Recently had three phase III readouts, and we are pleased to already being able to present this data today. This event has a presentation which is available for download at sanofi.com. We plan to spend about twenty to twenty-five minutes on the presentation, and then we got the same time available for Q&A. It is Friday afternoon, so we plan to end a bit before 5:00 P.M. local time. Before we get started, I would like to thank Elise, Marie, and Caroline from the IR team for organizing the call. I'll also remind everyone that questions can be asked via Zoom using the Raise Hand function or on your phone. There are instructions on the second last slide. Alternatively, please drop an email to thomas.larsen@sanofi.com. We'll make sure to include as many questions as we can in the Q&A session. After the introduction, slide three has our usual safe harbor statement. Slide four has today's agenda and presenters. I'm pleased to welcome Dr. Jiwon Oh, who is the primary investigator in the tolebrutinib Phase III program in relapsing MS, and presented the data at ECTRIMS earlier today. Also, a warm welcome to Dr. Robert Fox, who is the primary investigator in the Phase III study for tolebrutinib in non-relapsing secondary progressive MS, and also presented earlier today. We also got Houman here, who is Sanofi EVP and Head of Research and Development, with past treatment experience in MS. Please go to slide number five. In 2024, we are pleased to have shared lots of encouraging milestones from the new Sanofi pipeline, including a high number of regulatory approvals at the bottom of the slide. At the top, we have phase III data readouts and regulatory submissions and designations. Except two data points, all have been positive, and we are pleased with the recent progress in R&D productivity, the lifeblood in our industry, continuing to chase the miracles of science to improve people's lives. With this, I'll hand over to Dr. Oh on slide number six. Thank you very much. So I will now present a quick summary of the phase III relapsing MS clinical trial program in tolebrutinib. And I will be going through these slides pretty quickly, but if there are specific questions, I'm very happy to answer them during the Q&A session. So I know you're probably very familiar, but GEMINI 1 and 2 were the two phase III clinical trials evaluating the efficacy and safety of tolebrutinib in comparison to an active comparator, teriflunomide, in people with relapsing MS. This slide here summarizes what the study design looked like. And so this was a phase III, multicenter, randomized, double-blind, double-dummy, active-controlled, parallel group, event-driven trials, and there were two of them and were identical. Patients were randomized in a one-to-one ratio to either tolebrutinib at 60 milligrams, taken orally once daily, or teriflunomide at 14 milligrams, taken once daily. This was an event-driven trial, and so participants were in the trial until 162 confirmed disability worsening events that were confirmed at six months were observed. The key inclusion and exclusion criteria are summarized on the right hand of the slide, but this is quite typical of what contemporary relapsing MS clinical trials include. Next slide. So this slide summarizes what the participant disposition looked like in both GEMINI 1 and 2. And so, as you can see in GEMINI 1, a total of 974 relapsing MS patients were randomized. In GEMINI 2, a very similar number of nearly nine hundred participants were randomized. And then, when you look down, the vast majority of participants completed the study, so it was approximately 85% in both clinical trials, and this was balanced between both the teriflunomide and tolebrutinib treatment arms. Next slide. When you look at participant baseline characteristics, and as you can see in this slide, baseline characteristics are summarized by individual GEMINI clinical trial, as well as by treatment arm. It's reassuring because patient characteristics were quite well-balanced. And again, this is quite typical of what we see in contemporary relapsing MS clinical trials, in that most participants were in their mid to later thirties, most are predominantly female, had a lower EDSS score, and there were 60% of patients who were treatment naive. Next slide. So, when you look at the primary endpoint of interest, which is, again, typical for relapsing MS clinical trials, this endpoint was annualized relapse rate. And this endpoint was pre-specified to be analyzed individually in each GEMINI clinical trial. As you can see, there really was no difference in the annualized relapse rate for tolebrutinib in comparison to Teriflunomide in GEMINI 1 and 2. It's important to note the relapse rate was quite low. So you can see that a relapse rate of 0.12, 0.11 was quite low. And this is not to say that tolebrutinib did not have an effect on relapses. It's just simply to say that there was no difference in comparison to Teriflunomide, which is a pretty widely used platform agent in relapsing MS. Next slide. When you look at the key secondary endpoint, and this is where things get really interesting. The primary endpoint was obviously negative, and so I should also mention that there was a pre-specified statistical hierarchical analysis. Technically, when the primary endpoint is negative, subsequent endpoints, the p-value is considered nominal. Nonetheless, these data are very interesting to look at and important because they really inform the results of the HERCULES clinical trial that Dr. Fox will be presenting after me. Despite the fact that, when you look at annualized relapse rate, there really was no difference in tolebrutinib versus teriflunomide. It's really important to note that when you look at the secondary key endpoint, which was confirmed disability worsening, confirmed at six months, there was a clear 29% risk reduction in people treated with tolebrutinib versus teriflunomide, and the p-value was 0.02, which is below the typical threshold of 0.05, which we consider statistically significant. But again, because the primary endpoint was not met, this is considered nominal. Moving on, and sorry, I should mention in that slide, I apologize. Because there was such a low relapse rate, again, this is very interesting because what this tells us is that tolebrutinib really has a relapse-independent beneficial effect on reducing disability worsening, which is of high interest in the MS field and truly the greatest unmet clinical need. Next slide. Importantly, when we looked at adverse events, and this is a table that summarizes all of the adverse events, so any treatment emergent adverse event, as well as serious adverse events. As you can see, this was relatively well-balanced between Teriflunomide and tolebrutinib treatment arms. There was a single death in the tolebrutinib treatment