Good morning, everyone. Welcome to our second day of our Piper Sandler Healthcare Conference. My name is Yas Rahimi. I'm a Senior Biotech Analyst here at Piper and a Covering Analyst of Inventiva, and I've had the pleasure of knowing the team for a very, very long time and seeing really the tremendous progress the company has made with a very big year ahead of them in 2026, so lots to cover, team. Maybe the first place to start is congrats on the very successful fundraising recently. Now with the strong balance sheet on hand, maybe help us understand what are some of the key objectives for 2026.
Yes, well, we're certainly excited to have really addressed the balance sheet issue for Inventiva. As for those of us who don't know us well, we have a single asset, lanifibranor for MASH and it is a pan-PPAR agonist which has had fantastic phase IIb data that was published in New England Journal of Medicine. And we've now fully enrolled our Phase III as of April this year. We've spent this year as well bolstering the management team, adding Jason, who was previously the Chief Medical Officer at Intercept, and we've added Martine Zimmermann, who was the Head of Regulatory at Ipsen before. T hen, I joined in October. I was previously the CEO of bluebird b io. So all three of us have a lot of experience bringing assets Phase III to the market.
What you can look forward to next year is this team preparing the company for a data readout in the second half of next year and starting to prepare the market for the addition of another of a oral therapy for MASH for F2 and F3 patients.
Perfect. And team, before we go into and discuss details of the NATiV3 study that's reading out in the back half of next year, maybe help us understand sort of the studies in F2/F3 population. Definitely, maybe help us understand with a strong balance sheet if you're thinking also to start a cirrhosis study and whether that would be needed at the time of the approval.
Yeah. So, Jason, maybe take those and talk about kind of how we're studying lanifibranor, F2 and F3 and then what we're planning to do after that.
Yeah, yeah. So yeah, you're exactly right. We have the clinical trial NATiV3 that we'll read out at the back half of next year, is the surrogate approval study on histology. And all sponsors are then required to do an outcome study. There's a couple different flavors of those, some people run that F2/F3 study for longer and wait for outcomes to accrue. There are pluses and minuses to that approach. It's the approach Intercept took and Madrigal also took. And then what we're choosing to do is to run a study in compensated F4 cirrhotics. We'll be talking more next year about how we define that population specifically. But the idea is that in compensated F4 cirrhotics outcomes accrue, liver related outcomes, which are the approval endpoint, accrue more quickly.
And what we're excited about is that as Andrew hinted at, the biology of lanifibranor as a pan-PPAR agonist is really interesting. And when you look at MASH, that progression from F3 to F4, it's not a bright line. You know, you put a needle in the liver and you take it out, you look under a microscope at a section of it and it says, oh look, that's F3. Or you do it again and you're like, oh, that's F4. What you're missing in the middle is all the physiology that changes. It's the physiology that develops things like portal hypertension and that drives liver related outcomes and those things that portal hypertension begins increasing early in F3 disease. So when we begin to think about cirrhosis in that population, it's something we're really looking forward to talking about next year.
Perfect. That's very helpful team. Before we go into also discussing NATiV3, it would be great to kind of give an overview on how do you envision lanifibranor fitting into the MASH competitive landscape. I think lanifibranor will be the third agent entering the market after Rezdiffra and semaglutide.
Yeah, correct. So maybe I'll take that and you can layer on anything. So if you think about the MASH patient populations, you have F1, F2/F3, F4 and F4 compensated cirrhosis. And you have a number of entrants into this market. You have Wegovy and the GLP-1s that are really entering from the left from the F1 side. F1, F2, F3, really good at defatting the liver. They do have some antifibrotic effect. That antifibrotic effect tends to take place after the patient's been on it for over a year. Compliance, there's a little bit of an issue there. Patients aren't really staying on it for a year, but it's a very. We should expect that almost every single F2/F3 patient will be on a GLP-1 that will have either tried it or on it currently or will try it.
