Good afternoon and good morning, depending on where you are, and welcome to Sanofi's first year-end late-stage pipeline review. I'm Thomas Kudsk Larsen from the Investor Relations team, and I'm pleased to see so many people on the call today. Before we get started, I want to thank Alizé and the IR team for leading the work on today's call. I also want to remind everyone that our focus is on the clinical and regulatory aspects of the mid and late-stage pipeline, so we will aim at keeping any commercial or finance questions for another day. We want science and patience to take center stage. During the call, we'll highlight the most important events in 2025 across our pipeline in immunology, rare diseases, hemato-oncology, neurology, and vaccines, and provide the key news flow items for the first half and the second half of next year and 2027.
Because a couple of 2025 news items deflated expectations, we believe that next year's news flow comes with lower anticipation in general. The presentation will take about half an hour, and then we take your questions. As always, the presentation is available for download on sanofi.com. Please turn to slide two. Here we have the usual forward-looking statements. We'd like to remind you that information presented in this call contains some forward-looking statements which are subject to substantial risk and uncertainties that may cause actual results to differ materially. We encourage you to read the disclaimer in our slide presentation. In addition, we refer you to our Form 20-F on file with the U.S. SEC and our French universal registration document for description of these risk factors. Please turn to slide three. Today, we are joined by Houman, Head of R&D, and Jean-François, Head of R&D for vaccines.
Before I hand over to Houman, I want to thank everyone on the call for the interest in Sanofi and for your support during the year. It has been a busy year with news, some favorable, some unfavorable, and there are lots of changes in the world around us. However, as you will hear today, we are focused on moving forward with our pipeline-driven transformation. With this, I'll now hand you over to Houman.
Thanks, Thomas, and thank you everyone for joining us today. It's a pleasure to be with you to discuss the medicines and vaccines that we're most focused on in our pipeline. After a big welcome from my side to Jean-François, who will cover vaccines a little later. Now, over the past two years, we've made multiple new appointments across key functions in R&D. New hires include heads of development, translational medicine, digital research, regulatory affairs, and a new chief medical officer. We focused on building a skilled and thoughtful R&D experience leadership team, perhaps the best in the industry, combining internal expertise with external talent to drive innovation and change how we approach R&D and Sanofi. I'm pleased and proud to work with this team and the teams that they serve to advance our science and our pipeline further. Please turn to slide four.
As we refine the way we work and build a sustainable pipeline for the future, we've also defined several key performance indicators to track our progress. The Sanofi of the future will have a rigorous science-based culture, and therefore we're looking to scientific publications as one important leading indicator of progress. Scientific publications in top-tier journals reflect the quality and impact of Sanofi's R&D programs and strengthen the company's position in the scientific community. In parallel, we have seen an increasing trend for patent filings across our four main geographies and reached an all-time new high in 2024, the latest full year available. Patent filings demonstrate innovation across all major biopharma modalities, showcasing platform diversity and technological breadth. Other leading indicators include regulatory designation. For a few quarters, you have already been able to track those in the appendix to our quarterly results investor presentation. Please turn to slide five.
Ultimately, we're in the business of improving public health, and there's no better way of doing that than bringing innovation to patients in the form of new medicines and, of course, vaccines. In 2025, Qfitlia became the first RNAi RNA interference antithrombin medicine approved for hemophilia A and B in the U.S. and China, representing an innovative mechanism of action in hemophilia treatment. Wayrilz received approval as the first BTK inhibitor for ITP in the U.S., with regulatory reviews going on in Japan and China and a positive CHMP recommendation in the EU from October for this rare blood disorder. And NUVAXOVID achieved full approval as the first recombinant COVID-19 vaccine in both the U.S. and the EU, providing an important non-mRNA option for COVID-19 prevention. Slide six, please.
In addition to the approvals, we have several phase II and III readouts in the pipeline across immunology, rare disease, oncology, neurology, and vaccines. Importantly, Amlitelimab met primary and secondary endpoints in the first phase III study for atopic dermatitis, COAST 1, demonstrating clinically meaningful improvements in skin clearance and disease severity, and intriguingly promising potential for quarterly dosing. Itepekimab had met the primary phase III endpoint in AERIFY-1, one of the two studies in former smokers with COPD, showing significant reduction in moderate or severe exacerbations. However, the second study did not meet the primary endpoint, handing us a mixed outcome overall. Efdoralprin alfa met all primary and key secondary endpoints in alpha-1 antitrypsin deficiency emphysema, demonstrating superiority versus standard weekly plasma-derived therapy.
Tolebrutinib did not meet the primary endpoint in non-relapsing and primary progressive multiple sclerosis, but remains under active regulatory review in secondary progressive disease, where it could potentially become an option for patients with limited access to approved medicines today. Multiple vaccine candidates showed positive safety and immunogenicity results, including SP0087 for rabies prevention and combination vaccine SP0287 for influenza and COVID-19, and SP0289 for pandemic preparedness. As Thomas mentioned earlier, not all news items are favorable in 2025. It's important to recognize this, but also assure everyone that we are learning from the challenges we are faced with. For example, we're continuously and adaptively adjusting ongoing study with learnings from past studies. Biopharma development is inherently a risky business with a high potential rewards, which means we fail, learn, move on, and ultimately succeed. Slide seven, please.
We'll now take a closer look at the pipeline achievements in 2025 by disease area, starting with immunology and Dupixent. During the year, Dupixent received U.S. approval for bullous pemphigoid, with the regulatory decisions expected in the E.U., Japan, and China in the first half of next year, expanding the dermatology franchise into rare autoimmune blistering diseases. The LIBERTY-CUPID phase III program successfully reported approval for chronic spontaneous urticaria in the U.S., E.U., and Japan, providing a new regulatory option for patients with this challenging condition. In China, the regulatory submission is anticipated in the first half of next year. The LIBERTY- AIMS phase III study demonstrated that Dupixent clinically meaningfully improved radiographic, endoscopic, and symptom measures in allergic fungal rhinosinus patients. A U.S. regulatory decision is expected in the first half of next year.
