Okay, let's get started. My name is Mark Purcell. I'm one of the European pharmaceutical analysts here at Morgan Stanley, and Thibault, my esteemed colleague next to me as well. And we have the pleasure to have Sanofi. Dietmar, you know, thanks so much for joining us again.
And before we get started, for important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com for staff and research disclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. Dietmar, thanks so much for joining us again. We really appreciate it. We saw a press release today, you've got an R&D day on the seventh of December.
So we don't want to steal your thunder, but we want to get your insights into how to think as we close out the year. But I guess at a sort of high level, I was going to ask you a little bit about IRA, and I was going to ask you a little bit about the new head of R&D. And if we can start there, and we'll sort of dive into more details.
But there's been a lot of questions on IRA and how it might change the strategy of various companies and areas like oncology, you know, rare diseases, cardiovascular diseases. These are some of Sanofi's strengths.
And clearly you're looking, and you've been very active in terms of bringing on through BD different platforms and things like that, which might be impacted here as well. So, how has it changed the way you think and your organization thinks about R&D from a strategy and from a prioritization perspective?
Yeah, the IRA is obviously an important topic, and in my mind, it's a politicized and an arbitrary system of looking at pricing, right? For us, as we are focusing more and more on biologics, you know, more than 75-80% of the molecules in our portfolio are biologic at this point.
The impact is more limited, but just stepping back, when you think about, you know, the time you have to benefit from a product on the market, you have to rethink your strategy with regards to, you know, how fast do you develop, right? How much do you spend to bring molecules forward quickly? And that's especially true on the small molecule side.
As I said, you know, we're not as affected by that, but that's how it, it will impact R&D strategy, I think, more broadly. We see the reaction from other companies that are, that are hit to a larger extent. Obviously for us, it's, it's not that much of a topic at this time.
Yeah. And do you feel that you'll be doing parallel as opposed to sequential studies to try and speed up, if there's sort of multi-line opportunities, I guess, across some of your assets?
Yeah, that's exactly right. If you have assets that are affected, you need to think about if you have several indications. And oncology is a key example, because in oncology, you're often going from a late line indication, then you're working your way up to the second and first line, et cetera.
That's where it becomes, you know, most obvious in the small molecule setting, especially. What you have to think about is how can you do more in parallel? How can you be faster, specifically? And that means also that you're front-loading your risk more.
Yeah.
That's where it changes strategy. Are you accepting that risk? How do you build a portfolio? How do you manage risk in your portfolio? I think those are really important considerations.
In terms of something like immunology, where you're clearly really strong with a broad portfolio, the sort of luxury of doing a sort of signal finding study in a sensitive indication before moving into a broader program, presumably that's out of the window now as well, or you have to be more fleet of foot in terms of sort of moving into multiple indications up front?
In immunology, you have this really, how we are thinking about it, phenomenon of the immunologic node that you want to address. And if you have a molecule that really does that effectively, you have what we call a pipeline in a product, pipeline in a pill , pipe and an injectable.
And especially for the orals, again, you need to think about are you doing more in parallel? If you... A good example is Dupixent, which is not affected, right? It's an injectable, it's a biologic, but that has a really broad program. It has a really broad program across type 2 inflammation. Obviously, you know, we, we started with diseases like AD, like asthma, like chronic sinusitis.
Mm-hmm.
You've seen the data in COPD more recently, but those are programs that have been built over time. So there, the question also is, if you have molecules like that, do you need to develop them faster?
Yeah. Okay. This new head of R&D, I just asked you, you have spent time talking to each other, so, but you know, Houman comes from a venture capital background, so it's slightly different, sort of character compared to John Reed.
And John Reed, I guess, spent a lot of his tenure, sort of prioritizing various aspects across the pipeline, sort of bringing in platform capabilities with you. How are things going to change or not change? Sort of where are you in terms of the transformation and, and what do you think, what kind of new ideas do you think that Houman's going to come and bring on board?
I mean, first of all, we are proud of the transformation journey that we had already up to this point. If you look at Sanofi, like five years ago, I'm with the company four and a half years now. If you look at five years ago, it was primary care, cardiovascular.
Yeah.
It was not the same strong focus that we have now on first-in-class, best-in-class innovation. Immunology was virtually non-existent for us. So, what we have now, with a strong focus and its aspiration to be the leading company in immunology, with good success in other areas like vaccines, like neurology, rare disease, et cetera.
Mm.
It's an entirely changed company. And that's not only when you look at the portfolio, that's also when you look at capabilities, how are we developing drugs, both in the research setting but also in the development arena. I think we've really a great transformation journey behind us.
