Hi, I'm Siân Hammer . I'm from the pharma and biotech team at Jefferies in Europe. I'm delighted to announce that we'll be joined by Frédéric Cren from Inventiva, CEO, and then also Pierre Broqua, who's the Chief Scientific Officer. Thank you so much for joining. Firstly, we'll kick off with a sort of introduction of the Inventiva story. Perhaps could you give us some background on Inventiva and then your lead asset, lanifibranor, just to help us set the scene?
Of course. Inventiva is a French biotech. We're listed on Nasdaq and Euronext, and we're known for our lead asset called lanifibranor. It's a pan-PPAR, currently in phase III in NASH. We have shown after the phase II-B to be the first oral drug able to reduce at the same time fibrosis and also to resolve NASH. The trial in phase III is fully enrolled, and we expect to have data in the second half of 2026.
Perfect. Thank you. Madrigal's resmetirom was the first therapy approved for NASH in the U.S. last year. It's also an oral form like lanifibranor. You're currently on track to therefore be the second oral on the market with NDA applications or filing planned for 1H 2027. How do you think lanifibranor would sit alongside resmetirom in the treatment paradigm and whether actually being the second player on the market could work to your advantage?
Okay. If you look at the results, I think data speaks for itself. If we look at the impact of lanifibranor on fibrosis after six months, we had 18% of patients that had a reduction of fibrosis placebo adjusted, so 18% in six months. If you look at rosiglitazone, they had approximately 10% at 12 months. You see a larger efficacy of lanifibranor. Secondly, we're also a drug that is a potent insulin sensitivity drug. We really improve insulin sensitivity. We believe that for patients that have advanced fibrosis, with an urgent need to see their fibrosis reduced, and patients that have type-2 diabetes, lanifibranor will become the drug of reference and the first choice for this type of patients. To your second question, is there an advantage to be the second comer? I think this is correct.
NASH is a new disease, very large, of course. Expectation that the market could reach $20 million-$30 million in the U.S. alone, but there is a lot of education that needs to be done. This has been done very efficiently by Madrigal. We expect Novo with semaglutide to continue to enlarge the market. We will be the third entrant, but in a market that will be educated and where lanifibranor can definitely find its place.
Brilliant. Then let's dive a bit into the science. lanifibranor is a pan-PPAR, and the PPAR mechanism of action is one that has a perhaps mixed reputation. What drives your confidence in the PPAR mechanism and how is it differentiated versus resmetirom, which is a THR beta agonist, or even the newer FGF21s?
Yeah. Yeah, lanifibranor is pan-PPAR. It is activating concomitantly PPAR alpha, PPAR delta, and PPAR gamma. It is clearly differentiated from other PPARs, including pioglitazone, not only with regard to safety, but also on the efficacy side. The reason for that at the molecular level is that contrary to pio or to rosiglitazone, which are binding to PPAR gamma, of course, but then recruiting a very large amount of co-regulators that will drive multiple biological processes leading to a side effect profile, which is what we know, lanifibranor is much more specific for the recruitment of certain co-regulators, and that translates into a differentiated profile. I'll give you a couple of examples. In the carcinogenicity studies that you need to do for registration, it's a two-year study in rodents.
In rats, we haven't seen any increased incidence of whatever cancer, whereas with pio, there is an increased incidence of bladder cancer that is seen at clinical exposure, for example. When you look at clinical data, there's been quite a number of clinical studies performed with pioglitazone in matched patients, at least five of them. In none of these studies, you've seen an improvement in fibrosis, even after 18 months exposure to pio, which is very different to what we have from NATiV2 with after six months, an improvement in fibrosis in 40% of patients. On the side effect profile, edema for pio in some studies, the incidence can go up to 25% of patients. In NATiV2, we had only two cases, 2% of cases, and all cases were minor and moderate in terms of intensity and were reversible quite easily.