arm, but this was related to homicide and deemed to be unrelated to tolebrutinib, which is reassuring, and then when you look at the most common treatment-emergent adverse events, which were seen in 5% or more of people treated with tolebrutinib, as you can see, these were by far either COVID-19 infection or nasopharyngitis, and then a list of pretty common treatment-emergent adverse events that we see with many of our existing MS disease-modifying treatments. Next slide. When you look at liver safety in a bit more detail, and this is obviously important because there has been a signal that has emerged not just with tolebrutinib, but other BTKIs being investigated in MS, it's important to take a look at this. As you can see, there were 5.6% of people treated with tolebrutinib who did, at one point in the clinical trial, develop an elevation of their ALT of three times or more than the upper limit of normal, and this is summarized by the two bars on the left. So this is the total number of individuals in Gemini 1 and 2 that at any time point in the clinical trial developed elevation of their liver enzymes greater than three times the upper limit of normal. When you look more to the right of this figure here, the magnitude of liver enzyme elevation is summarized, and so, as you can see, with the elevations that were on the lower end, you can very clearly see that both teriflunomide and tolebrutinib have small proportions of people that did have elevations, but on the higher end, where the liver enzyme elevation was more than 20 times the upper limit of normal, there was a small proportion of people, 0.5%, treated with tolebrutinib, that did develop liver enzyme elevation more than 20 times the upper limit of normal, but all of these cases resolved without any sequelae, and importantly, they all occurred within the first 90 days of treatment. Once this liver signal was identified, there was a frequent monitoring of liver enzymes that was implemented across the entire clinical development program. Next slide. To conclude, I think these data show that, number one, there was no significant difference in the annualized relapse rate between tolebrutinib and teriflunomide. Again, this was the primary endpoint of interest in these clinical trials. However, what is really interesting, though, is that despite the fact that there was no difference on relapse rate, for tolebrutinib versus teriflunomide, there was a clear 29% risk reduction in six-month confirmed disability worsening of tolebrutinib-treated participants versus teriflunomide. We didn't present these MRI data, but we can go into a little more detail about this. What also emphasizes the fact that tolebrutinib likely has a very clear effect on disability worsening, that is independent of, focal inflammatory disease or what we often in the field refer to as relapse disease biology, is that, again, the annualized relapse rate was not different between tolebrutinib and Teriflunomide. And really interesting, tolebrutinib-treated patients had larger numbers of gadolinium-enhancing lesions that formed during the treatment period in comparison to Teriflunomide, but despite this, again, demonstrated a clear reduction in confirmed disability worsening. With respect to liver safety, again, 5.6% of participants treated with tolebrutinib developed at any time point in the clinical trial, an elevation of three times or more than the upper limit of normal, and again, this is a signal that's been reported with other BTKIs in MS, but reassuringly, all cases resolved without sequelae. All of these cases, again, took place within the first ninety days of treatment, and so because of these, this observation, as well as observations in the other clinical trials, frequent liver monitoring in the first ninety days has been implemented. So overall, based on these data, it seems clear that tolebrutinib showed a clear reduction in disability accumulation, despite no differences in relapses versus Teriflunomide, and these results are consistent with the hypothesis that acute focal inflammation and smoldering compartmentalized neuroinflammation are two distinct biological processes in MS. Thank you very much. All right, well, I'm Bob Fox from the Mellen Center at the Cleveland Clinic, and it's my pleasure to share with you the results of the non-relapsing secondary progressive phase III trial, the HERCULES trial. Next slide. So this was a phase III, multicenter, randomized, double-blind, placebo-controlled, event-driven trial in people with non-relapsing secondary progressive MS. The eligibility criteria, age up to sixty, a little bit older than many of our previous progressive trials, patients had to have a diagnosis of secondary progressive MS and documented evidence of disability progression in the previous twelve months. They also had to have had no clinical relapse in the last twenty-four months or two years, although we'll see shortly that the majority of these patients had a much longer time period since their last clinical relapse. And their disability score using the EDSS, which is a standard disability score, had to be between three and 6.5, inclusive, at screening. Patients were then randomized in a two to one ratio to receive tolebrutinib, 60 milligrams orally, one tablet daily, or a matching placebo, and followed over time. Clinical assessments were conducted every three months to assess disability and other clinical assessments. Brain MRI was conducted every six months for the first two years, and then annually thereafter. Patients who demonstrated sustained progression of disability were offered the opportunity to switch from their randomized treatment, which remained blinded, to open-label tolebrutinib for the remainder of the trial. As I mentioned previously, this was an event-driven trial, so all participants continued in the trial, in the arms they were randomized into, until 288 6- month confirmed disability progression events were observed, and that was when the trial was considered sufficiently powered to then close the trial, lock the database, and do the analysis. Next slide. 