Inventiva SA
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Good day, and thank you for standing by. Welcome to Inventiva's 2021 Full Year Results Presentation. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I'd now like to hand the conference over to your first speaker today, Frederic Cren. Please go ahead.
Thank you, and welcome, everybody, to the full year financial results presentation. As traditional, I would say, I will share the floor with Pierre, our CFO, who will go over lanifibranor; and Michael, our CMO also will present the clinical studies, the Phase II with -- 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 those figures.
But 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 native 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 have received a 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. Some highlights are certainly the fact that the Fast Track, which we had secured for patients with F2/F3 has been extended by FDA to cover patients 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 take 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 native study. So that's the highlight for lani.
But then I would say 2021 for us was the year of cedirogant with 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 to 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, is a direct translation in terms of finance because it triggered the EUR 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 U.S., where we host an important sizable cleanup team to follow our native Phase III study. We also reinforced the team with several recruitment in all departments and also reinforced the Board with the arrival of Martine Zimmerman. On the financials, 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 EUR 100 million, approximately EUR 30 million have already been used with -- to satisfy the reverse inquiry of long-term investor. And the cash run rate, so -- which run through Q1 '23.
So this is my quick intro. And now I'll give the floor to Pierre, who will give you a brief update on lanifibranor.
Okay. Thank you, Frederic. So, we are 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 3 PPAR isoforms. It's not a thiazolidinedione and it's not a fibrate.
You're very much aware about the number of technical 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-fibrotic activity of the compound, whereas the 3 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 native Phase IIb trial in non-cirrhotic 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 nonclinical tox package, which actually included long-term studies up to 2 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 a favorable tolerability 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. These kind of studies 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 used 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 dosed up to 2-fold higher than the maximal 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 next Slide. So, following the successful outcome of the native 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 3 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 rapidly recap on the design of the Phase III. So, in term of inclusion criteria, we are fully aligned with the patient population that has been included in the native Phase IIb trial. Simply the focus is more on F2 and F3 patients than in the native Phase IIb. The patients will be included in the study when showing an activity score, so a combined score of ballooning and inflammation, which is going to be equal or superior to 3 out of 4.
And as I mentioned, a fibrosis score of F2 and F3. The patient population will be stratified on type 2 diabetes and F2/F3 status. It's, of course, 3 arms. So, we'd be evaluating the 2 dose of lanifibranor 800 and 1,200 milligrams 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 3 pathologists.
Next Slide, please. So the endpoints 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 a patient would be qualified a responder if it shows both NASH resolution and improvement by one stage of the fibrosis score. And as a reminder, in the native Phase IIb study, in the population of patients with F2 and F3 fibrosis score, the placebo was 7% and the number of responders in the low dose were 24%, for the high dose 33%. Therefore, 3x and 4x more responders in the treated arms relatively to placebo. This was in the native Phase IIb trial for the same composite endpoint.
Secondary endpoints, of course, we will have NASH resolution and no worsening of fibrosis, improvement of fibrosis and no worsening of NASH and other endpoints will include 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 or cause mortality, hepatic decompensation events, a MELD score equal to or above 15 and/or liver transplantation.
Next Slide, please. So, where do we stand today? So the study is conducted by -- with us with ICON and 2 clinical research networks that are specialized in NASH Summit in the U.S. 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 U.S. 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 2 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 2 major CDMOs involved, both FDA approved with industrial capacities, ensuring the supply in U.S., Europe and rest of the world and likewise, for the drug product. In parallel, the pharmaceutical development plan in support of the commercial supply has been defined with them and this for both drug substance and drug product.
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'll cover 2 studies, which are -- which further support in profile lanifibranor with regard to its efficacy in patients with NASH and also patients with type 2 diabetes. First study on Slide 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 on how lanifibranor works as a pan-PPAR agonist in -- on several aspects of these metabolic diseases. So, the primary efficacy endpoint is a reduction in intrahepatic triglyceride accumulation, so hepatic fat.
And -- but also, we look quite in depth in how this is associated with changes in adipose in 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 cardiometabolic health in patients with NAFLD and type 2 diabetes are beneficially affected by lanifibranor.
As a background, nonalcoholic fatty liver disease or NASH and type 2 diabetes have an underlying -- a common underlying disease biology. And so in many -- in high percentage, these tissues overlap 70%. This is actually on the low estimates, the more progressed this disease become, the more frequently you find that they coincide, of course, together. And that has to do with the fact that diabetes -- patients have diabetes, NASH is more severe and vice versa. There is an interaction between the 2 conditions.