We're very proud of Dupixent, but of course, there's a lot more to Sanofi than Dupixent, so let's move on. Slide eight, please. Staying on immunology and now looking at how we can further augment the value we bring to patients in dermatology beyond Dupixent, Amlitelimab, our OX40 ligand monoclonal antibody targeting the fundamental immune node and TNF superfamily family member OX40- ligand, is intended to mitigate the impact of multiple different disease pathways that at different points in disease drive the heterogeneous disease that is atopic dermatitis. Amlitelimab demonstrated clinically meaningful improvement in skin clearance and disease severity in atopic dermatitis. While Amlitelimab's mechanism of action increases over time, the COAST 1 phase III study showed progressive efficacy increases with no plateau yet observed in some secondary endpoints like itch, which also showed early benefit. It also offers the potential of patient-friendly quarterly dosing that reduces the treatment burden.
No new safety burdens were identified in this study. In addition, Brivekimig, our TNF-alpha OX40- ligand nanobody conceived of and generated entirely within Sanofi, achieved its primary phase II objective in hidradenitis suppurativa with clinically meaningful improvements in high score 75 responses compared to placebo. Owing to the quality of the data and enthusiasm from the community, phase IIb study for Brivekimig is commenced dosing patients to further evaluate the efficacy and safety profile across different patient populations and disease severity. Amlitelimab and Brivekimig are expected to deepen Sanofi's presence in dermatology, broadening in atopic dermatitis and entering skin diseases such as HS, an area of large unmet medical need adjacent to atopic dermatitis. Next slide, please. Moving to respiratory, our second biggest area in immunology, Amlitelimab showed hypothesis-generating phase II efficacy in difficult-to-treat asthma with heterogeneous inflammation characterized by high eosinophils and elevated neutrophils.
Notably, this study also served to confirm the interval dosing we see in atopic dermatitis. In this study, based on our post-hoc analysis, we estimate that this subgroup is about one-fifth of the total asthma patient population. The next development steps are subject to a full understanding of the unmet medical need, portfolio prioritization, and ongoing regulatory discussions to determine the optimal development strategies across the pipeline. I continue to extol the virtues of dynamic capital allocation and careful financial stewardship, driving value creation, which I advocated from my very first day here at Sanofi. Itepekimab achieved a significant 27% reduction in moderate or severe COPD exacerbations in AERIFY-1 phase III study, but did not meet the primary endpoint in AERIFY-2.
Given the unmet medical need in COPD and the setback by other companies in this field, we're considering our strategy, including through ongoing discussions with our collaborator and partner Regeneron, as well as regulatory authorities, and we will communicate progress in due course. Slide 10. Staying in respiratory, Lunsekimig is a pentavalent nanobody that multi-specifically binds to both TSLP and IL-13 at two unique epitopes with additional human serum albumin binding to increase half-life and potentially enhance efficacy. Previous phase 1b data in mild to moderate asthma showed a rapid and significant reduction in FeNO levels at day 29, indicating meaningful anti-inflammatory activity. Biomarker reductions were observed across eosinophils, IL-5, Eotaxin 3, IgE, and TARC, with improvements in FEV1 and small airway function in patients with impaired lung function.
Phase II studies are underway in asthma, COPD, atopic dermatitis, and chronic rhinosinusitis with NP, with the first phase II readouts expected in the first half of next year. As we advance by specific nanobody molecules, it's important to remember that the platform has already demonstrated clinical and regulatory validation with CABLIVI for acquired TTP in our rare disease franchise. Slide 11. Moving to new areas in immunology, Balinatunfib, our oral small molecule TNF-R1 signaling inhibitor, showed nominally significant efficacy in phase II studies for psoriasis and rheumatoid arthritis, with more encouraging results on endpoints reflecting deeper disease control. The inhibitor was generally well tolerated, and we currently see potential in monotherapy and RA, subject to further evaluation, as well as combination backbone with other oral medicines, with the next steps currently under evaluation.
Duvakitug TL1A monoclonal antibody, not inhibiting the DR3 receptor, met all primary endpoints with a competitive profile at week 14 in phase IIb studies for Crohn's disease and ulcerative colitis, demonstrating efficacy across inflammatory bowel disease. The data were presented earlier this year. The molecule had leading endoscopic response rates in Crohn's disease compared to other TL1A class molecules, positioning it competitively in this area. Phase III studies for Duvakitug have recently commenced with subcutaneous dosing in both UC and Crohn's disease. The unmet medical need in IBD is, if anything, increasing, and Sanofi is committed to making a difference here. There are four more diseases to cover today. Slide 12. Leaving immunology, we're now moving on to rare disease and oncology.
Wayrilz is now approved in ITP in the US and under regulatory review in Japan and China and a positive CHMP recommendation in the EU from October, and with orphan designation in multiple regions reflecting its importance for rare disease patients. Phase II data in IgG4 disease showed a considerable reduction in disease flares as well as being glucocorticoid sparing, with a phase III study planned to start based on these encouraging results. Phase III studies have already been initiated in warm autoimmune hemolytic anemia based on exploratory phase II results showing clinical benefit and sickle cell disease based on clinical evidence. This medicine represents a potential new multi-immune modulation platform with disease-modifying potential across multiple rare autoimmune conditions, expanding beyond the initial ITP indication. Slide 13, please.
Staying with the intersection between INI and rare diseases and based on the strategic acquisition of Blueprint earlier this year, Sanofi is building a leading franchise in mastocytosis with Elenestinib as a potential next-generation D816V kit inhibitor in phase II-III development to follow on from Ayvakit. In addition, BLU-808 is being assessed as a highly potent and selective wild-type kit inhibitor in phase II, leveraging Blueprint's expertise in kit and mast cell biology. This has been a challenging and high-risk target from a TI perspective for the industry, but with world-class expertise of our Blueprint Sanofi colleagues, this will represent one of our approaches to the increasingly recognized role of mast cells in disease. Efdoralprin alfa , a recombinant AAT protein, demonstrated superiority versus weekly plasma-derived therapy with Q3 and Q4 dosing in alpha-1 antitrypsin deficiency emphysema patients.
The phase II study met all the primary and key secondary endpoints, with statistically significant superior functional AT trough levels at week 32, supporting potential for less frequent dosing with a regulatory submission planned for the second half of next year. Slide 14. Following solid clinical progress last year, Sarclisa continued to deliver for cancer patients in 2025. Sarclisa's subcutaneous formulation established non-inferiority to IV administration in refractory multiple myeloma in the IRAKLIA phase II study, providing patients with a more convenient treatment option. Further positive data have been generated across multiple regimens, including combinations with VRD in the newly diagnosed transplant-eligible and transplant-ineligible patients, expanding treatment options across disease stages. For eligible patients, the subcutaneous formulation demonstrated a similar safety profile to IV with no new safety concerns, and most patients and providers preferred the automated hands-free delivery system.
