Good morning and good afternoon, and welcome to Novartis conference call and live webcast. Please note that during the presentation, all participants will be in a listen-only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions by pressing star one and one at any time during the conference. Please limit yourselves to one question and return to the queue for any follow-ups. A recording of the conference call, including the Q&A session, will be available on our website after the call ends. With that, I would like to hand over to Mr. Inish O'Doherty, Executive Director, IR. Please go ahead, sir.
Thank you, Dylan. Good evening, and welcome to our conference call on remibrutinib in MS. I'll first read our safe harbor statement. The information presented today contains forward-looking statements that involve known and unknown risks, uncertainties, and other factors. These may cause actual results to be materially different from any future results, performance, or achievements expressed or implied by such statements. For a description of some of these factors, please refer to the company's Form 20-F and its most recent quarterly results, Form 6-K, that respectively were filed with and furnished to the U.S. Securities and Exchange Commission. Before we get started, I would also like to remind our analysts to please limit yourselves to one question at a time, and we'll cycle through the queue as needed. With that, I'll pass it over to Nazem.
Thank you, Inish. Good evening, everyone. My name is Nazem Atassi. I'm Global Head of Neuroscience Development Unit at Novartis. We are calling from MSToronto. I'm delighted to be here in the room with Victor Bultó from Novartis, President U.S. for Novartis, and Professor Heinz Wiendl, Professor Director of Department of Neurology and Neurophysiology at University of Freiburg. Next slide. The agenda. I'll start by giving an introduction about remibrutinib, and then Dr. Wiendl will walk us through the results of the REMODEL-1 and -2 trial. After that, Victor will go over the commercial opportunity in MS and beyond for remibrutinib. Next slide. Novartis has a long legacy in multiple sclerosis. This is a history that transformed MS care over the past two decades. Starting with Extavia, Gilenya, Mayzent, and Kesimpta.
Today we have remibrutinib results presented at MSToronto and with simultaneous publication at The Lancet. Remibrutinib is the next chapter in the MS legacy for Novartis and the focus of today's presentation. Slide number seven. Remibrutinib is a BTKI inhibitor with a pipeline-in-a-pill potential. As you can see on the slide, it is in multiple indications, including approved indications such as chronic spontaneous urticaria and chronic inducible urticaria in the U.S. In addition to RMS and SPMS, RMS is the focus of today's discussion, in addition to a number of late-phase development in immunology and dermatology. Next slide eight. The promise of BTK inhibition is in addressing both the relapses and the disability progression without chronic B-cell depletion. Remibrutinib has dual mechanism of action. It targets B-cell in the periphery with adaptive immunity to reduce acute inflammation and relapses.
It also targets microglia with innate immunity in the CNS to reduce chronic neurodegeneration and disability progression. Remibrutinib is very different than B-cell depleters, such as anti-CD20s. As opposed to anti-CD20s, it modulates B-cells without depleting them. It also targets not only B-cells, but also microglia in the CNS. It is a covalent binder with short half-life, which allows for fast start or stop if needed. It has, as you will see, a safety profile that is favorable. Next slide. Slide number nine. Remibrutinib is unique. It was designed to deliver the potential of BTK inhibition. It is a covalent, irreversible binder for sustained inhibition of BTK beyond the PK exposure. It is also CNS penetrant, reaching levels above microglial IC50 in the CNS. It is highly selective compared to other BTKI inhibitors. It allows for near-complete BTK occupancy and high potency versus other BTK inhibitors tested in vitro.
It has optimal PK and PD with short half-life, and as you can see in the middle, it has distinct chemistry compared to other BTKIs. Slide number 10. This is published data showing remibrutinib selectivity as highly selective compound tested in vitro, leading to fewer off-target effects and a differentiated benefit risk profile. As you can see, compared to other BTKIs, it achieves 100% BTK inhibition without off-target effects on other kinases. Next slide. Slide 11. As I mentioned, remibrutinib is approved in other indications. We have extensive clinical data that reinforces its proven and robust favorable safety profile. The comprehensive evidence of favorable safety profile includes not only the remibrutinib trial data that you will see today, but also includes more than 4,500 participants across 40 different studies, with dosages up to 600 mg, that took this drug.
There is no liver safety signal, including no Hy's Law cases in any of these programs or patients. In the CSU REMIX-1 and -2 phase III trials, the safety profile of remibrutinib was comparable to placebo. That includes adverse events, infections. Liver enzyme abnormalities were less than 2% in each of the arms, the placebo arm and in the treatment arm. In terms of discontinuation rates, low discontinuation rate to less than 3% in both arms. We also have more than 10,000 patients that were treated with remibrutinib for CSU commercially, with no liver safety signals reported. That translated to two FDA approvals for remibrutinib with a clean label. No black box warning, no contraindication, and no requirement for routine lab monitoring. With that, I will turn it over to Dr. Wiendl to walk us through REMODEL- 1 and -2 results in RMS. Dr. Wiendl.