Nothing will change with regards to let's drive an immunology, let's drive innovation, let's drive really bringing impactful medicine to patients. That's obviously the aspect I'm coming from. At the same time, Houman has a great, you know—Yes, he's coming from a VC background, but he's got a great, you know, scientific background, great medical background, is a very original thinker.
So I'm really looking forward to working with him and seeing what kind of new aspects he is bringing to the table. But even with these initial interactions, I'm very sure that the focus on innovation, on bringing impactful medicine to patients, on driving and leading in immunology will not change.
Okay. And in terms of balance between internal and external, which is a question we've been asked, I guess there's the recent Horizon deal which went to a competitor. Do you feel there's gonna be any change there in terms of the external R&D focus?
Again, you know, we, we've always had... As you know, we've done so many deals over recent years in order to build the portfolio, in order to also acquire capabilities from a research perspective. I've always been saying 99% of the innovation is external, and we need to tap into that external innovation.
Mm.
Having somebody, you know, with Houman background, with that openness for external innovation, I think is a great plus, so I'm really looking forward to that.
Great. Let's dive into a couple of products, and I'll start with two, and then I'll hand to Thibault. The first one is on your OX40 ligand for atopic dermatitis. I guess Dupixent been such a success. The safety, you know, has been one of the key aspects. This is about sort of like increasing, you know, I guess, the dosing intervals, sort of extending that. It's about efficacy, and then on the safety side, hopefully it'll be at least comparable.
But there's a competitor, they're ahead, big 3,000-patient program. You know, Bob was on the stage, a couple of sessions before. So can you sort of help us understand your perspective here?
I guess, you know, on their side, they think that, you know, targeting OX40 receptor is, is something that gives you selective depletion of OX40 activated T cells. Whereas from your side, I think you're saying that you don't between T-regs, and if you've got a safer product.
So it's gonna come down to a balance of efficacy and safety, and so dosing, and we don't have a lot of visibility in terms of how you're transitioning from phase 2 to phase 3. So there's a lot of questions there, but it'd be great 'cause it's such an important program in the context of Dupixent LOE. It'd be great to get your broader perspective on what we should think about as you move into phase 3.
Yeah, the Amlitelimab program, I'm really bullish on.
Mm.
You mentioned some of the key arguments already. We believe there's a key difference in targeting the ligand versus targeting the receptor. The key difference being, you know, what we have is a non-depleting antibody-
Mm.
that is not impacting regulatory T cells, right? Which then leaves, you know, for example, the anti-infectious response intact. Will also manage, you know, some of the potential autoimmunity aspects that, that you could have if you impact regulatory T cells.
You know, we've, we've communicated top level about the, the phase 2 study in, in, in AD. I'm very encouraged by, by the data. We're gonna see the data, we're gonna present the full data at a, at a conference later this year.
Mm.
I think amlitelimab has really broad potential because, you know, we're only starting to realize the importance of the OX40 pathway. Obviously, we've always been thinking about Dupixent as a type 2 inflammatory targeting asset. OX40 is broader than that, right? It can go beyond type 2 inflammation. We need to obviously present the data.
I'm very encouraged by the data. I think there's potential, you know, beyond atopic dermatitis. You gave me the clue before about the R&D day. We will present, you know, more at the R&D day, really what the plans for the molecules are, and I think there's a lot of potential across several indications.
Have we seen any or you've seen any sort of early stage, phase 1 data or other indications to give us a hint of what you may say on the seventh, any investigator studies where they've seen, you know, OX40 being relevant in other?
Well, you know that we've expanded the program into asthma, right? Again, we're waiting for data in that setting, and we are looking forward to really talk about the additional indications we're looking at.
Got it. Then I guess on a pivot into extending research on itepekimab, the IL-33 for COPD. Can you sort of help us understand a little bit about the phase 2 program and positioning? I guess question number one, you did a futility analysis.
Just like, I guess we get asked the question, was that similar to the futility analysis you did with BOREAS, the Dupixent COPD trial? So I guess sort of start there, sort of, you know, phase 2 perspective and anything you can say about the phase 3 program.
Yeah, the phase 2 data for itepekimab, the study was really started because we believed that IL-33 is playing a role in COPD. What the phase 2 data helped us understand is that, you know, the prior smoker population, which is about 70% of COPD-
Mm.
It is a population that demonstrated strong impact of itepekimab with a 42% reduction in exacerbation in the study, which in my mind is unprecedented in COPD, and specifically in the prior smoker population. In the phase 3 program, we have two phase 3 studies. We call them AERIFY 1 and 2.
