Hi. Good morning, everyone, and welcome to the Inventiva session. It is our pleasure to have CEO, Andrew Obenshain, Chief Medical Officer, Jason Campagna, and Chief Financial Officer, Axel-Sven Malkomes with us today. This is an exciting time for Inventiva as it approaches the long-awaited NATiV3 data for lanifibranor, which is probably the most advanced drug in development, and importantly, based on an understood PPAR mechanism that addresses the full spectrum of disease, and importantly, it is oral. Andrew, maybe you can give us a quick overview and what the opportunity was that you saw in Inventiva? What brought you to the company? And what do you see in lanifibranor right now?
Andrew, mute.
Mute. Andrew, you are on mute.
Well, it was really good.
There we go.
There we go. It was really good.
We can start all over again.
Yeah. Apologies. So thank you, Annabel. Let me start by saying that this is a very exciting time for the company. We are approaching an important inflection point, as you said, for the potential data for lanifibranor on patients with MASH, and our NATiV3 trial is fully enrolled. Last patient visit is done, and we expect the top-line results in Q4 2026. When I look at the opportunity we see in lanifibranor, it really comes down to three things: differentiation, late-stage validation, and market opportunity. Let me start with differentiation. The fundamental principle is simple. There is one disease, but there are two disease drivers, and we have one medicine that addresses both. MASH is driven both by intrahepatic and extrahepatic processes.
Lanifibranor is uniquely designed to address each side of that equation, and that's what we find particularly compelling about the science and the potential for lanifibranor. The next is validation. In our phase II-B study, lanifibranor showed improvement across all key histological endpoints, including an 18% placebo-adjusted improvement of fibrosis, 26% MASH resolution, and 24% on the composite endpoint, and all that in just six months, which up until that point when the trial was released, we really hadn't seen fibrosis come that quickly. Those results are really the foundation for our phase III, where we're now testing the therapy with over 1,000 patients in a very similar trial design to NATIVE 2. Then finally, there's the market opportunity and the unmet need of the market, and the market is being built in front of us right now.
If lanifibranor is approved, we will enter an established therapeutic area, one that's been established relatively recently in F2 and F3, but very robustly. We expect the market potential to exceed $15 billion by 2035. However, as I said, significant unmet need remains, and this represents a meaningful opportunity for Inventiva to potentially bring a differentiated treatment option to people diagnosed with MASH.
Okay, great. So, what can you tell us about lanifibranor? When we talk to investors, the first response is like, "It's a PPAR. They've been around for a while. They're dirty drugs, cause all sorts of adverse events." It's an older mechanism. MASH drugs are thought of as anti-diabetic agents. So just tell us why lanifibranor is different and how people should get comfortable with the fact that despite being a PPAR, it has stronger benefits than that.
Yeah, Annabel.
For that, I think I am going to hand this to Jason.
Thanks, Andrew.
Yeah.
Annabel, I think like every question like that, there is kernels of truth in it, and there are elements that are not. There have been many successful PPAR agonists in the world. Fenofibrate was a billion-dollar drug back in the day when actually a billion dollar meant something to people that were in the drug development business. We have recently two approved PPAR agonist, one alpha-delta, elafibranor for PBC, and one delta alone, seladelpar for PBC. Pioglitazone, as you mentioned, diabetic drug, had been on the market, still written 4 million- 5 million scripts a year in the U.S. So the class of drugs as agonists are very good, but your point is exactly the right one. Lanifibranor is completely different than all of them. When lanifibranor was built, everybody sort of knew the potential of the mechanism.
On the other hand, there have been some pretty notable failures, and there are a lot of tolerability concerns with some of these agents. Lanifibranor was intended to address all of that. In short, what the people that created lanifibranor did was they wanted to develop a drug that hit all three PPAR isoforms, and they wanted to do that in a balanced manner so that whatever exposures you have in the blood, you are getting them all at roughly the same amount, as opposed one hitting more dominant than the other one or other two. The second is that they wanted to find a way to make sure that when that drug bound, particularly to PPAR gamma, that it did so slightly differently because that is associated with minimizing the downstream tolerability concerns.
