Good day and thank you for standing by. Welcome to Inventiva’s 2021 Full Year Results Presentation. At this time, all participants are in a listen-only mode. After the speakers’ presentation, there will be a question-and-answer session. [Operator Instructions] Right now, I turn the conference over to your first speaker today, Frédéric Cren.

Please go ahead..

Thank you and welcome everybody to the full year financial results presentation. As traditionally, we’d say I will share the floor with Pierre, our CSO will go over lanifibranor; Michael, our CMO also will present the clinical studies of Phase II done by Professor Cusi and the LEGEND study, while Pierre will cover an update on the Phase III.

And then we’ll end up with Jean, our CFO, who will give more granularity on the seeker [phonetic]. So before we go into the details of the clinical update, I just would like to provide some of the key highlights of 2021 which I think has been, when you look at everything that has been achieved, quite successful.

So if we start with lani, so we had committed to start the NATiV3 Phase III pivotal study, which we did and on top of that, we also announced the design of the LEGEND study, our combination study between lani and SGLT2 inhibitor empagliflozin.

And this morning, you’ve seen that we’ve received positive feedback from FDA and the IND application has been accepted by the diabetes division. The interaction with FDA, I would say, overall, during the year has been very positive.

So my lights are certainly the fact that the past drug which we had secured for patients with F2-F3 has been extended by FDA to cover patient with compensated cirrhosis. We’re also extremely pleased by confirmation, the feedback, we got from FDA concerning the tox package, which FDA consider as adequate and complete to file an NDA in NASH.

This is extremely positive, because it means that we tick another box on the way to commercializing lani. We also continue to prepare and complete our package for filing and we positively concluded a QT/QTc study where lani demonstrated no impact on cardiac electrical activity.

And finally, as you all know, we had this fantastic publication by the New England Journal of Medicine of the study of the Phase IIb NATiV3 study. So, that’s the highlight for lani but then I would say 2021 for us was the year of cedirogant.

We -- the completion of the Phase Ib and, especially, we’re very proud and excited to see AbbVie moving forward with this trial confirming that they’ve seen Humira-like efficacy that they believe that cedirogant could be an efficacious drug in psoriasis and their decision to move Phase IIb because the data of the Phase Ib were available in April and I think in November the Phase IIb started, so that’s quite a fantastic accomplishment by the AbbVie clinical team.

And that, of course, has a direct translation in terms of finance, because it triggered the 4 million milestone when the first patient in the Phase IIb was included in the study. Odiparcil, we continue preparing for a meeting with the FDA.

The objective is to validate with FDA the design of a pivotal trial, which we think is key in finding a new home for Odiparcil. Other highlights, on the back, less visible, we opened Inventiva Inc. in the US where we host important and sizable cleanup team to follow our NATiV3 Phase III study.

We also reinforced the team with several recruitments in all departments and also reinforced the Board with the arrival of Martine Zimmermann.

On the financial, though Jean will cover that in detail, but we’re very pleased of being able to activate an At-The-Market program of a total envelope of 100 million, approximately 30 million have already been used to satisfy the reverse inquiry of long-term investor and the cash one way, which runs through Q1 ‘23.

So, this is my quick intro and now we’ll -- I’ll give the floor to Pierre, who will give you a brief update on lanifibranor..

Okay, thank you, Frédéric. So we’re now moving on Page 10. So as you know, lanifibranor is a pan-PPAR agonist in clinical development Phase III for the indication, treatment of NASH and improvement in liver fibrosis. It has unprecedented structure and pharmacological profile.

It’s a pan-PPAR agonist with moderate and well-balanced activity across the three PPAR isoforms. It’s not a thiazolidinedione and it’s not a fibrate.

You’re very much aware about the number of pre-clinical investigations that we have performed and showing that most, if not all, of the pathological features of NASH can be addressed by lanifibranor through the activation of several PPAR isoforms, for example, the delta and the gamma activation, we think is really important and leads to the strong anti-fibrosis activity of the compound, whereas the three isoforms are involved in the inhibition of inflammation and ballooning.

And the potential of lanifibranor to address most, if not all, pathological features in NASH has been, as you know, validated in the NATiV3 Phase IIb trial in non-psoriatic NASH patients and the results of this study actually supported breakthrough therapy designation by FDA, which came on top of the Fast Track designation that was already granted for lanifibranor.

From a safety point of view, as you know, the non-clinical tox package, which actually included long-term studies, up to two years, showed that lanifibranor had a good safety profile and FDA confirmed that this tox package is complete and acceptable to support the filing of a New Drug Application, NDA.

Lanifibranor in the clinic has also favorable to the reliability profile, evidence as of today now in close to 500 patients or healthy volunteers. So importantly, this year we have completed a thorough QT/QTc study, which is a standard component of all clinical development programs for any new therapeutic agent in support of NDA.

This kind of study is also of interest in the context of the targeted population, as QTc interval prolongation is common in patients with liver cirrhosis. So the design we use was the one recommended by FDA and intended to confidently identify drugs that may cause QT prolongation.

And in this study, repeated daily administration of lanifibranor dose up to two fold higher than the maximum therapeutic dose had no effect on the QT interval. And this study which meets the FDA requirements, therefore confirms once more the safety of lanifibranor on cardiac activity which was previously observed in our Phase II studies.

So if we move to a next slide. So, following the successful outcome of the NATiV3 Phase IIb trial with lanifibranor in NASH, we have agreed on the Phase III study design with FDA and EMA and this study is now initiated.

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, we have also initiated an additional profiling study in NASH patients, which is going to evaluate the potential of lanifibranor to be used in combination with empagliflozin in NASH patients with type 2 diabetes.