We communicated earlier this year that we had an interim analysis. We passed interim, we passed the futility. That was what I call a meaningful interim analysis across the two studies, across AERIFY-1 and 2, which then makes me really excited, you know, looking forward to see the phase 3 data. Between itepakimab and Dupixent, right?
We are addressing with the possibility with two biologics to, to literally address the vast majority of COPD between, you know, the prior smokers, but not limited to the type two, right, or the, to the full prior smoker population with itepekimab, and then the type two COPD population with, with Dupixent. So I think we have a, a really interesting opportunity, important opportunity to change the treatment paradigm for COPD patients.
Can you combine them together?
That is an interesting one. You know that patients with COPD are already receiving multiple therapies. We're always talking about the LAMA, LABA, ICS, the classic therapies, you know, the inhaled corticosteroids, et cetera, et cetera. So there is combination therapy already in COPD, and the question should be, is there a patient population that does require two biologics? Potentially, there is.
Okay. And in the spirit of the IRA conversations we started off with, others are pursuing things like diabetic kidney disease, acute respiratory syndrome, other things with an IL-33 antibody. Again, I don't wanna steal your thunder for the seventh, but, should we expect additional clinical trials or at least phase 2b trials to start in the near future?
We believe it's an important mechanism. IL-33, we're already, we've already spoken about asthma, and we are looking at additional indications. Yes.
Okay. Thibault?
Yeah, moving on to multiple sclerosis and your BTK inhibitor, tolebrutinib. So you recently gave an update to investors, indicating that your relapsing-remitting studies, as well as the secondary progressive sclerosis study were fully enrolled with the readouts in the middle of next year.
And there is still the primary progressive study, which is on a clinical hold with the FDA. So just if you could tell us what you learned on the safety profile of this drug for this process and the discussion with the FDA, maybe I will start for this asset.
Yeah. The tolebrutinib, in my mind, is a really important molecule. It hits BTK.
Mm-hmm.
It is the only BTK inhibitor that crosses the blood-brain barrier at a level to really impact pharmacology, to really inhibit BTK, for example, in microglial cells, in the brain. So the underlying scientific hypothesis is important, and we believe that progression of multiple sclerosis is linked to activity in these microglial cells and other components of even innate immunity, right, in the brain.
And BTK can target both the adaptive and the innate immunity. So I think that underlying hypothesis is really important. We did see some cases of liver injury. We've spoken about that at prior meetings as well.
What we've done over the recent months, basically, is trying to really understand some of that toxicity, and most importantly, understanding how can we mitigate it, right? How can we test patients? You've already seen at this point that, you know, the liver toxicity of BTK inhibitors is broader. It has been seen for various BTK inhibitors, interestingly, especially in MS, especially in this autoimmune phenomenon that's already ongoing.
We've always said we think it's an idiosyncratic immune reaction that we're seeing, so a linkage to the autoimmune nature of the underlying disease is possible because, you know, we've not seen the same phenomenon broadly with BTK in oncology, right? Where you have more of an immunosuppressive environment.
So at this point in time, we've, I think, learned how to, how to risk mitigate, how to, how to address, some of the toxicity. Since we have our mitigation program, we've not seen any of the same toxicities anymore. That's what encourages us also for the, for the ongoing studies. As you said, we've fully recruited, the relapsing-remitting and the, the secondary progressive. The progressive study was always recruiting a little slower.
Those are the, the most difficult, patients to recruit, so, so that study is still ongoing. And we're just looking forward to see the data, because eventually, this is a benefit/risk question, right? It is really a question of what type of benefit do you bring to these patients with these medicines? And currently, patients with secondary progressive MS have nothing.
There's no therapy approved in the secondary progressive setting, so I even feel it's important that we develop these medicines, and we look at what type of benefit can we bring to patients.
Thank you. And another exciting asset for multiple sclerosis is ofatumumab, your CD4/CD8 therapy. So still early stage, we only have seen some of the phase two data against placebo. But based on this data, how do you think the drug is fitting, you know, in the current treatment paradigm for MS, and in particular, where does it fit among, you think it can fit among the high efficacy end of the spectrum for multiple sclerosis?
Yeah, that, that's exactly what we believe. We believe it fits in the high efficacy category of MS, and that's where the unmet medical need is, right? We think that for two reasons. One is, when you look at the underlying mechanism, frexalimab works on, again, both innate and adaptive immunity, specifically the interaction between B and T cells.