This had all been worked out back in the day by the people that were working in PPAR biology. The challenge was, could you make a drug to do that? That's what lanifibranor was intended to do. I would say too much gamma, for example, had known to be tolerability. That's pioglitazone, rosiglitazone. Too little gamma, elafibranor, you don't quite have what you need to get over the hump in MASH. You do need gamma. We think that the inflammatory, metabolic, and the fibrotic pathways are all captured by lanifibranor. In the end, what we believe that we've created is a drug that's a balanced PPAR agonist at alpha, delta, gamma.
At gamma, it's only a partial agonist, which means that there's downstream tolerability concerns, fluid retention, peripheral edema, and the scale weight, but also some dilutional anemia we anticipate and we've shown in NATIVE should be moderated or blunted compared to what you see with the traditional gamma TZD like pioglitazone. That's the drug that we've taken into phase III, and Andrew said that we're anxiously awaiting top-line data here in Q4 of this year.
Okay. Can you tell us some of the highlights that you've seen for NATIVE that gets you very excited? Obviously, we know that it's the only one who's shown MASH fibrosis, or only oral has shown MASH fibrosis or MASH resolution and fibrosis, as well as very good differentiated fibrosis. Give us maybe some of the other factors that you think exhibit this extrahepatic as well as the intrahepatic effect?
Sure. Happy to. Maybe I'll give you three, one for each axis. If you think about adipose, the glucose pathway, and atherogenic lipids, three really critical drivers of extrahepatic influence on the liver. Adipose, our adiponectin level increases range from about three-fold to five-fold, depending on the dose, and we've shown that in four phase II clinical trials over the last decade. In comparison, efruxifermin, which is a very good development agent, also showed adiponectin increases of about two-fold at their highest dose. That was considered, when it was published, to be exceptional. We agree. We just happen to think that we've done slightly better than that. On the glucose pathway, we have shown improvements in hemoglobin A1c ranging from about 0.5%- 0.7%. In combination with a drug like an SGLT2 inhibitor in our LEGEND trial, we approach 1.2% reductions in A1c.
I think as everybody on this video call will know, those are really meaningful numbers in the world of diabetes. We've also showed improved insulin sensitivity, by HOMA-IR euglycemic clamp, very powerful effects on glycemic pathway. Lastly, on atherogenic lipids, we lower triglycerides about 30%, which in and of itself would be an approvable endpoint back in the day before outcomes. We improve the overall lipid profile like Apolipoprotein B, for example, and HDL. The drug at the dosages we're using in NATiV3 have impacted and continue to impact all of those pathways.
Great. One thing that's come up in a few conversations, that it's had a good response on MASH resolution, the fibrosis endpoints. Can you talk about some of the, what people characterize as inconsistencies in some of the biomarkers? Are they true inconsistencies or is it being misunderstood?
Go ahead, Jason.
Yeah. I think it's slightly misunderstood, but there are also some inconsistencies, but it's important, Annabel, to say that there are inconsistencies with all non-invasive data and histology. That therein lay their promise and also the challenge of them. They're very good at doing many things, but they're not good at doing all things. Depending on which one you look at and how you use it and how it's looked at, you can draw different conclusions. I think for our purposes, in the case of NATIVE and lanifibranor, what we've shown is that almost all of our serum and imaging-based biomarkers tracked pretty closely with histology. Things like PRO-C3, even just basic transaminase reductions, ALT, AST, the components of the ELF test. There are three of them. Two of those three track almost identically in a dose-dependent manner, all very strong.
I think many people tend to point to the FibroScan liver stiffness measurement, which was about a 10% reduction at six months. I think our view is that that's a reasonable number. The bounded conditions for all of the drugs out there are somewhere between 10% and maybe 25-ish, 30%, depending on when they read out. The longer the trial, the deeper you can go. Like the REGENERATE trial back at Intercept, you could get very close to a 2 kPA- 3 kPa, kilopascal, reduction. Also depends a little bit on where you start, but that's the one place where I think many people sort of fall into and say, "Well, compared to your very strong histologic benefit, that seemed a little flat." I think that's fair, and the explanation is pedantically straightforward. Lanifibranor, it's not free of gamma effects.
