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

Good afternoon, ladies and gentlemen, and thank you for standing by. Welcome to today's Inventiva's Full Year 2020 Results Presentation. [Operator Instructions] I must also advise you meeting is being recorded today on Friday, the 5th of March 2021. And may I hand the meeting over to your host today, Frédéric Cren, Chairman, CEO and Co-Founder of Inventiva. Please go ahead, sir.

Thank you, operator, and welcome, everybody. Good morning, and good afternoon. And I'm very pleased to launch this 2020 financial webcast. As you know, 2020 has been a fantastic year for Inventiva. I'll be doing some -- with my colleagues some forward-looking statements, so please look at the regulatory documentation that is available on our website. I'll be sharing the floor today with Pierre, our CFO and Co-Founder with me; with Michael Cooreman, our new CMO, he's been dialing from the U.S.; and Jean that will give us an overview of the figures. So let me go immediately in the core of the presentation and just give you some highlights of this fantastic 2020. So if we start with lani, our lead program in NASH, I don't want to spend too much time detailing the fantastic achievement that have been done in 2020. Pierre will go through the result of NATIVE that led us to obtain breakthrough designation and to very positive meetings with both FDA and EMA. And Michael will run you through the NATIVE 3 trial that is starting in a few weeks. I would -- nevertheless, would like to point out a very important news that we got from FDA very recently, it's a couple of days old. And that concerns the fact that the FDA has confirmed that the toxicology package is complete and acceptable to support NDA filing. This is another step in derisking the lanifibranor and another step towards a potential commercialization of the product in NASH. If we turn to odiparcil in MPS, as you know, we were truly fond of this program, of the clinical data we published late 2019. We also obtained, in 2020, Fast Track designation from FDA. But you've been following that, and you know that we have decided to focus our resources, both financially and human, in NASH. And decided to look for a new home for odiparcil to continue the program. This evaluation of the strategic option is currently ongoing, and we are confident we'll be able to update all of you in 2021 about the future of this comp. Looking to ABBV-157, actually, I should say cedirogant. This is a new name that has been awarded by the WHO, following the completion by AbbVie on the International Nonproprietary Name. We're extremely excited by this program. We have seen regularly AbbVie giving updates at JPM or during the annual webcast. And it's great to see that when they speak about early promising compound, they often mention cedirogant. So that's great, and we're looking to obtain the result, the clinical proof-of-concept in Q2 2021, a slight delay compared to Q1, as previously announced, due to COVID situation. On the news, of course, you know that we are actively preparing the launch of the Phase III of lani in NASH. And to do that, we have opened the U.S. subsidiary of Inventiva. It's open and live, and we're building our team there. This is one of the first task of Michael, who has joined us since a couple of months ago, and he's actively building the team. We've also reinforced our KOL network and we're extremely pleased of the collaboration we've established with Dr. Sanyal, who's been instrumental in our discussion with the FDA. Of course, financials also, we've been extremely busy with Jean and the rest of the team to reinforce our position. Several capital increases, several -- also 1 agreement with the French government for EUR 10 million, and especially the IPO in July on the back of the positive data. Now we have a comfortable and strong cash position, ensuring a cash runway through Q4 2022. Let me now turn to lani and to Pierre, who will go through the product, and Michael will then present you the NATIVE Phase III.