Then you have the FGF21s not approved yet. But in clinical trials they are entering from the F4 side injectables, direct antifibrotic effects. But we think that class of agents is going to have trouble penetrating into F3 and that's for a number of reasons. Number one, the GI tox is the overlapping tox with GLP-1, so it won't be easily combined. We think everything will be combined, t he GLP-1 and F2 and F3. There it is, they have some toxicities like bone mineral densities that they're going to limit them to the more severe patient population and they're injectable, competing with some orals in F2 and F3. So if you go then and say what's left in F2 and F3, you have Rezdiffra (resmetirom) as an oral and you will have lanifibranor.
Patients are gonna be choosing, I think, GLP-1 plus, you know, or choosing an oral Rezdiffra or lanifibranor plus or minus a GLP-1 for F2 and F3 patients. We think we're very well positioned there both because lanifibranor has both antidiabetic effect. For that 50% of patients that are diabetic, I think it's a natural choice. Also, I think we have really good antifibrotic data. We had an 18% effect size after six months versus Rezdiffra, which had a 12% effect size after 12 months. We think we'll be very well positioned for the whole patient population.
Jason, this is not your second rodeo, bringing Phase III MASH study to the finish line and collecting the data and reporting it. So maybe given your experience at Intercept, like what lessons have you learned as you're sort of now, you know, the study's fully enrolled and it's going to read out like what are sort of the QC aspects that is being taken place at Inventiva to just, you know, ensure very not it's going to be a robust data set, but just, just a very polished set. So help us understand what's going on behind the scenes.
Sure. I mean on the one hand it's like any other late stage clinical trial readout. They're big, they're bulky, they're in lots of countries and lots of sites. So from an operational standpoint it looks a lot at Inventiva like it would at any other late stage company. So a lot of just global touch, making sure that you're getting the data and the database cleaned and you're able to lock. What's unique about MASH trials is the role of histology in the primary endpoint. Obviously lots of other trials have histology, kidney studies, et cetera, but it's the fact that the primary endpoint is assessed by histology.
So the other thing we're doing is obviously of course making sure that we get every patient that's coming in and will get a biopsy, even if they discontinue treatment early, even if they c ome in for a visit after week 72 and they hadn't gotten a biopsy. We're essentially trying to get a biopsy from everyone that we can. And how the field matured, which changed its Intercept. The good news is the division at FDA has sort of grown. It was brand new during Intercept. It had carved off from the GI world. And there's now a more standard approach, a standard methodology to how biopsies should be collected and how long they should be, the quality and more importantly how they're read for the primary endpoint.
So it was a little bit like the Wild West back in the days of Intercept, it's much more standardized now. And what's going on in Inventiva would be the same thing that went on in Madrigal or Novo at the exact same time.
Perfect. And then, team. I think there are a few things. Obviously the Phase IIb NATIVE study was highly successful and NATiV3 built upon some of the findings, but definitely a couple things that stand out. Of course it's a much larger size. You know, 759 patients for the interim read out of the 1,900. It has 13% more type 2 diabetics. And I think at your R&D day earlier in the fall, you shared the a dditional benefits diabetics get. So that's another aspect. You have a larger percentage of F3 patients, but we see you have a more profound fibrotic benefit. So maybe help us put into context for investors who are maybe coming new to Inventiva and reviewing NATiV3, like sort of all these additional nuggets that helps to ensure NATiV3 is successful from enrolling more diabetic patients, having a larger size, going longer.
I think the easiest way to answer that question now is just look at the Phase IIb NATIVE data.
Yeah.
So in Phase IIb NATIVE, if you look at the top line primary endpoint, the dual improvement of MASH and fibrosis when we look at that effect size and we back out diabetics versus non diabetics, the drug behaves exactly the same in both populations. So that's consistent with its MOA. But those with the data show second, if you back out the F1's Phase IIb NATIVE at about 25% F1, so 247 randomized roughly 181 in the F2/F3 data set, the drug worked as well without the F1s as with the F1s. The effect size was nearly identical. So there's no one way to look at that is no free ride on the F1. The other way to look at it is the drug works equally well in the more severe population compared to a very mild population. So now when we get to NATiV3, we have more diabetics.