Yeah. Thanks, Nazem. My name is Heinz Wiendl. I am a neurologist participating in the REMODEL steering committee, and I am presenting the data that has been released in full transparency today. This is the trial design, and this is a trial design that is rather classical. Remibrutinib is tested against teriflunomide as an active comparator. Remibrutinib is given in the MS indication with twice a day 100 mg. Teriflunomide is given with 40 mg. The trial has been done in a double-blind, double-dummy fashion, so that means patients had to take three pills. The trial design was an event-driven trial design. That means that participants were actually in variable duration within the trial, and the trial endpoints were powered on events.
The inclusion was the diagnosis of relapsing MS, and patients had to have signs of activity based on either relapses or the presence of gadolinium-enhancing lesions on MRI. This is the list of the pre-specified endpoints. This trial was basically designed to show a superiority of remibrutinib against teriflunomide based on relapses. So reduction of relapses calculated by the annualized relapse rate. We know in contemporary trials in multiple sclerosis that the number of relapses, in general, but particularly also on the comparator arms, is going lower and lower, which makes the key secondary endpoint, such as MRI, even more relevant. Why is that? MRI is 10 times more sensitive than relapses, clinical relapses. That means a very objective measure of what a drug is doing in regard to suppressing focal lesion development or gadolinium-enhancing lesion development can be objectively measured on MRI.
The disability progression is then the next secondary endpoint, and in difference to the shown endpoint on the left side, I am on slide number 14, they have been done not independently in the both trials. There were two trials. One was REMODEL-1 and the other REMODEL-2. It was done on pooled trials to increase the likelihood of the number of events. I will explain later what the difference is between the three-month confirmed disability progression, which is CDP, and the six-month confirmed disability progression. Then there is a combination endpoint, which is called NEDA, no evidence of disease activity, and then there is a biological marker of neural degeneration, which is neurofilament light. There is then another endpoint which is secondary, which we will show is progression independent of relapse activity over six months. And of course, safety and tolerability, very importantly, as endpoints in addition.
Slide number 15 shows you the baseline characteristics. To run you through this graph and the table, first of all, you have to note that the balance between REMODEL-1 and REMODEL-2 looks very good. That means there is no major differences in age or sex ratio or in time since diagnosis, et cetera. This is a typical trial in relapsing MS population with rather mild affection of those patients, which you can see as measured by the expanded disability status scale, and what you also can see on the basis of the previous relapses. So it is not atypical to see this number of relapses and a rather mild affection of the EDSS score, which goes from 0 to 10, but it is a very typical relapsing MS population nowadays. On average, those patients had approximately six years since first MS symptoms and approximately four years since diagnosis.
This is in slide number 16 that shows you our primary endpoint. Remibrutinib demonstrated a strong relapse control, translating to approximately one relapse every 13 years. The independent analysis show in REMODEL-1, a 35% relative reduction of relapse rates, and in REMODEL-2, it is 31.2%. If you translate that, how often a relapse then occurs is, as written in the title, approximately one relapse every 13 year, which is a quite robust disease control. Next slide shows you the MRI outcome measures. I was mentioning already that they have to be looked at with equal attention despite being secondary outcomes because they are more sensitive to changes and therefore also to differences between the two arms. Here, remibrutinib reduced new enlarging T2 lesions on an annualized rate by 65.3% or 70.3% in the two trials.
When you look at contrast-enhancing lesions, you are seeing a reduction of 66% and 66% in both trials. When you look at the absolute numbers, you will realize there is virtually no more gadolinium-enhancing lesions, so it is 0.08 or 0.07. All in all, this is a very significant reduction on MRI. Why am I emphasizing this? We have seen now a couple of BTK inhibitors, and the first ones we have seen, they basically did not really have a superior effect on MRI efficacy parameters in contrast to teriflunomide. When you look at also comparative data from fenebrutinib, which is another compound that has been tested in relapsing MS population, these reductions are in the same ballpark region, suppressing new T2 lesions and gadolinium-enhancing lesions. When you look at the MRI, this is a quite impressive effect. Next slide.
This is now the combined analysis of the disability endpoint. You have heard from Nazem that this compound is expected to work in the body, both in the periphery, but have also the potential to penetrate into the central nervous system. We do have data that there is CNS measurable dosages, and therefore we assume that it penetrates into the CNS. When you calculate, you would assume that the dosages that reach the central nervous system have the potential to inhibit myeloid cells there. That is the explanation why an endpoint that is mostly dominated by not the relapses, but also a relapse-independent or relapse-dependent disability progression could depend on how well the effects in the CNS compartment are played out.
When you read this three-month and six-month confirmed disability progression graphs, you see there is a difference that is already starting quite early, and that actually is statistically a difference of 20% risk reduction of three-month confirmed disability progression, which is statistically not significant. But the six-month confirmed disability progression is statistically significant, but the pattern looks the same in both graphs. If you have a look at what this difference in three months versus six months means, it is actually the robustness of the measure. European health authorities, they only accept basically the six-month confirmed disability progression because they say it is less contaminated. You definitely have more events with three-month confirmed disability progression, but it is also contaminated by transient worsenings that might be picked up. Therefore, the more robust measure is, in the community, the six-month confirmed disability progression.
If you count this the other way around, if you look here that only 7.7% had a disability progression confirmed after six months. The rest is stable. That means over 92% of the patients remain free of this progression. This means they are stable on their disability score. This is all in all a quite remarkable difference that can be shown with a compound, and we also did not see that in all of the other BTK inhibitor trials that we have seen so far. When you combine all events that show you some sort of an instability of the disease, means either clinical relapses or a change in the disability score or the occurrence of new lesions, we call that evidence of disease activity, and the opposite is called no evidence of disease activity, and these three parameters make up this acronym NEDA, and it is NEDA-3.
