Thank you for joining me today at this fireside chat with CEO of Inventiva, Andrew Obenshain, and the CMO, Jason Campagna. I will do our quick disclosure from Morgan Stanley. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. Without further ado, let's get started. Andrew, before we get into details, could you give us a brief update on where Inventiva stands today and what investors should understand about the company as you approach a very pivotal phase III readout?
All right. Thank you, and those last words are the keywords. We are approaching a phase III readout for our sole asset, lanifibranor, and we've guided that that readout will happen in Q4, so it is imminent. For those of you that don't know Inventiva, we are a single product company based in France, and lanifibranor is our lead product. It is a product that treats the disease of MASH, which is one disease, but that has two disease drivers, and lanifibranor addresses both those drivers. Let me just give you a little bit of an overview of MASH. MASH is liver disease, and it's the second leading cause of liver transplant in the U.S. There's two drivers of the disease.
There's the scarring of the liver itself, so the scar deposit, and then the lack of the scar dissolving, and that can progress up until cirrhosis, and it can be a death sentence if you get to cirrhosis. But it's really driven by metabolic dysfunction, by dyslipidemia, by sugars, by adipose tissue health. The existing therapies on the market right now really address one of those two drivers. They either address the liver directly or they address the metabolism, but there's no therapy that actually does both, and lanifibranor is really the first that addresses both. We were very excited to see our readout in the phase II, which was published in the "New England Journal of Medicine," which showed the leading oral efficacy in this disease with an 18% reduction of fibrosis. We're looking forward to trying to duplicate that into phase III.
That's really super interesting. You've talked about this kind of dual mechanism for lanifibranor. MASH is often thought of primarily as a liver disease, and you've described it slightly differently. So why does understanding MASH as a systemic metabolic disease matter when you think about how you're going to treat it?
If you address just the liver, you are addressing just one half of the disease. You are not addressing both.
Right.
There has been some studies that have shown that you could give a patient the best liver drug that exists, which is a liver transplant, put a healthy liver into a patient with MASH, and within five years, they will all have MASH again.
Return.
About half of them will have fibrosis because you have not addressed the metabolic dysfunction.
In order to really get at a long-term solution for the disease, you need to be able to address both, and that is what lanifibranor has the possibility of doing.
With that in mind, what is fundamentally different about lanifibranor's pan-PPAR mechanism, and why do you believe that difference matters clinically?
I'm actually going to hand that over to Jason.
Yeah. We've known for the better part of 25 years, 30 years now that the PPAR pathway, alpha, delta, and gamma, are generally metabolic reprogrammers. They manage sort of the state of energy metabolism in an organism. So you think about glucose production, adipose tissue function, energy metabolism, et cetera. The pathways are very clear on what PPARs do. What's new is that, as Andrew was leading to, that in the last decade or so, since really Intercept came on the scene with the very first attempt at getting a drug approved in MASH, we've gone from thinking that this is primarily a liver-centric or liver-dominant disease, and it's more that the liver is sort of one organ manifestation of a larger metabolic problem. It's an important organ, and it's one that's really severely affected.
But when you think about a drug like lanifibranor that can target multiple nodes or axes in this pathway, it makes a very compelling argument that you may have a really better way to get control of both the intrahepatic and those extrahepatic drivers. It's not the only way to do that.
but it's certainly a very compelling way to do it.
Okay. And so there are already two therapies approved and on market that've got a significant amount of clinical data attached to them. Do you think there's still a need for additional MASH therapies?
Absolutely. The market's actually being built in front of us. If you go back a couple of years, there was a question about whether or not there was a real market for F2 and F3 treatments.
Now we have two therapies that have shown actually tremendous progress in proving that that market exists. And we have actually built a company in Inventiva with the people to actually go and bring lanifibranor into this growing market as well. Again, these two therapies that are on the market, they address either one element of the disease or the other, not both. They either address the liver aspect of it or the metabolic aspect, but not both together, and that's where lanifibranor really can make a difference.
What do you think the future of MASH treatment is going to look like?
I think that right now there's a greater understanding of the need to treat both of these elements, and then we're going to see a lot more combinations. There's a lot of more people on GLP-1s right now. Lanifibranor can combine well with the GLP-1. We'll actually, in our trial, have a number of patients actually on a GLP-1, and physicians are going to be looking to do those combinations going forward.
You've touched on GLP-1 therapies. I think the number of people that are on it, both kind of prescribed but also DTC, it's really transforming the obesity and metabolic medicine landscape. Do you think the emergence of GLP-1s changes the opportunity for MASH-specific therapies, like yours?