Yes. Thank you, Frédéric. So as you all know, lanifibranor is the only pan-PPAR agonist in clinical development for the indication, treatment of NASH, and improvement of liver fibrosis. You know that it has an unprecedented chemical structure and unprecedented pharmacological profile. It's pan-PPAR agonist with moderate and well-balanced activity across the 3 PPAR isoforms, non-TZD and non-fibrate. Recently, a few months ago, we obtained Breakthrough Therapy and Fast Track designations that was granted by FDA. When we turn on the next slide. So preclinical investigations have shown that most, if not all, of the pathological features of NASH can be addressed by lanifibranor through activation of several PPAR isoforms. So for example, the PPAR delta and gamma activation leads to a strong antifibrotic activity. The 3 isoforms are involved in the inhibition of inflammation and ballooning-induced lanifibranor, while the alpha and gamma isoform are involved in the reduction of anti-hepatic vascular resistance and portal pressure, which was observed in animal models of cirrhosis and the data has been published recently. Next slide. So in nonclinical tox studies with lanifibranor, a favorable tolerability profile was observed. This profile differentiated from what was previously reported by single or dual PPAR agonist from different chemical classes. And as mentioned by Frédéric, it's important to note today that recently FDA confirmed that this nonclinical tox package is complete and acceptable to support the filing of a New Drug Application. Next slide, please. So following the successful outcome of the NATIVE Phase IIb trial with lanifibranor in NASH, we have been, this last month, very busy discussing with regulatory authorities, FDA and EMA, to finalize the Phase III design. And Michael Cooreman, our CMO, will present the details and the key milestones of this study. To complete the clinical development plan of lanifibranor in NASH and besides the study in collaboration with Professor Cusi evaluating the effect of lanifibranor on liver, insulin resistance in diabetic patients with NAFLD. We are also working on the preparation of additional profiling studies evaluating, for example, the potential of lanifibranor in NASH-compensated cirrhosis. And this on the positive of -- on the back of this positive clinical finding. And we're also working on the -- investigating the potential of lanifibranor to be used in combination with other therapies to further strengthen its value proposition. Next slide. So before going into the details of the Phase III trial design, let me recap on the outcome of the Phase IIb NATIVE trial. As you all know, this study investigated the efficacy and safety of lanifibranor 800 and 1,200 milligram once daily in noncirrhotic NASH patients. Next slide, please. In the ITT population, all histological endpoints were met. The high dose had a significant effect on the improvement of fibrosis by at least 1 stage and no worsening of NASH. And both doses had a significant effect on resolution of NASH, and no worsening of fibrosis, as well as on the composite endpoint of resolution of NASH and improvement in fibrosis, where a responder is defined as a patient showing both NASH resolution and improvement in fibrosis. And for this composite endpoint, compared to placebo, we observed a 3 and 4x -- well, observed 3 and 4x more responders in the low and high dose group, respectively. Next slide. And if we actually focused on the F2-F3 subpopulation which represented 76% of the patients in NATIVE 2 and will be the target population investigated in NATIVE 3, we can see that the overall picture is similar with a statistically significant effect of the 2 doses on NASH resolution and no worsening of fibrosis as well as on the composite endpoint, and a statistically significant effect of the high dose on the improvement of fibrosis with no worsening of NASH. So consistent with this histological data and the mechanism of action of lanifibranor, we also observed an effect on several circulating biomarkers that are relevant of NASH pathophysiology, as exemplified here on fibrosis, apoptosis and inflammation. The native biomarker database actually includes data on more than 80 circulating biomarkers. And this database will be further analyzed by Professor Jérôme Boursier and his team in order to identify, one, several or a composite score of biomarkers linked to lanifibranor histological response. And this to be considered for use as the surrogate efficacy endpoint reasonably likely to predict histological improvement in the commercial setting. The selected biomarkers or the biomarker composite score would then be validated during the upcoming NATIVE 3 trial. Next slide, please. So additional data from a NATIVE Phase IIb trial on metabolic parameters of patients with NASH are following. So first, we see here the effect of lanifibranor on liver enzymes. As you recall, we had quite a quick normalization of ALT, AST and gamma-GT that was sustained all over the study duration. Next slide. Consistent with the PPAR-alpha and delta activation by lanifibranor, we also observed a positive effect on the lipid profile with an increase in HDL cholesterol, which achieved maximal effect already at week 4 as well as a sustained decrease of triglycerides. And there were no signs at all in the LDL cholesterol in those patients. Regarding glycemic control, so this is in diabetic patients, lanifibranor further improved glycemic control with a decrease of glycated hemoglobin by minus 0.5% that was already achieved by week 14 post treatment initiation. And this, of course, is the consequence of improved insulin sensitivity by lanifibranor. Next slide. So in terms of safety, lanifibranor continues to show a favorable safety profile with dropouts due to AE well balanced between those 3 arms. There was a modest body weight increase, which is a consequence of insulin sensitization, and I'll give you more details on that in the forthcoming slide. And there were 2 adverse events of peripheral edema that were considered drug related in each lanifibranor dose group. Next slide. So regarding SAEs, when we -- when excluding those linked to the biopsy procedure, we actually end up with 3 SAEs in the placebo group, 2 in the low dose and 4 in the high-dose group of lanifibranor, respectively. So peripheral edema. Those were not flagged as a concern by study investigators for several reasons before -- because they were limited, transient, mostly mild, and the majority were considered unrelated and not requiring specific treatment. And you can find the details of this analysis on this slide. Regarding body weight gain, so the increase is consistent with insulin-sensitizing pharmacology. There is scientific literature available on the topic, which indicates that the weight increase is not due to water retention. And finally, based in our previous study in systemic cirrhosis patients where lanifibranor was administered during 1 year, we observed that the weight gain was plateauing after 24 weeks of treatment. Next slide. So this data actually comes from work by Gastaldelli and Cusi in NASH patients, where we can see that insulin sensitization by pioglitazone leads to an increase in fat deposition in subcutaneous adipocyte, while decreasing visceral and ectopic fat deposition here exemplified in the liver. This redistribution of fat actually comes with an improvement of NASH, as shown by a decrease in NAS score. So this weight increase actually signs a shift to a healthier metabolic status. Finally, we believe that pan-PPR activation in NASH patients could lead to a reduction of the cardiovascular risk. And this is based again on several studies published with pioglitazone. For example, the PROactive study, which included more than 5,000 type 2 diabetic patients, where pio led to a significant reduction of cardiovascular deaths, nonfatal myocardial infarction and stroke. And this reduction in death, MI and stroke was also reported in a meta-analysis of 19 randomized controlled trials, including more than 16,000 patients with diabetes. Finally, in the IRIS study, which was performed in close to 4,000 nondiabetic patients with recent ischemic stroke or transient ischemic attack, pioglitazone reduced fatal and nonfatal stroke as well as myocardial infarction by 26%. And regarding increased risk of heart failure, there are many studies listed here showing no increase in heart failure with pioglitazone in patients without already preexisting or suspected heart failure. The next slide is to conclude this part. The NATIVE Phase IIb trial data has indicated that lanifibranor has the potential to address most, if not all, features of NASH in a safe and efficacious manner, justifying its Breakthrough Therapy designation and the start of NATIVE 3, our registration study in non-cirrhotic NASH patients. And with that, I will leave the floor to Michael, who will present the design of the Phase III trial. Thank you.