Next slide. So, the key dates relatively to these three studies are the following. We expect the results from the Part 1 of our Phase III second semester 2024. The results of the study on liver insulin resistance in NAFLD patients with type 2 diabetes will come second semester this year.

And the results from the combination lanifibranor plus empagliflozin in NASH patients with type 2 diabetes will come second semester 2023. Next slide please. So to happily recap on the design of the Phase III, so in terms of inclusion criteria, we are fully aligned with the patient population that has been included in the NATiV3 Phase IIb trial.

Simply, the focus is more on F2 and F3 patients than in the NATiV3 Phase IIb. The patients will be included in the study when showing an activity score, so combined score ballooning and inflammation, which is going to be equal or superior to three out of four. And as mentioned, the fibrosis score of F2 and F3.

The patient population will be stratified on type 2 diabetes F2-F3 status. It’s of course three arms, so we’ll be evaluating the two dose of lanifibranor 800 and 1200 milligram that were investigated in the Phase IIb trial.

The statistical powering is 90% and the central biopsy reading process has been agreed with regulatory authorities and will involve review done by three pathologists. Next slide please. So the end points for the first part, which will last 72 weeks and will include 900 patients.

This primary endpoint is the composite endpoint of NASH resolution and no worsening of fibrosis, meaning that patients would be qualified responder if he shows both NASH resolution and improvement by one stage of the fibrosis score.

And as a reminder, in the NATiV3 Phase IIb study, in the population of patients with F-2 and F-3 fibrosis score, the placebo was 7% and the number of responders in the low dose were 24%, for the high dose 33%, therefore three and four times more responders in the treated arms relatively to placebo.

This was in the NATiV3 Phase IIb trial for the same composite endpoint. A secondary endpoints of course, we will have a NASH resolution and no worsening of fibrosis, improvement of fibrosis and overseeing of NASH.

And other endpoints will include the glycemic control, improvement in renal function and reduction of cardiovascular risk, as a few examples. Next slide please.

So, relatively to the second part of the study, the endpoints are actually based on time to first clinical event, which can be defined by either histological progression to cirrhosis, all cause mortality, hepatic decompensation events, a MELD score equal to or both 15, and/or liver transplantation. Next slide please.

So where do we stand today, so the study is conducted by -- with us with by ICON and two clinical research networks that are specialized in NASH summit in the US, and AES in Europe. Today, we have 350 sites qualified. The study has been approved in 11 countries out of 25 and the regulatory review is ongoing in the 14 remaining countries.

We have 121 sites activated among which 77 in the US and 44 in Europe.

As you can understand, due to the current circumstances in Ukraine, all clinical sites in Ukraine and Russia have been put on hold and we are currently working on a mitigation plan with ICON to activate additional sites in other countries in order to compensate for the missing recruitment in those two countries. Next slide please.

So we are also actively working to put in place an efficient and secure drug substance and drug product commercial supply chain worldwide moving forward.

And for the drug substance, we will have two major CDMOs involved, both FDA approved with industrial capacities ensuring the supply in US, Europe, and rest of the world, and likewise for the drug products.

In parallel, the pharmaceutical development plan, in support of the commercial supply has been defined with them, and this is for both drug substance and drug products. So with this, I would like to hand over to Michael who will go through the presentation of our study in NAFLD patients with NASH collaboration with Professor Cusi.

Please Michael, go ahead..

Thank you, Pierre. So I will cover two studies, which further support and profile lanifibranor with regard to its efficacy in patients with NASH and also patients with type 2 diabetes.

First study on slide number 19 is a study in patients who have NASH and NAFLD and type 2 diabetes and this is really a study to further understand the mechanisms how lanifibranor works at a pan-PPAR agonist on several aspects of these metabolic diseases. So, the primary efficacy endpoint is a reduction in intrahepatic triglyceride accumulation.

So, I think that but also we look quite in depth in how this is associated with changes in adipose tissue and insulin resistance in the main organs, fat tissue, liver, and muscle, which are all affected by metabolic diseases and also to look at a broader picture of how the cardiometabolic risk profile, so the marks of cardio metabolic health in patients with NAFLD and type 2 diabetes are beneficially affected by lanifibranor.

As a background, non-alcoholic fatty liver disease on NASH and type 2 diabetes have a common underlying disease biology and so, in many, in high percentage these diseases overlap, 70% is actually on the low estimate. The more progress these diseases become, the more frequently you find that they coincide.

They occur together and it has to do with the fact that diabetes -- patients have diabetes, NASH is more severe and vice versa, there is an interaction between the two conditions.

So in diabetes itself, it becomes more difficult to control and patients with NASH need more medication, substantial proportion of these patients will have a more severe form of NAFLD with death of hepatocyte, which is described as ballooning, inflammation of the liver, and the progression of fibrosis towards cirrhosis, so more severe and progresses more rapidly in patients who are -- who have also type 2 diabetes.

The coexistence of these two diseases has also to do with the severity of insulin resistance in multiple organs.

And in fact, adipose tissue insulin resistance actually leads to the inability of fat tissue to store inert triglycerides to get a more increased load of fatty acids and deliver, which then is the cause of lack of toxic environments in the liver, which contributes in fact to the damage of liver cells and the resulting inflammation.

Hepatic insulin resistance again then leads to the inability or reduced ability of the liver to secrete fairly low density lipoproteins and increases de novo lipogenesis, altogether, leading to what we call an atherogenic dyslipidemia profile, which then explains increased cardiovascular risk in atherosclerosis that these patients have; so elevated triglycerides, low levels of beneficial HDL cholesterol levels, and smaller and denser LDL particles.

Slide number 20, the study that we are conducting with Dr. Cusi in Florida, he is the investigator and also the sponsor.