Finally, in terms of weight gain, we have seen in our blinded analysis of NATiV3 that the weight increase stabilized after 24 weeks-36 weeks. This is a confirmation of what we have observed in another trial of one year in another indication where this was unblinded with the high dose, identical plateau after 24 weeks. This is very different from pio, where you see a steady increase of weight across study duration up to 18 months, for example. All this really differentiates lanifibranor from pio and from other PPARs. Relatively to resmetirom, I think a big difference has been highlighted already by Frédéric, the effect size on fibrosis and the onset of action also is much better. With six months, you have an improvement of fibrosis with lani, whereas nine months on phase II with resmetirom, there was no impact on fibrosis.
You had to wait for one year of exposure to get something which was less meaningful than what lanifibranor demonstrated in six months. The additional impact on insulin sensitivity for lani is very important. As mentioned, patients with MASH and type-2 diabetes have a more aggressive form of MASH, progressing faster. We know insulin resistance is part of this mechanism. If you improve it, then you have a better drug, more suited for this category of patients than resmetirom could be.
Maybe I can add one comment. You mentioned the PPAR baggage. I think it's important to highlight that if you look at two recent approvals at FDA, there's been two PPARs. One is lanifibranor, a PPAR alpha approved in PBC, so close to NASH. Also, seladelpar from CymaBay approved in PBC as well. By the way, seladelpar was acquired for more than $4 billion by Gilead. There is FDA interest in PPAR. There is big pharma interest in PPAR. Lastly, pioglitazone in the U.S. A drug like pioglitazone, much less efficacious than lanifibranor, still records 6 million scripts in the U.S. alone. It proves that physicians are quite comfortable with the PPAR mechanism.
Brilliant. Thank you so much for that. You've previously spoken about the combination potential of lanifibranor with GLP-1s, which is a class that's also shown efficacy in MASH. What's the data shown today on this combination and how many patients are currently on some form of GLP-1 in the NATiV3 study?
Yeah. So we're actually very excited by the idea of this combination because, as you said, GLP-1 have shown some efficacy in NASH patients, especially on the defatting, on the NASH resolution, but they lack a direct antifibrotic activity. A patient that has advanced fibrosis on GLP-1, where you want to actively treat its fibrosis, you could reach that with lani. lani could, as we have shown, reduce fibrosis in six months. That would be an ideal combination. Oral, so you do not have to ask your patient to undergo a second biopsy. Also, if you look at the tolerability profile, we all know that GLP-1 comes with a GI side effect. There is one thing we know about lani, that we do not have any GI side effect, nor do they have vomiting, diarrhea. This is not something typical with lani.
The combination makes a lot of sense. We will have data from the phase III. In the second half of 2026, we will have data about combining lani with GLP-1 because in the phase III, there are approximately 15% of patients that are recruited at baseline with a stable dose of GLP-1 and a stable weight. We will have data on this very promising combination in the second half of 2026.
Brilliant. Thank you. Similarly, in your phase II LEGEND study, you showed a statistically significant reduction in glycated levels, glycated hemoglobin levels with the combination of lani and SGLT2 inhibitor in patients with MASH and diabetes. How many patients with MASH also have diabetes? What is the opportunity here?
MASH and diabetes, large portion. You have approximately 50% of patients with MASH that have also type-2 diabetes. In our study in the phase III, we have 55% of patients with type-2 diabetes. What is important to highlight is that the proportion of patients with type-2 diabetes tends to be higher in the F3 and in F2 population versus the F1. They tend to also have a more progressive form of fibrosis. They move to cirrhotic stage faster than the general population. It is a population that you really need to address.
As I was mentioning before, lanifibranor has a really attractive profile because not only will you resolve their NASH, not only will you address their fibrosis, but we have shown in the phase II-B that when you add lanifibranor to patients with type-2 diabetes, you help further control their HbA1c. We believe, and we will have data in the phase III because we regularly measure HbA1c at different points, that we will show that not only lani will help this patient control their MASH or resolve their MASH, reduce their fibrosis, but also further improve their control of type-2 diabetes.