I think, Andrew, that would definitely reflect the real world data that we're getting from our market work. Now, about half of all patients with MASH are diabetic and about 30% of all diabetics have MASH, so this is more reflective of the market, and I think that the additional F3s will play to exactly what Andrew was talking about, that when you look at that market map, there's not a lot of opportunity. Rezdiffra, it's a good drug, it's been approved and it's helping people, but it won't. When you get to F3, that physiology really, really toggles up and the risk of liver-related outcomes is very high and you need something more than a direct antifibrotic, so us having a larger proportion of F3s plays well to that market dynamic that Andrew laid out earlier.
Okay. And Andrew, do you think the success of the study is to reproduce the Phase IIb NATIVE data, even though it has all these additional benefits and could also play out to give even a better response than we saw the Phase IIb NATIVE . Like when you did your research, what product profile, what treatment response rate do we need to see in NATiV3 to be commercially successful?
I think if we repeated the Phase IIb, we would have a commercial success. With the Phase IIb data, we think we're super well positioned for the diabetic subpopulation and then we'd be competitive in the non-diabetic population as well. I think the physicians would be looking and would view the fibrosis effect of Rezdiffra and lanifibranor within the same ballpark, even if lanifibranor is slightly better. I think if we were able to show a fibrosis effect that was in the low 20s, a net effect. I think that lanifibranor would be the first choice in diabetic and non-diabetic patients.
Okay, that's very helpful, thank you, team.
And also, another nuance that I think gets always underappreciated when it comes to the NATiV3 study is that you're using a co-primary endpoint. So if you could just explain how that works and how it minimizes sort of placebo responses and maybe also contrasted what have other sponsors shown if they selected that dual endpoint.
This goes back to the origin of the approvable endpoints. But you can hit on fibrosis with no worsening of MASH. You could do the other one, hit on MASH with no worsening of fibrosis. The European Union had always required both and the thinking had been that this gets to the core of the disease. Andrew and I are fond of telling this anecdote, but if you look at a series of patients with MASH that have cirrhosis and transplant. Transplant them brand new liver. So it's the perfect hepatic drug. You give them a brand new liver, up to 30%-50% of those patients at a year to two years will develop fibrosis again in their new liver. NASH with fibrosis. So that tells you you need to do more than just get the liver effect.
The idea is that the MASH resolution reflects that extrahepatic biology. What's driving the inflammation and the fat accumulation is believed to be the glycemic control and the adipose tissue health. So by getting both, you're saying to the world we get more than one aspect of the disease. That's what I think the excitement was about in Phase IIb NATIVE because no one had ever shown that before that you get both. Since then, other products, particularly the FGF21 analogs, have shown dual resolution. It's not surprising we both go through adiponectin. So that's almost certainly what's driving the adipose tissue health that we see with FGF21. So how? And you noted there's a practical benefit too to get both in one patient.
The placebo response there is very low, and that's consistent across all trials at all time points that we're looking at, less than 10% placebo response in that group. It's an added benefit.
Okay. Just to kind of make sure investors who are new understand, the study is also powered to show the two individual endpoints as well. MASH resolution and one point of improvement.
The study is powered on the primary endpoint which is the critical part, because if you pass the primary endpoint, you can recycle your alpha and test the other elements sort of one after the other in perpetuity at both doses until the moment you fail. Okay, so if you look at Phase IIb NATIVE, we were successful on at the higher dose, all three of the endpoints. But there was no type 2 error control in that study. But with Phase III, there will be. As long as we're positive, we can just keep going at that 1,200 mg dose.