And I would argue that we still don't entirely know how the pathologic mechanisms of MS work, but we know that B cells play a role, T cells play a role, microglia plays a role. Obviously inhibiting that interaction between B and T cells, even peripherally, is really important, and then the impact on other components of the innate immunity also is important. And that's exactly where frexalimab is.
When you look at the phase 2 data that we have, that we have presented at the recent meeting of the MS society, at the CMSC meeting, we've seen strong activity on the formation of gadolinium-enhancing lesions. I think even unprecedented activity when you look further out, you know, we have the week 12 and the week 24 data.
Really strong activity there. So we're highly encouraged by the data that we've seen. Also, the safety data that we've seen, that has been very, very encouraging. We didn't see any safety issues. Based on a small early study, of course, based on a phase 2 study, so we need to demonstrate that into the, into the, in the phase 3.
But I think the profile of the drug at this point is very encouraging, and that's where I think, if that fits into the high efficacy group of medicines that are available with a really good safety profile, I think it absolutely can play a key role in the treatment of MS.
Mm-hmm. When we think about the design for the phase 3, what are the kind of key considerations you're thinking about?
Yeah, I think the most important question, and again, we will communicate that fully at a later point, is where's the unmet medical need, and what type of programs do you put together when you think about relapsing, remitting, progressive, and secondary progressive in MS? As I said, I think frexalimab has the potential to be a broadly active drug.
The large unmet medical need is in the progressive setting, so that's one aspect to think about. And then there's an aspect beyond that, which is, you know, as we talk about MS therapies, also from a regulatory perspective, what are the right endpoints to look at?
We believe progression per se, across the board, even relapsing-remitting patients, progress is a really important parameter to look at, and that should be a consideration also for the phase 3 study.
Thank you very much. And, maybe switching back to immunology, a little bit early stage, everyone is very excited about your overall anti-TNF drug. So you started the phase 2 in psoriasis, and I guess the question is, you know, if the data you get in psoriasis in phase 2 is in line with your expectations, could we see you starting a broad phase 3 program across all the indications, or at least the vast majority of indications, where today we see injectable anti-TNF?
Yeah, that's a great question. The TNF molecule, the oral TNF inhibitor, in my mind, is an important one because it's differentiated. Many people have tried to come up with an oral TNF, have failed in the classic way. This molecule is differentiated because it inhibits a specific trimeric form in the circulation, which then leads to inhibition of TNF receptor one, but not receptor two.
So it's differentiated as a more selective TNF receptor blocker, which we hope, and we see that in the early data, allows us to maintain efficacy, but to avoid some of the safety issues that we see classically with TNF inhibitors. For example, we believe that anti-infective responses should be maintained because we focus largely on TNF receptor one, not two. So the molecule is differentiated.
We've not fully presented the data, but we presented top level at this point, that, you know, we've hit on efficacy, which means this is an active and competitive TNF blocker. And again, we feel, you know, very encouraged by the data that we see because we feel this opens up the full spectrum of TNF-related disease, meaning rheumatological, rheumatoid arthritis, and rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, but then also looking at IBD, for example, ulcerative colitis, Crohn's.
So this is one of the cases where definitely we need to think about a broader program. We've not communicated details of the program yet. I hope we can do that later this year, obviously, but this is a molecule that I think is very exciting, and I'm really looking forward to developing.
Thank you. Do you want to take it from here?
Yeah, I've got two more left, then I'll hand it back to you, Thibault. I guess we all agree by... It sounds like an exciting molecule. I'm just not sure exactly where the focus is, 'cause there's so many different utilities, I guess. And one of your competitors has been talking about the importance of covalency when it comes to, also, potentially, differentiation on liver tox as well, but all on the liver signal we just discussed.
But you've sort of got phase 3 trials in ITP, you've got AD, you've got asthma, you've got hives, and then it fits the bill in terms of all these parallel files we've started talking about with an IRA perspective.
I presume it could go into CSU if cross beta, you know, anything go by also into MS potentially as well. So how should we think about this molecule? You know, which area do you feel is the most exciting, the biggest unmet need, and maybe the clearest route to first in class, best in class?
Yeah. With rilzabrutinib, it is another BTK inhibitor that we've also acquired. It's different from tolebrutinib in that tolebrutinib is a covalent binder. With rilzabrutinib is what we call tailored covalency, so it's more of an on/off binding, but it still maintains good activity at the target and at the kinase, at the BTK.
We started a broad program, actually not because of the IRA at the time, because the program was started some time ago, but because we really wanted to understand exactly your question, where does BTK inhibition play a role in immunology, right? And the first study that was read out for us, so that program is ITP, right, immune thrombocytopenia, at the phase three stage next year.