Brilliant. Thank you. If we shift to the NATiV3 trial again, biopsy sampling error and observer variability have been an issue in MASH trials historically. How is this mitigated for in the phase III programs?
We are using a triad of readers, so three pathologists. I would say now the standard, which is accepted to minimize as much as possible the variability of the reading. I would not say the placebo because it's not the number of pathologists that will actually reduce the placebo. If you look at the essence trial with semaglutide, actually there were six pathologists, and you have a placebo effect for MASH resolution that is 34%. It is not the number. It is more about what you control is the inter-reader variability by having two or three readers. To control the placebo effect, we have made a decision to have the combined NASH resolution and fibrosis improvement as a primary endpoint for the NATiV3 trial.
I mean, this has been published by many studies, but we've seen that with this endpoint, you have quite a stable placebo effect wherever the duration of the study basically ranges between 5% and 7%, which is much less than, for example, the placebo effect for the fibrosis improvement without worsening of NASH that can range from 10%- 30%. This is the way we are controlling the placebo effect in NATiV3.
Brilliant. Thanks. How well positioned is your partner, Sino Biopharm, to maximize the potential for lani in Greater China? What are the timelines for the study there?
Sure. In Inventiva, we have partnered lanifibranor in China to Sino Biopharm and also built a JV in Japan to address that market. In China, with Sino Biopharm, we are running a phase III. Actually, we have, I think, approximately 60 centers active in Greater China, participating in our global phase III. The big advantage to work locally with them is that they have, of course, a great clinical team, but also a very good connection with the regulatory authorities. The planning of Sino Biopharm is to file in China more or less at the same time as our filing in the U.S. We are planning to file in the first half of 2027, and Sino Biopharm has the same objective for China. I think if you take a step back, it is an incredible opportunity because first, China is, of course, a very large market.
It's unknown, but the prevalence of MASH is very high in China as well. If you look at who is present, semaglutide is running a phase III, was run the phase III, but Madrigal and the other actors, such as Akero or 89bio, are totally absent from the Chinese market. Lani could be the first oral drug approved in this large market. With a partner like Sino Biopharm, that is one of the leading pharma in China, a great opportunity for us. As typical in this agreement, we're eligible to milestone and to royalties. Japan is a bit of a different strategy. We have created a JV. The company is called Hepalys. We are shareholders. We are running a phase one in Japanese patients, and we're waiting for the phase III results to launch a specific development in patients with MASH in Japan.
Brilliant. Speaking on Japan, could you remind us of the deal with Hepalys, what the terms are there, and just speak a bit more on the JV?
Yeah. We are shareholders of the JV. We are entitled to milestone and royalties. On top of that, there is a possibility for Inventiva or an acquirer of Inventiva in the event of an M&A to get back the rights of lanifibranor or to acquire the JV at predetermined values.
Got it. Thank you. Last year, enrollment in the phase III study was temporarily paused due to a treatment-related suspected unexpected serious adverse reaction in one patient or a SUSAR. We understand this patient had raised suspicion of autoimmune hepatitis. What modifications did you make to the protocol to ensure that going forward, liver toxicity should not be a concern? How often do you perform liver function tests on patients in the study?
Yeah. Thank you for this question. Yes, we had a case of autoimmune hepatitis in the study that resolved, and the patient is doing very well. We have implemented a few things at inclusion criteria, mostly measuring the level of autoimmune antibodies to make sure that we control or we exclude patients that are at risk of having autoimmune hepatitis across our study. I think this worked very well. Today, everything is under control. We are monitoring liver enzymes every four weeks, which is what is, I would say, done in other studies as well. Yeah, so far, so good. We have very good safety in terms of liver safety. I think this is not necessarily the case in other studies.
For example, for the resmetirom on phase III, I think there were 11 cases of ISLO, one in the placebo arm and 10 in the treated arm. Some of them due to autoimmune hepatitis. It is clear that this case may be frequent in the NASH population, and we managed to exclude those patients at risk with this implementation of autoimmune antibodies measures at entry of the trial.
