Good morning, and welcome to the GENFIT virtual KOL event. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentations. If you would like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the GENFIT website following the conclusion of the event. I would now like to turn the call over to your host, Pascal Prigent, Chief Executive Officer at GENFIT. Please go ahead, Pascal.
Thank you, Tara, and thank you all for joining for this webcast. Good morning for those in the U.S. and good afternoon for those in Europe. The purpose of this webcast is to share our view about the MASH diagnostic market and to try and give a little bit more precise guidance about what to expect with specifically on this technology. Maybe let us start with the next slide and talk about GENFIT, and who we are for those of you who do not know us. These are the forward-looking statements. Next slide. Next. Yes. GENFIT was founded a little bit more than 25 years ago in France and started with some partnership with Big Pharma. That was around a specific expertise around PPAR in particular and nuclear receptors in general.
That lasted for about five to six years, but very early, GENFIT started to focus on its own research, and specifically the development of elafibranor. That development was really focused in MASH or NASH as it was called at the time. That lasted for almost 15 years, and GENFIT took elafibranor all the way from drug discovery to end of phase III. As some of you might know, that development did not end well for us because in 2020, the phase III was not supportive of the marketing approval. The product was safe and was very good, but the efficacy was not what was needed for marketing approval. At that time, GENFIT had to reinvent itself. Fortunately for us, we had also developed elafibranor in PBC. In PBC, it worked really well.
We partnered with Ipsen, eventually launched a product in the U.S. in June 2024, and in Europe at the end of 2024. It has been really successful ever since. Today, it is a very different company. We have the elafibranor business that is bringing in some cash. We have a new technology, which we are going to talk specifically today. Then we have a pipeline, an R&D pipeline that is focused on CCA and ACLF, and that will be the purpose of another call. The purpose of this quick introduction was really to say that we have been in MASH for a very, very long time. Actually, GENFIT was among the first company in MASH. We were one of the first companies to be in the Liver Forum, where we worked with clinicians and KOLs, but also regulatory agencies and patient associations.
We were among those that early on sort of discussed what were the right endpoint and what were the sort of key challenges for this market to develop. For over 15 years, MASH was our primary focus. Can we move to next slide? Very early on, we recognized the need for a non-invasive diagnostic solution because obviously at the time, biopsy was your way to identify those patients and also monitor progress. It was very clear to us that in order for this market to be all it could be, we had to have a non-invasive, scalable solution that was easier to use than the biopsy and more efficient than the tools that existed at the time. It is one of those situations where it is in everybody's interest to have such a solution.
Obviously, for a patient, they need to know that they are sick, and they are asymptomatic, so they cannot rely on how they feel. Therefore, they need a tool. Physician, very clear they need a tool to identify their patient. They want to know who to treat, and then they want to know whether their patients are getting better or not. The drug makers also need a tool to make sure that their drug is being used correctly, that they are not off-label, and that they are not missing out on some patients. Payers obviously are a very strong driving force for the need for diagnostic because they want to make sure that the drugs that they pay are being used properly.
They also want to make sure that the money that they spend is money well spent and that the patients actually do get better or at the very least do not get worse. Then, of course, diagnostic manufacturers have an incentive for that market to develop. Everybody wants this to be a success. Next slide. This technology is actually a decade-long program. We were, as I was saying, one of the first companies to start the phase III in MASH. I think at the time it was us and Intercept. What that meant is that we had a very large database of thousands of patients that we followed for 18 months with a biopsy at the beginning, a biopsy at the end, and many different measures of many different biomarkers in between.
What we did is we started to look at all those variables with the goal of identifying biomarkers that would best replicate what we saw on the biopsy. We tested hundreds of different variables, selected the most predictive one, and we did that by using AI. At the time it was called machine learning, but that was essentially what AI is today. We selected those most predictive variables, identified a small subset that could best replicate the biopsy, and developed a unique algorithm to produce a score. Of course, you can do that on a single cohort, but then you need to make sure on independent cohort that it has some destructive power. We did that against a series of independent cohorts.
Then we optimized the test, both from a standpoint of its efficiency, but also thinking about future industrialization and really thinking about IVD. We will talk about that later, but really thinking from the beginning that we needed to get that test to a mass market at some point. We published all of that in several scientific journals, but we will talk about that in more details. We were also used by several of the pharma manufacturers in a number of clinical trials in phase II, in phase III, and that was very important for us because, A, it exposed a number of very important player in this market to our test, and they could see it work. But also for us, it gave us access to additional data that in turn helped us to further refine the test.
Eventually, that test was included in a number of international guidelines in Europe, but also in the U.S. and in Asia. I think one of the most important thing, it was recognized by independent consortia. We have two especially significant, one in Europe, one in the U.S., and both of those independent consortia tested all the different diagnostic modalities on the market today, and both concluded that this was a very useful tool to identify and monitor those personalized patient. The product is now commercially available in the U.S. through LDT, through our partner, Labcorp. Then very recently, we got reimbursement by Medicare in the U.S. So if we move to the next slide.
We believe that we are now at an inflection point because for the longest time we felt we had a great product, but for a market that did not really exist, because obviously there was no therapy approved for MASH and therefore little incentive to try and find MASH patient. That has changed with the approval of resmetirom. They have been extremely successful, reaching blockbuster status in the first year, which I think is a testament to the potential of that market. We think it is just the beginning. Novo Nordisk is not alone. Eli Lilly and Company is not too far behind. There are also a number of other players starting, I think very soon with Intercept Pharmaceuticals, which is also French, that could potentially get approved.
With all those additional molecules in the market, we think this is going to skyrocket, and the need for diagnostic is going to become even greater. Physicians are now moving from a position of just watch and wait to we need to identify those patient and treat them. Therefore we are seeing a shift from a bottleneck that was essentially the availability of drugs to the ability to identify those patients and monitor them. So we believe that now is the right time, and we believe that we have the ideal product to take advantage of this burgeoning opportunity. With that, I am going to hand over to Professor Vlad Ratziu, which those of you who follow the MASH market undoubtedly know because that has been an important figure in that space for quite a while now. He will present a physician view about this and the MASH market.