Thank you, Pierre. So on slide -- next slide, the Phase III trial is meant to achieve registration for the indication of NASH with F2-F3 fibrosis. Next slide. This is a large study. It's a randomized, double-blind, placebo-controlled, multicenter, of course, Phase III study, evaluating the long-term efficacy and the safety of lanifibranor in adult patients with NASH and liver fibrosis. The study consists of 2 parts. Part 1 is -- consists of a treatment duration of 72 weeks, so 1.5 years. And Part 2 is the extension period, which is defined by events or end of the study. So clinical outcomes essentially. Inclusion is based on inclusion criteria, of course, and critical use of screening biopsy to define the activity of NASH and fibrosis grade and then patients are randomized into 3 arms; placebo, lanifibranor 800 milligram once daily, lanifibranor 1,200 milligrams once daily. And we have 2 doses in the Phase III study. Based on the results of the Phase II NATIVE study, 2 doses were shown to be efficacious. So the inclusion criteria are based on the SAF score. This is a score that is focusing on the activity of NASH and fibrosis, which is the other criteria that are important for treatment of NASH. And as I mentioned, randomization is 1:1:1. So it's equal randomization, the 3 groups. And patients are stratified according to whether or not they have type 2 diabetes. And as I mentioned, patients are F2-F3 fibrosis. The study will be conducted globally. At least 1/3 of the patients roughly will be from the United States. The study is powered for 90% power and that led us to -- or led us to a decision to a sample size calculation of circa 900 patients for part one. Histology. Liver histology is important for the inclusion and evaluation of efficacy. So there's a central biopsy review, which is done by 2 expert pathologists in this team. Next slide, please. Next slide. So yes, we had it. Part 1 is designed to obtain accelerated approval in the United States, according to Subpart H and conditional approval with the EMA in the European Union. Primary endpoint is at week 72 on those -- in those 900 patients. And it's a composite endpoint of patients having both resolution of NASH and fibrosis improvement of at least 1 stage. And that is very important as it differentiates lanifibranor from other compounds. Key secondary endpoints are NASH resolution and no worsening of fibrosis, and improvement of fibrosis and no worsening of NASH, corresponding to the endpoints in the guidances of the FDA and EMA. We have secondary endpoints. The most important ones, secondary and exploratory endpoints, are listed here. Glycemic parameters at -- during the study at week 12 and week 24 in patients who have type 2 diabetes who are not well controlled. So the proportion of patients who have that HbA1c back to normal. Composite endpoint of both NASH resolution and fibrosis improvement in type 2 diabetes patients. NASH goes along as a metabolic disease with chronic kidney disease -- with a risk for chronic kidney disease. So an effect on renal function is an endpoint as well. And then, of course, the reduction of cardiovascular risk, including the MACE score, or the major adverse cardiovascular events, which include nonfatal myocardial infarction, nonfatal stroke, cardiovascular death and hospitalization for unstable angina. And we have also included quality of life evaluations. So next slide, please. Part 2 is the extension period -- just waiting for the slide, yes. This is aimed -- or the objective is to obtain full approval in the United States and European Union. Part 2 is -- the objective is to show an outcome benefit in addition to the histological improvement, which is a surrogate endpoint. The key endpoints in Part 2 are based on clinical events in a total of circa 2,000 patients and that sample size is calculated on the expected clinical events. These include histological progression to cirrhosis. We include patients with F2-F3, so progression to F4. All cause mortality and then hepatic decompensation events, which is relevant to clinical outcome. These include hepatic encephalopathy; variceal bleeding as a manifestation of portal hypertension; ascites, new onset ascites during treatment and other complications of ascites such as spontaneous bacterial peritonitis; worsening of liver function, as measured with a MELD score, an increase of 15 or more; or liver transplantation. Those are the outcome measures for Part 2. And the trial ended is defined by a defined number of clinical events, which allows to the -- detect and effect size between active and placebo arms that is clinically significant. The timing of the final biopsy, which will evaluate the histological progression of the disease, is based on -- is done on a per patient basis. And we have screening tools which include imaging, FibroScan, that give us a revaluation on the progression to cirrhosis. So it's based on noninvasive testing. Or if there is no such progression on these noninvasive tests at the time the trial ends. Next slide, please. Next slide, yes. The composite endpoint which combines resolution of NASH and fibrosis improvement differentiates from other compounds which are in advanced clinical development in NASH. And this primary endpoint addresses the major pathways of the disease, upstream metabolic inflammation and downstream fibrosis. So achieving both of these serological outcomes reflects a stronger impact on disease modification compared with improvement in either the steatohepatitis alone or fibrosis alone. If met, a label for the treatment of NASH and the improvement of liver fibrosis of both these endpoints in adult patients with noncirrhotic NASH will be requested. Just a couple of samples here on how lanifibranor differentiates with -- from 2 other compounds in Phase III currently, obeticholic acid and the thyroid beta receptor agonist, Resmetirom. So we look at resolution of NASH and improvement of fibrosis as the primary efficacy endpoint for obeticholic acid. That was a secondary endpoint, and data has been made public on an interim analysis on this endpoint. Fibrosis improvement and no worsening of NASH and NASH resolution and no worsening of fibrosis are the components of the composite endpoint. They are, in our case, key secondary endpoints, and they are primary for obeticholic acid and Resmetirom. So again, lanifibranor is the only compound here that looks really at resolution of NASH and improvement of fibrosis. It's a primary efficacy readout. Looking at patients who have type 2 diabetes. So NASH resolution and fibrosis improvement in diabetic patients is a secondary endpoint in our study. And given the fact that roughly 50% of patients with NASH have diabetes, showing that the efficacy of lanifibranor is comparable with non-diabetes patients is also a differentiating factor. Next slide. The study is conducted globally. And this slide shows you the geographic areas where the study will be conducted. So North America, South and Middle America, Mexico and South America. Several countries in Europe, South Africa and Australia are the countries where the total of 300 sites will be included in the study based on experienced clinical research sites. Next slide. Next slide is an overview of the time lines. It's already mentioned by Frédéric at the beginning. So we'll start this year, in summer, the first patient first visit will be achieved. That's what we are planning. And it's -- planning is on track. In the end of -- towards the end of 2022, so the second half will have the last patient first visit for Part 1, which -- that's our goal, which should enable us to have last patient last visit at the beginning of 2024. And headline results of Part 1, which are the basis for the submission for accelerated approval and conditional approvals, respectively, will be available in the second half of 2024. So next slide. This was on the summary of the -- of our plans with regard to the pivotal study, aiming for approval of lanifibranor in noncirrhotic NASH patients with fibrosis. A couple of other studies are being planned and considered. And one is actually an ongoing study in collaboration with Dr. Ken Cusi at University of Florida in Gainesville, Florida. This study evaluates the safety, efficacy, mechanism