But we have this broad program, and you mentioned it, AD, asthma, CSU, other types of diseases, really to understand what is the role of an oral BTK inhibitor. We will have to see the data, right, to really understand, you know, where can we make a difference. The big, I mean, besides having a differentiated mechanism with BTK inhibition versus other immunologic mechanisms, the big differentiation also is in oral.
So we need to think about, can this be a safe oral in some of these diseases, right? And we can all think about if we had a safe oral, for example, for asthma, right, what would that mean from a perspective treatment paradigm? And we think about this, you know, with the patient journey in mind.
In asthma, patients go from classic therapies, inhaled therapy, ideally to an oral, right? But we don't have a lot of active orals available, so that's where the molecule would fit in. And then to a biologic. So really thinking about this journey and can we fill this gap, this unmet need of a safe oral, for example, in asthma therapy. And the same is true for the other indications. So it makes a lot of sense to evaluate the drug more broadly in different types of signal-generating studies, and then we'll look at the data, and we'll decide on what can we move forward.
Got it. The last one for me was the IL-13 TSLP bispecific. You've got a number of bispecifics, you know, pipeline, and I guess I'm trying to get my head around, does that result in more specificity, hitting two things, compared to the component parts? Just to try and understand are the Fc safety trade-offs between going bispecific versus two separate antibodies.
Mm-hmm. Yeah, there's different components to that. One is obviously, you know, we talked about combinations before in COPD, so combination is a really important concept. Generally thinking about combinations, you can do two things. You can double down on a pathway, right, and really try and impact that pathway even more, or you can try and hit on two separate pathways.
In the current world, doing that with one molecule has immediate advantages, right? From a cost perspective, from a clinical trial perspective, from perspective of potentially achieving synergy, right? And that's where IL-13 TSLP is a perfect example. We have other molecules in the pipeline, like for example, a TNF/OX40L -
Mm.
That goes along the same rationale. IL-13 TSLP tries to take what we've seen with addressing an IL-13 pathway and addressing a TSLP pathway.
Mm.
Really applying that to a disease like asthma, right? That's where we did the early signal generating study. We did the study in asthma because we know the field intimately, and the inhaled nitric oxide FeNO gives us the possibility to do a really quick study and know what we have.
Mm.
And then we talked about that, at our recent, Q2 call. The data that we've seen, the reduction in FeNO with IL-13 TSLP is actually unprecedented. You can put that side by side, and it's a cross-trial comparison of course, but you can put that side by side versus what you achieve with pure IL-13 or what you achieve with, with pure TSLP, and it appears that the effect is not additive, but synergistic.
When you look at just the depth of the reductions, you see an unprecedented reduction, and that's where we have high hopes that this could be a really highly, highly efficacious molecule in asthma. And then, of course, a molecule that can also be used beyond asthma in other types of, of diseases. Just as a side note, what this also does, it actually does validate our nanobody platform.
Sure.
Right? And this is a molecule that is active, that we can use clinically, and that gives us a really good way of trying to address different targets within one molecule.
So there's one last question for me. Okay, so last question quickly on, the few minutes we have left. Sanofi Oncology. You have, we are waiting, you know, for some proof of concept data and even pivotal data for, your CEACAM5 ADC . But beyond that, how, how much of a focus oncology is for your organization today compared to obviously oncology and disease, where we can, we can see, we can see the investments, going through?
Yeah, oncology for us at this point is much earlier, obviously, as a portfolio. We have molecules that... We have an oncology portfolio right now, commercially, right? We have Sarclisa. We're waiting for important data during the second half of the year. There will be another interim analysis for the IMROZ study in transplant-ineligible first line.
There will also be more data in transplant eligible that we're looking forward to. So that's one component of the late-stage portfolio. Then we have tusamitamab ravtansine breast cancer, which is our CEACAM5 anti antibody drug conjugate. We were waiting for phase three data also during the second half of the year.
But then we have, I think, an important early-stage portfolio that is focused largely on three components, on T-cell therapeutics and CAR-T-cell therapeutics, and antibody-drug conjugates. And that early portfolio, I think, is important to develop further. So it's an important part of the of our overall portfolio, but it is much earlier. And obviously, you know, we're trying to realize the benefits with that early portfolio over time. Thank you.
Great. Thank you, Dietmar.
Mm-hmm.
Thanks for joining us again. It's been a pleasure.
Thank you.
Thank you everyone for listening as well.
Thank you.