Morning and good afternoon to everyone. I'm Felix Lauscher with Sanofi Investor Relations. Welcome to today's Sanofi Neurology event, which coincides with the ACTRIMS Forum 2022 in West Palm Beach, Florida. We are looking forward to spending the next hour with you to review and discuss recent data for tolebrutinib and to share more information about our broader neurology portfolio. Moving to slide 3, I would like to remind you that information presented in this call contains forward-looking statements that involve known and unknown risks, uncertainties, and other factors that may cause actual results to differ materially. I refer you to our Form 20-F document on file with the SEC and also our documents. Now turning to slide 4, we will start with a presentation followed by a Q&A session. Let me now turn the call over to Dietmar Berger, Global Head of Development and Chief Medical Officer at Sanofi. Dietmar? Thank you, Felix. Moving to slide 5, I will start with short opening remarks followed by my colleague Tom Snow, Global Franchise Head for Neurology, who will share an overview of Sanofi's neurology strategy. Erik Wallström, Therapeutic Area Head, will then discuss our pipeline, focusing on several key programs which have advanced quickly in the past year. We will then delve more deeply into new data for our investigational product tolebrutinib. We're very pleased to have with us today Dr. Anthony Traboulsee, Professor and Research Chair of the MS Society of Canada at the University of British Columbia in Vancouver, who will review data from the 18-month extension of our phase II study in multiple sclerosis. Finally, Tim Turner, our Global Project Head for tolebrutinib, will present important data around the pharmacology of the molecule. This will be followed by a Q&A session. Moving to slide 6. Over the past two years, you've heard about the impressive strides Sanofi has made in strengthening our oncology portfolio and in building one of the most impressive immunology pipelines in the industry. What perhaps hasn't been as visible is the significant progress we've made in neurology, with clinical candidates targeting several high unmet need neurological conditions. Our investigational brain-penetrant BTK inhibitor tolebrutinib leads the way, with 4 ongoing studies across the full spectrum of multiple sclerosis as well as a phase III study in myasthenia gravis, which we initiated last year. Among our other investigational compounds, we also advanced SAR441344, our anti-CD40 ligand monoclonal antibody program, into phase II in relapsing MS. SAR445088, our anti-C1s monoclonal antibody, also started its phase II study in chronic inflammatory demyelinating polyneuropathy, or CIDP. CIDP is an acquired autoimmune disease of the peripheral nerves with significant disease burden and high unmet medical need, and SAR445088 has received orphan drug designation from the FDA. Last but certainly not least is SAR443820, the brain-penetrant inhibitor of RIP kinase 1, which we in-licensed from Denali. RIPK1 is implicated in necroptosis, and we believe that SAR443820 has strong potential in multiple neurodegenerative conditions. ALS, amyotrophic lateral sclerosis, will be the lead indication we pursue, for which we've received fast track designation from the FDA, and we're advancing the molecule quickly into phase II. Erik will provide more details about these exciting programs later. Along with advancing our internal pipeline, Sanofi has also been quite active on the business development and M&A front to further strengthen our neurology portfolio. We completed the acquisition of Principia in September 2020, which provides us full ownership of tolebrutinib as well as other interesting assets in the BTK inhibitor space. I mentioned our ongoing collaboration with Denali, which has given us the opportunity to bring a potential first-in-class RIPK1 forward in ALS and potentially other neurodegenerative diseases. Just recently, we also announced an exciting partnership with ABL Bio on a brain-penetrant bispecific antibody directly targeting alpha-synuclein, a key protein in the pathology of Parkinson's disease. We also continue to work closely with the broader neurology community. We're partnering with the International Progressive MS Alliance to explore AI, artificial intelligence-enabled MRI biomarkers to help discover new therapies faster. We're also working with the Parkinson's Foundation on PD GENEration, a research collaboration to advance the availability of genetic testing and counseling for people living with Parkinson's disease in the U.S. I will now turn the call over to Tom Snow, our Global Franchise Head for Neurology, who will share the overall strategy we have in neurology. Thank you very much, Dietmar. Moving on to slide 7. As you said, we made important progress over the past several years as we look to build on our global presence and expertise in MS to become global leaders in broader neurology. Turning to slide 8. First of all, it's important to point out that we're not starting from scratch. Over the past decade, Sanofi's built a leading global MS franchise. Aubagio continues to be an important contributor to Sanofi and is currently the number one selling oral disease modifying therapy in the U.S., thanks to its reliable combination of efficacy, safety, and once daily dosing. Lemtrada, by offering long-term disease control in the absence of continuous dosing, has significantly impacted thousands of patients worldwide, more than 24,000 of whom are currently controlled with no treatment. Of course, we hope to eventually offer even more to MS patients with tolebrutinib, our investigational brain-penetrant BTK inhibitor, which aims to treat the entire disease spectrum. We're on track to be the first-in-class and best-in-class BTKI in MS. One of the reasons we're excited about tolebrutinib is that, as you can see on the left, the MS market will remain highly attractive and will continue to shift towards higher efficacy therapies like anti-CD20s. Despite the entry of oral generics, the overall market is expected to grow to around $25 billion by 2026. Roughly half of that is expected to come from the anti-CD20, such as Ocrevus. We believe this would set up the market extremely well for tolebrutinib, with its proposed MOA of modulating B cells, plus inhibiting the microglia in the brain. In phase II, tolebrutinib has shown an effect on Gd lesions in the range of the anti-CD20s. If tolebrutinib meets its profile in phase III, then we believe it would capture a leading market position in the B-cell targeted class, plus benefit patients with progressive disease who have limited to no treatment options. Moving to