Well, I think there's a couple elements in terms of the answer to that question. The GLP-1s have an impact on NASH. But in order to have an impact, you have to be on a higher dose of GLP-1, and you have to be on it for the course of over a year before you see a difference.
Yep.
Certainly very useful in terms of treating the disease. But if you have a patient that has F3, for example, that is a patient that is pretty close to cirrhosis, you want something that is going to act fairly quickly. In our phase IIb, we showed an effect after six months. I think it is going to be unlikely that physicians are going to really want to wait a full year for effect-
Yep
with a GLP-1, especially for an F3 patient.
Working through one of those PPAR pathways, actually weight gain is a sign of clinical efficacy.
You have seen that in some of your trials. How do you think about lanifibranor's weight profile in a treatment landscape that is increasingly focused on weight loss?
I'm actually going to hand that over to you, Jason.
Yeah, I think it's a fair question, but it gets, I think, to the core of what we're trying to accomplish. Let's just step back a little bit. We knew for a long time that bariatric surgery, if it's effective at weight loss, can also be effective at improving MASH. You looked at histology, whether it's MASH resolution or fibrosis. We knew that bariatric surgery can do that. GLP-1s have clearly changed that landscape. The point is that it changed it in one very particular way, weight loss through the GLP-1 pathway, muscle, et cetera, does appear to be resetting a lot of that programming that's a problem. That's a very good thing.
With lanifibranor, the weight gain that we see has nothing to do with that pathway. It's really around a PPAR-γ-mediated effect, which is well-known and well-understood around fluid retention. The impact of that fluid, the goal of the lanifibranor program initially was to show that on the one hand, we can capture all of that biology in a single drug, alpha, delta, gamma. But on the other hand, the drug as designed could lead to a softer, gentler gamma effect. I believe that's what we're seeing. It's not that weight gain in the form of fluid is unimportant. It's that when you pair that more modest gamma effect with the benefits that a pan-PPAR agent might give you, that benefit risk might make a lot of sense in a patient population, particularly the later-stage patients where the urgency to treat gets pretty high.
You're beginning to think at that point not just, oh, you have MASH, but you have advanced fibrosis and you have several risk factors that if left unaddressed can lead to pretty severe outcomes over a period of time. That urgency to treat makes a drug like lanifibranor with a more, say, muted or balanced PPAR-γ effect with the other benefits that we hope to see in the clinical program make a lot of sense.
Yeah. We already touched on there's already two assets approved and in the market. Lanifibranor obviously has its clinical data this year and hopefully is soon to be on the market. But there is several years, obviously, that the two that are already on market have in terms of commercial but also real-world experience. Do you think that lanifibranor is at any kind of disadvantage for not being that first mover, or how do you see the commercial landscape?
No, I think quite the opposite, actually. I think what this did is the entry of these two therapies onto the market has grown a physician appreciation for the need to treat. You've seen actually that this was not something for which drugs were readily available before. So it has, I think, increased the diagnosis. You see more machines in offices that can do diagnosis now, and it's actually increasing the patient pool that is under treatment.
As we come to the market with a therapy that can address the multimodal etiology of this disease, we'll have an opportunity to go into that growing market as well.
Yeah. Let's turn to the exciting data that's coming up. So NATiV3, what do you think you need to see in the phase III data to confirm and build on the results that you've already demonstrated in phase IIb, which were very impressive?
Yep. In the phase II, just as a reminder, phase IIb, we demonstrated an 18% improvement in fibrosis versus placebo. We believe that if we duplicate that 18%, that we have a very successful therapy on our hands for patients.
Specifically, the way we think about this market is that we do a very simple 2- by- 2 grid. On one axis you have severity, so F2 and F3, right, just before you get to cirrhosis. On the other axis you have risk of progression, and for that we use as a proxy diabetes because you have non-diabetics and diabetics. If you have diabetes, you are at a higher risk for progression. You move faster. We imagine a future where a patient walks into a physician's office and let's say the patient gets diagnosed with F3 and they have diabetes. We think that lanifibranor is the first product that doctor's going to reach for, and they're going to reach for it for two reasons.
Number one, you want to pick up the biggest hammer you've got on fibrosis at that point in order for that patient not to go to F4, which can be a death sentence. We have an effect size of 18% versus the competitors that are in the low double digits.