This is a pre-specified endpoint that you can calculate, and that has been done by counting MRIs after a so-called rebaselining after month three. What you see is you're increasing the number of NEDA patients up to 55%, which is highly significant, and the odds ratio of 2.81x. We have also data on a biological marker that is meanwhile measurable in peripheral blood, and it's called neurofilament light. Neurofilament light is spilling out of the brain when there is subacute damage. It's mostly as a consequence of focal activity. It has established itself meanwhile as a marker to get an additional support for what a drug is doing in suppressing inflammation and reducing brain damage. What you do see is a reduction in this marker as a geometric mean over time, remibrutinib reducing 9% and 7% in the two trials.
Not part of the pre-specified endpoint, but very often and relevantly asked for, is a parameter we call PIRA. PIRA stands for progression independent of relapse activity, which means that you do not want to have a contamination by so-called focal disability or focal biology, which in essence means you're eliminating the clinical relapses, and you have to find ways to eliminate this. This is then called PIRA. You basically calculate how a drug affects disability accrual in the absence of any relapses. This has been done with a strict, actually, definition of PIRA. There are more definitions than you will see. On this graph, we are at slide 22, that you see the same pattern. Basically a separation of curves with an impact on PIRA that is pretty much looking like the CDP curves that you have seen previously.
Now we're showing that because the community meanwhile asks for this, and it is an indication that a drug or a compound or an intervention is doing something that has rather little, or in the best case, nothing to do with inflammatory activity outside of the central nervous system. It does something, obviously, in we call it non-focal disease biology. I'm moving to slide 23 and coming to the important safety profile. This is the major categories we are looking at, comparing remibrutinib and teriflunomide in the pooled analysis, thousands in each arm. What you do see immediately is that there is no major differences, even that you have to acknowledge that there is less percentage of discontinuations due to adverse events, which already speaks towards a good safety and tolerability. We've seen two deaths in the trial, both in the remibrutinib arm.
One was a carbon monoxide poisoning happening at day three, and another one was a suicide at month 12 in a patient that had a previous psychiatric illness, and both are considered not related to the investigated drug. The other section is infections. This is something, of course, any immunological therapy is to be looked at with caution, and you do see really no differences in either direction. A class effect that is also listed here that is known from the class of BTK inhibitors and which is known also from the dermatological indications where remibrutinib is approved, is bleeding events. Those bleeding events are predominantly minor, and they are actually skin manifestations that are transient and reversible, and in very few cases lead to discontinuation of the drug. They actually resolve even when you continue the drug.
I think you are all aware that one major red flag in this discussion around BTK inhibitors is liver toxicity. This is particularly carefully looked at also, of course, in comparison to teriflunomide. What you do see here is much less elevation of the most sensitive liver enzyme, ALT, in different, let's say, altitudes. The combination of a certain liver enzyme elevation over three times upper limit of normal with total bilirubin is called Hy's Law, which is actually considered a very clear red flag for liver toxicity. We did not see any cases of Hy's Law, and also the rates of liver enzyme elevation are comparably much lower than in teriflunomide, which is known to have a bit of a liver signal and also requires liver monitoring in the approved condition every month for the first six months.
By the way, this is also what has been done in this trial. So for the first, let's say, two-thirds of the patient, a teriflunomide liver monitoring was applied, so every month. When the signal in the trial programs from the BTK inhibitors came out, the monitoring requirements were intensified. The monitoring was then shifted to every two weeks, which did not really change the picture. What you see in the elevations is basically the background noise of any liver enzyme elevation that you would see in placebo-controlled trials. All in all, you can summarize that this trial is pretty clean in terms of showing a significant reduction in the primary endpoint relapses, which translates to a disease control showing up one relapse every 13 years.
For me, very important, the MRI activity reduction by 65%-70% with basically very few gadolinium-enhancing lesions that ever occur under the trial's product remibrutinib. You do see a population of more than 92% that are free from disability progression. You do increase the likelihood of no evidence of disease activity by times three, and we also show a six-month reduction of progression independent of relapse activity by approximately 30%. This all in combination with a very robust and favorable safety profile, particularly as a standout no liver safety signals. We do not yet have, this is a question I got today with my presentation at the late breaking news together with a publication from colleagues. We do not yet have data for how immunoglobulins develop over time and how B-cell levels develop over time.
It is not expected that this drug is really meaningfully depleting B-cells, definitely not in the way that antibodies would do it.
Well, thank you very much Professor Wiendl for this comprehensive review. Before we move to the next slide, I just wanted to pause on the next steps. We have global regulatory filings ongoing with the U.S. expected by the end of the year with a priority review voucher. Now moving on to slide 27. We are going to move to the next section where we will cover how we are planning to maximize remibrutinib opportunity in multiple sclerosis. Here in slide 27, based on this unique profile that Professor Wiendl described in the previous section, we believe that remibrutinib has a broad potential to address patient needs across the RMS treatment landscape. In this chart we outline the main patient segments that have the potential to benefit from this treatment. As you can see, there are three main patient segments in this market.