slide 9. Our ambition in neurology doesn't stop with tolebrutinib. We want to apply our expertise and understanding from MS to address a broader range of neurological conditions. Historically, neuro might have been viewed as a very risky area for companies to go into, but there are several reasons to believe that today neurology is actually a very good place to be. Over the next 5 years, as you can see on the left, neurology indications are projected to outpace most other therapeutic areas in terms of size, growth, and share of the overall market. There are several reasons why. Many neurological conditions strike early in life and have a very high burden of disease. For instance, on average, people with ALS survive just 2-5 years after their diagnosis. Parkinson's disease costs society an estimated $23 billion in the U.S. alone. The good news is that the science is advancing rapidly. Today, we have a better understanding of the mechanisms driving neurodegeneration. The understanding of human genetics and biology has also advanced, better facilitating forward and back translation. New enabling technologies are also making drug discovery and development more efficient. Advances in human brain imaging, including new PET tracers and AI-based analytics, are making it easier to select patients and to measure treatment response. New digital clinical tools employing wearables and fluid biomarkers like neurofilament light chain are making it easier to measure disease progression. Recognizing all of the above, stakeholders are highly engaged. Governments and payers understand the high individual and societal burden of neurological diseases. Regulators are enabling expedited registration and becoming more willing to consider surrogate endpoints for these serious and life-threatening neurological conditions. Turning to slide 10. With that vision of leadership and broader neurology in mind, our strategy focuses on three core pillars where we believe Sanofi can win. Neuroinflammation includes diseases like MS, where we obviously already have a strong presence and promising pipeline, as well as adjacent conditions such as myasthenia gravis and CIDP. Neurodegeneration includes devastating diseases like ALS, as well as important diseases which share key pathologies. These include synucleinopathies, such as Parkinson's disease and multiple system atrophy, which are characterized by alpha-synuclein aggregation, and tauopathies, such as Alzheimer's and progressive supranuclear palsy, where the aggregation of tau proteins is implicated in disease progression. A third pillar is genetic disorders, where Sanofi's expertise in rare diseases and a dedicated genetic medicines unit put us in a strong position to help change the practice of medicine in those conditions. I'll now hand it over to Erik Wallström, our Head of Development for Neurology, who will cover our pipeline and dive more deeply into a few specific programs. Erik? Thanks, Tom. I'm looking at the pipeline on slide 12. I'm sure that you're eager to hear about tolebrutinib, but I want to quickly run through three interesting development projects before that. Why are they interesting? Well, they are all first-in-class in development for their respective mode of action, and they all target significant unmet needs. Turning to slide 13. The first project is the bispecific anti-alpha-synuclein antibody from the license agreement with ABL Bio that was announced last month. We are excited about this project, both based on the brain shuttle, in this case, the insulin-like growth factor 1 receptor, and the specificity for pathological aggregates of alpha-synuclein. Both the brain shuttle and the specificity are important for the ability of the antibody to reach the central nervous system and avoid being bound too much to alpha-synuclein monomers. Preclinical experiment indicates that this bispecific antibody has the right properties to inhibit the spread of alpha-synuclein. That is what you see in the figure. Stopping the spread of alpha-synuclein results in protection of the dopaminergic neurons and prevented the loss of motor function in PD mouse models. As far as we are aware, this is the first anti-alpha-synuclein antibody with a brain shuttle in development. Parkinson's disease represents a major unmet need. It is the second most common neurodegenerative disease, and there is no treatment today that can delay progression. The next milestone for this project will be the generation of human phase I data next year. Turning to slide 14, the second project is the RIPK1 inhibitor project, the central RIPK1 inhibitor, called DNL788 or SAR443820. It is the first in development brain penetrant RIPK1 inhibitor that's a key regulator of inflammatory cell death and microglia-mediated neuroinflammation. Programmed inflammatory cell death or necroptosis is a relatively newly described pathway, and it's different from apoptosis and necrosis. This pathway is activated in several neurodegenerative and neuroinflammatory conditions, including ALS, MS, and Alzheimer's. As depicted in the figure, several cell types are involved, including microglia in the RIPK1-dependent necroptosis pathways. The next slide shows three different pieces of evidence that link ALS specifically to RIPK1. As you know, ALS has a very high unmet need. It's one of the fastest progressing neurodegenerative diseases, and it typically leads to death within 2-5 years. The left panel displays genes that have been associated with fALS and the year of their discovery, and the red rectangles indicate genes that are linked to the RIPK1 pathway. The middle shows an example of a SOD1 mouse model of ALS treated with the RIPK1 inhibitor. That is the blue line on the right, showing slower disease progression than in control mice, and that is the black line on the left, the controls. The right panel shows an analysis of spinal cord tissue from ALS patients, and RIPK1 is upregulated in the tissue as measured by Western blot. The combined genetic model and tissue data has led us to test SAR443820 in phase II in an ALS trial. On slide 16, we have the ALS trial. We call the trial HIMALAYA, and it's just about to start. We aim to have the first patient in the trial next month. I would like to highlight the relatively robust sample size, 261 people with ALS. That is important since it may be possible to approach regulators already after phase II if the data is robust enough. Longer-term data, including mortality, is also important, and therefore we have an extension trial. The next data point for that project is phase II data that we expect in the second half of 2023. Let's now turn to the third program. That is the CD40L MS program