Let's try this again. Let's go ahead and get started. Thank you everyone for joining us for the Inventiva Fireside Chat at the TD Cowen Healthcare Conference this year. I'm covering analyst Ritu Baral, with us from Inventiva, we have CMO Jason Campagna and Head of Investor Relations, David Nikodem. I guess let's get into it. Let's get into it. Someone doesn't want us to talk about phase III. Let's talk about your phase III NATiV3 trial that is ongoing with the readout later this year. Setting investor expectations, I think that's the top conversation I have about Inventiva. What magnitude of effect do you hope to see in the phase III readout? The primary endpoint is a different one. It's a combined primary endpoint of fibrosis and NASH resolution.
When we talk about magnitude of benefit, there's almost more focus on your secondary of just fibrosis, but also people will obviously be looking at that top one. Jason, can you talk to the I'm sorry, the effect size on both of those?
Sure. Just for context. That good? There we go. Just for context, by way of reminder, NATIVE two readout was published in 2021, and in that era it was quite the big deal. It was the first trial to show any histology improvement in phase II at 24 weeks. Certainly the first trial to show dual endpoint resolution. Because the totality of the datasets were so strong, not only on the dual endpoint, but fibrosis on a MASH resolution and the associated biomarkers, intrahepatic and extrahepatic elements that all gave us a lot of certitude that this effect was real, that we were seeing in six months, we constructed NATiV3 to look a lot like NATIVE two. At a minimum, what I think we're comfortable is that...
Longer.
Longer.
Right.
Exactly right. Similar population, similar design, one to one to one dosing, et cetera. The two big differences are no F1s, so that gives us a little bit of potentially of a tailwind because all of the patients in the trial have an opportunity to benefit F2, F3. The second is longer. If we hit NATIVE 2 dataset, we believe that we have a very, very strong contender to be quite competitive in the marketplace. Oral therapeutic, intra and extrahepatic drivers of disease. Direct acting liver, anti-fibrotic and indirect on a number of elements that are driving the overall trajectory of the disease. For the most part, all done with the dataset that show 18% fibrosis, 24% dual endpoint. That would be, from our view, incredibly strong. What would be.
That was at six months.
Exactly. What would, you know, fantastic look like?
Right. On fibrosis.
If we start getting into that 20% effect range on fibrosis, placebo adjusted, now you're bringing real pressure on existing market players that you're effectively doubling their effect sizes. When you do that, you have a very strong, we think, competitive argument to be made that drug should be given to even patients with earlier stage disease, F2, that are not diabetic. The drug will work equally well. Lanifibranor works equally well in diabetics and non-diabetics, the market right now, the players that are in market with that effect size and that sort of low teenage dominating the non-diabetic because they're many properties. If we were to show double, getting close to double that effect, I think that's be highly disruptive to the market.
How should we think about that primary endpoint, the sort of combined? Is that more meaningful to, say, insurance companies or doctors and the magnitude of benefit on that?
We think it is, it's the simplest explanation is the biology. No one's really clear on what the relationship is between fat, inflammation, and fibrosis. Only that fibrosis drives outcomes, and that you need to correct to some degree, both fibrosis and MASH. The existing endpoints get one or the other in different patients. The ability to walk into a physician's office, endocrinologist, family practitioner, and say, "Look, this one drug gets both elements that are driving the disease in the same patient." We think that message is really simple and really powerful.
Can you talk about the powering assumptions for NATiV3? How conservative are your assumptions, especially those assumptions driven off of phase II?
They're very conservative. We are powered to over 90% on the primary endpoint. That's dual resolution of MASH and improvement of fibrosis in one stage or more. We chose a higher placebo response than we saw in phase II, a lower treatment effect, and therefore a lower total effect size.
Lower treatment effect than 24 weeks.
Correct.
Okay.
24%. Correct.
Yep. Got it. How is safety going in the ongoing study? It's one of the major conversations when I bring up Inventiva with investors and is always like, "Wasn't there that safety thing?" It's always like very imprecise. Nobody quite remembers it, but it sort of sticks in their head. How has NATiV3 safety looked, DSMB looks, et cetera?