Okay, excellent, team. Maybe just some housekeeping. More specific questions around biopsy handling and readers, because that's very tied to the primary endpoint. Maybe help us understand what is the protocol. You noted that every patient made sure that the biopsy is read. So, like, how many readers do you have? How many? Like a single biopsies collected at the beginning, at the end of the treatment, maybe, how does the reading occur and how many readers are there? Like, what is the protocol behind it?
So we haven't disclosed much of this, but I think what we can say to be very helpful is that what we're doing is very similar, if not identical to what the two other approved sponsors in the field have done. Novo and Madrigal. I think second, a little bit more specific, our reading methodology for the primary endpoint is a consensus reading, 2 + 1 . And if the two readers agree, it's fine. And if they don't, we'll go to a consensus view. And that is both for the fibrosis and for the elements of NASH. I think third, you asked sort of about biopsy handling, et cetera. Obviously, in order for patients to come into the trial, they have a biopsy right at the beginning.
We at periodic points along the way, those biopsies are sort of batched, and then the way in which they're handled, things are scrambled and they're blinded by sequence. And there's a methodology by which the pathologist will read those and go to consensus and adjudicate. We have teams that follow the process, but not the data.
Okay.
So making sure the biopsy get to where they need to go, that they're being viewed, that the doctors signing off, the pathologists are signing off on work, but we have no visibility into the actual data.
Okay, that's very helpful. And I'm sure now that we're going into 2026, like those things are just now double checked and quadruple checked.
Quadruple checked, yes, that's right. Andrew mentioned earlier, I mean, he said it earlier. I think it's right. The benefit of the fundraise that we just did is that we can make sure those teams are getting what they need to get the data delivered.
Is there any. There's a big discussion going on in there at the regulatory agency to moving away from histology and there's definitely a proposal out. There's also some thoughts around the use of AI-based histology. Is that incorporated in NATiv3 to also have like an AI-based assessment in the study?
Yeah, as add-on but not part of the primary endpoint. We had a poster at AASLD where we just talked about this where we have an AI-based viewing of the biopsies. It's one day in the future, not today, but it will be an add-on, an appendage, but independent of the primary endpoint assessment.
Okay. And team, fast forward, you have NATiV3 reading out in the back half of the year. What is sort of how soon can you, and I know some of the fundraising was also helping to build the regulatory team together to get the filing in place. Like, what are you thinking around timing to file the NDA, EMA?
We haven't guided more than we will get the data the second half of next year and then we'll file expeditiously after that, 2027. In terms of timing with the EMA, we actually haven't had to determine that yet. We're definitely prioritizing the U.S. So the NDA will be first, the EMA will follow and we'll probably provide more information in that in 2026.
Okay. And team, what are obviously with the fundraising is also to kind of get company commercially ready and with your phenomenal background like how do you envision sort of like transitioning Inventiva now from a developmental company to a commercial company. You've done it several times in your career. This is a very important period. Maybe like what are sort of some of the sequence of steps that have to occur.
Right, and so it won't be an overnight process. Right, so I think this fundraiser puts.
You promised it would be.
Yeah, yeah. This fundraise put some of those building blocks in place now. So if you look forward to 2026, we are, you know the skill set in the clinical team to actually enroll a clinical trial versus the skill set you need to actually process that data, be able FDA inspection ready, put it into NDA file is actually slightly different. You need a different set of skill sets. You have to boost your quality assurance team. Right. You have your clinical operations teams now doing the data cleaning. So Jason's busy building up his team to do that. From the commercial side, we're really starting to look at the strategic commercial work. I'm talking about the market access, the value story, right. Give them different product profiles where you know, what is the value that this therapy brings and how will those discussions with payers go?
We'll do that work right now. Starting to staff up a medical affairs team really to interact with our KOLs and to be able to disseminate or to educate on the therapeutic area and eventually the therapy as well. That is, those are the kind of strategic things that we'll focus on in 2026. You won't see us put sales forces in place or anything like that until 2027. But we will be doing all that planning as well. And of course all the market research that goes into how is this drug be positioned in the market.