Yes. Thank you, Pascal. Good morning, everyone. I'm Vlad Ratziu. I'm a hepatologist working in academic hospital in Paris, and we have a longstanding interest in this disease, MASH, and in all aspects of diagnosis, natural history, and drug development. Next slide, please. As you might be aware, a significant progress has been done a few years ago, actually in 2023, when an international body of experts decided that it is time to redefine the diagnosis in more positive terms than the negative definition that used to be the one we were using until then, which was non-alcoholic steatohepatitis, recognizing that the problem for these patients is not that they don't drink enough, but it is that they have insulin resistance related to metabolic syndrome.
This whole effort was done first to give the opportunity to define a positive way, this new disease, and recognize that the underlying pathophysiological mechanism that drives the disease progression is related to hepatotoxicity and insulin resistance. The other important achievement of this redefinition of the nosological framework was to exclude the fact that was until then a dogma, which is that this diagnosis is an exclusionary diagnosis, and it can only be retained once you have excluded other causes of liver disease. In reality, many people have more than one cause of liver disease, and in particular, many people who have a metabolic syndrome also drink amounts of alcohol that are at risk for the liver condition.
The previous classification did not allow to label those patients in any specific diagnostic category, and the advantage of the new one is that it recognizes specifically the possibility of the association between metabolic steatosis with another condition. Most of these conditions occur rarely. One that is frequent is alcohol consumption. As you can see here on this diagram, the MetALD category is precisely the one identifying patients who do have all the MASH requirements for the disease, but who also consume amounts of alcohol that are above the thresholds that have been historically determined to diagnose MASH. It also allows to better identify these patients simply by looking at very simple clinical biological criteria.
These are people who have at least one of the five well-recognized and universally accepted metabolic risk factors, which are based either on BMI, body fat distribution with visceral adiposity, or glycoregulation disturbances, lipid disorders. All of these have come actually from the cardiologic and metabolic literature, and they have been adapted to serve the purpose here to very easily identify who is at risk. Basically, people who have one or several of these metabolic conditions, metabolic risk factors, if they have steatosis, that triggers investIgAtion procedures that aim to retain a final diagnosis. It can be either MASLD, MetALD, alcoholic liver disease, or more rare conditions. Next slide. Enormous simplification that fits the type of profile of patients we see nowadays.
This is more important than just an academic exercise because I remember 10, 15 years ago when we started the first industry-sponsored trials for MASH, one of the objections was that the delineation of this diagnostic category, the way we identified, diagnosed patients, wasn't very clear in everybody's mind. Now, I think nobody, having a clearer name, identifies clearly a disease, and nobody argues about whether this is a disease or not, or whether we are able to label patients as such. Now, why are we talking about this? Obviously, it is because there is a very high prevalence of metabolic steatosis worldwide. You can see here some estimates, and one of the things that is absolutely striking is that while until now, at least in the beginning, the way this disease was seen was a disease of affluent countries.
It turns out that it is now very frequent worldwide, and it is particularly frequent in developing countries. You can see here that surprisingly, people in Latin America or South America have higher prevalence of steatosis than in the U.S. That is a big achievement. But it is the same for North Africa, from the Middle East, and of course, not to mention India, where there is a particularly high prevalence of diabetes. So truly a worldwide disease, and one of the best examples of how this disease was able to enter the hepatology landscape and change the hierarchy in terms of prevalence of other liver diseases is China. In China, until not so long ago, 15, 20 years, HBV, hepatitis B infection, was a major liver disease.
Now it has been replaced, even in China, by metabolic steatosis, owing to the way the Chinese society evolved towards Western lifestyle. So truly a very prevalent disease, and please remember that nowadays, exposure to obesity happens earlier in life. So there are many adolescents that are obese. Some of them develop diabetes quite early in life, and therefore we expect that since the disease starts earlier, severe forms of this condition might occur maybe a decade earlier than it is currently. So that is also an important epidemiological shift. Next one. Now, the reason why there is such an increase in prevalence is because the underlying conditions that drive the disease, which are obesity and type 2 diabetes mainly, have also increased over the past years. You can see on the right-hand of the slide, the prevalence of diabetes worldwide with some hotspots again like India.
But it is truly a very prevalent disease, particularly in the U.S. Maybe 29 million patients might have glycoregulation issues, and only 8.1 million are undiagnosed with this disease. So there is a lag between the people who are exposed and people who are being diagnosed. So clearly, the increase in diabetes and the increase in obesity drive the increase in steatohepatitis. There are other factors related to lifestyle, sedentarity, related maybe to atmospheric pollution, other type of endocrine disruptors that can explain, to some extent, the increase in SLD. So the increase in SLD, which is shown on the left part of the slide, has been documented over the past three decades. Now, of course, part of that increase is also better recognition of the diagnostic framework. But also, a significant part is bona fide real increase in the factors that promote the development of this disease.
So clearly there is an increase, and we have to face that in the future. Next one. This funnel here shows you that one of the issues we're facing is that I would say exposure to risk factors is very prevalent, but not all people with the risk factors will develop. First, not all will be diagnosed, and second, among those diagnosed, not all will develop a concerning liver disease. That is the difficulty when you start with a very large base of people exposed to risk factors, and only some of them are at risk of developing the liver disease. You need to find a way to identify more precisely those people at risk.
Other than that, we will be flooded investIgAting too many people that don't have enough of a condition, and everybody's efforts will be wasted, and also the incentive and enthusiasm for achieving these goals will come down. So, we have to take into account the fact that here it is a difficult situation where we need to very precisely identify people at risk. Why is it difficult? It's because there are no symptoms for this disease. Therefore, we can only rely on laboratory or imaging studies, because the patient, how he feels or functions, cannot tell us who is at risk. Next one. This is a simple description, sort of natural history of the condition. So it all starts with a healthy liver. Normally, there should be no fat in the liver.
But then as the balance of energy intake versus energy expenditure is tilted in favor of energy intake and storage, most of that energy will be stored as triglycerides in different parts of the body. So it should be in the adipose tissue, but it sometimes overflows the adipose tissue, maybe because some people are not able to expand sufficiently the adipose tissue. But the fact is that at some point, this is being overwhelmed, and the fat starts going elsewhere, in ectopic places where it has no place to be. One of these places is the liver. Other places can be the muscle, you get myosteatosis. Other is the heart. As far as we're concerned here with the liver, the liver will start stocking, storing energy as triglycerides, and then you see a fatty liver. A fatty liver by itself is no big deal.