The event.
Yeah.
2024, February, March timeframe. A hepatic SUSAR with an unusual confluence of circumstance. It was a patient that had autoimmune disease with some evidence of autoimmune hepatitis that had a Hy's Law-like flavor to them. They had transaminase elevation and a small movement in their bilirubin. The company chose at the time, I think appropriately.
Mm-hmm.
... to not only share that publicly because
Bilirubin didn't go above two, upper limit of normal?
Correct.
It moved, but not-
It moved-
Okay.
... it was not. It would sort of have the shape of a Hy's Law, but not.
Okay.
... fully. More importantly, I think I wasn't there, David was. I think the company did the right thing. They paused and some of the assessments to get at this autoimmune, more frequent monitoring for risk for good. How's it going since I joined in? Obviously, I'm run on, I'm also the chief medical officer. I like what I see. I think more importantly, the fact that we don't have to talk about the DMC publicly is the best thing in the whole world.
Okay.
They meet once every six months. We never talk about it because there's nothing to talk about.
Another major discussion point has been the tolerability profile. What I mean tolerability profile, prior trials and mechanistically have shown a modest increase in weight and a modest increase in edema.
Yeah.
... with this mechanism and lanifibranor. What level of weight gain would be considered a concern by KOLs and regulators? What should investors expect to see move? How should investors look at the data on weight gain and edema when that finally comes out?
David, why don't we split that? I'll answer the question directly. Why don't you walk us through quickly what we know about weight gain, and then I'll get to what does it look like today?
Yeah. In the phase II, 50% of patients showed no weight gain whatsoever, and they still had a effect. Treatment effect is not dependent on weight gain. About one-third of the patients showed greater than 5% weight gain. In The New England Journal of Medicine publication there, you had a table of the investigator-reported weight gain, and that was only at 10%. Those 20% deemed that that weight gain that they saw greater than 5% was really not impactful.
5% of top line body weight.
Baseline body weight.
Baseline, yep.
Yeah, which was probably on a range of 90 kg-95 kg.
Mm-hmm.
you know, pretty heavy set individuals. 20% of those, that delta between the New England Journal publication, the actual weight gain shows that 20% just didn't deem that as any kind of issue at all in those patients.
We set up that framing to say that.
Mm-hmm.
... if we reproduce the NATIVE 2 dataset, our view is that most providers will look at that and say, "That makes sense to me.
Mm-hmm.
That's a trade that's absolutely worth making. The weight gain is relatively modest. It's more of a tolerability concern, and the drug is actually working quite well. We think that if the effect size is even better, as we were talking about earlier, that's even less of a concern. I think the three points we continue to try to make for now, and ultimately in the end, the data will show what it will show, but we make three points. David Nikodem hit two of them. Weight is, one way or the other, is not relevant to the effect of lanifibranor. If you gain weight or you don't gain weight, the drug works equally well. Second, the weight gain, generally speaking, is consistent with what we've seen with prior PPAR-gamma. Little bit of fluid retention, later a transition from sort of unhealthy to healthy fat-
Mm-hmm.
... the subcutaneous fat. Third, if you're unhappy with it, you can just stop the treatment. It's one of the reasons we'd like the 800 milligram dose and giving it an opportunity at 18 months, because if that looks like-
Mm-hmm.
... the 1,200 mg dose from week 24, that gives providers another option. They might be able to go down in dose to potentially manage weight a little bit better.
As we do think about weight and edema, with that top line, have you guys decided what you will disclose with that top line? If there is a creep in weight, being able to message around the metabolic activity of any increased fat mass, I think would be important. Have you discussed what you'll release with top line yet?
The short version is no. We have not landed on the finality of the top line data package. We expect to be, I think, guiding more consistently on that.
Mm-hmm.
... by when we get into the back half of the year, which is when we're guiding data.
Okay.
Contemporaneous with that transition to the back half, you should expect to hear more from us about what we'll be putting out at top line.