It just has less of them, but we still do retain fluid. Liver stiffness is nothing more than a sum of everything under that probe: fluid, fat, inflammation, and scarring. When you're adding fluid, it will mask the underlying fibrosis signal, particularly if that fibrosis signal is early. Most people, I think, generally believe me when I say that, but you can just go to the Echosens literature themselves, and they tell you that you're not supposed to use it in patients that are congested or have had a meal, for example, because the fluid will throw off the finding. Even cardiologists use liver stiffness today to actually assess for heart burden load congestion of the heart. It's actually quite good at detecting fluid. Therein lay the challenge when you also want it to detect fibrosis.
Okay. Got it. Moving on to NATiV3, obviously people get a little bit nervous as we go from phase II to phase III because MASH has been such a graveyard for drugs for so long. Maybe you can help us get comfortable with what you've done in NATiV3 that gives you confidence that this could be an easily replicated result, not easily, but a replicated result?
Yeah. I think Jason can walk through two things, but just high view, by patient population, right? We took a lot of learnings from that phase II as we went into the phase III and designed that phase III to look as similar as possible to that phase II, and with analysis of the populations. Number two, statistics, right? The powering of that trial was deliberately overpowered as well. Jason, maybe just walk through both of those elements.
Yeah, I think I'll only add to Andrew's points because they're spot on. Beyond the trial being longer and in more patients, the population is remarkably similar to what we saw in NATIVE from baseline characteristics. It's more contemporary. We have more F3s than diabetics because there are more F3s than diabetics in the world today, and they're the ones who need to come into clinical trials. Beyond that, it's remarkably similar. Andrew mentioned our powering is very conservative, that 24% composite in phase II had a 7% placebo response. We chose a higher- number on placebo and a lower drug effect. Then we over-enrolled the trial to account for termination. We feel really good about the powering.
The last part is actually in that composite endpoint itself. Most people talk about placebo as, it is a problem to be avoided. It is. If you really look beyond the math for a minute, it is actually telling you something really important. If you pull out the non-diabetics, for example, from our NATIVE population, and you look at just the treatment effect in F2, F3 diabetics, the placebo response is effectively zero. It is 3% or lower. What that tells you is that in the wild, these patients rarely ever get better, quote-unquote, better on their own. It just does not happen. In order to get true MASH resolution and improvement of fibrosis in the same patient, everything, all those axes, Annabel, we talked about earlier, they all have to go in the right direction.
Letting that happen spontaneously almost never happens. What that tells you is when you look, we had eight-fold more patients that had a response on lanifibranor compared to placebo. That is an enormous treatment benefit. Even if that benefit is blunted somewhat in NATiV3, it is still going to be a large number. That is why we feel confident that the trial with the powering and the similar population should read out and give us a favorable result. I would go back to something Andrew said, and Andrew, I will steal your thunder on this. Our win is defined as duplicating NATIVE 2.
We do not need those numbers to be any deeper to what we view as of a market-dominant entry, particularly into that diabetic F3 population group. It is a natural landing spot for lanifibranor. What we are looking to do is duplicate NATIVE. That is our goal.
Okay. Has the data been locked already?
The database?
Yeah.
No, we're not guiding on any specifics, only to say we're working very hard. We're a small company with a big trial, and we've got a lot going on.
Okay. Great. Fair enough. PPARs, as you had mentioned, comes with adverse events. Lanifibranor does not fully eliminate the problem, but obviously can be mitigated. I guess we just recently had a KOL call where a physician talked about the level of fibrosis that they needed to, I guess, offset some of the edema, and 18% is good, but 20% + or higher, obviously 20% or higher would be very favorable. Do you think that NATiV3 is well-positioned for that?
I'm going to answer that question a little bit of a different way, Annabel.
Okay.
I'm going to.
Yeah, sure it's going to do 25.
Yeah. We obviously can't. We obviously, we're anxious to wait on the data as well.
Right.
But let me just, from a physician perspective, if you move to commercial, how do we think physicians are going to view this? We do a very simple segmentation into four segments. On one axis, you have F2 and F3 patients. On the other axis, you have patients with low metabolic risk or high metabolic risk. You use diabetes as a proxy for that, which is something that lanifibranor can address. If you take those F3 diabetic patients, and that's about a third of the market right now, we think that that is where lanifibranor gets used first by physicians. Because it does two things, right? You're looking for the highest fibrosis factor you can find. If this hits 18%, we duplicate the phase II, that exceeds what's on the market right now. It happens within six months. You're worried about that patient progressing.