that we have highlighted on slide 17. This is the third development program that is first in development for the specific mode of action and indication. The CD40 ligand pathway is important for T and B cell interactions, and results from B-cell depleting therapies in MS indicate that T and B cell interactions are central for disease propagation. In contrast to B-cell depleters, this is a non-depleting antibody. As the figure indicates, there may also be innate immune effects. Together with the lack of B-cell depletion, the potential for innate effects provides differentiation for this anti-CD40 ligand approach in MS. On slide 18, we have highlighted two pieces of evidence that link CD40 ligand to MS. The left figure presents the conclusion of an analysis of quantitative trait locus data expression and methylation data and genome-wide association studies in people with MS. They were matched with a list of druggable genes that are not yet targeted by available MS therapies. Three genes came out on top: CD40, MERTK, and PARP-1. This analysis was performed by an academic group independent of Sanofi. On the right side of this slide, some of our own work is presented, and this is work on samples from people with MS before they started treatment in a clinical trial. We measured mRNA expression in peripheral blood mononuclear cell samples from 260 patients. We measured mRNA with RNA-seq, and we have ranked the patients according to the level of CD40 ligand pathway activation. This was quantified by something we call the CD40 ligand activation score. The score was developed based on in vitro activation of cells with or without anti-CD40 ligand antibody added. Based on this, we hypothesized that the CD40 ligand activation score before treatment may be linked to response to anti-CD40 ligand treatment with the monoclonal antibody SAR441344. The next slide shows how we test this. Turning to slide 19, we use an MS trial design with two doses of SAR441344 and new gadolinium-enhancing MRI lesions as primary endpoint. Treatment response will be linked to the CD40L activation score. In addition, we also explore CD40 ligand activation in a separate study in samples from patients with progressive MS. If we succeed to link the response to the biomarker, this could represent a new way of treating MS more rationally. Currently, MS patients are started on treatment and followed with MRI and relapse monitoring. If they have enough MRI activity or relapses, then treatment is typically switched. That goes on until hopefully disease activity stabilizes. We believe that there is a significant unmet need in finding a more rational biomarker-based approach to patient selection for a specific treatment. The next data point for the SAR441344 program in MS is the phase II data that is expected in the second half of this year. This concludes the quick overview of three different first-in-class development projects attempting to address significant unmet needs in their respective indication and mode of action. I will now hand over to Professor Traboulsee, who will update us on the 18-month phase II extension and data, and I hope also a little bit on his personal experience from treating people with MS with tolebrutinib. Great. Thanks, Erik Wallström, and hello everyone. It's a pleasure to be here. I'm Anthony Traboulsee. I'm a practicing neurologist and a researcher at the University of British Columbia in Canada. I've also been involved in clinical trials for over 20 years now with multiple different studies as a principal investigator, steering committee member, data safety and monitoring board member, as well as an imaging expert. I have personal experience with this with tolebrutinib as the principal investigator at our site and also involved in some of the steering committee member roles. I'm one of the co-authors on this poster that's the long title, looking essentially at the 18-month results of the long-term extension study of tolebrutinib. If we go to slide 21, this slide has so much invaluable information about this tolebrutinib. I just want to explain it a little bit. So you have four different lines or four different colors that represents the four different doses that were studied in the blinded phase II study, which is shown in the shaded area on the left side of the graph. This shows you the MRI disease activity called gad olinium-enhancing lesions, which is our surrogate for relapses, for inflammation, and is commonly used to determine the dose that's best for going into phase III. You can see again, the phase II results were the yellow line being the 60 milligram dose, had the greatest suppression of enhancing lesions, 85% suppression, which is amazing. Then what happens after that, we go into extension. Initially, patients are kept on the original dose of drug, but then once we determine 60 milligrams was the best dose, they all switched over, and look how those lines come together. By week 48, everybody's on 60 milligrams and a beautiful treatment response on the MRI disease activity. I think that's one of the key slides of this data. In addition, in the extension study, we also looked at some of the other MRI outcomes, including T2 lesion volume, and that you can see on the poster, and that remained quite low on the 60 milligram arm. Another biomarker that's more exploratory is a MRI marker called slowly evolving lesions. One of the reasons we're interested in that is it could be a future biomarker for progression to look for a more efficient way to determine if we're impacting on progression. Still being explored, of course, but it had the numerically lowest volume of these chronic active lesions in patients who started on 60 mg from the start. This data really makes me enthusiastic. If we go to the next slide, this is additional supportive data of efficacy. This is looking at clinical outcomes, which is the annualized relapse rate. Patients on 60 mg was quite low at 0.17, and about 85% of patients were free of relapses. It's difficult to compare across trials, we always say that, but from my personal experience, I would say this is in line with the strong effect on focal inflammation that we've seen in other core phase II trials. Turning to slide 23. So for me, I'm seeing a lovely efficacy picture. The other exciting thing for me was the safety profile. This was for me, a new type of drug to work with. I was so impressed with how well my patients did in terms of tolerability, so I think that's actually a good name for the drug, and as well as the lack of infections. during the study, as expected, during the extension, some patients did get COVID-19, which, you know, has gone through our world. There were 20 confirmed