It tells you something's wrong in the metabolic homeostasis, but it's no big deal in terms of risk of damaging the liver. The reason being that many patients are able to store the fat in neutral, inert deposits of triglycerides. Okay? Those do nothing to the hepatocytes. They simply enlarge the hepatocytes, but the hepatocytes keep their normal environment around them and assure all their functions appropriately. Now, in some other people, this inert storage is not sufficient, and some of the liver fat species, the bioactive lipids, will start promoting inflammation and lipotoxicity in the liver. That's when you get, on top of steatosis, inflammation and liver cell injury. That's when you cross the thresholds from steatosis to steatohepatitis. The problem with steatohepatitis is that like all longstanding inflammation liver cell injury, what's going to do to the organ?
Well, it's going to start triggering a fibrogenic response. If this persists one month, it's not a big deal. If it persists 20 years, it will end up building fibrosis in the liver. The ultimate stage for fibrosis building, of course, is called cirrhosis. Once you have cirrhosis, the reversibility of this whole process is being in danger and no longer is possible. The cirrhosis can go on and develop its own complications, which are clinical complications this time, which the patient feels and which can kill the patient if they're not taken care of. One of them is liver cancer, but it can be all sorts of complications of cirrhosis. Which means what? Which means that the whole challenge here in dealing with these patients is to try to stop the process before they develop cirrhosis.
If you do that before cirrhosis, then the whole process can be reversible. To a large extent, different stages, it can be reversible. What we want is that people don't develop cirrhosis. Now, you would say, now we have drugs that can help that process, delay fiber or slow down fibrogenesis. The problem is that, yes, there are drugs, but you can't give them to everyone. You could imagine very easily just targeting them on the left part of the site, people who already have steatosis. That would be the safest way. You treat everybody at that point, and very few people will develop that, rather than waiting until more advanced stages. Well, that is not possible. First, because those drugs are not without side effects. Second, because they cost a lot of money.
Third, because some people at the steatotic stage, or even at steatohepatitis, will not run into problems, will not develop fibrogenesis. So you would treat them, I would say, unnecessarily. Then the challenge becomes to identify those people at highest risk of developing cirrhosis. Who are those people at highest risk? Well, it's those that have, according to what I said earlier, sufficient disease activity, sufficient inflammation, cell injury, which will trigger a sufficient signal for fibrogenesis. So you have to be able to identify those people who have the active form of the disease, but also who develop enough fibrosis that their fibrolytic process in the liver is being overwhelmed. Because once you start developing fibrosis beyond a certain stage, and here it's stage 2, the risk that you go even further is higher.
The whole idea here, if you don't want to treat everybody, it would be to select those patients at highest risk of progression to cirrhosis, and you can do that by doing a liver biopsy, measuring the three cardinal lesions, which are steatosis, inflammation, ballooning, and also fibrosis separately with a different scale, and decide which one has the highest inflammatory activity, and which one already crossed the threshold of fibrosis and say, "Okay, these are the people where I have to concentrate in treating them with pharmacotherapy." That's fine. You can do that, but you'll need a liver biopsy to do that. Or in view of such a large number of patients that are being exposed to the risk, liver biopsy is not a solution.
And you've seen that, the package insert for resmetirom or semaglutide do not require a liver biopsy because it would be practical unfeasible. You would have to find something else than biopsy, something that's non-invasive, that is able to reliably identify that little right part of the spectrum here where the chances for progression are highest. Next one. That part of the spectrum is shown on the right-hand side. These people who have sufficient histological activity, so a score of activity at 4 or higher, and who already have developed fibrosis, at least stage 2 fibrosis, so stages 2, 3, and 4. These are the people who will progress.
The first step, I would say, if you're dealing with a large number of patients that have metabolic risk factors, one, two, three, or several of them, is to identify among those the people in the red rectangle. The people who have the most concerning forms of active disease. This is very different, as I'm trying to explain, from the large majority of people who have one or several metabolic risk factors. Most of them will not have steatohepatitis, and among those who have steatohepatitis, not all will have the active form of the disease. That's shown on the left side of the slide. So there's a subcategory of people who are exposed to metabolic risk factors, which are a lot in society at large, which would have this profile of disease progression. And the difficulty of diagnosing them without a liver biopsy is remarkably high.
And that's a fragment of the population, for instance, the general U.S. population, it has been estimated to be around 4.4%. It doesn't mean all of them will have cirrhosis by the end of the month. But it means that they are at higher risk in the next 10 years, I would say. And that percentage goes higher if you look into people who have more severe disease metabolically, like type 2 diabetes, because we know that type 2 diabetes is associated with more severe steatohepatitis. So then the percentage goes up. The whole challenge is here. Try to identify these patients. Next one. That challenge is particularly relevant nowadays. Until now, we have no drugs.
Even if you would try to identify those patients, people would object and, "Well, but fine, but then even then what do you do?" Because other than lifestyle and dietary changes, you will not be able to do more, and you can always recommend those without having to do a very fine phenotyping of the patient profile. Now it changed because we do have drugs that have their own side effects, their own price, that have their own constraints in terms of how you take them, how you inject them. So it becomes very important to do that identification of the patients. As you all know, the way it works is that a drug that is shown to be effective has done so in a well-conducted phase III registrational trial. Which means what? Which means that these trials identify for inclusion a particular patient profile. Okay?
There's a lot of people are excluded because they don't fit that profile, and only patients who fit that profile are being included in these trials. If the trials are positive, you can use the trial data to say, "I will treat you with this drug because it has been shown to be effective." However, it has been shown to be efficient, not in everybody with the disease, but in those who fit the patient profile that served for inclusion in that trial. If you want to treat patients, you have to identify people who have the same patient profile. Otherwise, you will be treating either people where the drug might not work as well, or those that might not benefit in the same way in terms of tolerance, or those that will not progress sufficiently fast to justify for a therapy.
It becomes absolutely crucial to be able to find people that are very similar to those included in pivotal trials. Okay? That's the concept. Next slide. It turns out that both trials that were positive, whether it's semaglutide or resmetirom, had included the same type of patients with active MASH, so MASH score higher than 4, or higher, and with sufficient fibrosis stage 2 or 3, that is called significant fibrosis. They both included this type of patient. That's the challenge. You have to identify this type of patient. Good. How do we do that? By looking at what the scientific societies have recommended as tools for identifying those patients.