Early use combination strategies in subcutaneous administration unlocked significant benefits for patients with multiple myeloma, representing very successful lifecycle management and execution by our hemato-oncology colleagues. Slide 15. Moving to neurology now, we have two main projects in late-stage development. Tolebrutinib, our second BTK inhibitor, and Frexalimab. Tolebrutinib demonstrated a convincing 31% delay in time to onset of six months, confirmed disability progression in secondary progressive multiple sclerosis, representing meaningful clinical benefit. We saw about a 4% rate in patients with elevated liver enzymes over three times the upper limits of normal, all within the first three months of starting therapy. In short, this is a benefit-risk equation that we navigate on Tolebrutinib in the SPMS setting. In primary progressive multiple sclerosis, Tolebrutinib did not meet the primary endpoint of composite confirmed disability progression in PPMS. Safety was consistent with previous studies.
Based on this result, we will not pursue regulatory submission in this setting. In SPMS, we anticipate a regulatory decision in the U.S. and in the E.U. during the first half of 2026. Frexalimab, second-generation Fc-modified CD40 ligand antibody blocking both innate and adaptive immune responses via the co-stimulatory CD40 pathway, previously showed a large reduction in new Gd-positive T1 lesions at week 12 in a phase II randomized RMS study with sustained reduction through week 96. This study was published in the New England Journal of Medicine. Phase II study, phase III studies for Frexalimab in RMS and SPMS are ongoing, with readouts expected in 2027.
While there were no significant clinical developments with Frexalimab in 2025, we wanted to remind everyone of our commitment to patients with MS and mention that we expect all earnings from Tolebrutinib and other MS medicines in development will help us strengthen the clinical program for Frexalimab ahead of the anticipated data readout in 2027. Please turn to slide 16. During the year, we shared updates on Riliprubart and CIDP. Patients treated with complement C1s inhibitor showed a 35% reduction in neurofilament light chain levels, with strong and sustained reduction of complement activity from baseline indicating target engagement. As previously reported in 2024, at 24 weeks, 87% of standard of care patients improved or remained stable after switching from their previous treatment to Riliprubart. As reported this year, at 76 weeks, 80% remained relapse-free, staying on Riliprubart.
For the second treatment group, the standard of care refractory patients, 89% improved or remained stable with Riliprubart at 24 weeks. The number at 76 weeks was commensurately 78%. And last, for the third group of patients, naive patients, the corresponding numbers were 92% and 86% respectively. Across treatment groups, this shows a solid durability of the treatment effect. The comprehensive subcutaneous phase III program includes two studies: Vitalize, the first head-to-head study, patients who are on IVIG and remain partial responders, and Mobilize, a study for standard of care refractory patients, which means patients who have experienced failure or inadequate response, standard of care therapy, which is IVIG or steroids, depending on the jurisdiction. We look forward to the phase III study readouts from these comprehensive programs in 2027.
In addition, a study is also underway in antibody-mediated rejection with orphan drug designation in the U.S., expanding the potential of complement inhibition beyond neuroinflammation. Please turn to slide 17, and with the greatest pleasure, I hand over to Jean-François.
Thank you very much, Houman. Hi everyone. I hope you're doing well and warm at the end of this year, so it's my pleasure to take the next five minutes to cover the progress that we've made in our vaccines pipeline, so as you all know, Sanofi has established a strong legacy in influenza vaccines, and we've recently expanded into broader respiratory disease prevention, including RSV and COVID-19, there we obviously leverage the expertise and the platform that we have developed for several cases. Meanwhile, as we speak, Beyfortus has now protected over 10 million infants across more than 40 countries.
In real-world evidence, Beyfortus has consistently demonstrated about 80% reduction in hospitalization, and it has allowed Sanofi to establish a leadership position in RSV prevention. NUVAXOVID on this side represents the first recommended COVID-19 vaccine with full approval in the U.S. and in Europe, and it offers healthcare providers and patients an important alternative to mRNA-based vaccines, obviously. When you look at the next projects in our pipeline, you see an important pneumococcal vaccine in phase III, combination vaccines for influenza plus COVID-19, pandemic preparedness solution for H5 influenza, and novel combination approaches using both mRNA and non-mRNA platforms to address diverse respiratory threats. We'll now go deeper into this year's achievement, first in influenza and COVID-19, and then in respiratory diseases. Please turn to slide 18. So this year, we have released Trinity IDO's phase IV study data.
This trial represents the world's largest influenza vaccine randomized effectiveness study with 466,000 older adults across two countries, so Spain and Denmark, and three influenza seasons. The study has demonstrated superior protection of high-dose versus standard-dose influenza vaccine against hospitalization endpoint in the older adult population, supporting again the excellent clinical value of Fluzone High-Dose. In the middle, you see that we have achieved positive phase one two results for both of our influenza plus COVID combo vaccines, combining either Fluzone High-Dose or Flublok with NUVAXOVID. These results support a high probability of demonstrating non-inferiority in phase III studies that would compare the new vaccine against the widely used regimen with flu and COVID-19 vaccine co-administered. You also remember that we decided four years ago to invest in mRNA technology to enhance our readiness for the next pandemic.
This year, we are very pleased to see that our H5 pandemic influenza mRNA vaccine showed 93% seroprotection rates across both age groups, basically the 18 years to 64-year-old adults and the above 65-year-old adults. This was achieved after the classic injection regimen and at the lowest dose that we tested. These data not only support the competitiveness of our proprietary mRNA platform, but also show how we have improved our pandemic readiness. Building on our solid pipeline progress in influenza and COVID-19, let me now cover the progress we have made in other respiratory diseases, and please turn to slide 19.
So here, I'm going to cover mainly RSV plus hMPV, and you remember that our strategy to enter the RSV older adult vaccine market has been to develop a bivalent RSV plus hMPV vaccine that would double the medical value for public health systems and patients compared to the two vaccines available today, which is RSV standalone vaccines. So this year, as you can see on the left part of this slide, we got the clinical evidence of the competitive performance of our RSV mRNA component, which we believe will be in line with competitors. So what you can see on the left table is that our monovalent RSV mRNA vaccine showed a high efficacy on several endpoints in a phase two study, including 75% vaccine efficacy against RSV LRTD at a median follow-up of 5.5 months.