Thinking about that sort of that element of the tolerability profile, you will have a subpopulation of patients on like background GLP-1s, background SGLT2s, et cetera, which in phase II trials has shown to offset some of these. What is your understanding right now of the size of that subpopulation, and do you think that subpopulation of patients will look different?
Less than 15% of the patients in NATiV3, both the exploratory and the randomized cohort-.
Mm-hmm.
Are on a GLP-1 diabetes or obesity dose at baseline.
Mm-hmm.
About half of those are some other long tail for other GLP-1s, Liraglutide, dulaglutide, et cetera.
Mm-hmm.
We have a small proportion of patients that are also on SGLT2s, but the numbers, 'cause the trials are so big.
Mm-hmm.
We're looking at maybe 300 patients on the GLP-1.
Mm-hmm.
Maybe another 100-ish, 115 or so on SGLT2. We think that those are large datasets. We're gonna do our very best to put those in to a top line mix. It might not be on day one.
Mm-hmm.
... of the top line, but in that first wave of data that would be coming out in meetings, wherever it would be, those are important datasets to us.
Can we expect narrowed guidance for timing of the data beyond second half of 2026? Will you announce?
We will narrow the guidance.
Okay.
Once we cross that midpoint threshold.
Mm-hmm.
We'll be able to narrow the guidance a little bit more.
Sorry, midpoint of the year?
Yeah.
Okay.
What's concluding us from doing it now is that there are operational things that are not entirely in our control.
Mm-hmm.
You know, example, we know exactly when every patient has their last visit scheduled.
Mm-hmm.
Getting them to the site, making sure they get there, get their biopsy done is an entirely different thing. Once we're all done that, at that point I shut the clock, and then-
Right.
... we'll be able to guide more.
Is it fair to say that maybe last patient, last visit, you may announce that and then leave open?
We haven't decided. It's not unreasonable to think that we will.
Okay. Right now, procedurally for clinical trials and getting biopsies read and stuff, has it gotten more efficient or, more crowded, I guess, to get eyeballs on the slides?
I think it's working well.
Okay.
I think it. There is a time component to-
Mm-hmm.
... human beings to sites, getting biopsies, getting them shipped off, read. There's just time involved. In the end, you know, we're used to the digital world, but biopsies, although we do digitize them, it's the actual slide, so they have to move from one physical location to another, and then they need to get put into a process. There is time involved.
Got it. In advance, and this is well in advance. You know, we talked a little bit about some of the commercial messaging. At this point, is there any market preparation just given the mechanism, maybe within the diabetic NASH population or market research that you're doing, that will help consolidate the potential market opportunity for investors?
Go ahead.
You know, we did to bring on a chief commercial strategy officer to help with pre-commercialization.
Mm-hmm.
She came from Sanofi and Madrigal. No, Intercept.
Intercept.
Intercept.
So she's very good, and she's doing the pre-commercialization market access. We brought on recently a medical affairs person to start talking to the important KOLs, et cetera, and just expanding what we've already started creating.
What are sort of the talking points, that this leadership is discussing with the, say, the KOL space that sort of pulls on the points of differentiation, I think, of lanifibranor? Do you know what I mean? Like, yeah.
I think it's just I'll start with, intra and extrahepatic.
Sure.
So direct-
Mm-hmm.
Anti-fibrotic effect-
Mm-hmm
... as well as out of the whole focusing on the whole body, extrahepatic, so triglyceride improvement, HDL improvement, and insulin sensitization properties for HbA1c lowering.
Yeah, then we'll click into that although there is at least one other oral agent.
Mm-hmm
Approved for NASH. We lean to that in a single oral agent, the ability to get all of the three drivers that we believe contribute to NASH, the unhealthy adipose tissue, the glycemic handling-
Mm-hmm.
... and the direct acting histology benefits on the liver are very powerful.
Right.
In a single agent.
'Cause the other oral.
Cannot do that.
Cannot answer the glycemic at all.
Right.
So.
Correct.