That's the first reason. The second reason is we do lower HBA1C. We do address diabetes. That is one element for a reason that the physician's going to pick up lanifibranor. The other is they're really worried about that patient progressing quickly because they have diabetes and they know in our phase IIb we showed that we can work as quickly as six months.
Right.
That is another reason to pick up lanifibranor. We think that is a very natural place for us to start. Then by extension, the physician will think about lanifibranor in those F3 non-diabetic patient populations. They want the biggest hammer.
Yeah.
In that F2 diabetic patient population, because they want to address the underlying diabetes.
What gives you confidence that what you saw in phase II is going to be reproducible in the NATiV3 study?
Jason, I'm going to hand that to you.
I think the first begins and ends with the trial design. NATiV3 is largely very similar to NATIVE in most of the key elements. Very similar, if not identical, patient population. We have narrowed it from F1 through F3 to only F2, F3. The baseline demographics are largely similar when you look at the severity of disease and the comorbidities, et cetera. Third, we are treating for longer, which is a good thing given that the mechanism of action of PPARs do take some time. Six months was aggressive and early, and we have already seen an effect. They are transcriptional modulators, so they take time to work. The underlying biology takes a little bit of time to work of the liver itself, so the 18 months favors both of those.
From a structural program, the trial looks largely similar to what we did in NATIVE, and we are letting it run longer with both doses. I think all of that lines up to give us a fair bit of confidence that if there is biology that is there, we should be able to see it and identify it.
Great. We touched a little bit on the safety profile, talking about weight gain that we have seen in the phase IIb results. There have been concerns, given the historical safety with some PPARs. What are you expecting to see in phase III? Weight gain, we already talked about. Decrease in hemoglobin, peripheral edema. What are your expectations?
Yeah, I am going to start, then I am going to hand it to Jason. I think when physicians look at this profile, the thing that they think about first is the efficacy or they want to use it.
Yeah.
You bring up some tolerability issues that we have with the drug in terms of weight gain, which is really fluid retention.
There's a class of physicians that have been using pioglitazone-
which is another PPAR-γ, and it's still 4 to 5 million scripts a year, especially with endocrinologists, who are very familiar with how to handle this type of profile.
Right.
There's no concerns in terms of the management in their minds.
They look primarily at the efficacy. Having said that, the fluid, or actually, I am going to just go ahead and take this. I am sorry, Jason. If you take a look at the fluid retention, which is what leads the weight gain, it is mechanistically understood, it is relatively modest, and it can be managed. Mechanistically, as I said, pioglitazone has a PPAR-γ. Physicians are comfortable with it, or it is mechanistically understood. Modest or a slightly attenuated version. We have about 80% PPAR agonist versus pioglitazone, which is about 100%. The edema that you see with pioglitazone, we have a more modest amount than pioglitazone. Then lastly, if you actually give a patient SGLT2 or a loop diuretic with SGLT2, and you combine these, that weight gain is totally mitigated then due to the fluid being essentially peed out.
Frankly, with the comorbidities that a lot of these patients have, there is every likelihood they may already be on one of these therapies, right?
There is a very high likelihood, yes.
Assuming NATiV3 is successful, how do you see lanifibranor fitting into the kind of future MASH treatment landscape?
Yeah. So I think Wy talked about that F3 patient with diabetes being a very natural place. I think that if we are able to show the greater than 18% effect size, say we got up into the low 20s, then I think actually the whole market, all the 400,000 patients that currently have F2 and F3 under a physician's care are patients that should consider lanifibranor. These are things that combine very well with the GLP-1, with SGLT2s, so really you can look at it as kind of a foundation of MASH therapy for the future.
Yeah. It is oral, it is very easy to take.
Yep
It has got a lot going for it.
Yeah.
There is an increasing focus on compensated cirrhosis in that F4 population. How do you think about the opportunity for lanifibranor beyond the F2, F3 population being studied in NATiV3?
Jason, go ahead.
Yeah. I think the F4 population is the most rapidly growing segment in the world now, and I think that's a function of two things. We're finding patients more frequently, which is great, but because the disease is chronic and it's subclinical, it's often very difficult to detect and therefore diagnose. When these patients are presenting, they're presenting very late in the stage of disease. I think the second driver is that the field has actually matured a fair bit in understanding what cirrhosis really looks like, so there's an anatomic distinction. Put a needle in somebody's liver, take it out, you look at it under a microscope, they have so-called bridging fibrosis or cirrhosis. But we also know that the physiology of cirrhosis, which is portal hypertension, actually appears much earlier than the scarring in the liver would suggest.