COVID-19 cases. They were either mild for 11 patients or moderate for 9. All patients had good recovery and remained in the study. tolebrutinib treatment continued uninterrupted in the majority of patients and only temporarily interrupted in 4 patients. There's more details on another poster at this ACTRIMS meeting. Again, the data's not suggesting any increased risk for severe COVID-19 or other infections. Also importantly, we're not seeing any suggestion that there's a dose effect for treatment emergent adverse events or serious adverse events in the long-term study. There's no emergence of new safety signals for participants who went from the lower dose to the 60 milligram dose throughout the extension study. These safety and tolerability results are really consistent with the experience that my patients have had in the study, and all of my patients have continued on this medication into the extension phase. It's going quite well. If we could have the next slide. I guess my very brief overview of what I think are the highlights of the efficacy and safety. I just want to conclude that all patients who enrolled in the long-term extension study have remained on study by the 18-month cutoff, and safety data continues to show a favorable tolerability without the emergence of new safety signals. really wanna emphasize no one dropped out of the study because of any side effects from the medication. That's remarkable in this day and age of clinical trials. I think that's really again from my personal experience really remarkable. New MRI gad-enhancing lesion counts remained low for the tolebrutinib 60 mg arm and became reduced in the low dose arms once they switched over to the 60 mg dose. Again, that reinforces the dose effect in that 60 mg is a good target dose. The annualized relapse rate in patients was low, and 85% of patients were free of relapses, which is again quite good. The disability EDSS scores remained stable throughout the study as well. 18 months is a good time frame for that. Given this promising data, I'm really looking forward to seeing the clinical efficacy and safety from the ongoing phase III trials. Truly looking forward to that. I think it's gonna be exciting to see. With that, I'm really pleased to hand over to Tim Turner, who will present some very interesting CNS pharmacology data that supports this hypothesis that tolebrutinib may have more value beyond the peripherally driven focal inflammation. Tim. Thank you, Tony. Moving to slide 25, as Dr. Traboulsee just explained, tolebrutinib had promising data on reducing focal inflammation in our phase II trial. You know, the remaining unmet need is to reduce disability accumulation that proceeds in the absence of relapses. Our working hypothesis is that neuroinflammation compartmentalized behind the blood-brain barrier is driving much of this disease activity. In order to slow these processes, we need to target inflammation within the CNS. Tolebrutinib was specifically designed and selected with the aim to penetrate into the CNS to modulate neuroinflammation. With this in mind, we set out to compare the pharmacological properties of the three investigational BTKi inhibitors with respect to potential to modulate BTK signaling inside the brain. We assessed the relative potency in biochemical assays and in vitro cellular assays, along with in vivo pharmacokinetic studies in non-human primates in an effort to learn whether these investigational candidates have the potential to engage BTK in the brain. Turning to slide 26, in these biochemical experiments, we assessed the potency of three BTK inhibitors to inhibit kinase activity using equilibrium measurements. The rank order of potency showed tolebrutinib inhibited BTK with subnanomolar potency, while fenebrutinib was 9-fold less potent, and evobrutinib was about 50-fold less potent. Further, in a separate series of experiments, we measured the rate at which these candidates blocked the kinase. Again, tolebrutinib reacted rapidly, approximately 64 times faster than evobrutinib and 1,780 times faster than fenebrutinib. The speed of action here is especially important for blocking BTK at the low concentrations seen in the CSF. Now moving to slide 27, this biochemical approach was translated to a cell biology context. Here we measured the ability of the three inhibitors to block activation of Ramos cells, which is an immortalized line of human B cells. Here, the apparent potency of all three inhibitors was shifted slightly to the right, but the rank order of potency was maintained. Now in slide 28, pharmacokinetic data from non-human primate allowed us to determine the intrinsic ability of these candidates to penetrate the CSF. This parameter labeled Kp,uu,CSF is a partition coefficient that's determined from the ratio of unbound drug in the plasma to that in the CSF. The higher the ratio, the more brain penetrant we would say a drug is. As you can see, the partition coefficient is 0.4 for tolebrutinib, which is about three times higher than that for the other two candidates. This is empirical confirmation that the medicinal chemists have delivered a potent inhibitor that's relatively brain penetrant, the two key features of an inhibitor with activity inside the brain. In conclusion, on slide 29, tolebrutinib was more potent in terms of BTK inhibition than evobrutinib or fenebrutinib, and the relative potency to inhibit B-cell activation was consistent with those biochemical results. Tolebrutinib demonstrated intrinsic CNS penetrance in those non-human primates based on unbound partition coefficient, approximately threefold higher than evobrutinib and fenebrutinib. That is sort of summarized in the figure on the left. It's this combination of high potency, high reaction rates, and CNS exposure that suggests tolebrutinib has the ability to inhibit BTK signaling in the pathways in the CSF by greater than 90%, conferring pharmacological activity inside the brain. With that, I'd like to turn it back to Dietmar for conclusions. Yeah. Thank you, Tim, and thank you to all of our presenters today. Moving on to slide 30, as you've seen, we're optimistic about neurology. We feel the science and the environment have advanced rapidly to support innovation, and we are excited about our neurology pipeline, which we're bringing forward in some high unmet need conditions. We believe that in tolebrutinib, we have the best profile of the BTK inhibitors currently in development for MS. With that, handing over to Felix. Everyone here in the room, we will now start the Q&A session. We would ask to limit your questions to one or two each. You have two options to participate in the Q&A. Option one, as usual, click