of action of lanifibranor in patients with type 2 diabetes and NAFLD, nonalcoholic fatty liver disease. It's a profiling study, which we mean it will provide valuable information on how lanifibranor works in patients with metabolic disease and fatty liver disease and what the therapeutic benefits are based on a large battery of metabolic markers -- biomarkers. The main objective is to show a beneficial therapeutic effect of lanifibranor on intrahepatic triglycerides. And as I mentioned, multiple additional markers of dysmetabolism in patients who have type 2 diabetes associated with NAFLD. There are -- the study design. There are 34 patients, which are randomized 1:1 to either lanifibranor 800 milligrams a day or placebo. Patients with diabetes which is well controlled, but HbA1C is up to 9.5%, so below -- between 6% and 9.5%. They have to have hepatic steatosis in this study defined as 10% or more. Liver fat measured by magnetic resonance spectroscopy, MRS. And the sample size is based on an assumed 35% reduction of intrahepatic triglycerides. There is also a control arm of 10 matched healthy subjects. Now these healthy subjects will not receive drug or placebo. They are actually -- they will have the noninvasive tests or the tests to measure the metabolic and -- the metabolic parameters through blood tests and imaging investigations. So it's a Phase II profiling study in NASH, type 2 diabetes patients to demonstrate the efficacy of lanifibranor on biomarkers of metabolism relevant to NASH -- NAFLD/NASH and, therefore, will be an important supported study. Next slide. Primary efficacy endpoint is a decrease of intrahepatic triglycerides from baseline to end of therapy, measured by MRS, as I mentioned. Responders defined as a patient who has a 30% or more reduction of hepatic fat from baseline, and there are -- and a proportion of patients having an intrahepatic triglyceride reduction to less than 5% at the end of treatment, week 24, that's considered NAFLD resolution. A lot of secondary endpoints to gain information about how lanifibranor works. Metabolic endpoints includes insulin sensitivity, gluconeogenesis, de novo lipogenesis, glycemia control and then, of course, on the lipid profile. There are -- several of these patients, given the fact that they have type 2 diabetes and NAFLD, will have liver fibrosis. So we'll also look at blood and imaging markers of liver fibrosis. And the noninvasive measurements of changes in fibrosis include a panel of plasma markers of fibrosis and then state-of-the-art imaging methods including ultrasound elastography, FibroScan; magnetic resonance elastography, MRE; and also a multiparametric MRI protocol to quantify fibrosis. Status and update on where we are in March 2021. As it is in 2020, there has been some delay in clinical research everywhere and of course no different in University of Florida. So 2020, the COVID epidemic has had an impact. Towards the end of 2020, however, clinical research activities have restarted again and are now really going back to normal levels as we recover from the epidemic. The site in Florida is actively recruiting -- screening and recruiting and has some network of several other institutions which help in screening patients. But given the impact of COVID-19, the study results are not expected in the first half of 2022 versus 2021 as originally planned. Next slide. Within the large indication of NASH, we are also preparing for additional studies and potentially additional indications. And one is, of course, those patients who do have cirrhosis, specifically compensated cirrhosis, which is a large unmet medical need. So we have data that provides a strong rationale for the study of lanifibranor in patients who have compensated cirrhosis based on in vivo data from the thiocetamide rodent model of liver cirrhosis, which is an established animal model for liver cirrhosis and decompensation of cirrhosis. And of course, there is a biology about the -- biology of the hepatic stellate cell and the liver endothelial cells where PPAR signaling plays a role also in the vascular aspects of cirrhosis and in the fibrosis aspects. So promising preclinical data are the basis for the rationale for a clinical study. In the TAA model, lanifibranor has shown to improve, quite importantly, portal hypertension through a reduction in intrahepatic vascular resistance and to have a significant effect on fibrosis markers, significant improvement in hepatic -- sorry, hepatic stellate cell phenotype and activation of hepatic stellate cells also in -- from in vitro data. In this animal model -- TAA animal model, there is also a beneficial effect, which is on the liver sinusoidal endothelial cells. And correspondingly, I think that's an effect of both the effects on fibrosis and the vascular aspects of lanifibranor, a reduction in ascites in a number of animals which had ascites. This data supports the TAA data of TAA-induced cirrhosis in rats that have been published in Journal of Hepatology in the December issue of 2020. So the clinical options to evaluate lanifibranor in patients with compensated F4 cirrhosis are currently being discussed and reviewed. Next slide, please. Lanifibranor has to be -- has the potential to be used in combination with other therapies to strengthen its value proposition. Combination in complex disease as NASH is an approach that is seen as a very valid way to improve the efficacy of treatments and several compounds are being combined. So in the case of lanifibranor, the potential benefits of combination use include complementary effects on the disease -- on the multistep disease of NASH given the fact that the dysregulation of metabolism, insulin resistance, inflammation, fibrosis all play a role, and there's a lot of opportunity to combine with other approaches that will increase the therapeutic efficacy further with regard to the histological endpoints, NASH resolution and fibrosis staging. So this is with regard to improving further the efficacy. At the same time, selection of the right combination and right compound for combination can manage the weight increase that has been seen with lanifibranor, the modest weight increase which Pierre mentioned, which is metabolically healthy, but it is still perceived as weight increase. So that can be managed with -- in a combination setting. And of course, the combination can generate new IP protection, and that's an additional benefit. The compounds that are attractive for combination therapy with lanifibranor include GLP-1 agonist, SGLT2 inhibitors and ACC inhibitors. So on the next slide, details on this combination options to illustrate that this is supported by data that are available from the type 2 diabetes field, where PPAR agonists have been approved to treatment. It's been shown that when a PPAR agonist is combined with a GLP-1 agonist, that the weight gain, as you can see on the upper left slide, can be compensated. In fact, you see a net weight gain -- weight loss with -- in the combination with the SGLT2 (sic) [ GLP-1 ] receptor agonist. Similarly, when PPR agonist, and in this case the one used is pioglitazone, is combined with an SGLT2 inhibitor, the weight gain on the right side that you see with the PPAR agonist is actually compensated for by the addition of an SGLT2 inhibitor. And actually, in net, these patients have weight loss, and that's been shown in several studies -- in total several studies with different SGLT2 inhibitors. In addition to the beneficial tolerability profile, this combination between -- the combination of a PPAR agonist and an SGLT2 inhibitor has also shown to be further improving the efficacy of these compounds. With regard to the PPAR and the ACC in combination, that too, there's a rationale to compensate for the modest weight gain. And there is also, based on animal data that we have obtained, the expected therapeutic benefit. You see here the results of rodent model where lanifibranor is combined with firsocostat. And there is some -- an increased effect on the NAS score when these 2 compounds are combined compared to each compound alone. So that's for the combination therapy. And that is the end of my presentation, so I'll give it back to Pierre -- to Frédéric for the AbbVie collaboration.