It is small study to [indiscernible], as I mentioned, detail further the mechanism of action of lanifibranor, so in total 34 patients are enrolled, they have type 2 diabetes, and they have to be not well controlled but in certain limits, of course, so their HbA1c not to be higher than 9.5%.

They should not be on insulin or should not have received pioglitazone in the past year and have to have NAFLD, which is diagnosed non-invasively for the purpose of this study. They have to have at least 10% hepatic fat determined by MRS.

And then they have to a stable weight, which is defined as no increase or decrease of body fat and within broader study starts. And then there are really a number of investigations, state-of-the-art that will provide a quite comprehensive picture of the metabolic effects and beneficial effects that lanifibranor has in these patients.

So in summary, we will do to ultrasound based imaging and FibroScan to evaluate the liver fat and fibrosis. We look at MRI, measurement of fat, PDFF, as well as elastography to assess fibrosis. And the study also includes an advanced corrected T1 way to MRI mapping, which provides a picture of inflammation and fibrosis in the liver quantified picture.

There are additional tests that will define the degree of insulin sensitivity using euglycemic clamp and insulin injections that enables us to measure the initial effects or the initial degree of incidence sensitivity and the improvement there of with lanifibranor and then a number of markers that in altogether correspond to cardiometabolic health markers and glycemia control markers, HbA1c, adiponectin and so forth, and also a panel of markers for liver fibrosis.

So the main imaging and metabolic results are based on spectroscopy, intrahepatic triglycerides, MRI-based fibrosis measurements, and inflammation fibrosis with the corrected T1 measurement, insulin sensitivity through lab tests, and then the profile of cardiometabolic risk factors and fibrosis markers. Slide 21.

I mentioned that the principal investigator is Dr. Cusi at University of Florida. The study has 34 patients who are randomized one on one to a placebo or active which is 800 milligram of lanifibranor a day.

And in addition to that in order to have reference values for these evaluations, specifically for the imaging tools, there will also be 10 Healthy non-obese individuals who provide these reference tests for metabolic and imaging tests. The sample size is calculated based on expected effect size on the intrahepatic fat content or triglyceride content.

And we have data which we published previously of the effect of lanifibranor on Hepatic steatosis, histologically and also kept FibroScan so that provides reference for this sample size calculations.

The primary efficacy endpoint is based on a change in the intrahepatic triglycerides at the end of treatment, which is after six months, week 24, again based on the effect -- an expected effect size and then broad panel of secondary endpoints that, as I mentioned before, we’ll look at the key metabolic markers associated with NAFLD and type 2 diabetes insulin resistance.

Proportion of responders defined as the percentage of patients who have decrease in intrahepatic triglyceride of 30% or more.

The percentage of patients who have a resolution of NASH defined as patients with less than 5% in intrahepatic triglyceride at the end of treatment, changes in hepatic fibrosis measured at different -- quantified with different tools, MRI or MRE, FibroScan, biomarkers and of course, also the safety evaluations. The study is ongoing. Dr.

Cusi expects this study to be completed by the end of this year. It’s no surprise that the enrollment of patients has suffered from the COVID pandemic until recently, but earlier this year, his enrollment has caught up, so expect that this aim can be reached.

Slide 22, I will move to another proof of concept study which we’re doing, which is a combination treatment. Evaluating combination therapies in patients with NASH is a very important topic, so we have chosen to start a study, proof of concepts combining lanifibranor and empagliflozin, which is an SGLT2 inhibitor.

We believe that this is a fairly attractive combination of compounds for patients with NASH and certainly also for patients with NASH who also have type 2 diabetes and that is the patient population we are studying in this population we are studying in this proof of concept study. So on slide 23, little bit of background information.

As I mentioned before, a large proportion of patients with type 2 diabetes and NASH have also other aspects of metabolic syndrome. Of course, often they are obese, not always, but often they have a dyslipidemic profile, they have hypertension, they have cardiovascular risk factors.

And underlying that is insulin resistance as a very foundational abnormality in metabolic diseases. Type 2 diabetes is increasingly prevalent, it’s already very prevalent, but it’s still increasing with half a billion people were affected globally.

And if you look at patients of type 2 diabetes, in those who have received or have undergone a liver biopsy, you actually find that it is prevalent in quite a high percentage. And as I mentioned before, the more advanced diseases are the sort of more often this co-occurrence will be described.

Insulin resistance is a key part of physiological events, leading to many downstream effects, inflammation, etc, and clinical manifestations, essentially, of the entire metabolic syndrome, including NASH and type 2 diabetes.

And so there’s a lot of good reasons to combine therapeutic compounds that address these upstream metabolic immune pathways of NASH and type 2 diabetes and would be beneficial for both conditions, as well as the other manifestations by extension of metabolic syndrome.

So that’s the rationale to combine drugs that have complementary mechanisms of action to show at least additive effects on the metabolic immune aspects of the disease, and it is expected that these upstream beneficial effects will then trickle through more downstream effects of the disease, which includes also, of course, fibrosis.

Slide 24 is a tool which further elaborates on the rational by lanifibranor and empagliflozin are a very attractive.

Coupled in the context of combination therapy, lanifibranor has really exploiting the benefits of the PPAR transcription factors alpha, beta, delta and gamma and having an effect on multiple organs and as a result, a combined effect on improving lipid metabolism, improving carbohydrate metabolism, adding an anti-inflammatory effect, well-defined effect of macrophages through differentiation to non-inflammatory phenotype, et cetera.