1,131 patients were randomized, again, in a two to one ratio between tolebrutinib and placebo. One can see here an equal discontinuation rate of about 23%, in each of the tolebrutinib and placebo trials. One can also see here, 12% and 17.8% patients shifted from the randomized treatment assignment to open-label tolebrutinib when they met the sustained progression of disability criteria. Next slide. At baseline, we can see that this was a fairly typical secondary progressive MS patient population, an average age of 49, a median disability, as measured by the EDSS scale, of 6.0, and about 12 to 13% of patients had gadolinium-enhancing lesions at baseline. Importantly, the average time since the last relapse was over 7 years in both groups. This patient population was very quiescent in terms of the relapsing pathology as manifest by clinical relapse. A truly non-relapsing secondary progressive patient population. Next slide. This is what we found. The primary outcome, which was time to a 6-month confirmed disability progression, meaning patients had to have had a progression on the clinical disability scale, EDSS, that was confirmed six months later. There was a 31% risk reduction, with 37% of the placebo patients achieving that confirmed disability progression in the placebo group, and 26.9% in the tolebrutinib group. One can see that right at the beginning, at three, six, and nine months, these lines are starting to separate, and they continue separating over the entire course. If one were to draw an imaginary line at the 25% range, one can see a rough doubling of the time to have 25% of the tolebrutinib group having sustained progression and disability relative to the placebo group. Next slide. Secondary outcome, six-month confirmed disability improvement. So this is flipping the disability progression analysis upside down, and instead, looking at the proportion of patients with an improvement. And one can see an 88% increase in the six-month confirmed disability improvement proportion, with 10% improvement in tolebrutinib compared to 5%. Next slide. Turning to safety, there was a similar overall treatment-emergent adverse event rate in the two treatment arms. But looking at the individual adverse events, one can see a little bit of differences. There was an increased rate of respiratory infections, as shown here by COVID-19 infection and nasopharyngitis, also called the common cold, a slight increase rate in the tolebrutinib group for each of these adverse events compared to placebo. Next slide. Turning to liver, a very important area of safety with tolebrutinib and BTK inhibitors in general. One can see on the left, 4% of the tolebrutinib-treated patients had a three times upper limit of normal or greater increase in their ALT, an important liver enzyme, and that compared to 1.6% of the placebo groups. One can see the individual breakdown of that above three times upper limit normal in each of the pairs of bars to the right. I'll draw your attention to the ALT over 20 times upper limit normal, and one can see that the tolebrutinib arm had 0.5%, which you can think of, of course, being about one in 200 patients, had a 20 times upper limit normal increase, and that is compared to none of the placebo groups. Similar to the GEMINI 1 trial, all of the subjects with a 20 times upper limit normal increase in their liver enzymes had that increase in the first 90 days, the first three months of taking tolebrutinib, so it identified the window where we have to be super vigilant. When this was recognized, there was an increased monitoring with weekly liver enzyme assessments between week 2 and week 12 to help have better granularity and better identification of cases. One of these above 20 times upper limit of normal enzyme patients, unfortunately, needed to undergo a liver transplant, and in the immediate post-operative period following liver transplant, passed away from complications of the liver transplant, so a reminder that these elevations of liver enzymes can be very serious. Next slide. In conclusion, treatment with tolebrutinib in a patient population of non-relapsing secondary progressive MS was associated with a 31% risk reduction in the time to six-month confirmed disability progression, and again, compared to placebo. It also increased the probability of achieving a six-month confirmed disability improvement. I didn't show you the data, but there was a reduction in the new and large T2 lesions, compared to placebo, and the liver enzymes, and similar to GEMINI 1 and 2, and similar to what has been seen with other BTK inhibitors, there are rare cases of very significant and serious liver irritation. The vast majority of these cases resolve without sequelae, and all of them occur within the first three months of treatment. and we are hoping that more intensive monitoring can help identify these cases very early, so we can intervene to stop treatment with tolebrutinib and hopefully avoid more serious liver injury. Putting together the results of this trial and the Gemini One and Two, we do seem to have a drug, tolebrutinib, that has a consistent impact on disability accumulation that appears to be driven by its effects within the central nervous system on the compartmentalized inflammation within the brain. Perfect. I'd like to start by thanking everybody who's participated in this trial, the legions of both Sanofi employees and patients who've submitted to this trial. I'd like to thank the investigators, two of which, esteemed guest colleagues, are sitting around the table with me. And, of course, the other investigators that are around the table. It's a particular pleasure to be here on a day where the moderator of the session described as a historic opportunity for patients. But I have a particular excitement to be here, but a humility in the face of disease. As you'll hear, there is more work to do, even after this drug hopefully gets approved. So, next slide, please. As has been our commitment to multiple sclerosis, tolebrutinib is the first and only medicine to demonstrate delay in the time of onset, confirmed disability progression in SPMS. That's been pretty clear, talking to physicians all day. Patients have experienced confirmed disability improvement at various points, nearly twofold higher than tolebrutinib, particularly in the HERCULES study, and of course, the pooled analysis, the secondary endpoint with a nominal significance in GEMINI 1 and 2 confirms that this disability is a consistent feature with the use of this drug. I'd like to add, actually, in addition to the slide, that, the data here provides not only a path to regulatory approval in our view, but also opens up a new vista to have a more nuanced view about the interpretation of the biology in SPMS and, multiple sclerosis, which will be not just the focus for further investigation by Sanofi and others. Bottom line is this is a potential for a new standard of care in SPMS, and we look forward to accelerating this as much as we can through the regulator to get it into the hands of patients as appropriate. Next slide, please. So, the two investigators have already clarified the importance of this drug in SPMS, but I want to make it clear that SPMS is a stage of disease that can develop after RMS. It's characterized by accumulation of disability regardless of relapse activity. This notion of PIRA has been something that's been prevalent at ECTRIMS this year, and I think will become more a topic of conversation as we go on. Progressive forms of disease in MS are genetically distinct from relapsing