Yes. Thank you, Michael. Very briefly on the AbbVie collaboration. I would say there are 2 key messages. The first one is that AbbVie has confirmed that the cedirogant proof of clinical trial -- POC is expected in Q2, slight delay versus Q1 due to COVID. The second point, once again, is that this trial is really important, and saying that it includes several efficacy biomarkers and the measurement of PASI score at week 4, which will give us the very valuable information in the pursuit of development of this -- of cedirogant. So with that, I'll hand the floor to Jean for a quick update on the financing position.

Good afternoon, everyone. Yes, as said in the intro, the year from the financial perspective has been a key and exciting year. We entered on the NASDAQ global market early July 2020 and just after -- and thanks to the positive results of the NATIVE Phase II study. We have reinforced our shareholders base with still U.S. and European shareholders of reference with now a balance of 60% European shareholders versus 40% American. So therefore, we have consolidated our cash position at EUR 113 million. And this situation allows us to operate through Q4 2022. We have, in 1 year, funded EUR 120 million, of which, of course, the EUR 95 million on the NASDAQ, EUR 15 million in Q1 '20 through an increase of capital and a EUR 10 million guaranteed loan from the French state, which leaves, by the way, a low level of indebtedness in Inventiva with less than 10% versus equity. We have, of course, in this momentum, extended the analyst coverage, as you can see. And in terms of market value, we are at less than EUR 500 million, EUR 471 million, and $538 million. We still know that there is a gap to close with our peers. Next slide, Frédéric, quick view on the profit and loss accounts. So it's quite straightforward. We still manage the expenses, they are under control. We had not expected revenues in 2020. Just to remind, last year, we got a milestone from AbbVie. So we hope next one in the future years. And we also had a revenue from Boehringer Ingelheim with the end of the collaboration last year. The other income still made up of the R&D French credits increasing a bit. We took benefit of a very interesting change in the regulation following a jurisprudence from the Conseil d'État with regards to the subcontracting studies and eligible expenses, and it's good for the company also. The key information is the decrease in R&D expenses at EUR 23.7 million. Remember that last year, we still had the sclerodermic systemic study. And we had also the full research population. While in 2020, following the restructuring plan implemented after the halt of SSc last year, we have, in 2020, the full effect of the savings in 2020 following the plan. And we had not started full boost, I may say, the Phase III expenses because still in construction, but we hope that soon we will increase the expenses and the investments in this Phase III on lanifibranor. Also as a consequence of the NASDAQ transaction, we incurred increased expenses in G&A plus 40% and this is -- this was completely expected. Also, this is now due to the first year of dual listing compliance expenses, in particular, as everybody knows, in insurance, audit legal fees to fit with the requirements from this market. And the cash position. Again, I talked about it, with a comfortable cash position to start this very exciting 2021 year with the Phase III on lanifibranor. Should you have, obviously, as usual, any questions, I will be pleased to answer. And let the -- I will let the conclusion to Frédéric.

Yes, Jean. So before we move to Q&A, just one last slide on the next milestone. When we talk about lanifibranor, of course, we're working day and night on the launch of the NATIVE 3 study. First site initiation Q2 of this year with the immediate start of patient screening and first patient for the visit plan for Q3. Odiparcil, we are optimistic and comfortable in saying that we'll give an update on the strategy for odiparcil moving forward in 2021. And concerning our exciting partnership with AbbVie for cedirogant, we are looking forward to the AbbVie achieving clinical proof-of-concept in the current trial in psoriasis. So this concludes this presentation, and let's now move to the Q&A session.

[Operator Instructions] And your first question is from the line of Etzer Darout from Guggenheim.

Great. Thanks for today's update. Just a couple of questions for me. Just wanted to know if you could talk a little bit about the time lines a bit? What it assumes about any sort of potential delays with COVID, which we've seen sort of affect some other trials? And just overall kind of the pushes and pulls you assume for your time lines? And then, if you could, a little bit more color on what potential options you're exploring for compensated cirrhosis with lani and when we could hear about them? And maybe sort of what proportion of F4 patients do compensated cirrhosis patients sort of represent?

Etzer, thanks for this question. So the first one concerning the COVID impact on the trial. Of course, this has been taken into account. Nevertheless, we are all aware that the situation is moving rapidly over the last weeks and months positively due to the beginning of the vaccination. So all of this is taken into account. We have also selected one of the few global CRO that are experienced in development of the global Phase III NASH. They have put in place many, I would say, tools and approaches to facilitate the monitoring of patients. Nevertheless, it's sure that we need the patient to feel comfortable in getting back to the hospital. So we need to continue on the good trend that we have seen over the past weeks. So then concerning the F4 cirrhotic patients, maybe I'll turn to Michael or -- yes, I'll turn to Michael, and maybe he can address that.

Thank you, Frédéric. And yes, I think the -- on COVID-19, in addition to the point that Frédéric made, there has been also an adaptation of how clinical research is done, and accepting more daily health visits, et cetera, lots of publications about that. So we are actually confident that 2021 will get to a normalization of clinical research activities. F4, we aim to study lanifibranor in patients with compensated cirrhosis, who have normal liver function. And as -- and that's corresponding to the [ focus ] in this field today. So the clinical outcome -- the relevant clinical outcomes are on patients developing signs of decompensation, which are clinical signs such as ascites or worsening of liver function which can be measured with the MELD score, for example, bilirubin or other value measures. So that's the proportion of patients that we are aiming for. There's a population of patients for which there is currently no treatment unless -- not so much clinical research activity, but represent a very high medical need.