The SGLT2 inhibitor have a more upstream effect, they’re essentially reduce the reuptake of glucose in the kidneys, the causes of poor inflammatory compounds as well, so it has itself a huge effect and of course, it improves the metabolic -- the underlying metabolic dysfunctionality of type 2 diabetes, but they also have diuretic effects so they reduce volume and their benefits in preventing heart failure, cardiac disease has been well-defined meanwhile, in very high profile studies, specifically also recently for empagliflozin.

So that makes them attractive as combination compounds. And slide 25 the study called LEGEND is based on acronym and that’s -- but it’s also I think, a very good name for the study. The expected benefit of the combination of these two compounds is obvious with regard to the efficacy.

And the one of the key aspects of interesting aspects that we will look at in the LEGEND study is the effect of the combination on the distribution of fat and the biology of fat.

Because lanifibranor has in about one-third of the patients you see an increase in weight, so it is important to remind the audience that weight increase that we see with lanifibranor is different metabolically from the weight gain that is seen in patients or people who don’t eat healthily or don’t have enough physical activity.

So this weight unit actually has been well-defined as being metabolically healthy. These patients also have the same improvement in insulin resistance and other markers that has also been described for pioglitazone. So the weight gain itself is not a metabolic concern, but it can of course be a concern for patients.

So there isn’t a need to or a benefit to have an answer for those patients who have a weight increase that may be of concern for them.

And given the fact that SGLT2 inhibitor have on weight reducing effect, the combination of the two can in addition to showing an improved efficacy also balance out the weight changes that you see with the lanifibranor.

What we will also do in the study is look at imaging using MRI, LiverMultiScan, which will give us the picture on the effect of [indiscernible] alone and the combination of a lanifibranor and with empagliflozin on liver fat on inflammation and fibrosis, but also on the distribution of fat in the body because if you give PPAR agonist specifically, PPAR from activity, there is a maturation of fatty acid towards more insulin sensitive fatty acid -- fat tissue that is more located in subcutaneous regions, and have shown fibranor reduction in liver fat, but this study will provide more details and is expected to re-distribution of fat towards more metabolically healthy fat.

The primary efficacy endpoint is HbA1c makes no sense because it’s obviously the main efficacy endpoints in diabetes studies, but it’s also biologically relevant link to insulin resistance in the pathogenesis of NASH and we do know about the effect of lanifibranor on HbA1c from the NATiV3 study. So slide 26, the design of the LEGEND study.

We -- this on top explains the acronym. The principal investigator suite doctors will be Dr. Michelle Lai and Holleboom from Harvard and University of Amsterdam respectively. The study will be conducted on both sides of the Atlantic in the US and four countries in Europe with an expected number of 50 sites.

And as Pierre mentioned, the diabetes division has accepted -- has approved the IND, so this study can proceed and we plan to start soon in the first half of this year, and we’ll have topline results in the second half of next year. The inclusion criteria will be adult patients who have diabetes, type 2 diabetes, and NASH obviously.

And it will be -- from a design aspect, it’s a proof of concept study, so it’s an exploratory study. The comparison between lanifibranor and placebo will be based on double-blind assessment and the combination of lanifibranor with empagliflozin will be an open label arm for empagliflozin, which is adequate for proof of concept purposes of the study.

The primary efficacy endpoint is changing HbA1c and again, as I mentioned before, we have a good measure to calculate that because we know the effect of lanifibranor from previous studies.

And then we’ll have some broad panel of secondary efficacy outcomes based on imaging, so the assessment of hepatic fat inflammation, fibrosis etc on markers of lipid and carbohydrate metabolism and markers of inflammation. And then again, these changes in body fat composition which actually are very complementary to the study from Dr.

Cusi in showing that the expected redistribution towards more healthy, metabolically healthy, subcutaneous fat. A number of other outcomes have also look at safety, adverse events, tolerability, body weight.

I mentioned before we expect that the combination of lanifibranor and SGLT2 inhibitor will be weight neutral, that has also been shown for pioglitazone and diverse SGLT2 inhibitors. We look at some kinetics in the study and, as I mentioned, imaging. And the bottom of the slide, you see the design of the study summarized again, as I mentioned.

So half year of treatment, four weeks of follow up and after treatment. In summary, on slide 27, there’s a lot to say. I think it’s very promising and we also receive a lot of enthusiastic feedback from pathologists and diabetologist alike on the combination of lanifibranor and empagliflozin.

It’s a proof of concept study that will provide – that will show us again, the effect of lanifibranor, of course, on the different metabolic immune aspects of NASH and type 2 diabetes, but also the effects of the combination with empagliflozin acting on upstream metabolic pathways. HBA1C, I mentioned as the primary efficacy endpoint.

The data on body composition, I think, would be very novel and important to look at. We expect this distribution of body fat towards more subcutaneous fat.

And then obviously, since we are positioning and developing lanifibranor for NASH, we look at the liver and liver markers, liver enzymes, markers of liver inflammation, hepatitis and fibrosis will all be assessed through blood tests as well as imaging. So with that, back to Pierre on cedirogant..

Thank you, Michael. So let’s indeed switch gear for cedirogant. So can we be on page 29, please. So, as you probably know, cedirogant is an oral, once daily administered ROR gamma inverse agonist which is currently investigated in the Phase IIb clinical trial for the treatment of moderate to severe psoriasis.

And this decision came out from, say, a successful Phase Ib study in patients with moderate to severe psoriasis. Cedirogant was discovered jointly by Inventiva and AbbVie and cedirogant royalties really have the potential to be an important source of revenues for Inventiva.

Indeed, if you consider the success of anti-IL17 or anti-IL23 biologics in the treatment of psoriasis, which is validating actually this IL23-IL17 pathway as an important target for therapy, then you may see that there is quite a significant market opportunity for an overall an efficacious treatment acting on ROR gamma in psoriasis, but there is also a potential market opportunity for this approach in other immunology indications where IL-17 is relevant.