The naive patients currently on an oral treatment, and patients currently treated with an anti-CD20 like Kesimpta. In the coming slides, we will go in depth into each segment, focusing first on the U.S. market to then describe the U.S. opportunity. Moving on to slide 28. The first segment represents naive patients, which are about 40,000 patients in the U.S. who are newly diagnosed with relapsing MS. The majority of these patients start on an anti-CD20, but about 30% of naive patients in the U.S. are not prescribed an anti-CD20, citing the safety trade-offs and/or route of administration preferences. As you can see in this chart, about 15% start on an oral treatment with the rest typically starting on injectables other than anti-CD20.
For this patient population, remibrutinib offers a comprehensive disease control with a robust favorable safety profile in an oral without the burden of frequent injections or infusion center visits. As we see it's a safe treatment to start early and stay on for the long term. Now moving on to slide 29. This next segment is characterized by patients that are currently treated with an oral therapy. It's about 60,000 patients in the U.S. These patients tend to have a strong preference for an oral treatment and/or safety concerns related to long-term B-cell depletion. 20% of oral patients actually switch treatment each year, and up to 40% are at risk of treatment failure due to efficacy or intolerance. For these patients, remibrutinib is a differentiated oral option, outperforming teriflunomide on comprehensive disease control and safety with 50% fewer discontinuations due to adverse events.
Our initial focus during the launch will be on the 40% of oral patients who are switching or continuing despite poor treatment outcomes, with the opportunity to expand over time to the entire oral population. We also expect, over time, growing safety focus to support a higher switch rate. Now, moving on to slide 30. This is the third segment and the largest one, with approximately 140,000 patients currently treated with an anti-CD20. Only 10% of these patients are switching each year, but we believe that with a new treatment option, up to 45% are eligible to sequence to another treatment like remibrutinib. As patients age and accumulate treatment exposure, concerns around infection risk and long-term B-cell depletion become more relevant.
And also, there are patients who are progressing on anti-CD20 and might want to switch to an oral that offers clinical benefit in terms of PIRA, as Professor Wiendl explained. Remibrutinib offers for these patients comprehensive disease control and a robust favorable safety profile without the need for chronic B-cell depletion. Just to note that we are currently enrolling the phase III-B RESHAPE study, which is expected to provide further evidence to inform post-anti-CD20 switch. Now, moving on to slide 31. Last, but certainly not least, the ex-U.S. opportunity also represents a significant one for remibrutinib as orals remain a sizable market, as you can see on the chart. There's about 440,000 patients treated in the top seven ex-U.S. markets, and about 60% of mild to moderate naive patients in EU5 start on orals. Anti-CD20 is the fastest-growing class, creating an increasing post-anti-CD20 opportunity as well.
And in these geographies, remibrutinib offers high efficacy oral option with a comprehensive disease control and favorable safety without the need for chronic B-cell depletion. Now, it's also important to note that we have very strong ex-U.S. commercial capabilities in multiple sclerosis to maximize this opportunity, where Kesimpta leads in NBRx share in seven out of top 10 markets. Now, moving on to slide 33. To further build remibrutinib's potential, we have several studies underway and on planning phase that I wanted to review to support switching in RMS and expansion into SPMS. So beyond the REMODEL trials that we just presented, we are now in recruiting phase for the RESHAPE trial, which is a phase III-B study that looks at patients switching from ocrelizumab. This study has the potential to build further evidence to establish remibrutinib as the oral option after anti-CD20s without the need for chronic B-cell depletion.
The earliest readout is expected in 2028. It's a non-inferiority trial versus ocrelizumab with new enlarging T2 lesions as primary endpoint, and a key secondary endpoint of no evidence of disease activity. We're also currently recruiting the REMASTER trial, which is a phase III study in non-relapsing SPMS, and we are studying the potential to slow disability progression six months CDP. The readout for this trial is expected in 2031 with that primary endpoint of six months confirmed disability. Finally, we're also planning additional studies in other settings and after other therapies to inform and support switching. Now, moving to slide 33. I want to bring it all together now to show you that remibrutinib has the potential to be a $4 billion-plus medicine in relapsing multiple sclerosis, with potential further upside from non-relapsing SPMS.
In the chart below, we have shaded in orange the populations who have the potential to most benefit from remibrutinib, and as you can see, it's north of 50% of the RMS population over time. And then also we have included an additional 85,000 non-relapsing SPMS as potential further upside if the REMASTER study shows a benefit in this population. So now moving on to slide 34. I want to highlight that to maximize this opportunity, it's important to note that remibrutinib launches into an established MS footprint in the U.S., but also across the globe. At Novartis, we have been commercializing MS drugs uninterruptedly since 2009. And many of our colleagues, including myself and Shreeram Aradhye , have been involved in the development and commercialization of Extavia, Gilenya, Mayzent, Kesimpta, and now remibrutinib.
During all these years, we have been compounding expertise and capabilities that we will now put in service of this medicine. As you can see below, in terms of HCP reach, remibrutinib will have 100% overlap with established Kesimpta prescribers. We also have an exceptionally strong marketing team who has been optimizing patient activation channels for years. Here you can see how, in terms of patient awareness, the team achieved very strong patient awareness increases for Kesimpta over the last years. Same in terms of market access. We have extraordinary expertise in market access, as demonstrated by our very strong Kesimpta access, as well as patient support programs to pull through patient requests as well. Now, moving on to slide 35.