If you look at the most frequent tools like FibroScan and liver stiffness measurements through VCTE, or you look at ELF, which is a blood-based biomarker, these are recommended as a tool to identify those patients. The problem is that these are fibrosis biomarkers almost exclusively. They're able to identify the fibrotic part of the disease but not the activity part of the disease. Moreover, if you look at the database from these trials where people had a biopsy, were included in the trial because they had this particular aspect of liver injury with activity and fibrosis, and you look at their VCTE baseline values or ELF baseline values, it is very surprising to see that a lot of them did not have a liver stiffness value within the bracket that is now currently recommended for identifying these patients.
For instance, 60% of them had a FibroScan value outside the 10-15 kilopascal, and actually almost 20% had a very low FibroScan value, which in real world you would say, "Okay, these people are not at risk, so you send them back home." Less than 8 kilopascal, and a third of them had a high positive, false positive, high rate of false positive of FibroScan, more than 15 kilopascal. If you look at ELF, it's the same. Between 21% and 25% of them, depending on whether you're looking at resmetirom or semaglutide, had an ELF score very low, which by fibrosis standards would identify people with no risk of fibrosis.
If you use those and you look at what the performance would be in a trial where people had a biopsy and was read correctly, you can see that you miss a lot of patients or you miscategorize a lot of them. These are the figures that come from these 2 AASLD guidance publications that are listed there. Not only do they only identify part of the liver injury spectrum, histologically speaking, but also not sufficiently precisely. What do you use? That's where NIS2+ becomes interesting because it was built in order to identify people with both high level of activity and high level of fibrosis. Next slide. Before NIS2+, the choice was between a liver biopsy, which can be done in individual cases, tertiary care centers.
Problem is that most patients refuse to do it in larger settings, especially in non-tertiary care settings. Even in liver clinics, many people forgot how to do liver biopsies. They are not used to performing liver biopsies anymore. That is a problem. It cannot be used at a large scale. Then we have imaging, and I have shown you the limitations of FibroScan. Of course, MRI-based imaging techniques are very precise in terms of measuring PDFF, probably better than FibroScan in terms of measuring stiffness. There is a clear issue of availability and cost. Then you have blood-based tests, which were most of them developed for fibrosis and not for a dual activity fibrotic spectrum of injury. They are insufficiently performant to identify what we are interested in.
That was the state of affairs before a specific marker was created, and I think GENFIT was clearly the first ones that created a biomarker with the precise objective of that particular identification. Others followed with the FAST score based on FibroScan, but that has their own issues. Next slide. Things got a little bit better now that GENFIT has developed this biomarker and tested it and started describing its context of use and limits and diagnostic performance. This is what I am going to show in the next few slides. Next slide. It all started with a very intensive effort from stored biobank samples from both the phase II elafibranor trial and the phase III elafibranor registration trial, and a lot of effort from the team of statisticians at Bioinformatics at GENFIT.
They screened through a very large number of compounds and identified those that have the best correlation with the histological lesions that we were interested in. It came down to four different biomarkers, alpha-2-macroglobulin, which is also present in FibroTest, FibroSure, sort of a universal marker of fibrosis. YKL-40, also a marker of fibrosis, but also of activity. Then HbA1c, which is an indicator of glyco dysregulation, given that diabetes plays such an important role in defining the severity of the disease. Also they screened more than 2,000 miRNAs, and they identified miR-34a as being one that is particularly related to some transcription factors involved in lipogenesis, but also apoptosis and inflammation. Putting all these together created initially, historically, the NIS4 score, which had a very good discriminative ability for an aggressive NASH.
The association of these four biomarkers would perform better than each one of them individually. You can see on the right side of the screen. That is how it all started, and it has been done from a large number of samples from the studies. The advantage being that both the phase II and the phase III were read by a central pathologist, which was the same actually in both studies. The level of variability in pathology, which is never zero, but was reduced because of the central reading. The data are very solid in terms of the outcome it refers to, the histological outcome it refers to. Next one.
This was the initial NIS4, but then, of course, if you want to move a step closer to optimizing it and to scale it in terms of industry production, you would have to make some adjustments to it. One of the things that was dropped was HbA1c. Although it is an important indicator of the glycemic status, it can change over time. Actually, it can change in a few months only if the patient gets optimized anti-diabetic therapy. Then, of course, fibrosis doesn't change in a few months, so that would induce a significant bias because of fluctuations of HbA1c. Alpha-2-macroglobulin, it is a little less available. It is possible to do it in clinical practice, but less available, and it would necessitate processing the specimen in a different way.
Getting rid of these two and only keeping the most performant ones, the miRNA and the YKL-40, with some replacement of the glycemic status by the sex information, meaning male or female, allowed the company to devise a simplified version which had the same prognostic value, actually a little bit better, I will show you on the next slide. But also which had the advantage of being testable simply on a serum sample and not on a serum and a plasma sample. It eliminates the need for a plasma sample, which of course needs to, of course, include in use in clinical practice, in any lab path. This was published after the NIS4 publication, and a lot of work has been done to show that. Next slide.
It has a performance that is equal or even a little bit better, you can see on the left side of the direct comparison with NIS4, than the historical NIS4 biomarker, and much better than what was available at the time before anything else. It is a quantitative score going from 0 to 1. It has been calibrated that way, and low values indicate low risk of having the aggressive form of the disease. High values indicate high risk of having the aggressive form of the disease. Therefore, two thresholds can be devised based on the best sensitivity to identify people without the disease, and the best specificity to identify people with the disease in order to, in the first case, reduce as much as possible false negatives. In the second case, to reduce as much as possible false positives.
That creates the two thresholds that are shown here. The lower threshold for ruling out has 85% sensitivity, which is a high value for these type of indicators. The ruling threshold for advanced disease has 85% specificity. This is how these two thresholds work. Of course, in the middle, there is an indeterminate zone where you cannot really tell. This is true for any biomarker. You would have to repeat that in some time and see how things evolve in order to make decisions based on that. Next one. Once this had been established, an important, and actually a large amount of work, was dedicated to understand whether external factors risk to bias the value of NIS2+ depending on things that are not necessarily related directly to fibrosis. For instance, age is a very important factor.