So in -- diabetes itself becomes more difficult to control in patients with NASH, needs more medication, a substantial proportion of these patients will have a more severe form of NAFLD with death of hepatocytes, 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 has also type 2 diabetes.
The coexistence of these 2 diseases has also to do with the severity of insulin resistance in multiple organs. And fat tissue and adipose tissue insulin resistance actually leads to the inability of fat issue to store inert triglycerides to get a more increased lot of fatty assets delivered, which then is the cause of lipotoxic environment 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 the reduced ability of the liver to secrete very low density lipoproteins and increases de novo lipogenesis, altogether leading to what we call an atherogenic dyslipidemia profiles, which then explains increased cardiovascular risk and atherosclerosis that these patients have. So elevated triglycerides, low levels of beneficial HDL cholesterol levels and small and denser LDL particles.
On Slide #20, the study that we are conducting with Dr. Cusi in Florida. He is the investigator and also the sponsor. It's a small study to really, 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 too well controlled within 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 they have to have NAFLD, which is diagnosed noninvasively for purpose of this study.
They have to have at least 10% hepatic fat determined by MRS and have to have a stable weight, which is defined as no increase or decrease of more than 5% within the period before the 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, beneficial effects that lanifibranor has in these patients. So, in summary, we'll do ultrasound-based imaging, FibroScan to evaluate liver fat and fibrosis.
We look at MRI measurement of fat with PDFF as well as elastography to assess fibrosis and study also includes an advanced corrected T1-weighted MRI mapping, which provides a picture of inflammation and fibrosis in the liver, a quantified picture. There are additional tests that will define the degree of insulin sensitivity using an euglycemic clamp and insulin injections that enables us to measure the initial effect on -- or the initial degree of insulin sensitivity and the improvement thereof with lanifibranor.
And then a number of markers that in altogether corresponds 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 milligrams of lanifibranor a day. And in addition to that, in order to have reference values from this evaluation, specifically for the imaging tools, there will also be 10 healthy non-obese individuals who provide this reference tests for metabolic and imaging tests. The sample size is calculated based on an expected effect size on the intrahepatic fat content or triglyceride content.
And we have data which we published previously on the effect of lanifibranor on hepatic steatosis histologically and also FibroScan, so that provides reference for these samples as calculations. The primary efficacy end point is based on a change in the intrahepatic triglycerides at the end of treatment, which is after 6 months, week 24, again, based on the -- an expected effect size and then broad panel of secondary endpoints that, as I mentioned before, we'll look at key metabolic markers associated with NAFLD and type 2 diabetes insulin resistance.
Proportion of responders defined as the percentage of patients, who have a decrease in intrahepatic triglycerides of 30% or more and the percentage of patients who have a resolution of NASH defined as patients with less than 5% intrahepatic glycerides 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, enrollment has called up. So, I expect that this aim can be reached.
Slide 22, I will move to another proof-of-concept study, which we are doing, which is a combination treatment. Evaluating combination therapies in patients with NASH is a very important topic. So, we have chosen to start the study, a proof-of-concept study combining lanifibranor and empagliflozin, which is an SGLT2 inhibitor and we believe that this is a very 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 proof-of-concept study.
So on Slide 23, a 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 there will be, 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 0.5 billion people affected globally.
And if you look at patients of type 2 diabetes and those who have received or have undergone the liver biopsy, you actually find that the NASH is prevalent in quite a high percentage. And as I mentioned before, there's some more advanced diseases or this will -- more often this co-occurrence will be described. Insulin resistance is a key part of physiological events leading to many downstream effects, inflammation, et cetera, 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 this upstream beneficial effect would 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 rationale by lanifibranor and empagliflozin are very attractive couple in the context of combination therapy. Lanifibranor is really exploiting the benefits of a PPAR transcription factors of beta, delta and gamma and having that effect on multiple organs and with -- as a result, a combined effect on improving lipid metabolism, improving carbohydrate metabolism, adding an anti-inflammatory effect -- well-defined effect on macrophages through differentiation to a noninflammatory phenotype, et cetera.
The SGLT2 have a more upstream effect. They essentially reduce the reuptake of glucose in the kidneys. Glucose is a core inflammatory compound 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 of cardiac disease has been well defined, meanwhile, in very high-profile studies, specifically also recently for empagliflozin. So that makes them attractive as a combination compounds.