Your next question is from the line of Lucy Codrington of Jefferies.

Just a couple from me. So just following up on the Phase III time lines. I just want to be clear, is there any room for an improvement on these? Or is that -- is the time line to be given already a blue sky scenario for the certain trial? And secondly, I just wanted to confirm that the cash run rate doesn't include any anticipated milestones within that. And then finally, just on the central histopathology review in the Phase III, is that -- can you remind me, is that standard practice in NASH Phase III trials? Or is that something that just you guys are doing?

Okay. So on the milestone, Lucy, so we're always extremely prudent. So we take into account all costs, and we never take into account any potential milestones. So if we receive a milestone from AbbVie or any other collaboration, that would be an upside. Blue Sky, I know this is, I would say, for the Phase III, these are the realistic, what we believe is achievable. We have been, I think, working with the right CRO. We have selected the right number of sites. And we've been going through, I would say, reinforcing our team at all levels. Of course, clinical operations, both in Europe and in the U.S., we're increasing the contracting team, we're increasing the regulatory team. So we feel confident as of today that we can achieve this might -- this -- the timing as we laid them out in the -- during the presentation. And concerning your question on the pathology approach, this was extensively discussed with the FDA, and I'll turn it to Pierre, he can explain that more in depth.

Yes, sure. Well, I will turn it to Michael afterwards, but it's true that we had -- this was a topic of discussion with FDA. And I think that we actually made the proposal and that was accepted and makes a lot of sense and would really guarantee us a good quality of the reading of the biopsies. But Michael, if you want to add on that, please?

Sure. But I can only confirm, yes, it's been -- our procedure is discussed with and agreed with by the FDA. So that's, I think, a relevant point. Histological evaluation of the therapeutic efficacy in NASH is a standard approach since the effect on fibrosis, specifically, has been shown to be -- or I would put it this way, fibrosis progression is an accepted surrogate marker for clinical endpoints as the most relevant element that determines the prognosis of patients. And the NASH activity reflects the necroinflammatory injury of the liver. So the combination of both reflects the entire spectrum of the disease biology of NASH. So this histological evaluation is accepted as the surrogate endpoint. And on procedure, the way we do it using 2 expert pathologists, by which we mean pathologists who have been -- who are recognized as really true experts in this field, one in -- on each side of the Atlantic. That's an accepted approach by the FDA following our discussions with the FDA.

Your next question is from the line of Derek Archila of Stifel.

This is Jacques, on for Derek. First, on the cedirogant program. How do you view this program? And are you looking to develop the drug in plaque psoriasis? Or are you looking at plaque psoriasis as more of a proof-of-concept? and if so, where are you looking to take the drug forward? And then also, could you help us understand, I guess, how it could be differentiated from others in development?

So from -- first of all, from a contractual point of view, the development and strategic orientation is in the hand of AbbVie. They will decide to -- where to position and how to develop this drug. It is actually -- we view that as a great opportunity for us because AbbVie has been -- has shown in the past, great ability to be able to develop compounds in several indications in the autoimmune field. So to your question, there is clearly a potential for cedirogant in moderate-to-severe psoriasis. Given its mechanism of action, it's actually eligible to other indications such as IBD, Crohn's, RA and others. Then to the last question about how we differentiate? I think the easiest way to say that is -- just to summarize, the target product profile of cedirogant [ in Humira in a pill ]. So clearly, due to the RhoGAM mechanism of controlling IL-17 expression, we clearly think that cedirogant has a potential and the efficacy of biologics, but with a great advantage of being an oral once-daily pill. And also, we expect higher safety due to a shorter half-life.

Your next question is from the line of Lenny Steenhuyse of KBC.

Pierre earlier mentioned, of course, an interest to explore lani's broader applicability, so both in the compensated cirrhosis setting and potential combination therapies. I was wondering for the short term, is this mainly something that's being looked at from the preclinical level? Or do you also consider clinical efforts in the relatively short term? And perhaps linking to that, given the current level of funding and budget for -- required for a Phase III NASH trial, are you confident that it's going to have sufficient funding to support such broader development of lanifibranor? And is this included already in your cash runway guidance up to fourth quarter of '22?

So concerning your question about the guidance, no, it does not include any potential clinical development of lani in combination with other drug or in F4 patients. And then to your question, do we -- is this a clinical or a preclinical effort? I would say it's more a clinical effort that we have in mind with exploratory study that could confirm the benefit of combining lani with other antidiabetic drugs or other NASH drug, as explained by Michael in his presentation.

All right. If I may squeeze in a second one, perhaps more on the R&D spending into 2021. I was wondering if we can expect similar level compared to 2020 given the end of the Phase IIb mid last year and likely the follow-on Phase III trial ramping up by mid of this year? Or should we expect some increases as the organization overall increases as well?

Yes. So maybe I'll turn to Jean that can explain how we have modeled the cash runway and the increase or evolution of R&D spending moving forward.

Sure. Yes, as Frédéric said, we have set up this cash runway with the current resources and with the current program on the Phase III for F2-F3. Also with regards to the existing cash position, it allows us to investigate really all the possibility to optimize our cash. And you can imagine that there are some options to work out, and we have the time to optimize those options. So obviously, the costs for '21 and '22 will increase with the Phase III. You know how this kind of study can cost. But the increase in '21, '22 is included in the guidance for the cash for the time being. And we will talk in 2 years from now, but we will probably be able to analyze additional funds that we will be able to get in the next year or so to match this very important Part 1 deadline.

Your next question is from the line of Jean-Jacques from Bryan Garnier.

