Inventiva S.A. (IVA) Earnings Call Transcript & Summary

Thanks for being with us today on the third day of the JPM Healthcare Conference. It's a pleasure to introduce Inventiva to you. We've got Frederic Cren, Pierre Broqua and Mark Pruzanski. They're going to take it off. We have some time for questions from the audience afterwards, so feel free to ask those after. And I'll hand it over now.

Thank you. Thank you. I'm Frederic. I'm the CEO and Co-Founder. Thank you for taking time on your busy schedule on this last day of JPM. Today, I will go over the Inventiva and the lanifibranor story. As usual, I'll be making forward-looking statements. So please have a look at our SEC filings that are available on our website. So what I'm going to be trying today to show you to explain is that we have with lani, the ideal drug candidate to treat patients with advanced fibrosis and type 2 diabetes and why we believe this is the case. First, we have a drug that is oral with, I would say, best-in-class efficacy. We have published Phase IIb data, where we have shown an 18% fibrosis placebo-adjusted improvement after only 6 months of treatment. And on top of that, we provide a series of cardiometabolic improvement, especially an improvement in insulin sensitivity. And this is particularly true and beneficial to patients, of course, with type 2 diabetes that, as you know, are the most difficult-to-treat patients. The second one, of course, is that when you look at the tolerability profile, it's an extremely well-tolerated drug. And also, it has an AE profile that make it compatible with combination with GLP-1. So we really think that lani, combined with GLP-1, will be also an ideal combination treatment for patients. The mechanism of action is also very particular. It's a differentiated pan-PPAR profile. And what is great is that we have seen recently two drugs, two PPARs being approved by the liver disease at the FDA. And so this gives us confidence that when we file for NDA approval after our data is published, you will be in a good situation for approval. And then of course, where do we stand? We've made tremendous progress over the past months. We have a trial now that is more than 95% enrolled. And I'm very pleased today to share with you that we have sent a message to all of our sites early January to stop screening because we have enough patient randomized or in the screening pool to meet our target. And so we definitely maintain our target for end of -- having the last patient randomized before the end of this semester and the data in the second half of '26. And then also most important, we have now a company that is well capitalized. We did a large raise, more than $400 million. You see here the lead investor, only top-tier investor. They've done extensive due diligence. And this does gives us comfort that if they've decided to support us is that's because they really believe in the data. We talk about PPAR. There's been a stigma in the industry about PPAR, but it's important to look at data. And what is really crucial is that when we look at the so-alleged issue of bladder cancer with rosiglitazone, they have been totally removed by meta-analyses, that they demonstrated there is no association of bladder cancer with rosiglitazone. And more importantly, pioglitazone has been shown to be actually cardio-protective. And as I mentioned, there have been two drugs approved by the FDA recently that are PPARs. Also very important, and this is extremely, I think, great news for us and great data, when you look at what happens in real life, we have in the U.S. alone, more than 6 million script of pio. So it means that in real life, doctors, so in this case, most likely endos, they know they like the drug. They see the benefit of this drug and can manage the side effects that come with pio. And this is a great news because, of course, you have in the endo's office, a huge number of patients with MASH. And so when we will come with a drug like lani, which is an extremely better version than pio, I think we will have a quick uptake in this population. So that's in real life. And then also, it's important to look at strategic, what -- how do they perceive the PPAR class. And I think the Gilead acquisition of CymaBay for more than $4 billion for drug -- actually, at the time, it was not approved, so they had the end of Phase III data. So $4 billion for drug in PBC also bodes well for how strategically it could react to positive data of lani. So lani, what is it? It's unique. It's the only pan-PPAR currently in development in NASH. It can activate the three isoforms moderately and at the same dose. It's oral. So it's really clearly differentiating factor versus other antifibrotic drug. It's well protected with IP running through 2040. Also, what is really important is why are those three isoforms so important in NASH? NASH is a complex disease. And you see on the bottom of the slide, how each PPARs -- why each isoforms act on each of the key feature of the disease. If I take, for example, only fibrosis, let's just focus on fibrosis, we have shown at 6 weeks a strong antifibrotic activity. It's because we have a direct activity and the engagement of PPAR delta and PPAR gamma are able to activate stellate cell and control the fibrogenesis process. If we look only at the bottom of this slide, sometimes we hear, "Well, your PPAR is not as fancy as other novel mechanism of action." True, but there is one advantage is that you know what are the potential liabilities that come with this class of drugs, and you can design your molecule to avoid all of these potential liabilities. And that's what we have done with lani. So all the potential liabilities that are typically seen with a single or dual PPARs have not been seen in all our tox studies, and we have done 1-year monkey and we've done the 2-year carcinogenicity study. All of that has been provided to the FDA, which has come back to us saying that they consider the tox package complete and adequate for a filing of an NDA in MASH patients. So let's talk about the results. So we conducted a Phase IIb, 247 patients treated for 6 months, important to retain this, only 6 months, 2 biopsies that were centrally read. The results were published in the New England Journal of Medicine concerning the histology benefit and for the cardiometabolic benefit in the Nature Communications. And on the back of this trial, we received breakthrough therapy designation and accelerated approval in F2, F3 and F4 patients. We were the first drug to show statistically effect on the three key endpoints of the FDA, so NASH resolution and fibrosis improvement, fibrosis improvement without NASH worsening and NASH resolution without worsening of fibrosis. So the first drug to achieve a statistical effect on all of these three markers. You see here the result of 6 months on the endpoint that we have retained for our Phase III, statistical effect by both doses. And when you look and you compare to the other drugs that have been approved such as Madrigal, you see that we have doubled the effect compared to Madrigal after 1 year of treatment. And to find a similar level of responders, you need to go to the injectable, that if you follow the space, come with some side effects that are not present with lani. And then of course, in patients that we tend to be, we say in France, polymedicalisation, so that receive