And Slide 25. The study is called LEGEND. It's based on acronym that's -- but it's also, I think, a very good name for the study. The expected benefit of the combination of these 2 compounds is obvious with regard to efficacy. And the -- one of the key aspects or 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 a lanifibranor has in about 1/3 of the patients, you see an increase in weight.
It's important to remind the audience that the weight increase that we see with lanifibranor is different metabolically from the weight gain that is seen in patients or the people who don't eat healthfully or don't have enough physical activity. So, this weight gain is actually -- has been well defined as being metabolically healthy. We've -- 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 is a need or a benefit to have an answer to -- for those patients who have a weight increase that may be of concern for them.
And given the fact that SGLT2 inhibitors have a weight reducing effect, the combination of the 2 can -- in addition to that showing an improved efficacy also to balance out the weight changes that you see with lanifibranor. What we will also do in the study is look at imaging using MRI, LiverMultiScan, which will give us picture on the effect of liver lanifibranor alone and the combination of lanifibranor 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 gamma activity. There is a maturation of fatty acid towards more insulin sensitive fatty acid -- fat tissue that is more located in subcutaneous regions. We have shown for lanifibranor a reduction in liver fat, but this study will provide more details and unexpected to reach distribution of fat towards more metabolically healthy fat. The primary efficacy endpoint is HbA1c, makes some sense because it's obviously the main efficacy endpoints in diabetes studies, but it's also biologic relevant linked to insulin resistance in the pathogenesis of NASH and we do know what the effect of lanifibranor of HbA1c is from the NATIVE study.
So Slide 26. The design of the LEGEND study. We -- and this on top explains the acronym. The principal investigators will be [indiscernible] from Harvard and University of Amsterdam respectively. The study will be conducted on both sides of the Atlantic in the U.S. and 4 countries in Europe with an expected number of 50 sites. And as Pierre mentioned, the division -- 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 top line 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 lanifibranor with empagliflozin will be an open-label arm or empagliflozin, which is adequate for proof-of-concept purposes of the study. The primary efficacy endpoint is a change in 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, et cetera, all markers of lipid and carbohydrates and metabolism and markers of inflammation. And then again, these changes in body fat composition, which actually are very complementary about the study from Dr. Cusi in showing that we expect the distribution towards more healthy -- metabolically healthy subcutaneous fat.
A number of other outcomes, of course, if you look at safety, adverse events, tolerability, body weight, as 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 pharmacokinetics in the study and as I mentioned, imaging and at the bottom of the slide, you see the design of the study summarized again, as I mentioned. So half year of treatment, 4 weeks of follow-up after treatment.
In summary, on Slide 27, there's a lot to say. I think it's very promising and we also received a lot of enthusiastic feedback from pathologists and diabetologists to like on the combination of lanifibranor and empagliflozin. It's a proof-of-concept study that will provide -- 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 effect of the combination with empagliflozin acting on upstream metabolic pathways.
HbA1c, I mentioned is the primary efficacy end point. The data on body composition, I think, will be very novel and important to look at. We expect this distribution of body fat and towards more subcutaneous fat. And then obviously, since we are positioning and developing a lanifibranor for NASH, we look at the 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.
Yes. 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 overall once daily administered or ROR gamma inverse agonist, which is currently investigated in a Phase IIb clinical trial for the treatment of moderate-to-severe psoriasis. And this decision came out from, I would 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-IL-17 or anti-IL-23 biologics in the treatment of psoriasis, which is validating actually this IL-23, IL-17 pathway as an important target for therapy then you may see that there is quite a significant market opportunity for an oral and 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 IL-23, IL-17 pathway so relevant in psoriasis. Actually, one of the primary drivers of the inflammatory response in psoriasis is IL-17, which is secreted from Tn17 cells. IL-17 regulates the proliferation of keratinocytes and down regulates their differentiation. It is -- it also induces keratinocytes to secrete chemokines 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 inhibits 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 oral ROR gamma inverse agonist that we discovered with AbbVie, reported in this paper that in vivo in a model of psoriasis induced by IL-23, which is actually an 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 of 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 rheumatoid arthritis, while those targeting IL-17 show promises. And here in a 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-of-concept for an orally available ROR-gamma inverse agonist in all these different preclinical models.