Most of the biomarkers that are being tested for MASH, and actually for fibrosis in MASH, are extremely sensitive to changes in age. There is, in most of them, an increase simply because the patient gets older. Yes, fibrosis increases with age, but a lot of people can get older without having more fibrosis. It would be good if the biomarker would not be impacted by age. The same can be said, for instance, about aminotransferase. Any biomarker that has aminotransferase values in it, like FIB-4, could be confounded by situations where enzymes level up or are normalized because you lose some weight or because you stop some other medication, and therefore part of the information is being lost. As you can see here, this is not the case for NIS2+.
If you look at the upper right-hand figure, different categories from blue light to dark blue of age, so less than 45 all the way to 65. You can see that the diagnostic performance of NIS2+ for entry MASH does not change depending on the age bracket. Age is not a factor that would influence, independent of histology, the value of NIS4. Whereas it does for all the others that are shown here. I apologize if it is too small to see, but it is the case for FIB-4 and FS Alpha. You can see on the bottom panel that on the left hand, the specificity, and on the right hand, the sensitivity for each one of the biomarkers is also not changing much with age in NIS4 and NIS2+, but it does so dramatically for the other biomarkers.
It is clear that it is a much better situation if there are no compounding factors. This has been done extensively. It has been studied for diabetes, it has been studied for BMI, in addition to what is shown here. All this shows the robustness of this biomarker, which depends to the largest extent we can determine to the histological lesions and not to external factors that can bias the calculation. Next slide. Once these studies have been performed and shown and shared with the larger scientific community by the promoter, GENFIT, with help from academics like myself, then independent studies started to use and test on their own the diagnostic performance of this and other biomarkers. Here we will have two examples. On this slide, a U.S.-based example, and next slide will be European-based example.
On the U.S.-based example, this is a NIMBLE consortium for testing biomarkers for NASH , and this has been done so independent of any GENFIT collaboration. It does confirm the same diagnostic value in terms of area under the curve. You can see here for steroid hepatitis or at-risk steroid hepatitis, it performs better than any of the other ones that are being tested, with values that are pretty much in line with the initial publications for this score. The current studies performed with this biomarker confirm that the performance is entirely acceptable for the identification of these people, and particularly for the soft spot of this category of patients, which are the ones with early significant fibrosis of stage 2, which are the most difficult to diagnose.
Of course, the more fibrosis you have, the more performable these biomarkers are, but for stage 2, it is particularly difficult. This one achieves good discrimination even for early stages of significant fibrosis. Next slide. This was confirmed, in fact, done at the same time in the European consortium, the LITMUS consortium, who tested head-to-head in the same patients who had all these biomarkers that were secure performed at the same time, including imaging biomarkers. You can see here the result. The only one that was, in terms of area under the curve above 0.8 for at-risk steroid hepatitis, was indeed NIS2+, ranking highest among all those that are being tested, thus confirming the initial results provided by GENFIT, also corroborating the data from the American consortium. Both large consortiums found the same thing.
What I am showing here on this slide is a prospective study. Not only a prospective study, it is a prospective study with centrally read biopsies by a whole panel of pathologists. That does not eliminate variability in pathological reading, but it reduces that variability to a reasonable extent. Next one. I like to show this slide because, in my view, it confirms the reality of what this test is truly indicating. What we try to do here is to understand whether the three category of patients, based on these two measurements, people at low risk, people at middle risk, and people at high risk, correspond to a patient profile that could be corroborated with other diagnostic markers. In other words, yes, the new score is different.
Yes, those are distinct categories, but do they really reflect a different level of injury, a different severity of liver injury, or a different severity of metabolic dysfunction. The answer is yes, because if you look at the table, it is very interesting to see that the percentage of people with high liver stiffness measured either by FibroScan or by MRE, which are slightly different techniques, but entirely different from a blood-based biomarker. It shows that with increasing values of NIS score, there is an increase in the same direction of liver stiffness. The three categories identified by using these thresholds with NIS2+ clearly are categories of patients that have more fibrosis as measured by FibroScan, and also more steatosis measured by CAP.
Not only that, but if you look at indicators, surrogate markers of insulin resistance, like the HOMA-IR level, here again, the percentage of people with high HOMA, so very insulin resistant, goes from 35% in those with a low NIS score to 82% in those with a high NIS score. This composite index of YKL, MIR5 and adjusted on sex, identifies people who have a bona fide, more severe liver disease, however else you measure it with other totally independent metrics, and more severe metabolic dysfunction. It clearly separates people with different levels of liver injury. This is very reassuring because otherwise it would be just an arithmetical construct.
That gives a lot of credibility, I think, to the fact that biologically speaking, this biomarker, although it has nothing to do with stiffness, it has nothing to do with insulin resistance directly, identifies people with more serious disease. Next slide. Finally, it is a quantitative score. There are thresholds, you have these categories, but you can also use the quantitative measurement of this score because it goes from 0 to 1. That allows you to monitor patients during their course of therapy or else otherwise. This has been very nicely shown here in this study, where people, I believe those were. Yeah, from a result phase III trial of elafibranor. Basically, this was a negative trial in the sense that there was improvement with elafibranor, but not significantly. It was numerically higher, but still not significant.
Nonetheless, some people did improve histologically, and when that was the case, NIS values went down. That is true for the activity part, and that is true also for fibrosis part. You see on the left-hand side, the graph there, you see the line is dropping, the pink line is dropping. Those are people who improved the activity level histologically or the fibrosis level. Their NIS values went down, whereas those where there is no histological improvements stayed more or less the same. Which means that this could be used for monitoring purposes on therapies, as the score is indeed reduced in people who get better. In those who do not get better, the score does not change. This could be very helpful in identifying responders versus non-responders when you start treating in everyday practice. Next slide. Well, since. No, the one before.
Since all this data have accumulated, both from the sponsor and independently, of course, in the end, it has to permeate and to be integrated into clinical practice guidelines. It did not take long before the major societies recognized that there is a clear place for this type of biomarker for identifying patients at risk of disease progression. This is why they are now listed as options in clinical patient management in everyday clinical practice. That is the left part of the slide. Consequently, there are very trials, industry-sponsored ones, started integrating among other biomarkers, NIS2+ as well. It is very fortunate that now we have data coming, independent data coming specifically from the Akero, a firoticidin trial, from tirzepatide from Lilly, also from AstraZeneca, a GLP glucagon agonist, cotadutide.