quite a large number of medication, an oral drug is always better. Same picture, if we only follow -- only focus on fibrosis, 18% delta, 12% for Madrigal and you need to go to injectables to find similar or to FGF21 to find similar effect size. And also NASH resolution, both doses being stat sig, higher effect compared to Madrigal and then you need to go to the other mechanism to find a similar effect. Importantly, the benefits of lani do not stop to the histology, but it also comes with cardiometabolic improvement. You have here the liver enzymes. They are normalized after 4 weeks. If you look at same data, for example, in semaglutide, it's 24 weeks. Not sure you can wait for 6 months to normalize enzymes in this type of patients. If you look at HDL and triglyceride, also there statistically -- statistical effect. And then very important, and we are extremely proud of this data, we had approximately 40% of patients in the trial that had type 2 diabetes. They continued on their treatment during the study. This is the black line. You see that the HbA1c did not change. But for those that were treated with lani, there were statistically significant improvement seen after 14 weeks. So it means that for those patients that have type 2 diabetes and NASH, we're able to help them control their diabetes, resolve their NASH, reduce their fibrosis. And when you look actually at the effect size in this patient population, it's actually larger than in the larger population. And that's why we will come back over and over saying if you have a patient that has NASH and has advanced fibrosis, F2, F3, and type 2 diabetes, there is one drug that is really ideal for this patient population, it's lani. And these results have also been replicated in a trial that we did in a combination with empagliflozin. And also, we did a clamp study in a third study. And there, we showed that we actually improved insulin resistance in key organs, including the liver. Weight gain. So of course, we improved insulin resistance, so we have some weight gain with lani, approximately 2 kilos, 2%, the patients have on average of 100 kilos. Importantly, it happens in only 33% of the patients. So 1/3 of the patients have a weight gain of approximately 2 kilos. What is great to see is that this weight gain comes with metabolic improvement. You take a patient in the same trial on placebo that gained weight, all these metabolic parameters worsen. You take a patient online that gained weight, its metabolic profile improved. So it means that we have a metabolically healthy weight gain. It's a shift from the visceral fat that is pro-inflammatory towards the adipose tissue. It's well-known. It has been shown by pio, but that's the mechanism of action. What is important is that -- so we have a metabolically health gain, but we have shown in two different studies, so one in a 1-year study in a different patient population that this weight gain plateaued after 6 months; and in a blinded analysis of our current Phase III, where we had more than 100 patients that had done the full study, the full 72 weeks, we see once again, the weight gain that stabilizes at 24 weeks. This is very different from pio, where in a study in a NASH population, this study is called PIVENS, went on for several years, 96 weeks, and you see a steady increase of the weight gain. It's probably due to this pan-PPAR activation with the PPAR delta helping to control the weight increase. And then lastly, if you really have an issue and you really want to control, we have shown that if you combine lani with SGLT2 inhibitor, you maintain the benefit of both drugs, but weight is totally controlled and it's not different from placebo. There have been similar study with pio and GLP-1, showing that similarly through our combination study, you can control the weight gain by combining pio and GLP-1. We have in our Phase III approximately 15, 1-5, patients on GLP-1, on the combination. So we will have data when we release the data, hopefully showing that the same effect happens. So where do we see and how do we compare lani to the key mechanism of action that are currently in development? I think the fact that we are oral gives us a tremendous advantage versus FGF21. Versus Madrigal, I think there are two important features of lani that are really also a great advantage for us. Actually, it's a direct antifibrotic activity. It's visible statistically effect after 6 months. Madrigal had to wait 1 year to show it. And then we are direct, we act on insulin-resistant. If there is one common feature of all patients with NASH is the fact that they are insulin-resistant. And also in terms of tolerability, no GI side effects. So when we talk about combination, we're clearly an ideal candidate to be combined with GLP-1. It's all for this reason that we really believe that we have a key spot that is patients with advanced fibrosis and type 2 diabetes. In terms of market, we focus on F2, F3. You see here in orange, the percentage, the estimate percentage of patients with type 2 diabetes. It's approximately 40% to 50%. In our trial, we have approximately 60% of patients with type 2 diabetes. So we're talking here quite a large size of the NASH population. You see here that when you are F2, F3, you have a tenfold or 17-fold risk to increase your liver-related mortality and that patients with type 2 diabetes and NASH, type 2 diabetes is an independent predictor of fibrosis progression, and actually, patients with NASH and type 2 diabetes have a faster progression of their fibrosis and that type 2 diabetes alone is an independent risk factor of mortality. So when we discussed with -- conduct marketing studies and where do these hepatologists and GIs see where lani fits with the other mechanism of action, you see here where lani is positioned. It's really patients that have an advanced fibrosis and type 2 diabetes, whether they have obesity or not, it's really clear that this is a key spot for us. And also, I would say, once again, that the combination of lani, oral lani with the GLP-1 is also an ideal product for treatment for patients with NASH. So where do we stand in terms of progression in the NATiV3, which is our Phase III. So very pleased to communicate, as I did in the intro, that we have stopped screening because we have enough patients enrolled in the study. Importantly, as I mentioned, we have a patient on GLP-1, approximately 15%, well-powered above 90%. And also over the summer, we run a blinded analysis comparing the Phase IIb results with NATiV3. We confirm that the baseline values are similar. It means that the patients we are recruiting are similar, have similar characteristic than the one of the Phase IIb. So that's encouraging, of course. And more importantly, the magnitude of changes that we saw in relevant biomarker are consistent between the two studies. And so with this good news on recruitment, we confirm our target to have the last patient randomized for the first half of '25. And as it is an 18-month study, we will have the result for the second half of '26 and we are already preparing for filing in 2027. We have -- thanks to the recent raise, we are well capitalized to execute on our clinical trial. And with all this, we are putting in place all the actions to be sure we are the second oral drug approved in MASH, the target of approval in 2028. So with that, I think we can move to the Q&A.