the raise hand icon at the bottom of your screen. You will be notified when your line is open and ask your question. At that time, please make sure you unmute your microphone. Option two, you can also submit your question by checking the Q&A icon at the bottom of the screen, and your question will be read by our panelists. With that, I think we have already the first question in the line, and I would ask Richard Vosser at JPMorgan for his first question. Richard. Thanks, Felix. Thanks very much. Two questions, please. Just looking first of all on tolebrutinib in terms of your recruitment, could you give us an update on the recruitment of tolebrutinib? It looks as though clinical trials, that's not finished. When I look at other BTKs, there's one that finished recruitment in October 2021. So just wanted some understanding of where you are in recruitment and whether that would potentially put you, I mean, very slightly splitting hairs behind that other BTK. And then the second question is on the brain penetrance. I think a couple of years ago or maybe a year ago when we first had a call about tolebrutinib, there was some discussion about the relative importance of brain penetrance in RMS versus PPMS. I just wanted to just touch on, you know, as you've developed the product and looked at it more, is that you know more important in RMS or more for PPMS to try and be superior to Ocrevus? And really maybe what sort of incremental benefit do you think that brings over, say, an Ocrevus? Thanks very much. Dietmar, do you want to? Yeah. Thank you for the questions. Let me start on those and then we can also ask Erik and Tim to comment obviously. Now with regards to the recruitment, we've not communicated the exact numbers of recruitment, but let me just reassure you that, you know, we see good recruitment on the studies. We see strong interest from investigators and the clinical and scientific community. If anything, Tony has transported some of that during our call here. We are still, you know, with the timelines that we have communicated before, which is the RMS studies will read out, you know, at the end of 2023, and then we'll file immediately in basically then in 2024. For the SPMS and PPMS studies, we're expecting readout end of 2024, and then filing in the beginning of 2025. We do not see any issues there. On the contrary, we see really good engagement from the scientific and investigator community. With regards to the different subtypes of MS, you know, it's really important to realize that we have these four phase III studies. We believe in the broad opportunity for tolebrutinib across the spectrum of disease. Really that's why we've structured the program as we've structured it. We think it's important because the unmet medical need is there really across the spectrum of disease and across the spectrum of disability development. Maybe I can call on Erik and Tom really to speak more about that positioning. Erik, do you want to start? Yeah. Yes. I mean, the simple answer I think we say, well, you know, is brain penetration important for RMS or PMS? That would be, say, yes, it's more important for progressive MS. But that's not the whole truth because there is also progression going on and probably very early in relapsing remitting MS. If you want to have a good long-term outcome in MS, it's important to try to touch upon these mechanisms already before the patients goes into progressive disease. I think the more complex and more correct answer is actually, yeah, it's important for both types of MS. We think with the pharmacological properties we have discussed today, the compound has the good potential to target mechanisms driving progression within the central nervous system, both in patients with progressive MS and relapsing MS. Richard, I hope that. Perfect. Thank you. Yeah. Thank you. Okay. Let's move on. Next question is from Graham Parry at Bank of America. Graham, please. Great. Thanks for taking my questions. Firstly, just if you give us more of the biologic rationale for tolebrutinib in MG, any clinical data you've got supporting trial start, and thinking ahead where you think in the treatment paradigm that could be positioned, just given oral administration. Secondly, on the CD40 ligand, in the past, we've seen a number of these sort of fail to make it through development. Thrombotic events I think was one of the issues there. Just wondering if what gives you confidence in this one and any sort of safety tolerability data you can share there. Then actually just a cheeky one for Dietmar. We noticed the AMEERA-3 primary completion date of February the fifteenth is now showing as actual. We just wondered if that study is now in data lock. Thank you. Let me just get the amcenestrant question out of the way, which is really yes, we're sticking to our current timelines. There's not been any change to those timelines. Erik, handing over to you with regards to tolebrutinib myasthenia gravis and also the CD40 ligand. I think both of those are indications that we're really excited about. Yes. Well, with myasthenia, it is a B-cell-driven disease, but it's also important with interaction between B and T-cells. We do think that the rationale for a BTK inhibitor in that indication is quite strong. Of course, we will need clinical data to actually confirm our hypothesis. When it comes to where it could fit in therapy, I mean, most of the or pretty much all of the escalation therapies and the sort of pipeline in myasthenia are monoclonal antibodies. It could fit very nicely to have an oral once-daily medication, small molecule to have. Perhaps ideally in the segment of patients before going to monoclonal antibodies. We think there is a significant amount of patients that could benefit from having such an oral treatment in myasthenia. When it comes to CD40L, definitely, you're absolutely right. Thrombotic events were associated with the first generation of these molecules. We do believe that has been engineered out in the second-generation molecules. We have not seen signs either in our preclinical models or so far in the clinic of any type of thrombotic events of concern. Thank you, Erik. The next question goes to Laura Sutcliffe at UBS. Please, Laura. Hello, I hope you can hear me. Thanks for taking my questions. First question is just on the trial program for tolebrutinib. It looks from clinical trials like you've got almost 40 trial sites in Russia and Ukraine in the phase III program. For obvious reasons, those patients might be in a position where they have to prioritize their safety and potentially not be making visits. How robust is your trial program to its geographical distribution? Apologies