You're worried about the metabolic function driving that disease faster. Therefore, you're going to pick up lanifibranor. As you move into the, by extension, right, you say, okay, F3 non-diabetic, same thing. Pick up the biggest hammer for fibrosis. F2 diabetic, hey, I want to address that driver, that underlying metabolic driver, I want to address that. Then you get into F2 non-diabetic. Well, maybe that's where the existing therapies have a stake. It's a little bit lower efficacy, but there's not as much urgency. However, I'd say that as the efficacy increases, so if you go above 18%, you expand. If you can think about it expanding into that F2, towards that F2 non-diabetic patient population and taking that market as well. As the efficacy goes down, as it goes down below 18%, you more go towards that F3 diabetic patient population.
So it's just really a question of market potential rather than a binary will they use it or not?
Are we going to see any data on F1 and F4 in this readout, or that's going to be later?
So we are—
For that exploratory cohort?
—the exploratory cohort, we are not guiding and we are showing a top line, but I think it would be safe to assume that given the amount that we have, that we are probably going to be sticking to the F2, the primary cohort.
Okay. And then speak—
That's not decided yet, though, so that's open.
—okay. Speaking of commercial again, as you think about these different quadrants that you have. How easy is it going to be to combine GLP-1s and SGLT2s? Are most of these patients on these drugs already, or is it a decision that physicians are going to have to make? Okay, if I'm going to put you on this drug, I need to get you on an SGLT2. I need to get you on a GLP-1. What is that decision factor in the actual treatment room?
Yeah. Well, first of all, in the trial itself, we do have patients on GLP-1s, we do have patients on SGLT2, so there is going to be data on the tolerability of that. I don't really view this as a sequencing type of decision. For every patient, decision's going to be different. There are going to be. A lot of patients that are already on a GLP-1 and are looking for an additive effect for MASH, then you could be layered on. There's going to be de novo patients as well, where the physician is going to be making an assessment of the patient. What's the metabolic risk versus the liver risk? Do I want to actually go right to elafibranor, or do I want to go to a GLP-1 first, and then elafibranor?
All of that will be extremely patient specific. The point is that we have a therapy here with good efficacy, a tolerable safety profile. It's another addition to the armamentarium that's going to be sequenced in to the therapy paradigm.
Okay. Do you think that GLP-1s, their approval in MASH have vastly changed the MASH landscape for you, or no?
I think first of all, the fact that there was nothing approved in this market as of three years ago, now we have two approvals, has been wonderful for everybody, for patients. This is a market now that's increasing diagnosis, there's increasing awareness. You're seeing installed base of FibroScans increase. That's done wonders for diagnosis. I think what we see in the market is that the use of GLP-1s in MASH is very much reflects the share of GLP-1s more broadly for metabolic disorders. It's really becoming, we assume that most patients will have been on, will soon be on, or have been on, or are currently on, sorry, a GLP-1. It's going to become pretty foundational.
Okay. It is just going to be background at this point.
Yeah.
All right. Maybe we can talk a little bit more about the commercial. Obviously, PPARs are well known. To what degree, what level of education do you think these physicians need around this PPAR and its utility in MASH, and how are you going to be approaching the market? What kind of investments are you going to have to make from the educational perspective?
Well, look, again, because of the two launches, a lot of education is ongoing already. We are moving into a market that is being built in front of us right now, which is a nice place to be. I think specific to PPARs, if you think about the prescriber groups, you have GIs and Heps who are the primary prescribers. You also have some endos as well. And within those physicians, there are a number that are very familiar with PPARs and still use a lot of pioglitazone. And for that group, it is a very easy leap to say, "Well, I like PPARs, I like pioglitazone. You give me a PPAR that then has a MASH benefit, well, this is kind of a no-brainer." This makes a lot of sense.
Then you have a group of physicians that are not as familiar with PPARs or pioglitazone. They don't currently use it. For them, the key question is, how do I manage the tolerability profile of a PPAR? That is an education endeavor that's been done already in the PPAR space, and it's something that's fairly, they just want to know how to manage the patient, which is a very digestible marketing challenge.