Thanks a lot, Fred. Any questions from the room? Otherwise, I can kick it off maybe with Mark, let's start with you. Can you comment on your appointment as Chairman of the Board and what made you decide Inventiva?

Sure. Is this on?

Yes.

Yes. So as you know, I recently joined the Board as Chair. I was long a leader, I guess, in the space, having put NASH, now MASH, on the map all the way back in the '00s to find the regulatory path. And of course, unfortunately, didn't get the first drug to patients, but now that's happened. But there's still clearly a huge unmet need. And I've been following the Inventiva and lanifibranor program for many years. As Frederic showed, it's demonstrated in Phase IIb in a relatively short course of treatment, 6 months, best in category, best in oral category, efficacy with a fairly clean profile. And you've got the precedent molecule, pioglitazone, which is a top 20 selling drug by volume in the United States still despite the fact that no one is promoting it and despite whatever lingering concerns there might be about the class. So I view this as a great opportunity to position the next oral drug that I hope will get to patients for, as Frederic mentioned, the most difficult, the most at-risk patient segment, specifically type 2 diabetics with advanced fibrosis. And there, you've got a uniquely differentiated profile represented by this drug. So I'm very happy to be involved with the story.

Just checking. As you mentioned already, but we're as well extremely excited by the recent financing of the EUR 48 million in equity financing to advance the trial further and additional EUR 30 million of milestone payments relating to your agreement with CTTQ. This financing follows a look at blinded data from around 500 patients on treatment for 6 months and 100 patients for 18 months. Can you elaborate a bit more on that data?

Sorry, you said what are the difference between the 6 months or 18 months?

Yes. Can you elaborate on the data available at this blinded level?

The blinded analysis? Yes, sorry.

I'm sorry.

Maybe, Pierre, you want to?

Yes, sure. So yes, we did a blinded analysis on 500 patients and 200 of which had completed week 72. So you know the principle of blinded analysis. We pool all the data and we follow several markers, including ALT, AST, glycemic control, lipid metabolism, some liver-related -- fibrosis-related NITs such as FAST and ELF, and we follow that over time. And to put this into the context of our Phase IIb data, which you have seen here, we have performed the exact, same blinded analysis on the pool of 247 patients from the Phase IIb. And what we saw, this was really a magic moment because, firstly, we observed that the baseline data for all these markers, with the exception of HbA1c because we have a higher population -- a higher percentage of diabetic patients in the Phase III, besides that, all the baseline values of those markers were exactly the same. And that indicates that we have really succeeded in enrolling the same kind of patients that we had in our Phase IIb. And when we follow the trends for change on these different markers for the first 6 months, it was really great to see a parallel decrease. So the curves were actually overlapping between the Phase IIb blinded analysis and the Phase III blinded analysis. On top of that, what we saw on certain fibrosis-related markers such as ELF, after 18 months, we had a greater decrease than after 6 months. So that means the way we interpret that is that we are confident that we are going to replicate the Phase IIb data and that because the treatment duration is longer, we may expect a greater benefit on fibrosis with lanifibranor in NATiV3.

And if we dig in a little bit more on lani's therapeutic profile and potential, can you compare and contrast lani with Rezdiffra, especially in terms of efficacy impact on fibrosis, tolerability and other biomarkers?