable context in my mind to discuss fenebrutinib, which would not be the case with the other profiles of BTK inhibitors we've seen to date.
Thanks, Amit. Regarding the question about our commercial modeling, of course, this is a very dynamic space. Our models have adjusted over time as we get different data from the competitors. At the moment, as you well know, there are many BTK inhibitors in development for multiple sclerosis. It perhaps would be premature to presume that fenebrutinib would be the only one there. We're considering multiple different models as we go forward. For where do we think we'll get the patients from? Of course, the U.S. is an important part of the MS market, but we think there are patients that would benefit from fenebrutinib globally, of course. In what type of patient segments, as Dr. Bar-Or has talked about, there's many different types of patients that could benefit from an oral drug like fenebrutinib.
We think that there are perhaps especially in Europe a significant segment of the population that is still on low-efficacy orals. We as a company, and I think in partnership with our steering committee, are really believers that all patients deserve to have high-efficacy therapy. There is that segment of the market. There is also the part of the market, as Amit discussed, in which patients have been on anti-CD20s for some time now and might need to switch to something else. Fenebrutinib could offer an opportunity there. We also should not forget that even today, in 2026, about 40% of MS patients are on no therapy at all. This is really shocking to find out.
But we're really hoping with having an oral high-efficacy agent that could treat both PPMS and RMS across the spectrum, we could perhaps continue to grow the market and extend high-efficacy care to those patients that have not received it at all yet.
I just want to jump in because I'm the only one of the three here that have to jump off, so apologies for that. I appreciate the questions around how we discuss with FDA because I just want to state very clearly that patient safety is the number one priority for Roche. We're going to work closely with FDA to get this to patients as quickly as possible and to protect patients and keep them safe as well. Appreciate those questions. I do have to jump off, so apologies for that.
Hi, Hideki. I think, Steve, did we answer all your questions?
It was just the one about superiority. Did you test for superiority?
Oh, did we test for superiority?
I can hand this to Amit, but also very happy to take that as well. We did also test for superiority. Fenebrutinib did not meet statistical significance on superiority.
Thank you. Very good.
Next one in the queue is then Richard Vosser from JP Morgan. Richard.
Thanks very much, Bruno. Couple of questions, please. Dr. Bar-Or, you mentioned on that ACTRIMS about the signal-to-noise ratio, about the composite CDP endpoint. And I just wondered whether EDSS alone would have—I mean, clearly, it would have changed the result here. So the question was, what CDP composite CDP endpoint was actually used in the FENhance trials? Is it the same, or is it a different CDP?
And have you the chance to use EDSS there because that seems like a less signal-to-noise ratio on the endpoint? So that's the first question. Second question was just on the proportion of patients that were actually subject to the biweekly testing during the ramp-up phase or the initiation of treatment during those first 20 weeks across FENhance and the FENtrepid trials, just so you can show the success of testing. It'd be nice to understand the proportion there. Thanks very much.
Go ahead, Alexandra. I'll let you take ramp-up.
Regarding the proportion, at this time, when we haven't yet to read out all of the studies, I think giving precision there is going to be really challenging. So at the moment, we can just say that the vast majority of patients had their first 20 weeks of therapy with monthly testing. And we'll be digging into that. But we were able to see, with following the blinded data across all three studies, that once the every two-week monitoring was in place, we were able to prevent higher-level elevations. But getting more precise for that, we're going to have to wait until we have the readouts of all three studies. Apologies.
And then the disability outcome, Alexandra, in FENhance?
Oh, yes. Apologies. The disability outcome measure used in the FENhance studies is also the composite CDP. Of course, we are capturing EDSS. As you likely well know, for EDSS alone, it's very tough to power phase III studies individually in RMS to be able to detect a treatment difference for CDP, which is why most MS studies, if not all, have identical or sister studies in which EDSS is pooled across both of them. We saw that going back to the Ocrevus trials. Same thing with the other anti-CD20s that have been used. So we will be looking at both the composite in the individual RMS studies as well as the pooled EDSS across both RMS studies.
And I might add that the discussion in the community is ongoing as to the utility of composites versus not. And again, I mentioned before that we keep learning. Maria Pia Sormani, who's one of the lead statisticians in the MS field, although not published, she's presented this data a couple of times, and it's okay to share, she did a meta-analysis comparing outcome measures of disability that used composites and used EDSS alone. The conclusion from all of that is that EDSS is no worse than the composites. But she acknowledges that as a meta-analysis, what you lose there are the contextual issues, which relate to different populations.
But depending on their status and what they are most likely to progress with clinically, there may actually be an advantage of thinking carefully about the value of composites, which allows more people to hit an endpoint than if you just limit it to one measure. The EDSS, of course, is not sensitive to a lot of progression of disability from the patient's perspective. And that gives you more events. And more events can be helpful in terms of your comparisons. But of course, if they introduce more noise, they're not that helpful.
Very good.
Perfect.
Richard?
Yep. Super, Bruno. Thanks very much, everyone. That's very helpful.
Next is Simon Baker from Redburn. Simon?