disease and have proved harder to treat. So it's important that tolebrutinib has been able to make an impact on this disease. At first glance, 172,000 patients have been diagnosed with this, 65,000 of which are in the US and EU5. One of the themes that has been emergent at ECTRIMS this year is that in different settings, these disease, this particular disease, SPMS, has been underdiagnosed and undertreated, probably due to both disease reclassification and due to lack of effective treatments. And we hope that tolebrutinib will be the first drug to provide a catalyst for the reclassification of these patients into the disease course and drug course that they will ultimately receive. One of my comments, next slide, please, since I joined Sanofi, is we are moving, and have moved, from an organization that thinks about single assets to franchises. Our plan is to be here for physicians today with our armamentarium of drugs for all substructure of disease. But our commitment in areas like MS, and others, is we will be here till the end of Sanofi's time to support them with this disease. frexalimab is an example of our commitment to this space. Hot on the heels of tolebrutinib, this really important CD40 ligand inhibitor is making important impacts, starting with the biology of this molecule. Of course, you may care to review a science journal review by Randolph Noelle three or four weeks ago, outlines beautifully in his and their words the ability of frexalimab to have an unbridled effect on the control of disease. And that relates both to its ability to license dendritic cells to activate T cells, but also its ability to drive tertiary lymphoid structures with B cells and humoral immune response, but also the importance of the majority of myeloid cells requiring CD40 ligand activation for their function. We believe that this provides a much broader, powerful impact on apical node disease than other therapies that are currently available in MS. That's played out nicely by the 72-week data on the phase 2 extension, which shows the gadolinium T1 lesions, new... The number of new T1 lesions and enlarging T1 lesions remain small, remarkably low ARR, which was 0.07, with EDSS being stable. This provides us with real optimism to continue our forays through the phase three of frexalimab, both in RRMS and SPMS, and our commitment to the space. Next slide, please. As a manifestation of our commitment to the space, we obviously, with Aubagio and Lemtrada, have a real depth of provenance here, both in terms of molecules and talent, but also relationship with investigators for whom we care a great deal. Our future looks the variety of molecules in the palette, which include, of course, the BTK inhibitor, a CD40 ligand antibody, but also our RIPK1 molecule, which is in phase II for a number of the structure of multiple sclerosis. With that, I'd like to hand back over to Thomas and his IR team, who've done a sterling job today. Thanks for this, Houman. Now we have time for Q&A. We kindly ask that only investors and analysts ask questions on this investor science call. To ask a question on the call, please raise your hand in Zoom or type star nine on your phone. Remember to unmute when time is. On the phone, that is star six, and it would be great if you could please limit questions to one or two, as we then have time to cover all participants. We can always do another round if needed. And with that, I would like to open up for first, Peter Verdult at Citi. Please go ahead, Peter. Thanks, Thomas. Can you hear me? Yes, we can. Yeah, good afternoon. Thanks for doing the call, Peter Verdult, Citi. Two questions. The liver tox slide you showed, on both Gemini and Hercules, would that slide look different if we just looked at the cases post the monitoring amendments? And if I can, just, open or ask Dr. Jiwon and Fox, you know, on their thoughts as to, you know, how manageable or bothering this is or not. And then secondly, Dr. Fox, great to reconnect. You've always been candid, and, about your views about the MS space. You correctly predicted that, you know, BTK would fail in relapse remitting when we called up in April. Can you, and if Dr. Jiwon wants to add as well, could you maybe opine on the clinical significance of the topline data in SPMS? And just, you know, rather, you know, just independently, what percentage of patients you see on a weekly basis that have SPMS? Thank you very much. So Peter, nice that you called in on a Friday afternoon. We'll hope to not keep you too long. Let me answer the first question, then hand over to the experts. The first question was, would things look different if we looked at the post-stringent monitoring, or should I say more regular monitoring protocol? It's early days, of course, yet. The data is currently under analysis, and patients are continually going through it. The one thing that I can say unequivocally is that we see nothing concerning in that group to date that would impede a regulatory filing. So with that, I'll hand over to Dr. Oh and Dr. Fox. So, just to address your first question about whether the frequent liver monitoring that will likely be required will be an impediment. The short answer is no, because it's clear that the frequent monitoring will only be required for a time-limited period, so you know, weekly is not ever something that's sustainable in the longer run, and of course, we don't know exactly what the monitoring requirements will be. But if it's only for a period of twelve weeks, that is doable. And it's likely after that twelve-week period, there will be less frequent monitoring. And this is something that is not foreign to MS specialists, just because we do monitor liver enzymes with many of our existing treatments. It's not on, necessarily on a weekly level, but again, because it's clear that that period will be time-limited, I don't see it as an impediment. Because obviously there is an inconvenience with frequent monitoring, even for twelve weeks. But if you are truly hitting an unmet need, the inconvenience will likely be well worth it. In terms of proportions of patients with the secondary progressive MS that I see. I can tell you that if there is a drug available that convincingly alters progression in MS, the proportion of patients that we are willing to diagnose with SPMS will increase quite a bit. Because right now, there's a lot of people in our clinical practices where we're actually cagey and hesitant to label them as having this diagnosis, because we simply don't have convincingly effective treatments. But any of those patients that are in that, we often call it transitional period, or I'm not sure of, but deep down, I know they have secondary progressive MS. I wouldn't have hesitation to diagnose if there was a treatment available that I know might meaningfully alter their