We now know that there's a proportion of F3s walking around that are late in their disease, and anatomically they look like an F3, but physiologically they behave and have the risk of an F4. That's a problem in the world. That's the so-called urgency to treat, getting a therapeutic. How we think about compensated cirrhosis is that we believe that in lanifibranor, the mechanism of action by the way that drug works hits on those nodes, those biologic nodes, that drive the portal hypertension, the physiology.
That leads to these liver-related outcomes. So that when we're thinking about designing our F4 trial, and the one that we would like to run, ideally you want to include a population of patients that are F3, that have evidence of portal hypertension. They look exactly the same as the F4, except when you put the needle in the F4, they happen to be anatomically F4, but they're really the same patient. Those are clinically significant portal hypertension. Right now, the field is very concentrated on being able to identify those patients. There are guidelines that are being put out on that. Then once you identify them, getting them into clinical trials to methodically test whether or not you have a therapeutic that can avoid liver-related outcomes.
We think that with lanifibranor, the mechanism of the drug, we've recently put out some really nice data over the last year or 2 talking about this, but we think that the mechanism of action of the drug strongly suggests that we might have a real meaningful impact there. It's something we're actually really excited to do and to sort of get on with it.
But step one is we've got to get through the data first in NATiV3, then we'll talk about that next year.
As you said, Jason, it's a growing population, but it's also a population where there is very, very little available to actually treat the patients. So the high, the unmet need is significant.
We agree.
What do you think investors misunderstand the most about Inventiva and lanifibranor today?
We get a lot of questions about fluid retention, about weight gain. I think what's misunderstood is the physician choice here. The first thing the physician is looking at is the efficacy, right? And they understand how to manage fluid.
Yeah.
They understand how to manage with diuretics, with SGLT2. What the physicians are seeking is really an option with a higher efficacy and really to help those patients not slip into F4, and that's what lanifibranor offers.
I'll be a little bit more philosophical.
Okay.
Recently in the oncology world, there's been some beautiful data on pancreatic cancer, right, and the KRAS inhibitors. When you look at the company that did that, they had one mission, to do that job. I think what people underestimate about Inventiva is that it's a 14-year-old company that was founded by a group of people that had one goal. They were PPAR biology experts. They had one goal. They wanted to make a drug that will solve the tolerability and safety issue that had plagued other PPAR therapeutics. Not all of them. Fenofibrate, successful. Bezafibrate. There are a lot of successful drugs in PPARs. But they wanted to solve that problem and apply that therapeutic to the field of MASH.
I think what people underestimate is that we've had people at Inventiva that have been there 35 years.
Wow.
Since long before the spin-out. The inventor of lanifibranor was still at the company until last year. So I think people, although we're new, the management team, the sort of intellectual wiring diagram of that company goes back decades, and they have been on one mission to solve that problem. I think when you find focused people like that, you sort of get out of their way because what they can do with that is pretty powerful. So I think we're very fortunate. We all believe in our management team, that we're sort of the recipients of all of that, and we don't want to mess it up in any way.
Yeah.
It's a pretty powerful story.
It's amazing to hear there's that conviction and that belief in this asset.
Exactly.
That it's-
Over a very long period of time.
Yep.
A very difficult capital environment for the company. I think Andrew and I both joined on the tailwind of a group of people recapitalizing this company in 2024 because they believed in the data and the power of it. While that company was in trouble, what we'll call the old Inventiva, those people were still there, still working away in the offices in France and still working on that problem. Good for them.
Absolutely. Happy to open it up to the audience for any questions for Andrew and Jason.
Talking about the potential to see additional benefit in a longer follow-up period, are there plans to follow any of the phase II patients to gather any other long-term data on them?
You're asking about the phase II patient population?
phase II.
No. That trial is long closed, and those patients are off to follow-up. But in the Phase III study, we have two mechanisms to follow them. After the trial, at week 72, they can go up to week 96 and remain on therapy for follow-up. Then if they choose, they are all eligible to roll into an active treatment extension that would get them out another 52 weeks. We have two ways in which we can follow both the main randomized cohort and the exploratory cohort, about a total of 1,500 patients.
Well, Andrew, Jason, thank you very much for your time today and joining us at the Morgan Stanley Healthcare Conference. I think it goes without saying that there is an exciting couple of months coming up for the company. I, for one, am really looking forward to seeing what is certainly probably one of the most highly anticipated phase III readouts left for the rest of 2026. Best of luck.
Thank you.
Thank you, and thank you for having us on stage.
Thanks a lot.