Actually, we also would have a predicted 100% efficacy if we were to use similar phase III endpoints as our competitors. Let's now have a look at the hMPV component in the middle panel. There you can see that our bivalent RSV and hMPV mRNA vaccine induced very competitive HMPV antibody level in a phase I/II study. Again, this was achieved with a bivalent vaccine. Finally, as you know, we also recently closed the acquisition of Vicebio, and I'm very pleased to show you on the right panel for the first time that Vicebio bivalent RSV and hMPV vaccine showed up to 15-fold increase in RSV neutralizing antibody levels and several-fold increase in hMPV neutralizing antibody level in the small phase I conducted by Vicebio.
So basically, this validates the recent acquisition of the company, the molecular clamp technology that they have developed, and the addition of this vaccine candidate into a phase IIb. As a next step, we plan to initiate next year the phase II study for the bivalent RSV plus hMPV vaccine candidate from Vicebio. Please turn to slide 20, and I'm back to Houman.
Thanks, Jean-François. Super clear and a great year for vaccines. Before we close the presentation, we wanted to cover the important topic of pipeline replenishment and new technology. We can replenish from inside Sanofi, and we can augment with external opportunities through business development, licensing, and acquisitions, as we saw earlier this year with both Blueprint and Vicebio.
Seven new molecules have been added to the phase 1 development, including CD20 bispecific antibody, a TREM2 agonist, a GPRC5D antibody showing continued innovation across multiple modalities. Based on Sanofi's capabilities in genetic medicine, three AAV gene therapy programs entered phase I, one in dry AMD, one in myotonic dystrophy type 1, and one in wet AMD, already having progressed rapidly to phase II. The Dren Bio acquisition earlier in the year provided CD20-directed myeloid cell engager just mentioned, with the potential for targeted phagocytosis and B-cell depletion to reset adaptive immunity. Also, new external partnerships have been established with Recludix and Earendil Labs to access novel targets, including STAT6 inhibitors and dual-targeting antibodies, supplementing our internal innovation efforts. The STAT6 inhibitor will advance to phase I very soon.
As we move forward, internal research and early development efforts supplemented by external innovation will further replenish and strengthen our early stage pipeline. Please turn to slide 21. On new technology, Sanofi's new digital R&D plans target more than 40% reductions in overall development cycle times from research through to approval across the entire value chain. It is an ambitious target for the next handful of years, but if we succeed, it will represent a much improved approach to drug development and a significant boost in productivity. The initiative spans drug discovery and design, clinical development, regulatory processes, and approval launch readiness activities, ensuring end-to-end optimization of the development process. Current development timelines include about four years for research, 18 months for preclinical research, seven and a half years for the clinical phases, and several months for the dossier preparation and ultimately registration.
Digital transformation will help accelerate this innovation and bring new medicines to patients faster while maintaining scientific rigor and regulatory compliance standards. Please turn to slide 22. Summarizing all key development projects, the immunology portfolio includes multiple phase III programs with Amlitelimab in atopic dermatitis, Duvakitug in IBD, Itepekimab in COPD, and with the only caveat, all representing significant opportunities to expand our presence in immunology. They're followed by phase II programs for the bispecifics in HS, asthma, and other areas of immunology. Neurology programs still feature Tolebrutinib in SPMS, Frexalimab in RMS and SPMS studies, and Riliprubart in phase III CIDP studies, addressing high unmet medical needs patients. The rare disease and oncology portfolios include Sarclisa with its subcutaneous formulation submitted, Wayrilz approved for ITP with lifecycle management potential, and multiple programs for Gaucher disease and Fabry disease.
The vaccines portfolio encompasses phase III programs for FLUZONE High-Dose in adults 50 years and over, SP0087 for rabies, SP0202 for pneumococcal disease in children, and the phase II programs for RSV combinations and pandemic influenza. We continuously review the pipeline and seek to allocate our resources and R&D investments into the opportunities that add the most value for patients and for the company. As a result, you will see changes from time to time. While there are projects being started and terminated, with a next update with Q4 results in January, the pipeline shared here today is the pipeline we will take into next year. Please turn to slide 23. As we look ahead, we're now providing the news flow for the first half and the second half of next year, and by 2027 for the first half.
In the first half of next year, regulatory decisions expected across different regions include Dupixent for AFRS, BP, and CSU in children, Teplizumab lifecycle, and Sarclisa subcutaneous, as mentioned so. First half clinical data readouts include more Amlitelimab data in AD, Lunsekimig in asthma, and multiple opportunities in rare disease, including Gaucher's and Fabry's, with a Venglustat potentially offering new opportunities for these patients. Second half of next year offers more data from the Dupixent lifecycle program and regulatory submissions of data from the first half and earlier, potentially including Efdoralprin alfa output for AATD. 2027 has several phase III readouts, including data for regulatory submission at Q1 outside the U.S. for Frexalimab in RMS, Riliprubart in CIDP, and multiple vaccine programs, including SP0202 and pneumococcal disease, anticipated to sustain long-term growth momentum.
As we move ahead with our pipeline, more news items will be added, both from our internal efforts augmented by business development opportunities. We are committed to a sustainable pipeline to take Sanofi forward. Before we close, our summary outlines the progress in building R&D capabilities and advancing our pipeline. The leadership changes we've made across research development and other key R&D functions strengthen our organization. Our 2025 approvals, Qfitlia, Wayrilz, and Novavax will demonstrate progress in bringing innovation to patients. Lifecycle management options for Dupixent, Sarclisa, and influenza vaccines are important for expanding the clinical benefit. For example, we hit the mark of 1.3 million patients treated with Dupixent in 2025. Our phase III programs have matured during the year, including Amlitelimab, Wayrilz, while our important bispecific nanobodies advance further into mid-stage development.
In 2026 and 2027, across biopharma and vaccines, we're currently expecting more than 15 regulatory submissions, more than 30 new regulatory submissions, sorry, 15 regulatory decisions, more than 30 regulatory submissions, and more than 15 phase III readouts, all representing significant new near-term activity. With this, also, my heartfelt thanks to all R&D colleagues and indeed colleagues around the company for their dedicated effort this year as we continue being committed to improving people's lives. Slide 25. With that, we will now open the call to your questions.