I want to highlight that beyond MS-specific commercial capabilities, I wanted to highlight that for this launch, we're building on capabilities compounded across multiple U.S. self-administered specialty launches. But with a fully owned patient support model, with industry-leading bridge program that enables between three and five days average time to dispense, with market access team that has enabled more than 70% access to label within six months across most recent launches, as well as free to paid conversions and a really strong customer engagement team that has driven a 20% improvement in engagement effectiveness over the last three years. As you can see, we are planning to launch remibrutinib with a proven launch engine that enables fast access, rapid onboarding, and effective engagement as well. Now moving on to slide 36.
In this last section before the Q&A, I want to quickly zoom out and provide a broader perspective on the opportunity that remibrutinib offers as a pipeline in a pill. So moving on to the next slide 37. Here we currently have this chart that shows that we have two approved indications in CSU and CIndU. We just discussed the MS opportunity. Now we will highlight our plans in hidradenitis suppurativa and food allergy. Before I do that, I just want to mention as well that there's two additional late-stage trials in chronic pruritus of unknown origin and in papulopustular rosacea. So now moving to the next slide, a quick summary on our launch performance in CSU as this is the first commercial proof point, sorry, for remibrutinib, with strong momentum building towards first-line leadership.
As of Q2, we had 200,000 U.S. patients treated, more than 4,000 prescribers across allergy and dermatology, with the majority of patients prescribed in first line right after antihistamines, and with strong access secured as well. As a reminder, it's a very large opportunity with above 500,000 U.S. CSU patients on control and antihistamines, and we have extra lab also ongoing. Just to highlight in terms of upcoming catalyst, an adolescent phase III readout this year, and also a phase III-B RECLAIM study, which is a head-to-head versus Dupixent with a readout in the first half of 2027. Now moving to slide 39, just briefly also mentioning that Rhapsido is also expanding into CIndU with the first and only FDA approval in symptomatic dermographism, building on that same prescriber base as CSU. We received approval in October 2026 for this subgroup, symptomatic dermographism, that represents two-thirds of CIndU patients.
In these populations, we saw twice as many adults taking Rhapsido achieving complete hive resolution by week 12. Again, a very important opportunity with about 100,000 patients in the U.S. with this indication. Now moving on to slide 40. Briefly in HS, our phase II data support remibrutinib as an oral option. HS, a large and undertreated market. Just as a reminder, HS is a chronic and debilitating disease characterized by painful nodules, abscesses, and tunnels with scarring, with about 440,000 moderate to severe patients. It's an underdeveloped and undertreated population. In our phase II, we observed biologic-like efficacy at week 16 versus placebo. We are now conducting the RECHARGE- 1 and -2 phase III trials, which are two identical trials with a primary endpoint of hidradenitis suppurativa clinical response 50 at week 16.
This week 16 readout is expected in Q4 2026, with the first filings in 2027 with 52-week data. Moving on to the next slide. In food allergy, we also saw a rapid dose-dependent phase II results that support remibrutinib's multi-allergen phase III program. In food allergy, there are more than 3.5 million high-risk eligible patients across major markets, with few targeted options and the constant risk of accidental exposure that create a need for a fast allergen-agnostic protection. As you can see in the chart, in our phase II trial, we observed dose-dependent response as early as week four. In the phase III trial, we're testing remibrutinib 75 mg versus placebo, with multi-allergen focus for the global market in patients 12 to 65 years old. In the phase III, just to note, it was initiating Q3 2026 with an expected readout beyond 2029.
Finally, moving to the slide 42. I just wanted to say in closing that with remibrutinib, we have a medicine that is differentiated by design, highly selective, potent covalent BTK inhibitor that enables immunomodulation without chronic B-cell depletion. With remibrutinib, we are able to offer comprehensive disease control with significant reductions in relapses and MRI lesion activity, as well as clinically meaningful delay in disability progression, coupled importantly with a robust, favorable safety profile with no liver safety signal, no infection imbalances versus the infliximab, and nearly 50% fewer discontinuations due to adverse events. We also saw how at Novartis, we have both the scale and the capabilities to maximize this opportunity that has broad potential across naive, oral, and anti-CD20 switch patients, and launching into an established MS footprint.
Finally, last but not least, with remibrutinib, we've seen that we have a pipeline in a pill. We've indicated a $4 billion peak sales potential in RMS with upside from non-relapsing SPMS, and also a $4 billion peak sales potential in CSU and CIndU, plus a phase III HS study reading out in Q4 2026, and additional studies ongoing in food allergy, CPUO, and papulopustular rosacea. With that, we will open the line for questions. Please, operator.
Thank you, sir. As a reminder, to ask a question, you will need to press star one one on your telephone. To withdraw your question, please press star one one again. We ask that you please limit your questions to no more than one, but feel free to go back into the queue, and if time permits, we will be happy to take your follow-up questions at that time. Please stand by while we compile the Q&A roster. I show our first question comes from the line of Michael Leuchten from Jefferies. Please go ahead.