for the background noise. Then just a second question also on tolebrutinib. Obviously, your dropout rate was quite low, but were there any specific reasons for the 6% of patients who did not make it to the end of the 18 months on therapy? Thanks. Yeah. Thank you, Laura, for those questions. I mean, obviously, we're following the Russia and Ukraine situation very closely. Both of these countries are countries where we and other companies across the industry are conducting clinical trials. Obviously our first concern here is for the patients, for the investigators, also for our staff, right, that we have in those countries. Also for that reason, we're following the situation very closely. It's very hard to comment on where the situation is going. I want to say at this point in time, we are obviously conducting our studies on a global level. That also includes the tolebrutinib studies. These are global studies involving sites in the U.S., in Europe, in Asia, in Latin America. This is a really global distribution of sites. We have the information, obviously, you know, how many patients do we have in individual countries and we have the ability to react to that quickly and mitigate the impact. I will leave it at that point, but I'm really quite confident that, you know, the impact can be mitigated. Right now, obviously, our main concern is for the patients in those countries, and especially in the Ukraine. For the question on dropouts, the dropout number was very small. I'm gonna hand over to Tim. Yeah. Thanks, Dietmar. We did have. We started out with 124 in the extension, and we went down to 118. Several of those patients dropped out early in the course of the long-term extension that were on what we call subtherapeutic doses. One patient in particular in the 5 mg arm suffered a severe relapse, and that patient was appropriately, I think, switched on to another therapy. We lost 2 participants because they moved. They moved out of the country, and we weren't able to follow them. Aside from that, you know, 6 out of 124 dropouts, so a very modest attrition in that trial. That's great. Thank you. Perfect. Thank you, Laura. Next question goes to Jo Walton at Credit Suisse, please. Jo, can you hear us? Yes, I can. Can you hear me now? Yep. We can. Yep. Perfect. I've got a couple of questions. One for the doctor first, please. By the time tolebrutinib is available, Gilenya and Aubagio will both be generic. How much better does tolebrutinib have to be to be the drug of choice to start patients off? Or do you think that it's going to be so compelling that those generics would not be used? My second question is a little bit. Well, it's sort of tied to tolebrutinib. You used a 60-milligram dose in the phase II. Given how well-tolerated that was, would there be any benefit in going to an even higher dose? My third question is a more sort of philosophical one. And it's about the other indications that you're going for. I can understand that you've got some biomarkers, and it's fairly clear how you choose patients, particularly in multiple sclerosis. Some of the other areas such as CIDP, do you think you're making progress there in biomarkers that this is going to become tractable? The reason that I ask is other companies have given up there with products that seem to work, but they can't work out an appropriate way to target the right patients. It's broader than MS. Many thanks. Right. Thank you, Jo, for these questions. Right. The first one is really a clinical one. Obviously, we don't have any data on the direct comparison, so we don't have head-to-head studies or anything. Obviously, you know, we think that from a disability perspective, from a perspective of how you dose, from perspective of the allowed benefit that we see and the strong tolerability that tolebrutinib has clear advantages. You wanna hear from Tony. Tony, your comments. Thank you, that's a great question. It's a crowded market, right? There's a lot of different medications out there. Where the advantages I see are, it looks like a safer profile. We're not seeing severe immune suppression like we can see with fingolimod-type drugs, where you get a lot of decrease in lymphocytes that increases the risk of infections, such as COVID. We're also the tolerability and safety margin is so much easier than a drug such as fingolimod. We don't have to do pre-cardiac monitoring for a day before they start the medication. It'll give us access to a broader group of patients, especially if this is effective for older patients with progression, they often have cardiac issues. A medication like fingolimod, which doesn't work in that group anyways, becomes unattractive. We don't have issues with what's called rebound, which can happen when you stop fingolimod. You can have this really unfortunate explosion of inflammatory activity, and that makes it very difficult. Well, it's very hard on the patient and I'm not seeing that at all with this class of drug. I guess finally, if we do need to switch to a different class of drug, we're not having lymphocyte suppression. It's gonna be much easier to switch to a different drug, if we had to switch off of a BTK inhibitor. I think the package to me as a clinician is much cleaner and better for my patients. Thanks, Tony. That's also what we're hearing from other people from the investor and physician community. It really speaks to the fact that, you know, despite the current medications that are available, there is still ongoing unmet medical need in multiple sclerosis. You see that especially from a disability perspective, and we believe with a brain-penetrant BTK inhibitor that can target microglia in the brain that can have a different effect there. We really hope we can address some of that unmet medical needs. We think there's a very clear differentiation here. Now with regards to the dosing question, the 60 mg dose has been highly effective, right? has been highly effective, and it has also been clearly tolerable in the data that we've seen so far. We believe we have a best-in-class profile here from a benefit risk perspective. Let me also ask Tim for additional comments, as we are exploring that. Yeah. Thanks, Dietmar. There is an opportunity, we think, to push the dose at some point. However, given the existing data, there's no evidence to suggest that we would improve efficacy, and there is a concern about when you increase exposure that you can increase adverse event profile. Where we stand right now with a very effective compound with an extremely favorable safety profile, there just isn't any incentive right now to try higher doses. Now, one caveat to that is that we don't know what tolebrutinib has the capacity