All of them have been tested in these trials, and all of them have shown that the levels go down in patients who respond to the drug. You can see that although it is very small, you can see the details here in terms of the level of change with increasing doses of tirzepatide versus placebo. So minus 0.02 in placebo, almost no change, versus minus 0.34, which is significant on a scale from 0 to 1 in people who had the high dose of tirzepatide, who induced the highest antifibrotic effect. Independently tested in clinical trials, clear dependence of the score, of the value with histological improvement. Next slide.
Speaking of trials, using a tool that would better identify people who should undergo liver biopsy in order to be selected for the trial would be a big advantage for the sponsors, because by using this tool rather than just based on FibroScan values, age, ALT, AST values, which is what we use routinely, would help identify better the patients who should not have the biopsy because you will not find enough lesions. Those, conversely, where biopsy should be done, because there is a much higher probability of finding active fibrotic MASH. This is clearly the case. You can see here in red the proportion of patients with active is fast increasing with increasing values of NIS2+, and the proportion of patients with not enough histological injury in blue decreasing with increasing values of NIS2+.
Well, if you fix the thresholds here, you could very easily help clinical trial recruitment by better targeting people who should have a biopsy. That has not only clinical consequences for patients who do not have to go unnecessarily through a biopsy, but also has cost consequences, because that would help you reduce the number of biopsies to find the same number of patients to be included. That was calculated that the biopsies could be reduced by 30%, and there could be a 16% reduction in overall costs, only for selecting patients for the trial. This should be used in trials, and that is probably why most of these trials have used that. But currently implementing it so far. Next one. In this final slide, I would like to reiterate again two important concepts.
The first one is that among the very large number of patients at large with metabolic risk factors, we need to identify those that are at risk of having severe liver injury and that need to be referred to a specialist in order to confirm that. Or not, sometimes it is not. Okay? We need something for better referral to the specialist. Because the specialist cannot take care and explore all these patients that we have seen, how many there are in the society at large. The second point is that now that these drugs are available, we need to be able to find, once these people reach the specialist care, those that fit to the clinical profile that was included in the phase III registration trials. So that you use the drug in the context of use where it was designed to work best.
Those two things can be achieved to a various degree with existing biomarkers. You see that many of them are not performant enough for these two purposes, whereas NIS2+ was, with the current body of data, the most performant one for fulfilling these objectives, these dual objectives. I would like to say that the patient profile to be treated with these drugs is, of course, derived from, again, from the clinical trials, phase III registration trials. It is not something we invented. The phase III registration trials are dictated by the FDA. Fundamentally, the FDA agreed upon a patient profile that is amenable to be treated with drugs if they work. That patient profile is exactly the one I have shown.
You can see the reference here, official reference by the FDA, saying that these are the patients that could benefit from some type of therapy. That is why it is important to have this active fibrotic MASH in mind, and have a good tool to identify these patients. I think this is the last slide as far as my input. Thank you very much.
Thank you so much, Vlad, and thank you for your presentation, because we have seen how large is the unmet medical need and the amazing amount of data supporting NIS2+. I am sure we will all agree, the scientific validation is only one part of the story. The next part of the presentation will focus on the commercial value. We will see that to create the commercial value, we need to have a technology that would address the huge bottleneck in the current medical journey for the MASH patients. That is exactly what we will address right now, especially because we have seen, due to the availability now of the treatment, for sure, the bottleneck is more than ever the opportunity to identify, diagnose, and then start monitoring later on patients. It is all about the diagnostic journey.
That is exactly the question we asked to IQVIA. You can see here that now the next part will focus on insight coming from the market research we did with IQVIA, asking them how large is this new diagnostic opportunity, and what is the role that NIS2+ could play to unlock this new diagnostic opportunity in MASH. Next slide, please. This market research has been performed by IQVIA on the quantitative aspect, where they had interviewed 50 physicians from GPs, endocrinologists, hepatologists, and gastroenterologists. They made also a qualitative part for this market research with the interview of five key opinion leaders. The main purpose was not only to understand or to get data on the awareness and the understanding about the value of NIS2+.
We wanted really to better understand what is the current patient journey for the NASH in this NASH field, and what are the main bottlenecks. Bottlenecks that for now, despite the availability of the drug, does not create a huge market opportunity yet for the pharma companies. That is what we will address. Next slide, please. The first insight, and then I will share later on more details, coming out from IQVIA is quite clear. Since the successful launch of resmetirom 1 year ago, more than 1 year ago, this MASH field has already totally changed and has entered in a new phase. In this new phase, again, back to what we discussed previously, because one drug has been already commercialized, the second one has been now approved, the availability of the drug is not anymore this bottleneck, the main bottleneck. All is about patient identification and monitoring of patients.
Next slide, please. I will not go back to the patient flow that has been already shared, but I will only focus on the 90 million patients, the ones that have elevated hepatic enzyme and at least one risk factor. Because as it has been described by Vlad, definitively those patients, those 90 million, they should be considered as being suspected of MASH. The key question is how we can reduce this already huge existing gap that we can see here, meaning despite the fact the prevalence is telling us between 5 million to 7 million of patients are at-risk MASH patients, it means the ones that are fully aligned with the approval that has been made for resmetirom and selective GLP. We can see that only 50,000 patients have been treated after 1 year with resmetirom.
It means we have a huge gap between this large addressable patient population and the less than 1% of patients that have been already treated. That is the first insight. The key question will be how we can somehow change this gap, change the momentum. One key recommendation coming out from this market research, if we do succeed to consider those 90 million patients suspected of MASH to be systematically screened by PCPs or later on, potentially also by hepatologists or gastroenterologists, it will give really an opportunity to identify and then diagnose this patient later on as at-risk MASH patient. That is really the first insight. We should, all of us, the pharma company and of course the diagnostic company with the physicians, see how we can compensate this huge first gap. Next slide, please.
We have seen a huge gap between the large population, and the second huge gap is the one that we can see here. Despite the fact that still only 50,000 patients have been treated, so less than 1%. On top of that, you can see on the right side of the slide that 50% of the 50,000 treated patients have been off of label, either because they were F0 or F1 patients, so meaning patients without enough fibrosis to be considered as being MASH patients with risk, or already F4 patients, meaning already cirrhotic patients. In both cases, meaning for the 50% of off-label patients, the lack of stratification, the lack of awareness, and the lack of access to a relevant test, diagnostic test to stratify the population is the reason why we have this second gap.