Okay. I guess, as we're coming to the end of this session, just given the expanding size of the market, can you talk about the level of interest you're still getting from pharma? Do you think you can launch this yourself? Pharma's kind of taken over the FGF21, and everyone's obviously pushing GLP-1s to this comorbidity. So—
Well, it's going to be.
—what is the level of interest, and how do you do this yourself?
Yeah. Well, first of all, right now we are building the company to do it ourselves. We've financed the company twice this year. We will, of course, look at more financing post-data, if positive. We've been building up the leadership team. We just recently announced the addition of Chris Benecchi as our COO, which should indicate kind of our forward-leaning posture into launch. This is something that we do intend to commercialize ourselves. Pharma clearly has a lot of interest in this area. It fits into the broad metabolic space where there's been a lot of acquisitions, as you said, with the FGF21s.
We certainly still feel the interest that's out there from the pharmaceutical world in this area. There is a possibility that along the way, that we get acquired, but certainly the way we're building ourself right now is to go it alone.
Okay. Now you have the funds to be able to at least get you through NDA filing and approval?
Yeah. Axel, maybe you can just address that one.
Yeah. Axel, I do not want to ignore you.
Yeah.
You are right there, so I need you to talk.
Yes. We have a cash runway until end of Q2 2027, and in case of positive data, and we can, so to speak, unlock Tranche 3 and Tranche C of the refinancing, we can extend that until the beginning of 2028. So we are well-funded until not only the data readout, but also until NDA filing. That is correct. Yeah.
Okay. Any last thoughts about other areas of It is a little premature, but other areas of expansion. I know you mentioned CACKLED on your call this week, which is the first time I have heard the word CACKLED, so that is new. So maybe you want to just define what that population is and any other liver diseases you may be going into?
Yeah. Jason, go ahead and talk about the F4 population.
Yeah. Briefly. So CACKLED is a relatively new term over the last couple of years that literally means later F3 patients and compensated F4 that have one, that they share an underlying physiology, and that they have developed elevated blood pressure within the portal circulation called clinically significant portal hypertension. That is important because it is the portal hypertension that drives liver-related outcomes. Very similar, Annabel, to systemic hypertension, driving cardiovascular outcomes, stroke, et c. Same idea. That population is where the highest risk of both progression and occurrence of liver-related outcomes occur, and we think that lanifibranor has got some really interesting and kind of cool data that suggests that it might actually be helpful in that population. So we are looking forward to talking more about that study as the year goes on and once we get through top line. I think it is-
Still within the spectrum of MASH, though, right?
Yeah, absolutely. These are the same patients that are walking around that could be anatomic F4 by biopsy, and you put a needle in them, and they're like, "Oh, you're F4 or you're F3, but you're very late." You have almost bridging fibrosis everywhere. But they're not quite fully F4. The problem is that that physiology, you look at their platelets or you look at their liver stiffness measurement, and those numbers together might say, "Wow, they have a pretty high risk of having this clinically significant portal hypertension." Once you get on that clock, you're talking just a few years before you could have a meaningful liver-related outcome. That's a big deal out in the world, and that gets back to this urgency to treat these patients, particularly that F3 population that are diabetic.
They are at extremely high risk of progression into that group, and then it gets very difficult to manage them. On the back end of that—
Got it.
—the only thing I would offer is there's an interesting overlap here in the population of MASH. Those extrahepatic drivers also are associated with causing HFpEF, heart failure with preserved ejection fraction, and many of those underlying drivers map to that same PPAR biology you and I opened with on that very first question. It's very much of interest to us, and that's something we also hope to be talking about soon.
Even though heart failure is a possible risk factor for some of these patients, right?—
Yeah. Exactly right.
—to take PPAR.
Like everything in drug development, there's subtleties involved. But I think sticking to you ask us where we're interested in going, it's very appealing to us.
Okay. Great. We are just about done. The time goes very quickly. Thank you so much for your time, and obviously, we are very excited to see the data.
Great. Well, Annabel, thanks for having us and for the good discussion.
Okay.
Thank you, Annabel.
Take care. Thanks.
Thank you.