As we always try to say, we would ask you to keep your questions to one or two each. It's Christmas, remember. You'll be notified when the line is open for your question. At that time, please make sure you unmute your microphone, option one, or option two, submit your question by clicking the Q&A function. With that, we move to the Q&A.
Very good, so the first question comes from Peter Verdult at CT. Hi, Pete. Sorry, Peter Verdult at BNP.
I think it's Peter Verdult at BNP, but at least I didn't make a mistake. Can you hear? But lots of people.
We love you any which way, Pete.
Lots of people are laughing anyway, but yeah, Peter Verdult at BNP, formerly of CT. Just a couple, and maybe the first one is not to pummel you on some minute detail or asset, but maybe given that it's two years since December, the December R&D day when you were appointed. I mean, there have been some successes, and let's be blunt, there's been quite a few setbacks.
But if you were just to reflect on the last two years, where the biggest challenges are and what are you, apart from strengthening your R&D leadership team, any learnings and things you can do differently going forward? That'd be question number one. And then just more topical. SPMS has been talked about as being a big area of high unmet need. So high unmet need means to me that the risk-benefit profile might be more skewed towards more tolerable. So how concerned should we be about the actual provability of Tolebrutinib in SPMS given the recent updates? Thank you.
Pete, thank you as always for great questions. Number one is thank you for reminding me. Since we're in details, I think it was December 7, 2023, when we met in R&D Day. And at the time, I was pretty clear that I had three fairly immediate goals.
One was to take what was an excellent team at the time and make them better. I hope that by looking at the profiles of both the existing team and those recruited, you'll see that we've recruited a stellar team, internationally recognized, highly experienced, and innovative working together. So lesson one was to surround myself with even better people who are genuinely incredible and work as a team. A t some point, I hope that you'll see all of them. The second lesson was, of course, that we knew we'd have failures and successes. The key was to learn from those failures and successes.
I've said to you and more publicly that both Sanofi and the broader pharma community this year have learned that in areas where there is an existing standard of care, phase III trials have a different profile of patients that come in, and we have to be mindful of how we adjust our clinical trials, both adaptively as they're in flight, but also mindful of what the existing standard of care is, and that's a lesson we've learned deeply, and you'll hear as we go through questions, we've continued to adjust our clinical trials. Then the third commentary is, while we have had mixed results, and we should be measured in the context of those mixed results, I don't want anyone going away from this call perceiving that, for example, Amlitelimab in any way was a negative result.
A study that did everything we asked of it hit its primary and secondary endpoints and provided patients with a Q4W, Q12W dosing. We have a slew of data coming next year, and I think that if we get real replication of those studies, we'll have a genuinely registrational or at least a filable product with a major impact for patients, and then to your second question, you made an excellent point about Tolebrutinib. Just to be clear, firstly, the data on Tole was super clear when you look at CDP and disability, etc. In SPMS, the Kaplan-Meier curves diverge consistently and early. I think if you look at the data, pretty convincing. You're right that we have to be extremely thoughtful about patient safety. We always are.
As we've gone forward with productive conversations with our regulatory colleagues at the FDA and elsewhere, we've taken the kind of direction that you've pointed to, which is to ensure that we've got maximal risk and benefit, including making liver function testing available to patients. Any more than that said during an active regulatory review would be unwise.
Next question. So it's coming from Louisa Hector at Berenberg. Louisa?
Hi, Louisa.
There we go. Can you hear me?
Beautifully.
Wonderful. Thank you very much for taking my question and for the presentation. I wonder whether we could touch a little bit on key learnings with Tolebrutinib, the Principia acquisition, and that model, and how things may have changed over the past couple of years, Houman. So I'm thinking Sanofi had a position in multiple sclerosis. We have the BTK inhibitors.
The safety issues came up during the course of development. So are there things you would do differently now in terms of ensuring that that sort of early stage knowledge that comes through acquisition is somehow retained and would allow you to maybe bring a next generation, which is superior when you do face some of these issues? So it's really around, I guess, investment into our early development and how you ensure with your next round of acquisitions and partnerships that you can keep all of that going so that you don't hit these stumbling blocks at the late stage. And then I'm thinking Blueprint and some of the other deals that you've done, just how you might be approaching that differently. And then since you showed the slide on your KPIs, nice uptick in patents for 2024, yes, but it seems to come from devices. What is that?
Louisa, thank you for your eagle eyes. Without you, I think we'd be lost. Just to really move very quickly through your questions, number one is I don't want to I don't want anyone to walk away from this call thinking the Principia deal was a bad deal. As you heard on this call, Wayrilz has already been approved. It's an excellent product serving multiple patient needs. And I think there was quite a lot of smartness around different forms of BTK, covalent, then non-covalent with different residence times on molecules and also the ability to be blood-brain barrier penetrant. So what I don't want to do is in any way convey the view that that was a wrong deal to do. And indeed, while some of those studies were negative, I think in retrospect, I wouldn't have sadly changed anything, honestly.
I think it was an entirely reasonable thing to go across the multiple sclerosis waterfront, bearing in mind even the modern McDonald criteria, seeing multiple sclerosis as a continuum. So I think that the criteria came out in the last two months. So number one is I think we have to salute our colleagues for having been thoughtful and generated a real drug that's come to the benefit of patients and developed it in the appropriate way. Your comment on what we can learn from these studies is number one, I think that being thoughtful about early diligence as we do these studies is going to be important. Of course, the diligence start was done here. We have an exemplary team who are highly experienced in diligence and BD to augment what was already amazing at Sanofi. But actually having scientific rigor is going to be important.
You said something very clever in your comment about taking learnings. Of course, this is the era of digital and AI, and without giving away any trade secrets, we have applied digital and AI to the BTKs and have some thoughts about how you can modify their biology and their chemistry to maximize value. And then on your KPIs, great question. As I say, thank you for your eagle eyes. We've got an excellent device group that sits beautifully between Brendan Callahan and myself. They've been incredibly productive. As you will know, in 2025 and 2026, there's an increasing value to devices. They are a heavily neglected area of drug development, and with the combination of RF feedback, the ability to figure out the temperature of medicines as they're given, the ability to think about dosing schedules, compliance, etc., those devices generate huge amounts of value.
I think that firstly, those patents that you'll see are broad and wide relating to a number of device types. I won't give away any trade secrets. But the first wave of those devices, as you can see, came from Sarclisa, which provided an on-body device that's excellent and is the source of real patient value.
Okay. The next question comes from Richard Vosser at J.P. Morgan.