Okay, and I think one of the things we're seeing right now is that you know, obviously Rezdiffra has been a focus for them to be in specialty centers, hepatologists and GIs. And it seems like semaglutide is more being positioned awareness for endocrinologists. So now that lanifibranor comes on onto the play, how do you think sort of which specialty is going to gravitate more towards lanifibranor or its product profile? That would be sort of maybe the first group to reach out to.
I think one of the things that all this, all this market awareness and preparation is going on right now has meant that the diagnosed F2/F3 patient population under treaters' care has increased by 70% over four years and we see that increasing. So this activity is going to absolutely increase the awareness of MASH and the number of potential patients that will be launching into. So there's a lot, so there's a lot of market creation going on right now. We will have to make a strategic decision about where we want to enter. Do we want to follow, do we want to do a more specialty sales force or limited sales force in GI and hepatologists to start or do we want to go right into endocrinology as well? Because clearly with the diabetic sub patient population, endocrinology should be a very natural fit for us.
We haven't made that decision yet, but that'll be some of the work that we do in 2026 to determine how b roadly we go in terms of call point.
Yeah. The only thing I would add to that is with endocrinologists, you know, pioglitazone, which is a mono- PPAR gamma agonist, it's about six million scripts a year still in the U.S . Those are endocrinologists prescribing that drug. So they're very familiar and comfortable with the idea of PPAR. So as Andrew said, we're not sure where we're going to land yet, but it's an appealing opportunity to begin to engage. But back to the medical affairs. I think when we begin to get those teams in place and really engage, we'll have a much better feel for how that looks.
Yeah. And to me for the endocrinologist who obviously the first therapy used in NASH was the PIVENS study. Right. The pioglitazone data that came out. How do endocrinologists, what is their perception of differentiation of lanifibranor when they think of pioglitazone? Do they understand the integration of the difference in the biology? And obviously you're going to have a successful randomized, Phase III study.
As a doctor, I'm always mindful. I don't practice anymore, but I'm always mindful of speaking for a whole profession. That being said, I have talked to a number of endocrinologists at the liver meeting, and when we talk about the weight gain, for example, with PIO, what they say is that PIO goes on, you give the drug, they're healthy, their diabetes is getting under better control, they're storing subcutaneous fat. It's healthy. The challenge with pioglitazone is that that sort of on mode, that build mode is never tempered by anything else. So it sort of goes in perpetuity. But the drug works, they like it.
What they know already about lanifibranor is that you sort of dial up the burn side of the equation later with the agonist and the muscle comes online where you begin to balance out that healthy weight gain, but you blunt the effect so that it sort of normalizes over time. Endocrinologists naturally understand that biology. That's been my experience of talking to them when we were at the liver meeting.
Yeah. And team, also, as you noted, majority of patients are going to be. Right now, a third of patients are already on a GLP-1 plus Rezdiffra. So over the next few years, that's going to substantially change. What work have you done to understand sort of the if there's a synergy between lanifibranor and semaglutide? Like, I don't know if you've looked into that or there's a decent cohort in NATiV3.
We've not done any formal work, but as you're hinting at, within the NATiV3 study, we have a reasonably sized population that will be on baseline stable low dose GLP-1, so roughly 15% of the cohort, so that's a sizable data set that will allow us to get knowledge enough that could potentially end up in a label about prescribing and instructions. We also have a smaller percentage, less than 10% of patients that start low dose GLP-1. That'll be very interesting also, and that's again in a 1,400 patient data set. That's a meaningful sample size.
Yeah.
So I think we'll have a lot more to say about this. It won't be a top line necessarily, but as part of the full data reveal.
Okay, yeah, that's going to be very, very helpful to get there. Team, thank you so much. I mean, we could go on for another 30 minutes or an hour to talk about the MASH landscape. A very big year ahead of you as you are, you know, preparing to read out NATiV3, getting ready for regulatory filing, getting commercially ready. A very important period of time for the Inventiva company. Super excited for next year and let's give the company a big applause and say thank you.