We had the DSMB in February of this year. They unblinded, and the DSMB looked at 1,200 patients, and their conclusion was to continue the trial without modification to the protocol. Nothing to report during that meeting.
Okay. Great. Following from that, what's been the feedback from KOLs on lani's efficacy and safety profile?
You know the safety profile of lani is very good. We don't see much. Every time we tested the profile of lani, of course, when you do that, like an authority, you look at the benefit and the risk. The return was always very positive. What really strikes out is the antifibrotic activity. This is really what the pathologists, GI or endocrinologists focus on. They clearly see in lani a drug that could treat many of their patients, really address their fibrosis, and for endocrinologists also address the type-2 diabetes issue of their patients.
Brilliant. Thank you. Now moving on to sort of financial. Last October, you secured EUR 348 million in a multi-charge equity financing program. These charges are contingent on meeting certain conditions. Last month, you received EUR 116 million, if I'm not mistaken, upon randomization of your last patient in the main cohort of the study ahead of 30th April, as well as achieving a study dropout rate of under 30% before week 72. However, you've acknowledged this previously. Even with this cash injection, your runway projection is 3Q 2026, which is quite tight to reach your headline data in 2H 2026. Could you just run us through the current options on the table to raise additional funds, and when do you anticipate sort of executing on this?
I think the importance is to highlight the size of this raise and also the quality of the investor. It was led by NEA, BVF, and Samsara. Other m ajor investor, were all long top quality investors, Eventide , Invus, and Sofinnova. Great support that I think shows the quality of the data because this was done after extensive due diligence. We also are eligible to a third tranche soon after the publication of the data, an additional EUR 125 million. As you said, we have guided for cash runway through Q3 of 2026.
From now to Q3 and to data, there are several options that we have to either extend our cash runway or reduce our spend to make sure we reach the data, which, as I said, are expected in the second half of 2026 with last patient, last visit that is expected in August of 2026.
Got it. Outside of an outright acquisition of the company, a partnership would be probably the most ideal scenario for cash. Are you currently in conversation with potential partners? At what point during lani's development do you think a partner would step in to see the phase III data? I guess following off the back of that, would you be open to an outright acquisition of the company?
Of course, I cannot comment on any potential discussion we have with Strategic. There is, of course, an interest by big pharma in this indication as shown by the recent acquisition by GSK of Boston Pharmaceuticals. For us, the focus is on delivering quality data. It's also following the example of Madrigal because they've shown that the biotech of our size, because when you look at Madrigal at the same time of development as us, they were more or less the same size. We have 60-70 people now at Inventiva. We're looking at Madrigal, and they are successfully launching resmetirom, showing that a company like us can launch a drug like lanifibranor. If big pharma knocks on the door, we will listen and see what is the best option for our shareholders and employees.
Brilliant. Is there anything else that we have not spoken about that you think is important to touch on and just sort of speak to investors about?
Yeah. I think the most important, I think, is to realize that with lanifibranor, we have a great drug that I think can address a large chunk of the MASH population and what you need to address in this patient. This MASH patient has metabolic issues, and we have shown that lani can address these issues. Many of them are diabetics or prediabetics, and lani is a potent insulin sensitizer, and that's a key differentiator. This patient needs antifibrotic activities, and they need an antifibrotic drug that can act quickly. Once again, lani was the first drug to show that in six months, you can resolve NASH and you can reduce fibrosis. Finally, of course, GLP-1 will be largely used in this population because most of them are overweight, and lani is a perfect match to be combined with a GLP-1.
I think we have a drug that ticks all the boxes of what you need to treat MASH patients. Given we have fully recruited the trial, that we are funded, and that we have data coming up in 2026, Inventiva store is quite attractive for investors, strategics, and most important, lani is a great drug that will reach the market and treat MASH patients.
Brilliant. Thank you so much. Are there any questions? All right. I'll leave it there. Thank you so much.
Thank you.