disease course. So to extend on Dr. Oh's comments, we don't have a clear sense as to how the more intensive monitoring is going to impact the overall course of the liver enzyme elevations. We do know that the frequent monitoring does not completely prevent cases of 20 times upper limit normal, but we didn't expect that. What we're hoping to do is to identify those severe liver irritation, liver enzyme elevation cases very quickly so that we can intervene, which is a very straightforward intervention. Stop tolebrutinib. It's, it's very simple and easy to do, but we have to recognize it. So, I agree with Dr. Oh, although weekly is inconvenient to say, "Hey, the next three months, you got to get this liver enzyme assessed. It's in your interest. You want to get it done. Commit to that for the next three months, and then we can go with an easier course of the liver enzyme monitoring." And so there have been some cases, and I forget if it's one or more than one, but there's at least one case of liver enzyme elevation above 20 times upper limit of normal, with the intensive monitoring. But with that very quick recognition, we could stop, say, discontinue tolebrutinib, and the patient's liver irritation resolves spontaneously, and that is the most important thing and the most encouraging. I agree with Dr. Oh, there are a lot of patients in my practice with secondary progressive MS without relapses who are going to have that, who have that little by little decline, for which I tell them quite honestly, "I don't have a therapy that will slow down this gradual little by little decline," and now we do. Thank you. Next question is from Colin White at Jefferies, please. Hi, sorry, it's Colin White at UBS. I had a question about the group of patients within the HERCULES study that had gadolinium lesions at baseline, and I was just curious. Obviously, these are non-relapsing patients. They haven't relapsed in a while, but is that a subgroup within the non-relapsing patients that has more active disease? Is that an indication of that, or is that not the case? And then my second question was just around trying to understand the acceptable level of liver toxicity with the drugs that you use in treating multiple sclerosis patients. You know, like, what is generally viewed as an acceptable level of these, or like a rate of these types of elevations that you see? And then particularly, there hasn't been any more severe events since the liver monitoring, but what would be the rate of severe, you know, liver sequelae that would perhaps dissuade you from using this drug in patients? So the first question, the gadolinium-enhancing lesions. To have a rate of about 10, 11, 12% of gadolinium-enhancing lesions in non-relapsing secondary progressive MS is a little bit what we would expect. Now, remember, these are non-relapsing secondary progressive MS patients that are off any other immune-modulating therapies. So I would expect it a little bit lower in my general clinical practice, but most of those patients are on an MS disease-modifying therapy. So this is among patients that are off an MS disease-modifying therapy, and they do represent a different population of patients. Now, it is a small proportion. It is only 12% to 13%. And so although a subgroup analysis hasn't been done, I don't expect that that small proportion would be significantly driving what we see, given the larger, much larger proportion of patients who have the sustained progression of disability. In terms of the rate of liver enzyme elevations, the 4 to 6% of any elevation is about one in twenty. So to have one in twenty patients have any elevation of the liver enzymes over the course of several years of follow-up, and they have a rate of point oh five in each study, so one in two hundred patients have a very severe elevation, to me, that's acceptable. I mean, I'd rather none. I'd rather it as low as can be. But to have one in twenty have any elevation and one in two hundred to have a severe elevation, that I think if I identify it quickly and say, "Stop tolebrutinib," that is very encouraging, and particularly given that we don't have any treatment options for this form of MS, I think patients are going to be willing to accept that. Thank you. Please. Sorry, I don't have much to add. I agree entirely with Dr. Fox. I think the numbers that we see here are entirely acceptable, and I know. Earlier, someone asked a question about, after frequent liver monitoring, is there a change in the distribution of liver enzyme elevations that we see? And you know, just common sense-wise, I would expect there might be. And so those numbers might even be smaller than what Dr. Fox quoted. But even with the numbers that we see, I think it would be an entirely acceptable risk, again, because this meets an unmet need that we have in clinical practice. But over the next 6 months, as patients get rolled over from the placebo group or from the Teriflunomide in the GEMINI 1 and 2 to tolebrutinib, we will get a much better sense of the frequency of these severe enzyme elevations and understand how it compares to before the intensive liver monitoring. Thank you for that. So the next question is from Luisa Hector, and hopefully I get the bank right with you on that. That's right, Thomas. Thank you. And thank you, Houman, and the investigators. It's great to be discussing the data finally. First, for Dr. Oh and Dr. Fox, another question on the target patient group for Hercules. I think you just said that they were not actively using therapies, so I'm wondering what the sort of treatment history was, and what triggered these patients to then enter Hercules? What made you sort of put them into the trial? And then maybe I could just ask, moving on to frexalimab, because we see the relapsing trial set up there comparing to Aubagio with a relapse endpoint. So given the performance of Aubagio in the recent trials, how do you feel on your confidence levels here? Is there anything you can do to kind of accrue higher relapse rate patients into that trial? Thank you. This is Bob Fox. I'll take on the Hercules question, and the three quarters of the patients were on an MS disease-modifying therapy at some point prior to enrollment into the trial. As is typical of these phase III trials, all patients were required to be off of an MS disease-modifying therapy, and that's important because we don't have safety experience of combining these therapies together, and it's most straightforward to evaluate them as monotherapy. As to why these patients enrolled, you know, I don't know all the details of each patient, but I can imagine it's because they had progression of disability in the last year prior to entering the study, which was a requirement. Even though they had no relapses, and by having no relapses, meaning there is no active focal episodic