Got it. Let's move to F4. That is another big topic of investor conversations. What are the plans and timelines for your confirmatory trial in F4 MASH? How is NATiV3 going to both inform that trial and the extension of F3? How will that sort of complement the data?
Yeah, good. The stacks are easy. We are required to run an outcome study for full approval in F2, F3, and we will do that. Two, we've chosen to look at compensated cirrhosis and potentially late, very late F3 that looks like they have cirrhotic physiology. These are known as cACLD patients.
Sorry, what?
Chronic advan-
cACLD?
cACLD, c-A-C-L-D. Chronic advanced compensated liver disease.
Okay.
This is a group of patients that are physiologically F4.
Mm-hmm.
All you care about is outcomes. There's no requirement to run an F4 study.
Mm-hmm.
We just need to run an outcome study.
Mm-hmm.
Those patients are at incredibly high risk of early hepatic outcomes. The third is that the requirement from FDA to be discussed with them when we meet with them at pre-NDA filing is that that trial needs to be meaningfully progressed by the time of full approval. What that means in practice is that that trial gets going around the time we file. What we're guiding for filing now is that sometime in 2027-
Mm-hmm
... obviously, depending on data.
That F4.
That F4, that outcome study.
cACLD F3. Okay.
Yeah.
Got it. It's not gonna be the extension part.
No.
... NATiV3.
Which gets to the what is NATiV3 gonna help us with.
Yes.
one, in that exploratory cohort, we have about 75, it's about 400 patients total.
Mm-hmm.
These were screen fails in NATiV3 that are on treatment.
Mm-hmm.
We have about 75 F4 cirrhotics in there, obviously incredibly helpful.
Mm-hmm.
There's no efficacy being measured in that exploratory cohort, but we do have efficacy markers that we'll be able to look at, and more importantly, safety.
Okay.
Both of which will be obviously very critical to engage with FDA for dose selection in that trial. We like that. Of course, the data from NATiV3 will matter.
Right.
Does the drug work in that dose?
Right.
Lastly, sort of baked into the question, Ritu, is why are we so excited about this? You even saw how animated I got.
For F4. Yeah.
The biology of lanifibranor is really interesting. We have a lot of data that we put out on this. All of it is preclinical. The drug has direct acting hepatic effects on the things that drive liver related outcomes. If you want to improve outcomes in patients with NASH, cardiovascular is over here, but liver, you have to get in the way of portal hypertension. You have to. Otherwise, you do not improve liver related outcomes. We have a really nice sort of dataset, preclinical dataset, that show the drug works directly on hepatic stellate cells for fibrosis improvement-
Mm-hmm.
... and works on hepatic vasculature to lower portal pressures. To the extent that either or both of those translate into people, we're pretty excited about it, and that's why we're really excited about this outcome study.
Do you have any concerns about frailty in F4 patients in general?
The doctor in me, and even David, the non-doctor, would say, "Yeah, we're always worried about safety." I mean.
Mm-hmm
we're drug developers. You always worry about that. Is there anything sort of intrinsic in that F4 population?
Mm-hmm.
... and lanifibranor that gets us bothered? No.
Mm-hmm.
Not that we see now. Again, the final dataset in NATiV3 will help us with this, but there's nothing about our pharmacology or our toxicology program that say sort of, "Danger, don't go there.
How do you address investor concerns about all the F4 studies in the sense that, you know, even your competitors who are running F4 studies? One of the most common questions I get is like, is it going to be powered enough in the sense that is the event rate going to be high enough to translate to a positive outcome, for, you know, for a reasonable timeframe? How would you select your F4 patients and the F3 cACLD patients, to choose those that will give adequate powering?
Yeah, these are great questions. Let's keep it as simple as we can.
Mm-hmm.
The caveat is until we get in front of FDA gets a vote too, and they'll obviously have a say in the final protocol. Our thinking on this.
Mm-hmm.
Is very straightforward. Number one, If you can enroll any patient population you want, you can enroll non-cirrhotics in an outcomes trial. You just have to be prepared to wait a very long time for outcomes.
Mm-hmm. Yep.