Next slide please. So why is the IL23-IL17 pathways so relevant in psoriasis. Actually one of the primary drivers of the inflammatory response in psoriasis is IL-17, which is secreted from Th17 cells. IL-17 regulates the proliferation of keratinocytes and down regulates their differentiation.

It also induces keratinocytes to secrete chemokine that drive the influx of immune cells including neutrophils and dendritic cells.

ROR gamma is a nuclear receptor, which controls Th17 cell differentiation and effector function, regulating the transcription of IL-17A and IL-17F and blocking ROR gamma actually prevents Th17 differentiation and in a bit IL-17 production. Next slide please.

And this is actually illustrated in one of our publication exemplified here; so, for example, if we consider A-9758, which is one of the early POR gamma inverse agonist that we discovered with AbbVie.

We reported in this paper that in vivo in a model of psoriasis induced by IL-23, which is actually interesting model because we see there a time dependent accumulation of ROR gamma t expressing cells across both the dermis and the epidermis.

In this model, A-9578 was effective in reducing here inflammation driven by IL-23 and attenuated epidermal thickening. A-9578 was also effective in suppressing the gene signature associated with IL-23 exposure, including a significant decrease in IL-17A and IL-17F gene expression.

And the treatment with A-9578 also reduced the number ROR gamma t positive cells that were induced by IL-23. And this was seen both on prophylactic and therapeutic administration. And therapeutic administration actually led to 85% reduction of IL-23 driven skin inflammation and reduced IL-17A as well as IL-17F gene expression and protein levels.

In addition to that, we know that clinical studies have shown that biologics against IL-23 are relatively ineffective against rheumatic arthritis, while those targeting IL-17 show premises.

And here in the model of rheumatoid arthritis, A-9578 was capable of reducing post swelling by 41% to 84% depending on the timing of administration, which compares favorably to anti-TNF therapy. So this is actually a good proof concept for an orally available ROR gamma inverse agonist in all these different preclinical models. Next slide, please.

So, indeed, substantial commercial opportunity exists in psoriasis for an oral and efficacious treatment. As you all know, psoriasis is a common skin condition that affects 2% to 4% of the population in western countries, with global sales in 2020 of approximately $20 billion.

The market today is dominated by injectable, anti-IL23, IL-17 and TNF alpha biologics, which account for more than 80% of the market. However, Otezla, an oral drug PDE4 inhibitor, despite an inferior efficacy and tolerability profile compared to approved injectables generated $2.2 billion of sales and was acquired by Amgen for 13.4 billion in 2019.

So there are also a number of other orally available therapeutic candidates that has been investigated as potential therapeutics for the treatment of psoriasis. Clinical results from Phase III clinical trials found that kinase inhibitors were able to induce encouraging PASI-75 responses that approach biologic like therapeutic benefits.

However, the high efficacy seen with some drugs was of this class was associated with increased risk of adverse events, resulting in discontinuation of development for this indication. There is a current clinical development focus on inhibitors of tyrosine kinase 2, TYK2, which is a distantly related JAK family member.

BMS actually recently reported that its TYK2 inhibitor deucravacitinib achieved PASI 75 response in about 50% of patients by week 16. Next slide please. Cedirogant is currently evaluated in Phase IIB trial in adults with moderate to severe psoriasis with an estimated completion date of March 23.

And Michael Severino, the AbbVie’s Vice Chairman and President noted that cedirogant showed promising activity in the previous Phase Ib in patients with chronic plague psoriasis.

So next slide, if we look at the design of the Phase IIb study, which has started, it’s a double-blind placebo control trial, evaluating the safety and efficacy of three doses of cedirogant in 200 patients with moderate to severe psoriasis.

And the primary outcome is the percentage of participants achieving at least 75% reduction from baseline in PASI score. Like I mentioned, the results of the study will be available in first semester 2023.

So, next slide please, if we look at the ROR gamma competitive landscape, we actually believe that this competitive landscape today is limited with three compounds including cedirogant in the Phase II; Bevurogant from BI, which status is not clear considering that it is not mentioned anymore in BI annual reports; Aurigene product AUR101, which is a BID product, starting Phase II in the US as we speak; JTE-451 out of Japan Tobacco, which has actually limited efficacy result from the studies actually available on clinicaltrials.gov showing that at the top dose, JTE-451 was able to achieve PASI 75 in 22% of patients and this after 16 weeks of treatment; and finally, the Immunic product IMU-935 with a Phase Ib ongoing exploring the efficacy of 150 milligram QD and BID in patients with moderate to severe psoriasis and this during 28 days.

So next slide please.

So as mentioned, Inventiva is eligible to receive development, regulatory commercial milestones, and tier royalties, and these royalties range from the mid-single to low-double digits in actually a therapeutic space where you can see that competitors have all reached blockbuster status and relatively to the limited exclusivity for the patent, patent has been filed in 2016, studied up to 2036, and if you include five years ago expansion period, you will have -- we have a limit of exclusivity of 2041.

And with that, I would like to leave the floor to Jean for the financial results..

Good afternoon and good morning. So we will review the financial performance in two slides. First of all, the big picture of the shareholder base, which is stable, and has even been consolidated, thanks to the ATM of 32 million US dollars, so embarking existing shareholders plus opening to new comer in the shoulder base.

So the market cap is at $450 million. The performance on the market was quite positive in 2021, although, as all the business sectors, and biotechs in particular, we are suffering from the Ukrainian crisis.