inflammation for an immune-modulating therapy to address. And so that is the exact patient that I say, "I don't have anything to help you with," and that this trial is an option for them. So it's the exact patients that we struggle with every day that would enroll into this trial. Luisa, how are you, my friend? Let me just help you with frexalimab. Three quick comments. Number one, obviously, we will review Frexa through the lens of what we've learned from Gemini one and two. We have to. However, point two is the biology, right? If you think about the way Frexa works, it has a much broader impact than just B-cell biology, more than the humoral component. And the phase II data and the phase II extension data really do support the notion that Frexa could, A, be differentiated from an efficacy perspective. But actually, COVID educated many of us that profound B-cell depletion, while biologically attractive, for example, depleting EBV, EBV-targeted cells, may come with sequelae, which we don't wanna carry. So there's certainly a space for frexalimab, both in efficacy and safety, as part of the armamentarium of patients with MS. And the final part of that is that going away from this conference, we will redouble our efforts around frexalimab to figure out exactly the path we should take with it forward, and you'll be the first to know. Thanks, Houman. Just a reminder to maybe keep it to one question, because otherwise we may run out of time. Next up is Emily Field from Barclays. Hi, thanks for taking my question, and I will keep it to one, given the rules. I guess then it's a question for the doctors. You know, just it's sort of, you know, from a practical perspective, one of the things that we've heard in our KOL discussions is the desire to not necessarily keep patients on some of these B-cell depleting CD20 therapies for super long periods of time. So, you know, with the introduction of an agent like tolebrutinib, what would be the practical considerations from switching a patient over? I know, obviously in the clinical trial, they had to be off therapy, but I'm just sort of wondering how this would play out in the real world. Thank you. So I can start. I think even at today's platform session, a similar question came up about kinda treatment strategies that we might use in the field, given that we have this new agent that again addresses this great unmet clinical need. And so probably using B-cell therapy for a short period, followed by a drug like tolebrutinib, will be a natural sequencing strategy for... And that will be applicable, actually likely, to a pretty good proportion of people with MS. Everyone's practice will differ about this, and I'm sure as it becomes available, treatment guidelines will develop. But most people will wait a few months to approximately six months after a B-cell therapy, just because the most commonly used one, ocrelizumab, is dosed once every six months. Some people will monitor for B-cell return. But in general, there probably won't be too much hesitation after a number of months to start a therapy like this, just because they also have very different mechanisms of action, and tolebrutinib is not a B-cell depleter. ... Very good. We'll move on with the next question from Simon Baker at Redburn Atlantic. Please, please, Simon. Thomas, thank you very much, and thank you, everyone, for the presentation. I will stick to one, but I will ask you just a quick clarification. I may have missed the answer to Pete's earlier question, Dr. Fox, on the proportion of your patients that you see who are non-relapsing SPMS. I think I may have missed that number. And then my question on HERCULES was again on adverse events. I noticed the incidence of hypertension was five point one on active, two point nine on placebo. I just wondered if you had any additional commentary on that. Is there anything in there, what was the manifestation of the hypertension that you saw on the tolebrutinib arm? Thanks so much. Yeah, so the reason you don't remember the answer is I didn't give an exact proportion. So I will give that now. And I don't know if Pete gets credit or, or you. But I would estimate about 30% of my patient population have secondary progressive MS without relapses, have progression of their disability, and are desirous of a therapy that will slow this down. About 30, maybe even a little bit higher, 35%. This is pretty common. And the most common story is a patient says, "Doc, I haven't had any relapses. You tell me that my MRI is stable, but I am getting worse little by little. What's the deal?" And that is the typical non-relapsing secondary progressive MS. In terms of the hypertension, these are adverse events reported by the investigator, and we just use what they report to us. If I were an investigator, and I were to report hypertension as an adverse event, it's because their blood pressure went up. And more than just a single reading of a blood pressure going up, usually it's, "Well, it's been up a couple times," and, you know, I might send them back to their family doc to get it addressed, and it would get recorded as hypertension. Or if they had a new antihypertensive added, and I say, "Well, where did that medicine come from?" And they say, "Well, my family doc said I have hypertension and put me on this blood pressure medication." So it's just those numbers. We haven't delved into the actual blood pressure readings as they're recorded in the database and how severe they were, and so on. It's a small increase, and it's an increase we've seen with some of the other therapies. S1P therapies can increase blood pressure and are associated with hypertension. So it's not something that we're not used to and can talk through and help keep an eye on and work with a family doctor manage. Thank you. Next question is from Richard Vosser at JP Morgan, please. Thanks, Thomas. One question, please. Just to go back to the change in the monitoring requirements. So I was wondering what proportion of patients in HERCULES and GEMINI actually went through the enhanced monitoring during the first ninety days of their treatment, so that they got that all-important period? And then just on top of that, you know, regulators obviously are going to be hot on this, so do you think you have enough of those patients to prove that first ninety days is good at this point? Thanks very much. Well, what we know is that all of the 20x upper limit of normal liver enzyme elevations were within the first 90 days. So have we treated a million patients to know all the cases will be? No. We just know from the number of patients that we have. We will get a lot more experience as the patients roll over to open-label tolebrutinib. We will have a big bulk of patients who will be newly exposed to tolebrutinib, and we will get a very good sense of what is the