Hello. Thank you very much. I was wondering if you could speak to the split of efficacy between treatment-naive and treatment-experienced patients. You had 60% of patients naive in the trial, and the Professor talked to how this is a pretty standard patient population that he would see. Is there any data you could share on the efficacy, naive versus experienced, please?
Well, thank you very much for the question. Michael, Nazem?
Michael, so the results are for the overall population, and this population, 60/40 breakdown between naive and prior treated patient is relatively typical for MS population. We have not looked at subgroup analysis at this point, but we will for sure. When we have this information, we will be happy to share it at future conferences. Thank you for your question.
Thank you.
Thank you. Our next question comes from the line of Trung Huynh. Please go ahead.
Hi, guys. Thanks for hosting the presentation. I just have a question on the label. The six-month confirmed disability progression that was reduced by around 30%, it had a nominal P value. The three-month CDP, it showed a trend, 20% with a P value of 0.09. Do you think you can get the six-month CDP benefit on your label? Then just your thoughts on if FDA could impose a class-wide liver monitoring requirement for all BTK inhibitors in MS. I know your data showed no Hy's Law cases, and I appreciate that CSU, that is 3 , but that was 25 mg versus 100 mg for MS. Just thoughts on the label, please.
Well, thank you very much for your questions, Trung. On the first one, in terms of what is going to come in the label, these will be further discussed with regulatory agencies across the globe. Overall, we feel very confident that we have a package that is solid and broad enough that will allow us to promote this drug appropriately, both across comprehensive disease control and safety. Now, in terms of the FDA liver monitoring potential, Nazem, do you want to take that one?
Yeah. No, absolutely. I can take this one. When it comes to safety, I would say that remibrutinib is a class on its own. We don't expect to have monitoring in the label. Obviously, this is pending discussions with the regulators. But we believe we have a very strong case to make to the regulators. Both the data that we have in REMODEL-1 and -2, which is a pretty substantial number of patients that were exposed to remibrutinib, were clean, as you have seen. No liver enzyme elevations and no Hy's Law cases. This is in addition to the 4,500 patients that were treated in trials up to 600 mg dosages and the 10,000 patients that took this drug on the market for CSU. As you have seen in the CSU label, we don't have monitoring requirements or a black box for this one.
Because of all of these things, we don't expect that to have monitoring in the label. One thing maybe I would add that having monitoring in clinical trials does not automatically translate to having the same monitoring in the label. The CSU trial is a good example for that. We had to monitor for remibrutinib in the REMIX-1 and -2 trials, but there were no requirements in the label. That's a good example. But it's an important question, and I know you're asking about the monitoring, which is the burden both on the physician, the HCPs, and on the patients to come in and do these tests, which sometimes also can be false positive or slightly elevated. They have to come back, and it is a big burden. But also, I think we should not forget the real problem, which is the liver tox.
Hy's Law cases in other programs. Having a Hy's Law case in drugs is not a simple thing. It's really a major safety risk that we need to keep in mind. Monitoring is important. We don't expect to have that in the label, but also safety is even more important than that. Thanks for your question.
Thank you. I show our next question comes from the line of Alek Ebbeling from UBS. Please go ahead.
Hi. Thanks for taking my question. It is on fatalities. You noted one suicide in the remibrutinib arm, which I understand was in a patient with a history of psychiatric illness. Given that the fenebrutinib RMS and PPMS trials both had suicides in the active arm and not in the comparator arm, and since BTKIs are brain penetrant, how do you rationalize this? To further to that, would you consider adding a mood scale or something similar in other remibrutinib MS trials? Thank you.
Thank you, Alek, for your question. I am going to ask Professor Wiendl to offer his perspective.
Well, first of all, given the high number of more than 2,000 patients, a suicide in such a population might very well be a background noise. That is one thing. The other thing is, I already noted that this patient specifically had a history of psychiatric illness and depression. So it is rather unlikely and by the principal investigator, not related to the drug described. I know the fenebrutinib data and these cases look really different, and they are hard to explain because they seemingly be associated with the drug. I do not see this being a real question to come up with remibrutinib, honestly. I also do not think this is a class effect, but this is a good pick that you made. This is a struggle that fenebrutinib has to solve.
I do not think that this is really something that is seriously coming up with this percentage or number we have seen.
Thank you, Professor Wiendl.
Thank you. Our next question in the queue comes from the line of Thibault Boutherin from Morgan Stanley. Please go ahead.
Yes. Thank you. Maybe a question for Victor. Just considering the different dosing across indications, how should we think about potential for different brands for each indication and sort of style of pricing? You are thinking about this and sort of balancing the arbitrage between dosing and indications.
Yeah. Thank you very much, Thibault. We are, of course, thinking about it very carefully. What I can tell you is that we have aligned with the FDA to have separate brands in immunology and in multiple sclerosis. These will be filed as separate NDAs. In terms of pricing, we will, as we always do, disclose that at launch.
Thank you.
Thank you. Our next question comes from the line of James Quigley from Goldman Sachs. Please go ahead.