Next Slide, please. So indeed substantial commercial opportunity exist in psoriasis for an overall 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 IL-23, 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 proved 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 -- JAK kinase inhibitors were able to induce encouraging PASI 75 responses that approached biologic like therapeutic benefit. 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 focused 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. So cedirogant is currently evaluated in a Phase IIb trial in adults with moderate to severe psoriasis with an estimated trial completion date of March 23. And Michael Severino, the AbbVie Vice Chairman and President noted that cedirogant showed promising activity in the previous Phase 1b in patients with chronic plaque psoriasis.
So next Slide. If we look at the design of the Phase IIb study, which are started. It's a double-blind placebo-controlled trial, evaluating the safety and the efficacy of 3 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. And I mentioned the results of this study would be available in the 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 3 compounds including cedirogant in 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 results from the study is actually available on clinicaltrial.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 the 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 tiered 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 that's been filed in 2016, valid up to 2036. And if you include 5 years extension 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.
Yes. Good afternoon. Good morning. So we'll review the financial performance in 2 Slides. First of all, the big picture, the shareholder base, which is stable and has even been consolidated, thanks to the ATM of USD 32 million, so embarking existing shareholders plus opening newcomer in the shareholder base. So the market cap is at $450 million. The performance and 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 EUR4 million milestones received in January from AbbVie, and our estimate for the cash runway is one year from now.
Next Slide, please. So the figures are quite easy to read. They are in continuity of what we have discussed for the H1 financial performance. The revenues are made up of the milestone from AbbVie at 4.2 million. The key information for us is the R&D expense, which has doubled in '21 compared to 2020 with 48.4 million -- 48.5 million.
The G&A of course, it's definitely related to what has been explained in the activity of further clinical development and on our assets in particular on lanifibranor. The G&A as expected had increased by 31%. It was fully expected. It's the first year for Inventiva, complete year with the dual-listing status. So no surprise on this line. It's under control.
And cash wise, as I said, we're close to 100 million, exactly 95.4 million. On 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 been offset by the ATM that took place end of September, raising gross proceed 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 detailed 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 key milestone, I'll focus here only on the clinical readouts. We start with lani, this year we will have, in the second half, the clinical results, the top line result of the study in patient with type II diabetics, a study conducted by Dr. Cusi. Early '23, we'll 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 of AbbVie.
Then concerning always in '23, another important clinical readout that the combo study, lani plus empagliflozin, and all of course, I'll say, the very important top line result in second half of '24 of the NATiV3 Phase III. So that's for the lani and cedirogant.
And then, 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 that hopefully 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 highlights of 2021. And we will be ready to take questions. And the operator will give you the detailed procedure to follow.
Thank you. [Operator Instructions] Your first question is from the line of Lucy Codrington from Jefferies.
Firstly on the cash runway. Can I confirm, does that include the cost of the LEGEND trial. And I'm assuming does it include any other potential milestones from AbbVie or anything from odiparcil?
And secondly -- and apologies if I 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 going to -- this won't lead to a delay in the data?
And then just finally on the milestones remaining from AbbVie. I believe it's 35 million, and we've had 2. So am I right in thinking this EUR 27.5 million is left for those milestones?
Thank you, Lucy. For the cash runway, maybe Jean, you want to take it.
Your question about LEGEND, the budget is definitely taking into consideration this additional study. It's clear. Considering the milestones in AbbVie, there is no milestones planned in '22 according to the development plan. We may hope that in '23, if there are good news, we could have an additional milestone, as per the contract.
The second question there...
It was on the remaining milestone from AbbVie. I don't have them by hand. So we can get back to you.
Yes. We can come back to you. It will be specified in the filing, in the URD and the 20-F, that will be filed tentatively next Friday. But if it's not written down in these documents, but I think it is documented we -- you can back to us.
Once again, what is important, of course, these milestones are always nice to receive, but what really make 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 -- is part of one of the 11 countries that are currently open. And we had 3 sites that had started screening patients, the other 7 were not open. And as you can imagine, these 10 sites, all activity have been paused given the situation. I would say that we have very limited hope that activity will resume there.
The other 12 sites are in Russia. Russia is not a country that is open yet, but we -- the regulatory filing are still ongoing. So no impact I would say on the current screening activity for Russia.