Hi, thanks for taking my questions. Firstly, maybe a question on the Amlitelimab readouts. I think on the slide, it suggests first half 2026 for all the data. Maybe you could just give us, if possible, a bit of direction on the cadence of events across the COAST or AQUA and S3 trials. It suggests they're all in H1. Perhaps you could give us a little bit more color there. And then secondly, a question on vaccines.
We've recently seen the Cidara data or a deal for buying Cidara and the data from CD388, which showed pretty strong, I think, flu prevention efficacy in phase II. Just what's your thinking about this technology impact on flu vaccine strategy and how you're thinking about that within the development of future flu treatments on your side or vaccines? Thanks very much.
Yeah, Richard, let me take Amlitelimab and Jean will take the Cidara questions very happily. So just on Amli, I'll be succinct. You're right, the majority of the data, if not all of it, will be available H1 or at the border of H1 H2, the cadence is pretty straightforward. At some early point-ish in H1, we will have the COAST 2 and the SHORE studies. Those studies, as you remember, COAST 2 being a replicate of COAST 1, broadly speaking, SHORE being the combination of topical corticosteroids.
We'll then subsequently have one that we don't talk a lot about, which is a HYDRO study, which is a combination of vaccines and AQUA, which is for patients which are advanced biologic refractory, and then ultimately, as we walk through H1, we'll then very quickly move to S3. It's a matter of great interest to me that we'll also have some open label studies that we'll read out during that point and we'll present throughout the year at medical conferences, so it's going to be very exciting, and then handing over to Jean-François on Cidara.
Yeah, thanks for the question. Of course, as you can imagine, we had a look at the Cidara molecule and we had some interesting discussion within the company. Basically, the data that they have generated are very supportive, as you mentioned, so certainly efficacy reach level that are compatible with vaccines.
What we believe basically is that the Cidara molecule will be complementary to vaccine and not replacing vaccines. And there are a couple of elements to believe that. And by the way, you probably noted that the phase III is in a flu vaccinated population. So again, another element supporting that it will be complementary. We believe it will be a complement to vaccination because we believe it's going to be mainly focusing on the people that have an extra need, have extra complication coming from flu infection, people that are immunosuppressed, people with a chronic kidney disease, etc. For sure, the molecule is not very convenient to be administered. As you noted, it's probably a 3 ml injection and probably three different injections one time, probably not something that can happen in the retail.
From a commercialization point of view, the commercialization channel needs to be built for sure, including reimbursement for that kind of molecule that cannot be given in the retail. The cost of goods for such a molecule, so a molecule is doing a great job, but you need a significant dose driving the volume and the number of ml you need to administer. But it also drives a cost of goods and a cost of goods that will be more Specialty Care product than Vaccines. So when you put all of it together, we really believe that actually it will be a complement to vaccine and not a replacement, and I must say this is also what we heard from the Cidara team in the past.
And also it seems to me that the Merck team was also going in that direction when they positioned the product in line with the specialty care and oncology product. So again, complement and not a replacement at this stage, at least that's how we see it.
Thank you. So the next questions come from Sachin Jain from Bank of America.
Hi there. Thanks for my questions. Two, if I may. So firstly on Frexalimab, Houman, you referenced a couple of times taking learnings from the Tole programs. One of you just, I don't know, fleshed that out a little bit as to how you're thinking about comparator arm trial design endpoints and where you are with the regulatory discussion of any changes you want to put through. And then the second question is on Dupi lifecycle management.
Regeneron talks to having, I think, some sort of follow-on candidate, potentially less frequently dosed. Is there anything you're able to comment to today or when do you think we could get some updates there? Thank you.
Sachin, great questions. You're right. We've taken learnings, particularly in RMS. As you know, teriflunomide ARR rates have now fallen to one every eight years. With that very low, I'm sorry, background ARR rates fallen to one every eight years. Powering to allow us to differentiate against teriflunomide requires more patience. As you may appreciate, I'm not going to go into the details of exactly that, but we've had both thoughts about powering and interesting discussions with the regulator regarding exactly the SAP, the statistical plan.
So yes, A., we've learned from the evolution of the RMS studies that happened over the last three years during the life of the Tole study . I was asked by Louisa, how do we adjust and learn? I think one of the things we've done is we've learned on the fly to adjust our trials to incipient conditions. And I think everyone will have to do that in the industry going forward. Your second question was on Dupi. Incredibly excited by our thoughtful partners. And they're always incredibly insightful about Dupi lifecycle management and stuff. At this stage, I have no more to say, but I'm excited that George and Len have counseled .
Okay, so the next question is from Simon Baker at Rothschild Redburn.
Thank you for taking my questions and for doing the call. Two, if I may, please. Firstly, on Tolebrutinib and going back really to yesterday, Houman, I absolutely get that for clarity and purity of application, it makes sense to leave PPMS and focus on non-relapsing secondary. But based on the work done in the Holmes paper that you flagged up yesterday, once the dust has settled on the main indication for Tolebrutinib, do you think there's a way back for reappraising the potential for Tole in primary progressive? And then secondly, changing the subject a little bit, looking at immunology, one of your competitors sees, quote, "mega blockbuster opportunities for sub-Q therapy" in the autoimmune immunology space. Be keen to get what your perspectives are on the usefulness and potential of sub-Q therapy there. Thanks so much.
Perfect. Yeah. So Simon, thanks for the questions. I think that just to be super clear, and that Holmes paper, which I think was in August 2025 in Nature Medicine, was super clear that the traditional, what I took away is that the simple traditional definitions of MS are going to change over the next few years. I think for the moment, the path of least resistance in order to generate value for patients is in SPMS. But I think as the definitions, both McDonald and otherwise, and indeed the G35.0 code from the ICD-10 changes occur for reimbursement, I think we will all have to review endpoints and stratification for MS, including, of course, with MRI-based definitions which that paper went into. I think that's as much as I really want to say about Tolebrutinib. And then Thomas has reminded me very kindly about your comment on self-therapy.
I think you've seen a veritable explosion of value in cell therapy in bispecifics that are T-cell engagers as well as myeloid cell engagers, but also an interesting emergence of in vivo reprogramming relevant to all of these disorders, both in oncology and immunology. You'll know that while cell therapy is excellent as a proof of concept, and I think that various allo approaches may work in due course, they're not simple therapies to deliver. Our view is, as we said in December 2023, in vivo reprogramming and our approach to bispecifics where we're strong in large molecules and biologics is where we're focusing. But they're certainly a great proof of concept.