So very few patients are treated, and even when those patients are treated, 50% of them are off-label if we do consider the approval made by the FDA. Next slide, please. What we tried to do also with IQVIA was to best understand what are the main bottleneck that could explain why so few patients are treated despite this large eligible population, so more from a qualitative aspect. We will see on the next two slides, so this one and the following one, that six bottlenecks have been clearly identified that may justify more than 80% of the gaps. The first important message, because we won't go into the details of this part of the presentation, five of the six bottleneck are diagnostic issues or related to diagnostic technologies.
It means, and that's the first confirmation, the important confirmation, because the drugs are now available, definitively the main bottleneck, as it could have been the case in the past, is not anymore the lack of availability of a drug, but definitively the capability for the market, for physicians to really diagnose and monitor those patients. I will just list the main bottleneck. Starting first is, of course, up to today, and that's something we can easily understand based on the presentation made by Vlad. Up to today and before NIS2+ will be available later on in the market via an IVD kit, we will come back to this topic. The market is missing a really relevant way to identify at-risk patients at scale. That's the first bottleneck today.
The second one, I will not come back to the topic and the presentation made on the liver biopsy, but of course, we are well aware, following the presentation, about all the issues related to liver biopsy. But the fact is, up to today, liver biopsy remains the diagnostic gold standard. We are seeing it's not suitable. Definitively, it's expensive. It's associated with risk for patients, but still the gold standard. The third bottleneck is about the limited physician's confidence in the current first-line blood test, and the one that is the more used being FIB-4. The main reason for that, and again, it has been part of the data shared by Vlad, this type of current first-line blood test have not been developed to really address, diagnose, and monitor the at-risk MASH patients. A concrete example, FIB-4 is not able to measure the disease activity.
So in the end, you get data, or you get a stratification of your patient with a very limited ability to detect the disease activity, what is definitively key for the at-risk MASH patients. Next slide. The next bottleneck is, for now, the test, the diagnostic test that is the most used being FibroScan. Here, two main comments came out from this market research. The first one, FibroScan is mainly impacted negatively by limited accessibility. Of course, it's easily understandable because FibroScan can be performed only by specialists. If we link with the 90 million patients that are suspected of at-risk MASH, of course, the bottleneck, the quantitative bottleneck, is easily understandable. But of course, on top of that, we have also a limitation in terms of performance with FibroScan.
Because this diagnostic test has not been developed with a specific focus on at-risk MASH, it can deliver specific data on fibrosis level. No MASH disease activity data will come out from any FibroScan that will be performed. So at the end, we do not have a fit between the use of FibroScan and what we are looking in the specific at-risk MASH population. The second bottleneck here may be somehow linked with the last one, meaning the lack of awareness. This lack of awareness is still a fact, not only at physician level, but also at the patient level. It means majority of the MASH, at-risk MASH patients, they are not aware, in some cases, they are sick, because they do not have so early symptoms. Without symptoms, without an early diagnostic tool, relevant diagnostic tool, at the end, you do not know that you are sick.
Because you do not know that you are sick, your physicians will not take care of this potential risk. That is a very negative circle, where this limited awareness of MASH leads to a missed or at least a delayed recognition of the disease and a delayed start of the management of the MASH patients. That is one of the key learning from today. The last one, that is the link between the lack of awareness or the low awareness, and up to last year, the lack of drug. This, somehow, the fact that no drug were available in the market, was not supportive of a high motivation by physicians with no incentive to actively identify and start managing patients. So at the end, the clinical and the economic value of a broad screening was really difficult to demonstrate without available therapy.
What has been now changed, with the launch of the resmetirom drug. What is clear, the summary of those six bottlenecks, it is for the market, for physicians, the next breakthrough in MASH is not another drug. Even if many of them will be in the market, that is what is expected. But the next breakthrough in MASH is definitely the ability to identify patients at scale, and thanks to a diagnostic tool, and thanks we hope so to a new subclass. Next slide, please. In this part, the key message coming out from the IgA market research is the collaboration, the partnership, and the huge investment that will come from by the pharma companies in terms of market building. It is quite obvious, and it has been well qualified in this market research, pharma companies will be the primary driver of the MASH market development. Why?
Because by launching new therapies, they want to increase the awareness and the education from physicians. The more they will increase the education of physicians, the more physicians will start prescribing, diagnosing, and prescribing treatment to the eligible patient that should be notified. The more they will diagnose, prescribe, the more you will need treatment monitoring. So it is a very positive virtuous cycle where this huge investment that I will share more details in the next slide, will, coming out from the pharma action plan, will support increasing the education and the awareness. More patients will be treated, and it will require more monitoring. Next slide. Here, in a little bit more detailed view, why the pharma companies, they will need scalable diagnostic tool in their market building action plan. Innovation has been already and is already in the market coming out from the therapeutic launches.
That's already done. The primary bottleneck, again, as it has been seen, is definitively the lack of relevant identification and very well-documented selection of patients that are currently eligible but are not well-identified. That's the first primary bottleneck. It means if we stop here a few seconds, if you try as a pharma company to build your market building action plan, the first lever will be definitively to invest in a huge implementation of the diagnostic tools that will help to identify and diagnose, and later on stratify the risk of your patients. That's definitively the first activity they will do in terms of market building. They cannot expect to have a huge acceleration in the commercialization of their drugs without having access to a better and earlier identification of the eligible patient that should be treated.
That's why a relevant diagnostic solution will be essential, and that's also the reason why we started many discussions in terms of potential partnerships with pharma companies, and I will come back later on to this type of activity. The key value also for the pharma company, and it's also in this slide, is how differentiated is NIS2+ in regards of the current blood test or imaging tests that are available. The good news for us from a qualitative view, we can see for the specialists, but also for PCPs and NPs, all of them following a quick presentation of NIS2+, they see the huge differentiation compared to the current tests that are available, and especially if we compare with the other blood-based panels. You can see here the three main value that have been identified by the physician.