to do inside the brain. It's very difficult to measure impact on processes behind the blood-brain barrier in the brain. We don't have good biomarkers. We have a collaboration with the NIH with a 7 Tesla imaging trial where we're attempting to explore that. For the time being, we're convinced that 60 milligrams will deliver a highly effective product that's very safe for use by the patients. If you look at the data that we're presenting here also at ECTRIMS, you can see more information on the biological rationale, on the IC90, on the relevant concentration in the brain. You also see more information from the long-term study. I think all those data really support the profile that we see for tolebrutinib. Finally, the more philosophical question. You know, it's really why we are thinking that neurology has so much potential and so much opportunity. Our understanding of the underlying disease mechanisms, our understanding of biomarkers, our understanding of, you know, imaging also is becoming deeper and deeper. similar to other therapeutic areas with that deeper scientific understanding, that opens up additional, you know, possibilities for targeting those disease mechanisms. Erik, do you wanna comment further also on CIDP? Yes, absolutely. I mean, first, yeah, it's correct. I mean, we don't have the equivalent of MRI as we have for MS for CIDP, so that's correct. The approach we have taken though is to actually subgroup the patients on clinical grounds. We have separately segmented the patients into therapy-refractory patients, naive patients, and standard of care treated patients, and we looked at them in separate cohorts. Specifically for our approach, which is a C1s inhibitor, there are pathway biomarkers. There are complement-based biomarkers that we are investigating in the study. That's our approach we're taking to CIDP. Perfect. Thank you. Thank you. We move on to Peter Welford at Jefferies, please. Hi. Thanks for taking my questions. So the two questions I would ask is, firstly, just with regards to the patients who are on the long-term extension or I guess maybe in any of the other studies, I wonder whether you have patients who have been vaccinated while on drug. If you can comment a little bit about whether you've studied at all the vaccination, the antibodies and whether or not there's any impact at all on vaccination rates and whether any additional studies could be done to show that while studies are ongoing. Secondly, just wondering whether you've done any comparison also, either internally or otherwise, also comparing to remibrutinib and oral ibrutinib, two other obviously BTK inhibitors in development and whether you've got any comment versus those with regards to the CNS or otherwise potency and on time. Thank you. Very good. Thank you, Peter. The question on the long-term safety and COVID, we have some information as you've seen from the also from the presentation here at ACTRIMS. Tim, do you wanna speak further about that? I'm sorry, Dietmar. What was the question? The question was whether we have any further information with regards to the COVID patients in the long-term safety study. No, particularly. where its impact on vaccination, et cetera. Exactly. It's particularly the vaccination because obviously there's been a lot of discussion, I think the CD20s and perhaps the Dr. Traboulsee would like to comment a bit, you know, just regards to CD20 antibodies and vaccination and whether or not tolebrutinib you've vaccinated people in the long-term extension and that you've done any studies showing their responses. We've not collected those data in the extension. I mean, we try to record vaccination or adverse events, but it's not, you know, it wasn't pre-specified, it wasn't part of our, investigational plan to begin with. I believe there are pretty good data on BTK in the oncology setting in terms of COVID vaccine response, and I think that's been fairly positive. It certainly hasn't been the issue that we've seen with the anti-CD20s and the failure to mount a humoral response. Maybe one more general comment with regards to this, right? If you use an anti-CD20, you have a pretty lasting effect on your B cell population that's pretty much a B cell depleting effect versus a BTK inhibitor that allows much more modulation from a timing perspective, right? It's a shorter lived impact, and that has in our view or can have advantages also from a safety perspective. Obviously when we talk about vaccination, it's a bit more complex because you need B cell help. You need T-cell impact, obviously. You need antibodies to be generated. It's a more complex immunological phenomenon, but the fact that you do allow for the impact on B cells to be much more modulated than with an anti-CD20 should theoretically clearly have advantages. We don't have data to support that at this point as Tim said. With regards to your question on remibrutinib or orelabrutinib, the data we're presenting here at ACTRIMS is really data comparing to ibrutinib and fenebrutinib. At this point in time, we don't have data on the other BTK inhibitors. Yeah. Just to point out that, as you know, it's become such a crowded space that we can't possibly work on all of our competitor products. We focused our attention on those three candidates that are in phase III. Having said that, at the end of the poster, there are some theoretical predictions on brain penetration for a couple of other BTK inhibitors. Certainly remibrutinib looks to be fairly low down that list, but of course we don't have any data. No. I think orelabrutinib looks like it could be brain penetrant. However, we don't know much about its potency. Secondly, orelabrutinib is fair distance behind us. You know, right now we're focused on our phase III activities. Perfect. Let's continue with the Q&A. Peter Verdult at Citi, please. Thank you. Peter Verdult, Citi. Firstly for Erik or Tom, I know evobrutinib trials recruited or finished recruiting in October, but I understand that their trial design is slightly different. I think they are observing each patient over two years. Q4 next year is definitely when they'll have their data. I just wondered, I think yours is slightly different, more sort of event related. Just wondered on, of any of the four trials that you're doing, could we see a readout sooner than end of next year? And then my second question is to Dr. Traboulsee. You know, every sponsor that we hear talking about BTK and MS claims they're brain-penetrant, they've got great AIR, SLE biomarker data. They're all best and first in class. I mean, we've heard the Sanofi pitch today. Just wondered whether, you know, how you handicap the phase III assets, you know, in