Okay, the next question comes from James Quigley at Goldman Sachs. James?
Hello, yep, I've just unmuted. Thank you for taking my questions. I've got two, please. Firstly, on Itepekimab, can you obviously speak? It was back in May or the end of May that the trials were read out. So what are the potential options here? Is there any additional data that you're waiting for in order to make a final decision about whether to either start new trials or whether to stop the program altogether? So what are the potential outcomes and what are the sort of options and data you're looking for? And then secondly, on GP and CSU, could you compare the data package you have versus what Novartis has for Remibrutinib? There's a lot of excitement about the Remibrutinib drug out there amongst the investor community.
So just wondering how you think about the data and how it compares and whether across your BTK portfolio, you could also look to potentially bring forward other assets, whether it's Rilzabrutinib or any other BTKs in development into these immunology spaces as well. Thank you.
Pleasure, James. Your latter question was with Dupi and CSU. Just to be super clear. Oh, yeah, yeah. Thank you. I think it's not a helpful comparison to look through Dupi and comparing it to any other molecules there. Obviously, Dupi has been in 1.3 million patients. CSU is a complicated condition. Dupi clearly works and is safe and is actually growing beautifully commercially. And so while there's no direct comparison, I think Dupi will continue to grow. And what's really exciting is the halo Dupi has developed in multiple inflammatory skin conditions and then moving into other organs.
Your first question was on Itepekimab. Your comment is right about when the results came out. Remember, what we had to do is look around, look left, look right, understand what other molecules we're doing in the space, which we have reflected on. We also had to reflect on what a replicate trial design would look like. As you know, there's a bit of a delay between writing a briefing book and then having a conversation with the regulators to the most thoughtful path forward. That reflects the timing that's been taken. I should say here that we've had, as always, a productive interaction with our alliance partner, Regeneron. We'll go to the regulator together and give you advice as soon as we have it.
Thank you. The next question comes from Sarita Kapila from Morgan Stanley.
Hi, thanks for taking my question. Just a quick one on the Alpha-1 . Perhaps you could give us some insights into your early discussions with the regulator. How confident are you that you can file on phase II biomarker data, or will you need to do an outcome study? And I suppose how much of an unmet need is there given recombinants for an early approval? Thank you.
Thank you. It's a great question. Number one is, remember that most standard of care seeks to get to an 11 micromolar level, half the lower limit of normal for most of these therapies, both the Q3 and Q4W dosing substantially went above that. And the Q3W dosing was really meaningful in terms of its concentration. So point one, the data is striking and clear. Point two is it's premature to provide any specific insights from the regulator.
Suffice it to say that we've got very positive interactions with the regulator at this very early stage after we're at phase II and we're figuring out the path forward.
Thank you. So the next question comes from Graham Parry.
Graham Parry. Sorry, just trying to mute myself. Thank you. Yeah, I think Pete's popped out for a coffee, so I'll ask one from Citi. So just on M&A, you talked about augmenting the pipeline with M&A on top of replenishing internally, but just maybe help us understand how you see the balance between those two. Is it 50-50, are you leaning more towards augmenting with M&A at the moment? And rationale for going into new areas? So I just see you've licensed a tau molecule in Alzheimer's. So are you starting to look to expand your therapeutic breadth?
And then secondly, the regulators have flagged that in the U.S., they'll look at Beyfortus safety again. Just any comments on that would be useful at this point. And then on Brivekimig, moving into later phase II, obviously by the time you get to the market, therefore there could be three plus biologics and oral BTKI in the market as well. So just help us understand differentiation positioning for that molecule in that setting. Thanks.
Great. So I will take 1A, 1B, and three and hand two to Jean. So Graham, you know, and I'm sorry, Pete's gone out for a coffee just like him. Pete, bring me a coffee, please. I think the comment on M&A is pretty straightforward.
In my two and a half years here, I've been super clear that we'll be financially disciplined, but I regard my reflexes from where I came are very clear that we're agnostic as to the source of the molecules. We'll take the molecules wherever they come. We've got an incredible now disciplined research team under Mike Quigley, who both generates the molecules internally, but is in a position to do excellent diligence in our skill development team under Chris, etc , is incredible. So honestly, we've got a really, really strong team. Molecules will come internally and externally, and they're all experienced in that regard. But we also have additional tools like Sanofi Capital, which allows us to take stakes in companies as well as our Sanofi Ventures activity. So punchline, we're agnostic as to the source of the molecules.
We've got great teams that can pick the molecules up at any stage in their development or even earlier and move those molecules forward. And you'll see that our pipeline, my key responsibility is pipeline replenishment and sustainability. We will always be good stewards of our shareholders and the company's capitals. On tau, there's been a whole scurrilous history with tau as there has been for A beta.
As you know, different forms of tau, which is an intracellular protein in its extracellular form, phosphorylated in many ways and leading to different protein isoforms recently characterized by electron microscopy, has been well established. And I think that the jury's out on whether tau is a great target. This is an opportunity for us to take a thoughtful move into neurodegeneration. T he answer to your question, of course, is we are in neurology, and it is one of our key areas.
You know we've done more than just this molecule. We did the TREM2 with Vigil recently too. I'll come back with the HS comment, but let me hand over to JF on Beyfortus.
Yeah, thank you for the question on the P3s. So of course, you may see it surprising to see the new request coming from FDA, given the confidence I've shown on the safety profile of this intervention. I stay with where I was on this one. Very clearly, we have no signal that has emerged recently or in the clinical development. Yes, we have received additional requests from regulators. So far, no surprises. Requests that are requesting actually an update on the exposure, what we have seen, the analysis we have done, how it compares to background rate. There are no questions that we cannot answer.
I just want to remind you that, yes, we are confident in the safety profile of Beyfortus and the favorable benefit-risk of Beyfortus because we have done quite a bit of a randomized control trial pre-licensure. The pooled phase IIb phase II analysis showed the same rate of deaths, for example, in placebo versus Beyfortus recipient. Since that time, we've done real-world evidence in more than 400,000 infants, and again, no signals emerged, and so, of course, we have conducted state-of-the-art pharmacovigilance. We have administered more than 10 million doses of Beyfortus in more than 40 countries, and nothing to be seen from a safety point of view, nothing to be reported from a safety point of view, so again, it's normal that the regulator asks for an update, especially when there is a change in the FDA.