Hi there. Thanks for taking our questions. One for Dr. Wiendl. Reading the stats plan in The Lancet, the trial was initially powered to detect a 45% reduction in ARR and a 40% benefit on CDP, and this looks fairly consistent across all the other phase III designs. Is that what would have been considered clinically meaningful? How do you put the data here in the context of that? You mentioned that the MRI was similar to fenebrutinib, but the ARR endpoints are not. What could be the reasoning here?
The line was not perfect. If I understand, your question is, would I consider this reductions of clinical relapses clinically meaningful? The answer is, while it's definitely statistically meaningful, and if you translate what it means to a patient with MS to have one relapse in, let's say, 13 or 14 years, that's clearly meaningful because to eliminate relapses, we're considering the goal of zero disease activity or zero tolerance. That's definitely worth. The difference to fenebrutinib is another question, and I already referred to it's hard to compare across trial. What can be said is that the fenebrutinib trial had a different population. They were more active. There were more patients that were treatment naive, and they had for that reason, higher, let's say, relapse activity when they were included.
This partly explains to me why the relative relapse rate reduction numerically seemed higher at 50% +. When you look at the MRI, which I already alluded to, is, in my opinion the more objective and sensitive measure what a drug is statistically also doing, there is not that much difference, okay? The problem is, and I guess this has to be really sensed, very few relapse events in a condition where there are not that many events actually change the numbers quite significantly. When you look in this high number of recruited patients, there were very few events, and this is what I mentioned with it's a rather low active contemporary population. Therefore, the reduction would be considered, yes, definitely clinically meaningful. It's hard to say whether there is so much of a difference in regard to fenebrutinib.
Thank you. I show our next question comes from the line of Richard Vosser from JP Morgan. Please go ahead.
Hi. Thanks for taking my question. Just a question about your ability to continue to grow Kesimpta at the same time as launching remibrutinib. Obviously, Victor, you outlined significant patients where you could use remibrutinib, but how are you going to differentiate between the two products to ensure continued growth of Kesimpta? Thanks very much.
Well, thank you very much, Richard. Very good question. If you go back to the three categories that I described of patients that can benefit from remibrutinib, I started with a naive population, stating that about 70% of those patients are currently started on anti-CD20, and we don't expect that to change significantly. Those high efficacy therapies are a great drug for patients to start, and we expect that to continue to be the case. But after so many years of B-cell therapies being commercialized, including Kesimpta, there's still a substantial proportion, 30% of those patients, that are not starting on CD20. So we believe that's a great first step that will not affect the performance of Kesimpta. Then I described the oral population that obviously does not affect Kesimpta or anti-CD20, so those patients are on more legacy products.
When it comes to the anti-CD20 population, I did share that about 45% of that population, we believe, will be eligible to sequence. There we expect a modest impact on Kesimpta just because about 75% of those patients currently are not on Kesimpta. They are on other anti-CD20s in the U.S. So although there might be some effect on Kesimpta, it will be predominantly affecting other therapies. That is why also the phase III study, RESHAPE, is actually a switch off ocrelizumab, which is the predominantly used therapy. So we continue to see a $6 billion plus opportunity for Kesimpta not affected by this launch. I will also lastly mention that ex-U.S., where Kesimpta also has a very strong performance, the majority of patients are still on oral therapies. Therefore, a lot of opportunity there to continue to grow.
So all in all, Richard, to your question, we believe we can grow these two brands concurrently. We also have very clear positioning for one or the other that will allow us to use the same field teams and create substantial synergies as we promote them both.
Thank you. I show our next question comes from the line of Simon Baker from Rothschild & Co Redburn. Please go ahead.
Thank you. Thank you for my question. I hope you can hear me, there is not too much background noise. I just wanted to drill down with Professor Wiendl on the clinician and patient perspective on switch motivation. If a therapy is working, is there much appetite to change? It would be good to get an idea of what really does drive change of therapy other than relapse. Thanks so much.
Simon, just to confirm, you're thinking about switching post-CD20 or in general?
Switches in general. I mean—
Okay.
—really going back to your slide about the opportunity for remibrutinib. Yeah.
Totally fair question. So what are reasons to switch? I mean, we're usually categorizing in a so-called vertical and horizontal switch. What is meant by this is, if you're on a drug and you're doing fine, so the disease is totally okay, you might have, for example, tolerability problems, so you're not well tolerating the drug. In the group of orals, we do have this problem, but maybe also in the group of injectables. So you're doing it because you're not doing perfectly well, but the disease activity is not the reason. So that is one reason. The other is if the previous therapy is not optimally controlling the disease, so you're optimizing the disease. So this is the, let's say, a more medical disease-controlling reason. Then there is a third reason, which is a so-called conceptual switch or a, let's say, switch for other reasons.
Let's say lifetime decisions, changing business. You don't want to infuse anymore, you don't want to inject anymore. For all of those switchings, which happen relatively frequently, one has to say, remibrutinib is an option.
Yes, thank you very much, Professor Wiendl. Simon, just to put a point on that and link it to the presentation. In slides 30 and 31, what we did is actually note what are the patients that actually comply with those conditions Professor Wiendl has described, right? The patients currently on oral, up to 40% are at risk of treatment failure because of either one of those. Then slide 31, you see for the post anti-CD20, we looked at that eligibility to sequence as well based on those considerations, right? We excluded patients who are stable on those therapies, which, as you pointed out, would not be inclined to switch.
Right. Thank you very much.