frequency and whether we... Again, the most important thing isn't having the elevation, it's whether we can recognize it, intervene, stop the investigational product, in this case, tolebrutinib, and have the liver recover without serious long-term consequences. That is the ultimate key, and that's what I would, if I were a regulator, be most concerned about, is identifying and intervening. So I think we will know more information in the future, to understand whether that truly is helping to bring down the rate of this complication. Thank you so much, Dr. Fox. Then next up is Emmanuel Papadakis from Deutsche Bank, please. Thank you for taking the question, Emmanuel Papadakis, Deutsche Bank. Maybe I'll take a question on, FDA labeling, potential FDA labeling, should the molecule be approved. So, Houman, you mentioned hoping to drive a reclassification. We had a couple of comments from the physicians on the call around, this potentially driving an increased diagnosis of SPMS. So I guess the question is, to what extent are you expecting to see that reflected in potential labeling? Are you expecting to see something unique rather than the historical paradigm of the FDA approving drugs for RMS, including SPMS? And if so, what exactly would that wording look like? And to what extent, Doctors Fox and Dr. Oh, is that- would that be important for you in driving that additional potential diagnosis you referenced? Thank you. Thanks, Emmanuel, happy Friday. I'm going to keep this very brief. We're working through our FDA labeling strategy. We've already committed to taking this to the FDA this year. Obviously, we will increasingly focus on SPMS and disability, and the historical precedent has been that the FDA has adhered pretty closely to the Phase Three recruitment inclusion criteria. Any more than that would be speculation at this stage. Thank you, Houman. Next question is from Graham Parry at Bank of America, please. ... Great, thanks for taking the question. So just wondering, actually, so far, what proportion of patients have transferred into the open-label extension? So have you had most of the placebo patients now transfer over and go through the intense monitoring program without seeing any liver issues? And then question for Doctors Fox and Oh, just wondered what you see as clinically meaningful benefit here. So 31% 6-month CDP, but 24% 3-month CDP benefit, it isn't materially different, let's say, from Ocrevus and PPMS, which I think was seen as sort of mediocre. So just perhaps put that 31, 24% into context, and which is most important to you, 3- month or 6-month CDP? We'll try and answer your question very briefly. Graham, nice to speak to you again, of course. We're going to get Erik Wahlstrom to provide as exact a number as we can provide at this stage. It's still early days. We're within a month of unblinding, so it's important that we don't over-index on these numbers. But Eric will answer your first question, and then I'll hand over to Doctors Oh and Fox to answer your second question. Mm-hmm. Yeah, the number of patients that have undergone weekly monitoring is changing pretty much day by day since patients now are transferring into the long-term extension. But we estimate by mid of December that we will have around nine hundred patients in total that have undergone the weekly monitoring. Just, first, to get to whether a 6-month or three-month CDP is more meaningful, in the field, we are starting to use 6- month CDP as the primary outcome of interest for progressive MS, mainly because it's more stringent. So we think it's more of a robust measure of disability progression, and so that number is more meaningful. But the reason to show the three-month data as well is because it's consistent, and this is in HERCULES as well as the secondary endpoints for GEMINI 1 and 2 as well. In terms of what this means in the grander scheme of things, again, there's never been a trial that has exclusively looked at people with non-relapsing SPMS, and when you look at that relative reduction, yes, it is, you know, actually a bit greater in magnitude than what was seen in, say, siponimod in active SPMS, as well as ocrelizumab in PPMS. But when you look at the demographic variables that Dr. Fox displayed earlier, the proportion of people with gadolinium-enhancing lesions was much lower in HERCULES in comparison to those progressive MS clinical trials that occurred recently as well. So what this tells us in practical terms as a clinician is that we are really seeing this reduction in disability progression, and this is as far as a clinical trial population goes, as close to a non-active population as we've ever gotten. And so that's why even though the magnitude may not be that much greater, because we've selected for a group of people that we really think have very little evidence of activity, that's why it's so much more meaningful, because the... it's that need in clinical practice. What Dr. Fox was saying earlier, these are the patients right now where I throw up my hands, and I'm kind of like, "I don't really know what else to offer you." And so that's why that number is so meaningful. Very good. Thank you so much. Next question is from Seamus Fernandez at Guggenheim. Please go ahead. Yes, thank you for the question. So, really just wanted to maybe ask you to contextualize the results, the clinical meaningfulness of that 30% difference, the 24% difference, and then perhaps the improvement in some patients relative to the patient's willingness to take on this liver risk and intensive weekly monitoring. You know, there are multiple Hy's Law cases in both arms, so, you know, it just seems like there's a fairly significant potential regulatory barrier in the context of those Hy's Law cases. And then, you know, a patient's willingness and the physician's willingness to treat, admittedly, given the limited number of options, I understand the argument, but what do you feel the patient's willingness to take on that liver safety risk is going to be? Thanks. In talking to patients with secondary progressive MS without relapses, they are desperate for treatment. They want to slow down this obvious, clear today decline in their function and are willing to do a lot. And if what we're asking them to do is willing to get a blood test every week for three months, and then intermittently thereafter, and to accept a 1 in 200 risk of a significant liver elevation, and, you know, it's even lower risk of liver failure if our frequent monitoring doesn't prevent that, I think, you know, we have a lot of patients willing to take natalizumab, despite risk of PML. Our other MS therapies also have risk of PML. Our patients are used to these risks. They are used to having to balance slowing down the progression of their disease or the activity of their disease and the risks of some