In terms of cash, it’s quite easy to remember the figures, we are close to 100 million, if we take into consideration the 4 million Euros milestones received in January from AbbVie. And our estimate for the cash runway is one year from now. And next slide, perfect thanks. So the figures are quite easy to read.

They are in continuity of what were discussed for the H1 financial performance. The revenues are made up of the milestone from AbbVie, it is 4.2 million. The key information for us is the R&D expense, which has doubled in ‘21 compared to 2020 with 48.4 – 48.5 million.

The G&A -- of course, it’s technically related to what has been explained in the activity of clinical development and on our assets, in particular on lanifibranor. The G&A, as expected, increased by 31%. It was fully expected. It is the first year for Inventiva, complete year with the dual listing status.

So no surprise on this line, it is under control. And cash wise, as I said, we’re close to 100, exactly 95.4 million and top of which we can consider the 4 million received in January, so it gives us, as I said, one year of cash to operate. And the way it has been built is in line with the operational expense.

The net operating cash flow used in ‘21 reached close to 50 million compared to 30 million last year. And in terms of cash investing activity and financing activity has being offset by the ATM that took place end of September, raising gross proceeds of $32 million, as we said.

So the cash level is quite comfortable for the next 12 months in our sector -- industry. So of course I will be happy to answer any details, further information if you need more colors on the financials. Thank you..

And then the last slide before we move to the Q&A are the anticipated a key milestone. I’ll focus here only on the clinical readouts. We start with lani. This year we’ll have, in the second half, the clinical results, the top line results of the study in patient with type 2 diabetes, a study conducted by Dr. Cusi.

Early ‘23, we will have the cedirogant end of the Phase IIb. Of course, once again, the publication of these results, like the publication of the Phase Ib are on the end AbbVie.

Then confirming also in ‘23 another important clinical readout that the combo study lani plus empagliflozin, and all of course exciting very important top line results in second half of ‘24 of the NATiV3 Phase III.

So that’s for the lani and cedirogant and then on Odiparcil, as I mentioned in my introduction, we continue to work to prepare a meeting with the FDA to validate the clinical development plan, the pivotal trial, and hopefully it is an important piece of information for identifying a way or a new home for Odiparcil. So these are the key milestone.

So this concludes the highlight of 2021 and we will be ready to take questions, and the operator will give you the detailed procedure to follow..

[Operator Instructions] Your first question is from the line of Lucy Codrington from Jefferies. Please go ahead..

Hi, there. Thanks for taking my questions. Just a few please. Firstly, on the cash runway, Jean, can I confirm, does that include the costs for the LEGEND trial? And I’m assuming, it doesn’t include any other potential milestones from AbbVie or other things from other parcel.

And secondly, and apologies if I’ve missed it, regarding the Phase III recruitment, is that progressing as planned? I noticed on the slides that it looked like Russia and Ukraine account for about 22 sites, which is about half of the EU sites currently active, how many of those 22 sites were active and what drives confidence that there is -- this won’t lead to a delay in the data? And then just finally, on the milestones remaining from AbbVie, I believe it was 35 million and we’ve had two, so am I right in thinking there’s 27.5 million Euro is left for those milestones? Thank you..

Thank you, Lucia. For the cash runway, maybe Jean you want address..

To your question about LEGEND, the budget is definitely taking into consideration this additional study. It’s clear. Considering the milestones from AbbVie, there are no milestones planned in ‘22, according to the development plan. We may hope that in ‘23, if they are good news, we could have an additional milestone, as per the contract.

The second question –.

It was on the remaining milestones from AbbVie. I don’t have that one hand, we can get back to you on that. .

We can come back to you. It will be specified in the filing, in the URD and the 20-F that will be filed the tentatively next Friday. But if it’s not written down in this document, but I think is it is documented, we you can call back to us..

Yeah. But once again, what is important, of course, it is nice and always nice to receive but what really makes the value of this contract are the royalties, which are we view them as very meaningful. And the double digit level is triggered at the sales level where I am personally very confident this program will reach.

Then to your question about the Ukrainian and Russian site, so we have -- we were planning to open 10 sites in Ukraine. So Ukraine is one of – it is part of one of the 11 countries that are currently open. And we had three sites that had started screening patient, the other seven were not open.

And as you can imagine, these 10 sites all activities have been paused. Given the situation, I would say that we have very limited hope that activity will we resume there. The other 12 sites are in Russia, Russia is not a country that is open yet.

So we -- regulatory filing are still going, so no impact I would say on the current screening activity for Russia. And overall, so we have 22 sites that we need to recover, so if you look at our various presentation, you will know that we have increased the number of target sites. We are now targeting 350 or above.

We were -- I think when we started this trial looking at 250 and we have increased that.

For example, as Pierre mentioned, we recently contracted with Summit [phonetic], which is specialized in recruitment in NASH, very efficient organization, which sites mostly in US but also in Europe and so that also will contribute to reduce the impact of the situation.

Of course, in addition to that, we are working with ICON to see if we can find the additional sites..

Thank you very much..

Thank you. The next question is from the line of Jeroen Van den Bossche from KBC Securities. Please go ahead..

Yeah, thank you, and congratulations on yet another great year, definitely with lanifibranor. Building on maybe the question from my company, really quick a first question.

Looking at empagliflozin, the data today, as it stands, is that based only on existing data or is there currently also other information that you’ve been used preclinical data to build the LEGEND trial? And then maybe going further, how are you looking at the future of lani and cedirogant and Odiparcil? Are you still open to potential other collaboration building the market together with other organizations or are you really focusing on bringing it to market yourself?.

Okay, thank you, Jeroen.

So, maybe for the empa rationale and data available in odi, Pierre or Michael, you want to take this question?.