And overall, therefore, 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're now targeting 350, that's above, you know, we were I think when we started this prior looking at 250, and we have increased that, for example. As Pierre mentioned, we recently contracted with Summit, which is specialized in recruitment in NASH, very efficient organization with sites mostly in U.S., but also in Europe. And so, that also will contribute to reduce the impact of the situation. And of course, in addition to that working with ICON to see if we can find additional sites.
Thank you. The next question is from the line of Jeroen Van den Bossche from KBC Securities.
Yes. Thank you and congratulations on yet another great year, definitely with lanifibranor. Building on maybe the question from my [indiscernible] really quick first question. Looking at empagliflozin, the data today as it stands, is that based only on existing data [indiscernible] or is there currently also other information that you've been used pre-clinical 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 collaborations building the market together with other organizations or are you really focusing on bringing it to market yourself?
Thank you, Jeroen. So maybe for the empa rationale and data available, I don't know, if Pierre or Michael, you want to take this question?
Yes. I can -- I think we can refer to -- revert to Michael because the rationale is very much coming out of a number of clinical trials, where empa or other SGLT2 inhibitors 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 don't know, Michael, if you want to elaborate on that.
Well, just, this is -- that summarizes it well here. But it's -- the mechanism of action of these compounds is well known, and that's true for lanifibranor. It's a pan-PPAR agonist, and it's true for empagliflozin, as an SGLT2 inhibitor. And the efficacy in humans is also well known. Empagliflozin has been approved for a while, and there are many, many data from patients in diabetes and in cardiology. So that provides a strong rationale for the combination right. So we do not need for this purpose non-clinical data.
So if I understand it correctly, there is, in your view, enough, let's say, circumstantial data through which you don't expect any -- to the combination of the use of the drug?
Correct. Well, empagliflozin is approved anyway. And so in patients with metabolic immune diseases, which includes atherosclerosis and diabetes and so on, these patients have multiple drugs and combination is automatically the case. We -- many patients have statins for example. So this is not an unusual combination.
We are actually studying it in -- for the purposes that I explained to show that such a combination can have additional benefits on the efficacy readouts in NASH in type II diabetes, and as a weight management plan for those patients, who may need it. But there is no need to look at the supportive, if you wish, non-clinical data in order to have a strong rationale.
And specifically for pioglitazone and there have been 4 large studies published that were conducted in basically every -- globally, combining pioglitazone with all 4 major SGLT2 inhibitors on the market. And the findings are very consistent, you always have [Technical Difficulty].
Sorry. So in these indications, would it be open, would it be ideal to market them by yourself or in combination with other partners, or how do you see that going forward?
[Technical Difficulty] Frederic, you want to continue or...
Yes. On the [indiscernible] to ask -- 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 a 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. Most likely, we will 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 products, the easy one is cedirogant. So everything is in the end of AbbVie. They decided to start development in psoriasis. They can decide to look at other indications, but that's clearly on their end, and they are in charge of fully funding the development as well as the commercialization costs.
And then the last one is odiparcil, there we have not changed our strategy. 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, a new home, because we believe the patient with MPS VI deserve to have a new treatment and odiparcil could be this new oral treatment that they are looking.
Thank you. The next question is from the line of Jean-Jacques Le Fur from Bryan, Garnier.
Yes, sir. Good afternoon, and congrats again for this good -- year very strong year. 3 question, if I may. The first one is -- hello, can you hear me?
Yes, yes. Perfectly, Jean-Jacques.
Hello?
Yes, we can hear you.
Can you hear me?
Yes.
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 1,200 since the 800 milligram was not the best during NATIVE trial, especially regarding efficacy?
The second question is, you well highlighted that you are quite busy with lani, but could we have an update on the YAP, TEAD for example, program, or do you have all the 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 a 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. Maybe, Michael, you can take the LEGEND, Pierre can go over YAP 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.
Very good. So maybe Pierre can you cover YAP?
Yes. Sure. I think I can cover partly lani 800 milligram. So the choice was basically made on the fact that the -- as you've seen heard from Michael, that the primary endpoint is HbA1c, 800 milligram is actually a dose that is producing already a maximal efficacy on HbA1c. There is no difference between 800 milligram and 1,200 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 is reconnected.
I am reconnected.
Okay. Do you want to comment, Michael, add some...
Yes. Sorry. I was reconnected briefly. But yes, the -- it's true that if you look at histology and the fibrosis classification of histology of staging, specifically 1,200 milligram is better than 800 milligram after 6 months, which is actually a very short time frame to evaluate fibrosis. But on many other markers, there was 2 doses. The 2 doses were actually pretty equipotent with regard to efficacy, specifically on metabolic markers.