Jean-Jacques Le Fur from Bryan Garnier. The first one is regarding the biomarkers study you started with Jérôme Boursier. In case if you -- it would be positive, you can be able to identify some of them as really being linked to lanifibranor. Could we think or could you think to try to develop a sort of company-owned diagnostic for lanifibranor? And my second question is regarding the combo you want to study or you have in mind. And particularly the PPAR plus SGLT2 or lani plus SGLT2. Since SGLT2 were not particularly a NASH drug, if I may say, with the clinical results we have in hand right now. So my understanding is that you want to use the SGLT2 to reduce the weight loss or to mitigate the weight increase from lanifibranor. Don't you think if it's the case, I may be wrong, but if it's the case, it could be a very costly option just to control the weight gain or the weight loss?

So maybe for the biomarkers, I'll let Pierre answer, and then we'll -- Michael will answer the part about the rationale for developing lani with SGLT2 without anticipating events are, of course, there are, beyond the potential control of weight, many other benefits that could be expected for such a combination. But maybe, first of all, biomarkers, so maybe Pierre?

Yes. Yes. So to your point -- to your question related to biomarkers. So the objective of the collaboration we have put in place with Jérôme Boursier is that while we're using the NATIVE database of 80 biomarkers and the results obtained in our patients under lanifibranor treatment is to identify where we will perform a multivariate analysis of this database. And that should end up with the identification of the biomarker or several biomarkers or a composite score that would help identify the patients that are currently responding histologically to lanifibranor. Once we have made this hypothesis to this core, we will test this hypothesis during the NATIVE 3 trial to see if we confirm that patients that are improving histologically show also the same biomarker signal. And I think that this is going to be very useful in the commercial setting. It's, of course, well validated for what is discussions on pricing and reimbursement because it's clearly an asset. If you can provide, as you say, a kind of companion diagnostic to be able to monitor -- without doing a biopsy to monitor the responders on the patient -- how the patient responds to the drug in the real life. So that is the overall objective of this work. And Michael, regarding the combination with SGLT2, if you want to reply?

Sure. And thanks for the question. So SGLT2 and lanifibranor indeed provide a good rationale for combination. And I believe it's both -- it's both the efficacy and the weight gain, as was mentioned. So weight gain is perceived as something that is not desirable, even though we know that weight gain with lanifibranor is metabolically healthy in a sense that it's not visceral fat, but less active or not active triglyceride accumulation and subcutaneous fat. Having said that, weight loss, given that -- or a reduction in weight, given that the majority of patients with NASH are overweight, is a benefit of the combination therapy, of course. But there is also the rationale to further improve the efficacy. Lanifibranor is potent on itself, stand-alone treatment, and that's shown by the Phase II study and the data of the Phase II study. Yet, there's still room to improve on efficacy for every pharmacological agent. So that's an additional benefit. Now the SGLT2 inhibitors by themselves as monotherapy for NASH are not very promising. That is true. And the clinical data which had been done in that regard were not strongly supportive, I would say, of developing this kind of compounds for NASH by themselves. But on the other hand, they are in part of a combination treatment where there is complementarity in addressing the underlying disease biology of NASH. There is a good reason to anticipate that there is an improved effect of the combination on markers of insulin resistance, glycemia control, lipid metabolites, where SGLT2 inhibitors do have an effect and which are important upstream mechanisms of NASH. So I do believe that the rationale is both to improve -- to further improve the efficacy as well as to address aspects of weight gain.

Your next question is from the line of Zegbeh Jallah.

Just have 2 quick ones. So the first is the FDA recently noted kind of being interested in prognostic or efficacy biomarkers and kind of welcome data from sponsors to help build evidence around it. So we're just wondering if you can give us a sense of how the EMA might be thinking about that based on some of your recent discussions?

So if I understand your question, Zegbeh, you're interested in understanding the regulatory position on the development of biomarker and now those could replace biopsy, that's the core of your question?

Exactly right.

And the alignment -- I think the alignment between the 2 regulatory agencies, right, FDA and EMA?

Correct.

Yes. So well, I think the EMA is really in the same line of -- same position than FDA. So very supportive of having sponsors, exploring and developing biomarker noninvasive technologies during their Phase III trial in order to optimize the use of those in -- as you said, as diagnostic and prognostic also in the commercial setting. So both agencies are totally aligned. And I think that the program that we have put in place within our NATIVE 3 trial totally matched the expectations of those regulatory agencies.

And then just a quick one. The FDA also expressed an interest in seeing positive effects on lipids, glucose until the cardiovascular benefits you showed in lani was really nice to see. But I was just wondering from a commercial perspective, how differentiating the benefits on cardiovascular risk could be based on some of your recent discussions that you've been having with KOLs?

Well, in terms of differentiation, so I think that if we simply look at the metabolic aspect of the drug, both improving glycemic control and dyslipidemia in NASH patients with diabetes or NASH patients with insulin resistance, which actually would represent close to 100% of the NASH cases, this is clearly a differentiating factor over the current competition. Also I don't think that -- well, besides maybe semaglutide, none of the other competitors are capable of improving glycemic control in those patients. And regarding cardiovascular risk reduction, what I tried to say is that, of course, improving the diabetic condition, improving the dyslipidemic condition is something that would likely go into a reduction of cardiovascular risk. But there is also a past history with pioglitazone that you can refer to where in large studies, like PROactive or like high risk, you actually see a reduction of cardiovascular death, number of myocardial infarction, a reduction of number of strokes. So there is already a history of -- clearly of reduction of cardiovascular risk with compounds activating PPAR gamma like pioglitazone, for example. So altogether, I think that, yes, with pan-PPR activation, there is a probability -- likelihood that we will also see an improvement in the cardiovascular risk in NASH patients.

Looking forward to the Phase III study start. And then can you just lastly let us know if you anticipate providing any regular enrollment updates or any updates on the study progress?

Yes. So usually, what we've been doing in the past is to communicate on key events. So the next review that is important will be the first patient first visit, and we certainly will communicate when we achieve this important milestone.

Your next question is from the line of Michael Morabito from Chardan Markets.