Yeah, I can -- I think we can refer to Michael because the rationale is very much coming out of a number of clinical trials, where empa or other SGLT2 inhibitor were given on top of patients being treated by pioglitazone, for example, and where you would see there a decrease in body weight. So I know, Michael, if you want to elaborate on that..

Well, just you know, that this summarizes itself, yeah, but the mechanism of action of these compounds is well known. And that’s true for lanifibranor, it is pan-PPAR agonist and it’s true for empagliflozin as an NASH SGLT2 inhibitor and the efficacy in humans is also well known.

Empagliflozin has been approved for a while and there are many data on patient in diabetes and in cardiology. So, that provides a strong rationale for the combination right, so we do not need for this purposed, non-clinical data..

So if I understand this correctly, there is, in your view, enough, let’s say, circumstantial data through which you don’t expect any combinational use of the drug..

Correct. Well, empagliflozin is approved anyway and so, in patients with metabolic immune diseases, which includes atherosclerosis in diabetes and so on, these patients have multiple drugs and combinations automatically the case. Many patients have statins for example. So, this is not an unusual combination.

We are actually studying it in for the purposes that explained to show that such a combination can have additional benefits on the efficacy readouts in NASH and type 2 diabetes and as a weight management plan for those patients who may need it.

But there is no need to look at the support, if you wish, not in clinical data in order to have a strong rationale.

And specifically for pioglitazone, there have been four large studies published that were conducted in basically every -- globally combining pioglitazone with all four major SGLT2 inhibitors on the markets and the findings are very consistent. .

Sorry.

So in these indications, would it be open to the idea to market them by yourself or in combination with other partners or how do you see that going forward?.

Right now we are moving – Frédéric, you want to continue or --.

Yeah, yeah, on the [indiscernible] to answer the second part of your question, so, for lani, we view it as a tremendous opportunity for big pharma and NASH is certainly a very large market, but you need the muscle, the experience, the commercial capabilities of big pharma.

So, our objective is to find a partner, we believe that the asset has great value, great chance to make it to the finish line. And we are open to find a partner, so most likely, we’ll be in a better position once we have the Phase III data but of course, if somebody knocks on the door before, we are certainly open to discuss.

For the other product, the easy one is the cedirogant, so everything is in the end of AbbVie, they decided to start developing in psoriasis, they can decide to look at the other indication, but that’s clearly on their end and they are in charge of fully funding the development as well as the commercialization cost.

And then the last one is odiparcil, there we have not changed our strategy. We were not -- we do not have the capabilities to develop NASH lani in NASH, and Odiparcil in MPS VI in parallel.

So, we remain committed to find an opportunity or new home because we believe the patient with MPS VI deserve to have a new treatment and Odiparcil could be this new form treatment that they are looking..

Okay. Clear. Thank you..

Thank you. The next question is from the line of Jean-Jacques Le Fur from Bryan, Garnier. Please go ahead.

Yeah, good afternoon and congrats again for this good year -- very strong year. Three question if I may.

The first one is on -- hello, can you hear me?.

Yes, yes, perfectly. Go ahead..

Hello. .

Yes, we can hear you..

Can you hear me?.

Yes. .

Okay, so sorry. So, okay, great. First on the LEGEND trial, could you remind us why you have chosen the lani 800 milligram and not the 1200, I think the 800 milligram was not the best during NATiV3 trial, especially regarding efficacy.

The second question is, you well highlighted that you are quite busy with lani but could we -- can we have an update on the -- any update, for example, program or do you have other products in the pipeline which may move forward in the next few months, for example, or this year, for which we may have some news, even if they are preclinical or very early stage.

And the last one is back to the envelope calculation, is that -- since you have cash runway until -- for one year, that means you are expected to spend about 100 million this year.

So what are the main drivers for the significant increase compared to last year? Is it mainly the Phase III for lani, the addition of LEGEND, what are the key drivers there? Thank you..

Okay. Thank you. Maybe Michael you can take the LEGEND. Pierre can go over emp and Jean will talk about the cash..

We’ve just lost Michael’s line from the call. We are just going to try and reconnect him..

Okay, very good. So, maybe Pierre, can you cover emp..

Yeah, sure. I think I can cover partly lani 800 milligram and also the choice was basically made on the fact that the -- as you seen, heard Michael, the primary endpoint is HbA1c 800 milligram is actually a dose that is producing already a maximum efficacy.

On HbA1c, there is no difference between 800, 1200 milligram and then this is I think the major reason why this dose was chosen in this study, but Michael can elaborate maybe more once he’s reconnected. .

I have reconnected..

Okay.

Do you want to commend, Michael?.

Sorry, I was reconnected briefly but it’s true that if you look at histology and the fibrosis qualification of histology or staging or specifically 1200 milligram is better than 800 milligram after six months, which is actually a very short time frame to evaluate fibrosis.

But on many other markets, there was two doses, the two doses were actually pretty equally potent with regard to efficacy, specifically on metabolic markers. And since fibrosis is driven by metabolic abnormalities and inflammation, it is actually an expectation and if you treat longer, both doses maybe compatible.

We don’t know that, of course, NATiV3 will tell us that but that’s also a main reason why we kept two doses in NATiV3, and why we chose 800 milligram in LEGEND because in that study, we don’t look at fibrosis histologically, we look manly at metabolic immune markers, and we expect an additive effect from the combination therapy.

So, these are the main reasons why we chose the 800 milligrams for LEGEND..

And for emp, so we have identified lead compounds, couple of lead compounds that we are now progressing in vivo in models of a hepatic cancer and renal cancer, why because we have seen quite interesting and potent [indiscernible] effects in vitro in a number of renal cancer cell lines, and a couple of HCC or liver cancer cell lines, plus these are products that are quite well distributed to the liver and the kidney.