complications. Now, there are some patients who will say, "I don't want to take that risk," and of course, then this isn't the right therapy for them. There are some that say, "I don't want to have to get a blood draw every week for three months. That sounds very onerous." That's less of an issue because it's not that hard to go get a blood test every week, and as Dr. Oh was saying, it's a limited time. It's three months as that window. It's not every week for the rest of your life. I think there are a significant proportion of patients who would be delighted to accept this benefit, which isn't a guaranteed benefit. I mean, it's not a guaranteed stopping of their disease. But it's a lot better than the 0% treatment that we have right now. It's about 31% better. I think there's a very large proportion that would accept those risks. On that note, Dr. Oh, did you have something to add to that? I just wanted to say, I mean, Bob really nicely highlighted this, but this is the patient population that's desperate, and these are the people that are actually asking us if there's any clinical trials, any experimental therapies, if they can get bone marrow transplants, if they can fly to Puerto Rico to get, you know, odd treatments. And so, you know, the option of actually having a proven therapy, despite the fact that there may be a one in 200 liver risk, these are the people that would, for the most part, gladly accept that risk. And I'll correct you just a little bit. They don't have limited treatment options for non-relapsing secondary progressive MS. They have no treatment options, and so this is something where they have nothing. Thank you both. Back to you. Yeah, that's very clear. We have three more people in line here. Peter, Erik, and Steve. We'll take all of you, and then close the call. So next up is Peter Welford, and this time Peter is from Jefferies. Yep, certainly still here at the minute. Just a quick one, which is, thank you for all the commentary on SPMS. But I guess my question is, on the GEMINI data, is there any way you think you can get the GEMINI CDP data onto the label in either the US and Europe? And I'm not asking for an indication necessarily, but, you know, is this a case of just publishing and being able to show it to clinicians? Or is there some way you can manage to get that data, perhaps as supportive for the drug's mechanism or something, onto an actual package insert label? Thank you. So Pete, nice to speak to you again. The simple answer to that is we're going to focus on SPMS for now, this year. That doesn't mean we forget about relapsing remitting MS. It's just that our focus for regulatory is there. The support data from the disability is valuable and important, and as I said, we'll have the discussion with the regulator about the appropriate label. But the rest of the strategy with RMS, we will return to in the future. Thank you. Then next up is Eric Walstrom. Please go ahead, Erik. Yeah, thank you, Thomas. If I may, two very short. Any subgroup analysis, maybe in particular about EDSS score at baseline, there were different criteria depending on whether EDSS was below or over five. Did you see any difference in those two subgroups based on any kind of severity at entry into the trial? And then secondly, any read to make out of this non-relapsing SPMS population out of the PPMS coming next year? Would you say two different diseases, two different indications, or should we think about having kind of a read-across from one to the other? So this is a rich trial data set. Just the three trials that are complete, and then the primary progressive trial that is coming. We have a lot of questions we want to ask in the subgroup analysis, and a lot of ways we want to slice this and dice this and take deep dives, and we've done none of it yet. So you have mentioned just one of about a hundred that we have heard suggested and recommended, and we've thought of on our own. So very important question for us as clinicians. We look forward to delving into that and diving down. Now, in terms of the similarities of primary progressive and secondary progressive, they are very similar, although some studies have seen some differences in the treatment response in primary progressive versus secondary progressive. But the underlying pathology that is driving progression in primary progressive and secondary progressive, I believe is very similar. And so I expect the primary progressive to be positive, given the positive results from HERCULES. But, it's one of those things where we just have to wait to see. Yeah. We're, as I said at the beginning, we're humble in the face of disease, and while we're optimistic for patients with primary progressive disease, we're going to be careful and guarded in our interpretation. Mm-hmm. Thomas, back to you. Thanks, sir. Thanks, last question today from Steve Scala at TD Cowen. Please go ahead, Steve. Thanks so much. A question for the doctors: What profile would you need to see from frexalimab in phase III to convert the majority of your RMS patients on CD20s now to frexalimab? Thank you. So I can start. You know, I think it's very clear that the highest efficacy agents that we currently have right now for relapsing disease that are approved are the anti-CD20 agents, and they're by far the most widely used therapies. So in terms of a profile, I would like to see efficacy in the range of the anti-CD20 agents. And then it would basically boil down to safety, as well as convenience. And so yeah, I think the safety data will determine. There is you know, kind of widespread concern in the field about really long-term therapy with the anti-CD20 agents. And of course, we won't necessarily have that data with the phase three frexalimab data. But I think depending on the safety as well as the convenience, that is what would determine likelihood of using that treatment over anti-CD20 agents. We are seeing more and more over time, as patients are on anti-CD20 therapies longer and longer, they are depleting their immune system. They are not responding to novel pathogens, whether it be COVID or this year's flu vaccine or the chickenpox vaccine. They are not fighting their infections, particularly respiratory infections, the way we would expect. So particularly as patients get further and further into the anti-CD20, we are a treatment paradigm. We are looking for alternatives. So if there is a similar efficacy against the disease, with a good safety, particularly when it comes to infections, that would be a very attractive treatment option. Thanks for that, and thanks for that look to the future. Steve, thanks for the last question, and thanks to Dr. Oh and Dr. Fox for their insights today. Thanks also for the interest in Sanofi. We'll now close the call here in Copenhagen and wish everyone a great weekend. Thank you.