terms of runners and riders and whether, you know, the twice daily dosing for evobrutinib counts against that product. Thank you. All right. Let's start with Tim, Erik, any information on the studies. Let's keep the answers a little shorter because we only have a few minutes, and there are several people who still want to ask questions. The quick answer to that is unlikely that we have data earlier. Then I hand over to Tom. Thanks Peter. Great question. Only two of the three products have phase II data. The phase II data is critical to getting the right dose. Then when I look at that from the one parameter, which is enhancing lesion, which is our classic Phase II outcome, the best data I think is still with tolebrutinib. I think, you know, Sanofi got the right dose, and I think, evobrutinib could actually be pushed more to get the right dose. Their dropout rate was higher, their discontinued rate was higher. I think part of that was pre-planned when they saw elevation in liver enzymes. They didn't tolerate that, and so they stopped the drug. Also, I think this once-a-day dosing is gonna be the way to go anyways, but that's probably more of a, you know. I'm basing my crystal ball, so to speak, on the MRI outcomes, which I think is a very valuable outcome. When you're comparing these phase II studies, that's what I would recommend you look at, is that. If I could quickly jump to Graham Parry's question about why there was a slow response when switching over to 60. That's artificial. In fact, the drug works really quickly. The 60 milligrams decreases inflammatory activity really quickly. Why it looks slower in that crossover phase is because patients crossed over at different time points, and there is a longer time period between the MRIs and in the blinded phase II. So it looks like a delay, but it's not gonna be a delay. It's gonna be just as fast as a response. Okay. Thank you. Let's continue with Luisa Hector at Berenberg. Luisa, maybe one question only since we have a few minutes left only. Sure. Thank you. My question is for Dr. Traboulsee. Based on the data you have today, in which patients would you first want to use tolebrutinib? And is there a rationale to be combining the BTK inhibitors, assuming they're successful, any potential for combination with other agents in MS? Thank you. Oh, well, great. Great question. I see this as a very, you know... Assuming that the phase II data is translated to excellent phase III data, I would see this as a very broad from first line to second line treatment, so treatment-naive patients. We also looked at patients that have very highly active disease and so those are higher risk patients. They had a beautiful response, similar magnitude of impact with the treatment. So this is going to be, I'm predicting it's gonna be a what's considered a high-efficacy oral therapy, and so you're gonna have a wide range. Now, what we're hoping is it's gonna have a big impact or a significant impact on progression, and that's a realistic expectation, but it has to be proven. If that's the case, and going back to some of the earlier discussion, progression is a process that's happening under the surface from day one of diagnosis. Therefore, this really puts some interest in starting with a drug that has potential dual mechanism of action, both anti-inflammatory and anti-progressive, as your starting point. That's why I'm really excited about this broad program that Sanofi has, not just with relapsing but progressive disease. Are we gonna hit those targets? It's very exciting times in the field. Yes. Let me just quickly, Luisa, take the question on combinations. Obviously, if you combine different BTK inhibitors, you're doubling down on one mechanism. And we already think that, you know, if you look at the IC90s that you get with tolebrutinib, you get pretty much maximal inhibition. So that combination, we would not prioritize that. But we have different mechanisms actually that we're studying in MS, as you've heard, for example, the CD40 ligand molecule. So we believe, looking at further progress. If you want to combine, for example, in progressive MS, you would rather look at those different mechanisms to be combined. Okay. Thank you. Maybe we have only room for one last question from Wimal. Wimal Kapadia at Bernstein. Can you hear us? Oh, yes. Great. Thank you. Thank you for allowing me to ask the question. We've had a lot of tolebrutinib questions, so I'll go a little bit left field. I want to ask about the brain shuttle instead, if that's okay. Clearly, a very interesting technology. Can I just ask, you know, you're targeting the insulin-like growth factor 1 receptor. Now one of your peers is also developing a brain shuttle targeting the transferrin receptor. Just how should we think about the two differences between, you know, the differences between these two approaches in their ability to really trigger penetration of the brain? Thank you. All right, Erik, that one goes to you. That's a great question. It's actually quite difficult to compare because there is relatively limited data, and there's no data comparing them against each other. We do think that both work, and actually we do have in-house technology also looking at the transferrin receptor. So we're actually in both areas in Sanofi. Yeah, I think we just need to generate more data to really compare the two. I think that that's really where we are at this point, and we're exploring both as well. Agree. Great. Thank you. Okay. With that, I think we should conclude the call. Dietmar, do you wanna provide a few concluding comments? Thanks a lot for all the questions. I think it really highlights the discussion and the interest in both the neurology portfolio, because we're not only focusing on tolebrutinib, but also then in tolebrutinib specifically. I hope what you've heard really answered some of those questions. Specifically, we're very confident that tolebrutinib has the potential when you look at the tolerability, look at the efficacy, look at how many patients are really staying on the long-term safety study, look at the biology and what we were able to show with regards to active concentration in the brain, that all these different components really come together as a story that clearly positions tolebrutinib as a potential best in class in the BTK field. We just really hope that we can make a difference for patients with MS with that approach and for the broader patient community in neurology with our neurology portfolio. Thank you very much. Thank you very much. We had a number of other questions on the line, but with that, we would conclude the call. Please reach out with any questions. Thank you so much.