But we have provided the data and we remain confident in the safety profile of that molecule, no doubt.
Great. Thanks, JF. And briefly on Brivekimig, HS remains a large unmet medical need, carries huge morbidity and some mortality, actually. There are multiple stages of diseases. And actually, if you look at the transcriptomic data published in JCI four or five years ago, it's clear that there's substantial heterogeneity, not only clinically, but also in terms of its molecular profile. I think there's very substantial space to make a difference. And Brivekimig, albeit early, showed a very striking result, both the high score 50 and high score 75. So you're right, it will be a slightly congested market, but biologic penetration is low. And I think we have an opportunity to make a big impact on those diseases in mono or combination therapy. Next question, please.
Thank you. We'll take maybe five more questions and then we'll close the call. The next question comes from Paul Kuhn from TD Cowen.
Hi, this is Chris. I'm with Steve Scala. First question on vaccines. What are your latest thoughts on whether clinical efficacy trials are required to file new vaccines in the U.S., specifically your COVID flu combo with Novavax and your pneumococcal vaccine with SK bio? Second question is on IBD. You have several phase II programs in UC and Crohn's. What specific unmet needs or market segments are you looking to address as you think about the target product profiles of these assets? Thank you.
Yeah, so thanks for the question. As you mentioned, the policy environment is changing at the FDA and in the U.S. Certainly, we've engaged with the regulators on the different studies that we are conducting.
I think so far we remain confident on pneumo and the fact that the design phase III, so I didn't mention in detail, but actually we've designed six phase III. We had the productive and the phase III meeting with FDA, and actually we've enrolled multiple thousands of kids in these studies, so progressing extremely well. We had discussions on regulators. We had some minor adjustment to address the request, but we remain confident the pathway we have selected is the one that we will pursue for this one, for the PCV pneumo 21, then you came with a flu COVID combo. The use of the data. I think they're very supportive. We have multiple options. The answer and the pathway might be different depending on the option that we put on the table.
So this is a discussion that we're having with regulators and we'll be smarter in February when we have had the end of phase II meeting with them. And then maybe you didn't ask for flu for RSV hMPV. For this one, clearly, we are committed from the get-go to generate efficacy data and having a randomized control trial to demonstrate efficacy for both components. So there the question is not relevant for this one. That's why you probably did not include it. Thanks.
And then very quickly on IBD, three comments on your TPP question. Number one is IBD remains a large unmet medical need even patients on standard of care either have inadequate response or a failed response. Only 30% of patients approximately at 18 months are still on their primary therapy. There are real opportunities left out there.
I should say, not just in common or garden IBD, but in fibrous stenosing Crohn's, in patients with advanced age with IBD, with young patients with IBD. There's a real opportunity to replace some of the existing and potentially relatively toxic drugs. We've started, obviously, our first move into IBD with Dupixent in EOE, which is often neglected, but is a really important disorder which Dupixent really works in. But also with Duvakitug, which I would argue is based on the current data, the best in class molecule, albeit at phase II, we should wait to see the results in phase III. The TPP we're looking for is different in multiple disease populations. I think we'll end up working in multiple patients with IBD.
Okay, so the next question comes from Emmanuel Papadakis at Deutsche Bank.
Hi, Emmanuel.
Hello, sir. Just a few follow-ups, if I may. So perhaps on Tolebrutinib , just timings, it's not on your 2027 list, which I was a little surprised about. So could you talk about timings for the readouts in both UC and Crohn's? Efdoralprin , you said it's quite ambiguous commentary in terms of potential timing, but the slide says H2 2026. So could you just clarify which one is like, is that actually uncertain, contingent on regulatory feedback? And then SAR441566, sounds like you're still working through phase III clinical development planning. Is it unequivocally going to be only combination studies, or is there any scenario in which you take it forward as a monotherapy in either RA or dermatologic indications? Thank you.
So thanks for the question. So Efdoralprin definitely subject to regulatory discussions, which are going to be interesting. Duvakitug goes beyond 2027. We've just engaged in the recruitment of the first patient into the phase III, literally, and we'll refine that as we go forward, and you'll be the first to know, obviously, Emmanuel, and then thirdly, on Bali, we're just reflecting deeply on the data. I think at this stage, it's premature to comment. I would say that the, as we said in the last quarterly earnings, and we spoke a little, the ACR 50s and 70s look pretty good, even though they weren't the primary endpoint.
We're reflective of how we think about that going forward, not made any decisions, and in combination therapy, there is certainly a position to combine it with various molecules, and we're working with partners to figure out how we go forward. That's not just an active discussion, it's subject to some biological work too.
Okay, and so we'll take your last questions. It's Luisa Hector again from Berenberg. Luisa.
Oh, sorry. Thank you for letting me come on again. I'm still a little bit confused, Jean-François, with the RSV, like what the next steps are. Is it going to be both mRNA and the ViceBio? And just any thoughts on whether you might need comparator arms for pivotal trials and multi-year protection, just how you're thinking about those as you move forward? And which of the options is the favorite at the moment? Thank you.
Sure. What we've shown today is that we have an mRNA-based candidate, and we like the data that we have seen. We have reviewed them in the company, and we believe these data on their own would warrant progressing this asset to the next stage, potentially to a large efficacy phase III trial.
In the meantime, we also like the Vicebio data, and we believe that there is a world where potentially customers want to choose between one and the other, so we like the data. You know, Luisa, we also turn around a little bit the R&D organization in vaccines. We have accelerated the pace at which we generate data, and as we speak, while we like the data we have in mRNA, we keep having additional data coming to us, additional data coming from Vicebio, so certainly, beginning of next year, we'll decide which asset we progress, if we progress one or two, and if it's only one, which is the one that we progress, but basically, today, we have multiple options in front of us.
I think we are poised to lead the field in RSV plus HMPV, and the data you have seen so that we are competitive on both fronts, so more to come, and especially after discussion with regulators as well on these programs.
With that, we'll close out the call. Thank you, Jean-François. Thank you. The whole IR team have been incredible. I wish you happy holidays and look forward to seeing you in January. We hope you've enjoyed spending an hour with us to review our scientific progress this year, and we look forward to keeping you updated as we enter 2026 with a pipeline just shared. Before closing, I wish everyone a good upcoming festive period, and I look forward to connecting with all of you next year.