First, I just wanted to know what type of data -- what kind of readouts should we expect when AbbVie reports the initial clinical proof-of-concept data in the second quarter? And secondly, I was just wondering, can you clarify -- you mentioned that patients will be stratified in the Phase III NASH trial based on F2-F3 status. So is this F2 versus F3 or F2 and 3 versus other levels of fibrosis that might enter the study?

So on AbbVie. So the current trial will include several biomarker efficacy, including PASI score at 4 weeks. And these are the, you would say, the measurements that will allow to determine if the drug has achieved or not proof-of-clinical concept. Concerning what level of communication AbbVie will do, this I'm unable to answer because, of course, they are in control of the communication and the data they want to release. Then on your question about the trial, I'll try to give it -- give the answer. I think I know the answer, but if I'm wrong, Michael, please correct me. It's going to be a certification F3 versus F2 with an enrichment of F3 patients, I think we're targeting 55% of F3 patients in the study.

Yes, that is correct.

[Operator Instructions] And we also have a question here from the line of Ed Arce from H.C. Wainwright.

Great. And congrats on all the progress lately. I have 3. First is your surrogate primary endpoint for the Phase III depends on both NASH resolution and fibrosis improvement, really a precedent setting endpoint there. In addition to the NATIVE results, which were clearly robust and positive, what gives you the confidence in lani's activity on fibrosis, especially with regards to work that you've done that shows that lani has not just indirect effects on fibrosis but direct effects? That's one. Two is why did you choose to evaluate both doses in the pivotal Phase III? Is that perhaps to allow for titration or a better ability to manage the disease on the label once approved? And then third and finally, given that your cash runway is through the fourth quarter of '22, and your readout is expected in the second half of '24, how do you plan on covering the shortfall for the Phase III? I mean are you perhaps looking at out-licensing in certain regions? Or are there any potential options for perhaps nondilutive financing?

Well, thank you, Ed. Three very good questions. So maybe I'll let Pierre and Michael cover the question about the fibrotic activity of lani and the rationale for the 2 doses, and will cover the cash runway.

Yes. So I'll start, Michael. You please complete when you see fit. So your point is the confidence in lanifibranor antifibrotic effect, I think, is strong. We've seen with the high dose that in 6 months, we were able to meet the endpoint of improvement of fibrosis by 1 point without worsening of NASH in more than 40% of the patients treated with lanifibranor high dose. Looking at the biomarker data, we've seen that the 800-milligram dose produced a significant decrease in fibrosis-related biomarkers such as Pro-C3. So we think actually that the low dose would be more antifibrotic on a longer term trial. So by extending the duration of the trial from 6 to -- 6 months to 18 months, we think that will give a good chance for the low dose to show a more potent antifibrotic activity than it did in the 6-month trial. And finally, as you know, there is a lot of technical evidence supporting the direct antifibrotic effect of lanifibranor. We have notably published a lot of work done in isolated human hepatic stellate cells, where we see an inhibition of the activation of those cells by lanifibranor under different type of simulation, under TGF-beta or stiffness. So there is quite a consistent biology between the in vitro, the in vivo clinical results and the clinical results including histology and biomarkers, which, for us, give us really good confidence that the drug will be able to have a high chance -- high probability of success in this composite surrogate primary endpoint.

The second question was about the rationale for the 2 doses. And then the third question was for?

Cash runway.

Cash runway. So the cash runway, yes, you're right. So as Jean said, we have EUR 113 million at the end of the year. That's more than enough to launch the NATIVE 3, but we need to close the gap if we want to finance that study until the readout of Part 1. And we are currently with the team which are looking at many options. They go from dilutive options like going back to the market, to doing licensing on lani for regional or global deal, licensing for odiparcil. We're also looking at other more creative approaches such as debt or royalty deals. And I would say that given our current cash position, we have the time to analyze the several options and really take the right decision at the right moment. What is important to retain is that currently, we are really not slowed down in any way in the launch of the Phase III by our cash position.

For the question on the 2 doses in Phase III. So before maybe, Michael, you can intervene, I would say that, of course, we are aiming at the registration of the 2 dose. Because as you said, this will bring a lot of flexibility in the clinic or in patients, investigators once the drug is on the market. But maybe Michael, you want to add some on this question?

Thanks, Pierre. I think an important rationale to evaluate 2 doses is the effect on the relevant endpoints. And I would say fibrosis important, so the native Phase II study was half a year, 26 weeks. And we see a somewhat larger effect size with 1.2 grams on fibrosis at that point. So there is an expectation that the 800 milligram may have an increased effect size on fibrosis the longer you treat. So the -- taking 2 doses forward will give us a lot of information about the 800 milligram as well with regard to its efficacy compared to the 1,200 milligram.

Great. Fantastic. And then perhaps just one quick last one, if I may. Given the long lead up time for the Phase III, I'm just wondering if there is any opportunities for sort of interim results? Or is that perhaps really -- we're looking at milestones from perhaps other studies like in the F4 patient population?

Yes. You're totally right. I think the key milestone and key news will come from other trials, both with lani. So we touch about some options that we're looking in combination in F4 patient. There is a study with Professor Cusi that will be -- and it's really interesting study, confirming the strong antidiabetic properties of lani. We will also have updates on cedirogant. This is an important trial that is going on. If we obtain POC, the program will be much more visible in AbbVie pipeline, and that will be certainly an exciting stream of news from the -- for the company. And then as I also said, we also have odiparcil. And we are convinced about the potential of this drug in MPS. We are convinced about our strategic decision to find a company that has the resources financially and human to carry it forward, and that also will provide updates for the company.

There are no further telephone questions at this time. Please continue.

Very good. Thank you, because I'm looking, is there any question on the net, but that is not the case. And we have actually run out a little about our time. I just can only thank you for attending and following us. As you know, it's been an extremely exciting 2020. And I can assure you that 2021 looks even better. So we are very excited by the future, and we are very grateful for your support and the time you spent working with us. Thank you very much, and have a great day.

Thank you. Bye-bye.

Thank you.

Bye-bye.

That does conclude the presentation today. Thank you for participating. You may now disconnect.