Thank you. I show our next question in the queue comes from the line of Steve Scala from TD Cowen. Please go ahead.
Thank you very much. A question for Professor Wiendl. In two or three years, what do you anticipate the share split between remibrutinib and fenebrutinib to be in your practice? For instance, might it be 50/50 or 60/40 favoring remibrutinib? Since safety is probably a factor in your answer, I think Roche has said the seven deaths on fenebrutinib are not drug-related. Do you think that that is a flawed conclusion?
I do think that particularly with this decision-making, the complete medication profile is key, and this is very much influenced if they are considered pretty equally efficacious, it's safety and it's monitoring burden. I think this is crucial, and Nazem did mention there is a very high likelihood that there is no monitoring requirement, and this is something that eases the job tremendously. The monitoring situation I'm practicing in the E.U., we have tolebrutinib approved, which is a very harsh monitoring requirement every week, basically, for a couple of months. Given the low burden of monitoring with the contemporary medications, particularly B-cell depletion and other orals, this is a drawback. So that would be one clearly strong discriminator that you can outbeat with a highly significant, better maybe efficacy, which we don't see.
Thank you.
Thank you. Our next question in the queue comes from the line of Michael Leuchten from Jefferies. Please go ahead.
Thank you for my follow-up. A question for Professor Wiendl. There are different ways of looking at disability as you outlined. So there is the standard CDP, there is NEDA, there is PIRA. I think for fenebrutinib, they looked at a composite CDP score. What is the best yardstick to measure disability from your perspective?
Thanks for the question. I am coming from a meeting where we discussed about how do we best measure disability, and what is the best measure. The simple answer is, probably the most accepted one is the six months confirmed disability progression. This is the most often used one. It is based on a clinical score. Then there is a couple of very sophisticated approaches on this combined measures to measure disability, combining with nine hole peg test with 25-foot walk test to, simply spoken, increase event rates. So if either of the three shows up, then you are changing in terms of disability. What we have seen is that they are maybe increasing event rates, but they are not really increasing power. So basically, my clean answer to it is, it is nowadays CDP.
PIRA is very often asked, but it is very much depending on the definition you are using, and combined endpoints are having not really shown consistently that they are so much superior, depending on whom you talk to. The only combination that it probably makes sense is the combination of EDSS, which is the basis for CDP in combination with the nine hole peg test, which is testing the upper arm functions. So it is a different functional system in a way. But to simplify the answer, I guess with a CDP endpoint, we are on safe grounds.
Thank you. Our next question in the queue comes from the line of Richard Vosser from JP Morgan. Please go ahead.
Thanks for taking my follow-up. Just one on MFN pricing in Europe. You mentioned, Victor, I think that this will be a separate NDA. Does that mean that you will come under the MFN pricing regulations with respect to Europe, and how do you think that might impact the uptake in Europe, if that is indeed the case? Thanks very much.
Yeah, no. Thank you very much, Richard. The MFN agreement actually contemplates products at a molecule level, independently of whether they are the same NDA or separate NDAs. So answering your question directly, ex-U.S. prices will only affect the Medicaid segment in the United States, which in multiple sclerosis was around 10%. So that will be a difference. That is basically because we already launched remibrutinib in chronic spontaneous urticaria before we signed that agreement with the U.S. government. So that will be in contrast with drugs that will get approved after those deals were signed. So we expect a minor impact that we have already incorporated into the guidance that we have provided.
Of course, we will work in coordinating to make sure that we both ensure broad access ex-U.S., which as you can see is a very large market, while also being mindful of the Medicaid price in the U.S.
Excellent. Thank you.
Thank you. Our last question in the queue comes from the line of Steve Scala from TD Cowen. Please go ahead.
Thank you very much. I have a question for Victor, but before I ask that, Dr. Wiendl, I assume based on the answer to the share question, remibrutinib will be the only BTK you prescribe. If you can just confirm that. For Victor, given how strong Novartis sees the remibrutinib data and a handful of concerns about fenebrutinib tox, why isn't Novartis raising the $4 billion remibrutinib sales target? I have to say, you sounded more confident in the HS data than I would have expected. Is the data in-house? Thank you.
Steve, to your last question on the HS data, no, it is not in-house. I was talking on the basis of what we've seen in the phase II trial. Of course, that will have to be confirmed in the phase III. In terms of the opportunity, Steve, we are very optimistic on this profile. As Professor Wiendl, we concur with Professor Wiendl's perspective on the benefit risk profile of this drug. At this point, we're guiding to this $4 billion-plus opportunity. I'll ask Professor Wiendl to answer the first question.
Well, in medicine, I would never. I'm practicing in an academic environment where we are obliged to also get experience with all approved drugs. But in tendency, my preference clearly would be given the rather not that divergent efficacy profile remibrutinib. There is another part of the answer that is the label. In case there is a label that is potentially primary progressive MS in fenebrutinib, then there would be a place for fenebrutinib because there would currently not be an expected label for remibrutinib.
Okay. Well, thank you very much, Professor Wiendl. With that, I think we've come to end of the call. I want to take this opportunity to thank Professor Wiendl for joining us tonight. Thank you very much to all of you for joining us, and I wish everyone a wonderful weekend ahead. Thank you very much.
Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.