The intent of enrolling these cACLD patients, whether they're late F3 or early F4, is that by routine non-invasive assessments, platelet count, for example, FibroScan, you can quantify whether or not the patient has significant portal hypertension.
Mm-hmm.
If they do, we know that those patients with clinically significant portal hypertension will go on to develop liver-related outcomes at a rate that is much higher.
Their slide says F3, but their portal hypertension says F4.
Correct.
That is your prediction.
The anatomy, you put a needle in, they may very well anatomically be an F3 on scarring. Physiology, platelet count might be below 100,000, 110,000.
What proportion of F3 patients are we talking about for the cACLD?
Very difficult to come by, but, what we can say is that every F3 patient will eventually look like that.
Mm-hmm.
They have to, or else you're not F4.
Mm-hmm.
It depends on when you look. What you're really looking for are patients that, in an ideal world, they're F4 that have this physiology or they're F3 that have the physiology. At some point, all F3s eventually look like this.
That's the work we're doing now is designing that trial.
Mm-hmm.
getting ready for that.
going back again, sorry, to this F3 cACLD patient. This is a new concept, are they going to have event rates that will align with like true proper F4s?
Yes.
Okay.
Yes.
They're not gonna drag down powering of an F4.
No. In fact, it goes the other way. The idea that.
Mm-hmm.
be able to find non-cirrhotic patients. Meaning anatomically cirrhotic only helps enrollment.
Mm-hmm.
Only helps bring that up. I think the context here is that the Baveno group now codified in guidelines. They're called the Baveno criteria. We're on Baveno seven, I think is happening in March in Baveno, Italy. It's a location. They have sort of worked out very quietly and patiently over the last decade or so exactly what these criteria are and exactly what the risk is. The point is that this population, if your goal is to run a trial in patients with NASH that are more likely to have liver-related outcomes in a relatively short period of time, like four years or less, that's the population you want. They are at the highest risk of hepatic decompensation until you get to patients with more advanced cirrhosis.
Mm-hmm.
When they catch up.
How do you sort of model the TAM for F4 and, you know, maybe we can call them rapidly progressing or...
Sure. Yeah.
-most severe F3s. you know, as we have MASH model market discussions with yourself and competitors. You know, other competitors say it should be equal to the F2, F3. Is that how you guys are looking at the F4 opportunity as well?
There is, and it escapes me now, but there was a position paper published last year. It begins with an N. It's not NAVIGATE NASH, it's something else, but has outlined exactly what the probability models show-
Mm-hmm.
-for liver-related outcomes. It can be easily done.
Mm-hmm.
If you call an event rate at baseline in F2, F3, call it 3% or less.
Mm-hmm.
The cACLD population looks something closer to seven-ish to 10% on an annualized basis. If you look at two-three years, 25%-30% of that cohort could have had a liver-related event.
Of F2, F3, or the cACLD?
Of this cACLD population.
Of the cACLD. For F4s? Between the 25-
If they're compensated, it looks pretty similar.
Like 20%.
Even in the F4, you're looking for those patients that have portal hypertension.
It's the need to treat the F4 population that balances the potential market opportunity.
Correct.
-versus the F2, F3.
Correct.
Um-
yeah, I don't think internally we're focused on the F2, F3.
Mm-hmm.
I think even the sell-side analyst models don't have any, gives any credit for F4.
No, they do not. To be fair.
That's all upside.
You would need to, as Jason mentioned, you need to have that trial started and up and going by the time of filing.
Meaningful moving by the time.
Yeah.
by the time we're approved. Correct.
as we think about that versus, your current sort of cash position, how should we think about cost, essentially? Cost of that study and cash runway?
Yeah, we haven't guided to the cost of that study. What we've budgeted for our current cash is to, you know, get that analysis of the outcome study going.
Mm-hmm.
Be prepared to get that started. We did EUR 149 million raise last November. We have EUR 231 million cash at the end of 2025. That takes us through third quarter 2027, so through the data. That runway assumes two things. One is that we will pay back EUR 65 million in EIB, European Investment Bank debt, at the end of this year and the first quarter of next year. It also assumes that data is positive. If the data is positive, we will get EUR 116 million in a third tranche investment after the data.