And since fibrosis is driven by metabolic abnormalities and inflammation, it is actually an expectation that if you treat longer both doses may be comparable. We don't know that of course, maybe history will tell us that. But that's also a main reason why we kept 2 doses in NATiV3. And why we chose 800 milligram in LEGEND, because in that study we don't look at fibrosis histologically, we look at mainly 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 milligram for LEGEND.
And for YAP, TEAD, so we have identified lead compounds -- couple of lead compounds that we are now progressing in vivo in models of hepatic cancer and renal cancer, why? Because we have seen quite interesting and potent anti-proliferative 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 deliver in 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.
And the last question on the cash, yes, I mean, no, I think everything is mostly driven by NATIVE.
Yes. Definitely we finished 2020 with a slow H2 after the result of the Phase II. So in '21, the increase is 80%, 90% due to NATIVE to the preparation and launch of the studies. And we have also, we tripled the cost of CROs, and CDMOs in '21. And we also consolidated development and pharma team, pharmacovigilance regulatory team to face the Phase III and the trend for '22 will be in this direction to get [ fittest quasi ] for the Phase III expense this year. Yes, so driven essentially by NATIVE, to get the [ fittest quasi ] for the Phase III expense.
If I may just a quick -- if I may just a quick add on. If you need to, you will need to have new funds or new financing during early this year. Do you have idea right now of what could be, and how you can deal such raise. Will it be dilutive, non-dilutive and so on.
Well, I think all the options are 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 low royalty deals. And of course as mentioned we also have an ATM in place. So we'll see now at the right moment what is the best option for the Company to move forward.
The next question is from the line of Seamus Fernandez from Guggenheim Securities.
This is Evan Wang on for Seamus. Just a question on the ROR-gamma program. Can you talk more about the profile observed in Phase 1 and how that gives confidence heading 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 any specifics on future indications, but what other indications may be most appropriate for this kind of target?
Pierre, do 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 you know AbbVie made the decision to enter into Phase b -- Phase IIb, which as you see -- you've 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 yes, so we'll see if the data will be published this year.
And relatively to your questions -- your question about additional indications, where basically there are several indications, where -- immunology indications, 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 et cetera, et cetera. Based on the data we have obtained with this early ROR-gamma inverse agonist we discovered with AbbVie on animal model of rheumatoid arthritis, where we see quite a significant reduction of co-inflammation. It could be that rheumatoid arthritis would also makes sense for such a molecule. And we know also that, ulcerative colitis is a potential, additional indication for this type of mechanism of action.
[Operator Instructions] And the next is from the line of [ Delphine Le Louet ] from Societe Generale.
Just to be back on the runaway regarding the cash position for '22 and '23 and possibly going forward '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 extrapolated for the following years. Jean, can you confirm that to me, please?
And secondly, Frederic, a question for you. Regarding the situation in Eastern Europe. And so, when I make the calculation more or less 46% of the patient for the NATIVE trial will be impacted. So do you think yourself, you are at risk [Technical Difficulty] the last patient first visit time lines. How do you see the completion of the trial so far, despite the fact you get another CRO on board, CMO on board, how -- you're optimistic? Or do you think we are -- unfortunately will have to see some delay going forward? And how would that impact between the European population and the U.S., I mean, the other type of population can you make in Europe, other site, recruiting more patient 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 estimate, the projections in '23 are in the same amplitude, as for 2022.
And then 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'll need to find and monitor, I would say, monitor the situation and also find other option in a certain sense we had also anticipated or we had also increased the overall number of sites.
Once again we have now 350 sites on target. This is above what we had planned at the beginning. And so, we are looking with ICON 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 option is to go into new countries. But of course, if we do that, this would be patient, given the regulatory time lines that could come in most likely for the part 2 rather than the part one.
On the web, we had question on the -- via Internet that I think we've covered most of them. The only one we did not cover was, there was a question, if we believe, we can do a partnership before or after the data. And of course, we cannot give any input on that, that 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 the 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. Also thank you very much for attending and the good level of question and discussion. Next event for us is EASL in June in person, we're very much looking forward to do that. As you can imagine, we have submitted new data abstracts. We hope that they will get accepted. And we will organize and host the KOL webcast to go over the NASH space, the key data presented and also the new data that we -- that will be presented at 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.