Thanks very much, Bruno. And thank you for doing the call. A couple of questions for me. Firstly, Dr. Bar-Or, really going back to a theme that's been talked about repeatedly, but now I want to ask it in a slightly different way. With fenebrutinib ultimately approved, let's assume, what are the choices you would make in deciding whether a patient received Ocrevus or fenebrutinib? Just giving us an idea of the process that one would go through there.
And then secondly, looking at baseline Gd-enhancing lesions, is the ratio of present to absent in the study typical of your broader clinical practice? And related to that, and I appreciate this has got no regulatory legitimacy, if you reanalyze the data excluding those with baseline lesions present, what does that do to the non-inferiority and superiority of the study? Given that you're so close on the upper confidence interval to 1, would the removal of that low-responding group actually tip it so it was a superior result? I know it's purely nominal, but it'd be interesting enough that analysis has been done. Thank you.
Right. So while the point estimate of the hazard ratio for the large population that did not have Gd lesions was more favorable for fenebrutinib versus ocrelizumab, the confidence interval just marginally kind of clipped the edge of unity. So you might say that as a single subpopulation analysis, that didn't meet the mark. But I think that the relative contribution is important to note. And it really reinforces the notion that this drug is acting on the biology of interest that we're trying to target, which is the non-focal inflammatory lesion.
Of course, when you see gad lesions there, you can say that they're there. When you don't see them, you can't exclude the possibility that a patient still harbors that biology and may manifest with it during the trial and will be interested in seeing additional subgroup analyses, including people on trial who do or don't develop new lesions. With respect to the question, the first one, so I think that if indeed we will see that fenebrutinib has an important impact on relapsing disease activity relative to teriflunomide, I would be very comfortable positioning this as a first-line therapy. We now, in our program, are very much about high-efficacy upfront.
But again, when you combine the understanding that there's a biology there that is not just a relapsing biology, an agent that has a profile on that as well would be viewed as favorable. One of the things that we now can do, not everywhere, but more and more places are doing this, is you can actually ascertain whether someone does or does not have chronic active lesions based on the presence of these paramagnetic rim lesions to indicate that the biology is there.
That's only one aspect of progressive disease. We hope to have better and additional biomarkers. My sense at the moment is that with a high-efficacy profile on relapsing disease and what we've learned from FENtrepid in terms of non-relapsing progressive biology, that this would be absolutely in the discussion in terms of first front-line therapy. Then we monitor people as they go along. And if there's any reason to think that this is not the right medicine for them, we can adjust. But it would be a great medicine for people to be able to start with as well.
Very good. We have one final question. Luisa Hector from Berenberg is back. Luisa, please, the final question for today.
Thank you, Bruno. Hopefully, they're quick. Was the composite endpoint mandated by the FDA, or could you choose? And then I just wanted to check on the imbalance of death. So once that was observed within FENtrepid, did that trigger a look across the whole program, i.e., can we be confident that there is no imbalance in the FENhance trials, the FENhance 1?
I'm happy to start on the CDP question. As we were thinking about putting together a PPMS study, of course, one of the challenges is that disability events accrue very slowly. And we, as an organization, of course, want to develop drugs as quickly as possible and get them to patients who need them as quickly as possible. So EDSS has been very challenging in that, in that it is not that sensitive to change. So that is what has prompted the MS community to be looking for more sensitive markers for disability progression.
Therefore, we put together the EDSS plus Nine-Hole Peg Test and Timed 25-Foot Walk, hoping that Timed 25-Foot Walk would be a much more sensitive measure to pick up disability progression sooner. So that was not mandated. It was us really going out and trying to develop drugs for progressive MS quickly. Unfortunately, as Dr. Bar-Or explained in some detail, we certainly captured more events with Timed 25-Foot Walk, but unclear if those were meaningful or if that was just capturing a lot of noise.
Thanks.
I might respond to the other question. Obviously, we're going to wait to see what happens with the FENhance program in terms of fatalities. But it's worth noting that there have been in the order of 1,500 individuals who've been exposed to fenebrutinib in other contexts and a good 1,200 or so in non-malignant contexts, so conditions that include rheumatoid arthritis, systemic lupus, and chronic spontaneous urticaria. There was no imbalance in AEs with fatal outcome for fenebrutinib in all of those contexts and in people who, you might imagine, are perhaps on additional therapies or sicker than the average MS patient. So that is, I think, noteworthy in the context of fatalities. I don't know if you have anything else to add to that, Alexandra.
Just that we, of course, are working very closely with our IDMC and sharing all data. They, of course, have access to the unblinded data from across the phase III program throughout. So we've been in close contact with them and, of course, with the FDA as well.
Very clear. Thank you.
Very good. I think with that, we can close the Q&A session. Let me quickly thank again our speakers for their time and their efforts exploring new treatments here, treatment options for MS patients. Let me also thank the IR team members who worked on the slides and prepared this event. I have to call out here Alex Mora and Loren Kalm and also Melanie Wolf and Celeste Lloyd for the event organization. I hope the event was helpful in providing here a timely update on the MS franchise. If there's any remaining questions, please reach out to the Roche IR team. We're happy to follow up. I think with that, we close the call. Bye.
Thanks, everyone. Bye-bye.