That was part of an October 2024 fundraise, a third tranche of that deal.
Got it. Moving to where the NASH space is evolving to, the idea of combination therapies. We have other developers talking about potential combination therapies. How do you view, if we think about the long term, the potential for lanifibranor to be combined? What mechanisms. Just given this three-prong mechanism of this drug itself, what combination strategies are make sense from an efficacy perspective, and what's feasible given sort of the chemistry of the drug?
You know, it's a direct question, but it's actually a difficult answer because lanifibranor is somewhat unique-
Mm-hmm.
... in the field, right? Oral agent that has both intra and extrahepatic effects. It would be right now the only therapy that would do that.
Yep.
It depends on which stage we're talking about. If you're talking maybe about an F2 non-diabetic, lanifibranor could probably do it on its own, right? You're gonna get the really, really strong anti-fibrotic benefit. Nobody really cares about anything more.
Mm-hmm.
Begin to dial up things. Add on diabetes.
Mm-hmm.
Maybe lanifibranor helps. Add on cardiovascular risk. We get to some degree, we address, you know, triglycerides, et cetera. In that population, it may make sense to layer those drugs on with other agents that have been shown to have really strong benefit, right? It's not gonna be one. We all know this. It's gonna be not winner take all, but that's where GLP-1s really become powerful. Will they be GLP-1s? Will they be background anyway? They will, but in the world in which a patient is not on a GLP-1, GLP-1s make a ton of sense if you're looking to dial back those cardiovascular outcomes. I think as you get to later stage of FGF21s get interesting to us. Their benefit risk, we'll see what their data show, but the phase II benefit risk suggests that in earlier patients it might be a little tricky.
Questions of bone mineral density. I think we'll see. I'm optimistic that the phase three data will give us a clearer view, but right now my view of those drugs is that they could be quite helpful in that late stage F3 , F4 patient particularly. That is a natural combination point as well for lanifibranor.
Got it. Just going back, this reminds me, as you start your market research and market strategy, right now, is the diabetic population going to be a focus right now as you do KOL work, as you do market research work? What I'm trying to get at is, as you approach the potential launch, will the diabetic NASH population be the focus of commercial energy, just given the mechanistic and clinical data that we have in hand?
Go ahead.
I think we need to see the data.
Mm-hmm.
right now we're focused on the full spectrum of F2, F3.
Mm-hmm.
...with, type 2 diabetic patients as an opportunity.
When we see competitors expanding into targeting diabetologists, even without any glycemic improvement in glycemic control...
Correct.
...is that something that would make sense? do you really
I th-
...diabetologists as unwilling to meddle in NASH?
Well, for us, with a, you know, 0.5% or better drop in HbA1c with lanifibranor, then it certainly makes sense for endocrinologists to use-.
Mm-hmm.
...lanifibranor for their type 2 diabetic NASH patient.
Mm-hmm.
We view that as definitely an opportunity.
Yeah, the only other thing I'll add is that, only about 30% of diabetics have MASH, but if you have MASH, about 70% of them have diabetes.
Mm-hmm.
one way or the other, you've got to play in the diabetes space-
Mm-hmm.
...whether you want to or not.
Right.
I think really what we're trying to get at is that we're open-minded. We don't require a focus on diabetes, I think, for us to be able to build a successful commercial enterprise. On the other hand, you're gonna have to nod to it at some point.
Mm-hmm.
Particularly the later stage patients, F3, they're much more likely to be diabetic. That's why they're later stage patients.
Is that the 70% that you were talking about?
Yeah.
Is that the broader population?
It's all comers. If you survey all patients, if you say, "I have fibrotic NASH-
Mm-hmm.
...more than 65% of those patients have diabetes. They are clustered in the later stage fibrosis scales.
Got it. Very helpful. All right, we are at time. Thank you guys so much.
Thank you for having us.
Thank you, Jason. Thank you, David.
Appreciate it. Thank you.