So we are now starting to profile those compounds in animal models of hepatic cancer, HCC, and renal cancer and we’ll keep you posted on that..

The last question of the cash, yeah, I mean, I think everything is mostly driven by NATiV3..

Yes definitely. We finished 2020 with a slow H2 after the result of the Phase II.

So, in ‘21 the increases 80%, 90% due to NATiV3 to the preparation and launch of the studies and we have also -- tripled the cost of CROs and CDMOs in ‘21 and we also consolidated the development and pharma team, pharmacovigilance regulatory team, to phase the phase three and the trend for ‘22 will be in this direction to get the fittest quasi for the phase three expense this year.

Yes, so driven essentially by NATiV3..

Okay. If I may just a quick add on, if you need to -- you will need to have new funds or new financing during probably this year.

Do you have any idea right now of what could be -- how you can deal such raise? Would it be dilutive, non-dilutive and so on?.

Well, I think all the options on the table, non-dilutive with potentially business development activity on our pipeline in especially non-strategic area like Asia. We are also looking at loans for deals and of course, as mentioned, we also have an ATM in place.

So we’ll see at the right moment, what is the best option for the company to move forward?.

Okay. Great. Thank you. .

Thank you. The next question is from the line of Seamus Fernandez from Guggenheim Securities. Please go ahead..

Hi, this is Ivan Wang on Seamus. So question on the ROR gamma program, can you talk more about the proof observed in Phase I and how that gives confidence setting into the Phase IIb, especially for a competitive program, product profile, I guess relative to other upcoming orals for psoriasis.

And I know you can’t give me specifics on future indications, but what other indications may be most appropriate for this kind of target? Thanks..

Pierre, you want to try to answer that?.

Well, I think the Phase Ib data are not public. So they are going to be -- well it might be that AbbVie will this year present the data of the Phase Ib in a dedicated conference but these data are not available.

I think AbbVie made the decision to enter into Phase B – Phase IIb, which, as you see -- have seen is quite an important study with 200 patients, 16 weeks, based on data that were convincing. So I trust very much on the decision of AbbVie moving forward with cedirogant. And yeah, so we’ll see if the data will be published this year.

And relatively to your question about additional indications where basically there are several indications where immunology indication where we know IL-17 inhibition is relevant. Maybe well, you probably know them, this is basically axial spondyloarthritis, ankylosing spondylitis, psoriatic arthritis, idiopathic arthritis, etc, etc.

Based on the data we have obtained with this early ROR gamma inverse agonist we could discovered with AbbVie on animal model for rheumatoid arthritis, where we see quite a significant reduction of toe inflammation, it could be that rheumatoid arthritis would also make sense for such a molecule.

And we know also that spondylitis colitis is a potential additional indication for this type of mechanism of action..

Thank you. [Operator Instructions] And the next is from the line of Delphine Le Louët from Société Générale. Please go ahead..

Thank you. Good afternoon and good morning, everybody. Just to be back on the run away regarding the cash position for ‘22 and ‘23 and possibly doing for ‘24. I don’t see any reason so far to have a massive cut into the R&D in ‘23, ‘24. So, meaning that more or less ‘22 number could be extrapolate for the following year.

Jean, can you confirm that to me, please. And secondly, Frédéric a quick question for you, regarding the situation in eastern Europe and so when I make the calculation more or less for 46% of the patient for the NATiV3 trial will be will be impacted.

So do you think yourself you are [Technical Difficulty] broadening the last patient first visit timelines? How do you see the completion of the trials so far, despite the fact you get another shareholder on board, CMO on board, how you’re optimistic or do you think we are -- unfortunately we’ll have to see some delay going forward? And how will that impact between the European population and the US, I mean, the other type of population can you make in Europe other site recruiting more patients to get the same Caucasian population?.

Good afternoon, Delphine. I take the first questions you are right about the range of expense that we may incur in ‘23. According to our best estimates, the projections in ‘23 are in the same amplitude as for 2022..

Okay, thank you..

On the question about what is the impact of Ukraine and Russia situation on the trial, so we don’t think that this jeopardizes the overall recruitment of the trial. So we stick to the guideline we provided, which is to finalize the recruitment this year.

Of course, we need to find and monitor – I would say monitor the situation and also find the other option in a certain sense, we had also anticipated or we had also increased the overall number of sites. Once again, we are now 350 sites on target. This is above what we had planned at the beginning. And so we are looking with ICON at alternative.

First is to find in the countries that are open sites that have the capabilities to recruit efficiently the patient for the part one. And then the second alternative is to go into new countries, but of course, if we do that this would be patient given the regulatory timelines that could come in most likely for the part two rather than the part one..

Okay, thank you..

Otherwise we had a question on the -- via internet, I think we covered most of most of them. The only one we did not cover, well, there was a question if we believe we can do a partnership before or after the data.

And, of course, I cannot give any input on that as we -- what we can say that we believe NASH is a playground for big pharma, we’re open to do a partnership. If the terms are good, we can do it in the short term, otherwise, it will have to be post Phase III..

And we don’t have any other questions over the phones at the moment..

Okay. So, then I think it’s a moment to conclude. So, thank you very much for attending and the good level of question and discussion. Next event for us is EASL in June, in person, because we were very much looking forward to do that. As you can imagine, we have submitted the new data abstract, we hope that that will get accepted.

And we will organize an off the KOL webcast to go over the NASH base, the key data presented, and also the new data that will be presented at the EASL in June in London. And so I really hope to see all of you in London in June. Thank you very much and have a great day..

Thank you. This does conclude the conference for today. Thank you for participating. You may now disconnect..