First, NIS2+ will give accessibility at any point of care. It means definitively, and of course, it will be also linked to the development and the commercialization of the IVD kit. It will become easier for patients and physicians to go to the point of care and to get your blood test outcome, the NIS2+ outcome. The second big added value that is seen by physicians is this dual sensitivity for, on one hand, the inflammation, and on the other hand, the fibrosis staging. Again, linked to the presentation made by Vlad. I'm sure we are all aware now it's critical because for selecting the right at-risk MASH patients, you need both data, meaning inflammation and fibrosis staging. The third added value by commercializing NIS2+ will come from the workflow simplicity also for PCPs and NPs. Again, back to what has been said earlier.
Here, if we are trying to change the current MASH journey for the patients, starting first with an important screening activity at PCPs and NPs to better refer or to refer more selected patients to the specialist, this workflow simplicity will be key for the future success of NIS2+. I will not come back to the competitive landscape, I think we shared already many data. The summary of this differentiation, it's also the opportunity to identify a new value proposition and clearly identified by PCPs and NPs as referral efficiency by using a test that will give you both disease activity and fibrosis staging. It's a huge plus in terms of screening, referral, tool, and activity that we would like to implement later on. Next slide, please.
Only one comment, because on the previous slide it was the differentiation seen from a qualitative perspective in this IQVIA market research. It is not often that you can link a qualitative market research with real data. This slide has been already shared and presented by Vlad Ratziu. If you link both, you can see the view, the differentiation view, shared just in the previous slide. The differentiated data coming out from the LITMUS data, but also the NIMBLE work that has been done. At the end, we have one clear message. If you combine the plus that NIS2+ will bring to the market, so inflammation data and fibrosis staging, that is exactly the mechanism of action of all the drugs that have been already commercialized or that are currently in phase III clinical studies.
It means we have a perfect fit because the differentiation, the positive differentiation NIS2+ will bring to the market is exactly what will be needed for the pharma company, first to select the right patients, and then later on to monitor the efficacy of their mechanism of action, the efficacy of their therapies. It is a perfect fit between our design, the data that we have been sharing, and definitively the positive perception by the market. Next slide, please. If we go a little bit further in terms of data, again, we have seen the medical need. If we focus now from a diagnostic side, maybe the first important message on this slide. Of course, the first activity with NIS2+ will be to diagnose a new patient that potentially can be treated.
Here you can see in terms of volume, if we look at picture 2033, we should get 1.7 million in volume coming out of the diagnosis testing. Part of the base case, it is also a huge volume will come out from the monitoring activities and the monitoring testing with NIS2+. The split will be more or less 75% coming out from monitoring, 25% of the volume coming out from the diagnosis. The total picture will be 7.4 million NIS2+ volume combining the LDT testing and the IVD testing.
Then you can see on the right the value that those monitoring aspects, key in terms of volume, key in terms of the size of this opportunity, will bring value on one hand for the pharma company, because they will need to get access to monitoring data to engage with payers, to confirm the efficacy of their drug with real world data. For GENFIT, of course, then we switch from a diagnostic business with only one test, to a recurring testing revenue via the monitoring aspect. It is a totally game changer with this focus on the monitoring development. The next slide, please. One comment on the split between the LDT market and the IVD. First of all, at GENFIT, we do not see at all any competition between the LDT and the IVD market.
We started many years ago to develop and working with our partner, it's public information, with Labcorp, because it gave us the opportunity to access earlier to the market, to generate many additional data, to give access to the pharma company to somehow already a test that has been industrialized. We have been able to perform thousands of NIS2+ tests already. This access, this early access to the market via the LDT, has been quite important in our journey at GENFIT. Starting a few months ago, and with a targeted completion date in 2028, we have started already our activity to develop the IVD kit. Of course, then in the future, we will combine both an LDT business and an IVD business. That's the combination of the two that will optimize the access to the market, the opportunity to partner with pharma companies.
Thanks also to the LDT that gave us already access to the reimbursement. Again, we'll come back to that just in the next slide. Thanks to this work, Labcorp has been able to get the reimbursement by Medicare. As you can imagine, the big part of the dossier that has been evaluated and granted by Medicare will support all the future direction also for the IVD development. The same in terms of technical development, all the work that has been done with Labcorp will be more or less 70% of the IVD dossier that will be needed for the approval of the kit in the future. That's why we are first, definitively, we see both as a complementary business model, and we are really confident, thanks to the work already done, that we will be successful to launch the IVD kit in 2028.
Next slide, please. Now we will give you a little bit more of precise data to support our guidance and to better understand what are the assumptions behind our guidance. To the next slide, please. Again, few words, but just to explain, and not to come back to the 10 years of development, but as it has been said by Pascal as introduction, this diagnostic journey at GENFIT started more than 10 years ago. Coming back to where we are today and what are the key activities that make us quite confident in the future success. First of all, it has been said, that's the recognition by independent consortia like LITMUS and Liver Forum. We have already been able to deploy in large scale clinical trials, more than 20 phase II of them, three used NIS2+ and NIS4 also.
On top of it means definitively with Labcorp, we have been able to perform thousand of tests already. So in terms of industrialization, we have a huge expertise, and we know exactly how to handle with the good quality approach in terms of execution of this test. Two outcomes. We have already many scientific publication, and it's also important because to get an IVD approval, you need to bring in your dossier many clinical data. Often the challenging part of the discussion with the FDA or the EMA is based on the lack of relevant data. Here, based on the scientific publication, based on the clinical trials, based on the evaluation made by Medicare for the reimbursement, the evaluation that has been made with our partner to develop the IVD kit makes us very confident in our opportunity to get this kit approval quite soon, meaning early 2028.
If we move to what will happen between what started already in 2026 and up to the end of 2028 on the commercial aspect. I hope at the end of this presentation, the question for all of you will not be anymore, do we have a test that will bring value to patients, to physicians, to the market? The only question should be, how fast will be the commercial success? Because we started already to meet some of the goals, to achieve some of the goals that we have identified in terms of commercialization. The first one, our test is already available in the U.S. market via Labcorp, so we are already commercial stage. The second one, always key, you may have a good test, a reliable test. If you do not get it reimbursed, it becomes very difficult in terms of commercial opportunity.
We got already this reimbursement of NASHnext granted by Medicare for patients meeting the eligibility criteria in this quarter. For the two last goals, critical in terms of commercialization, they have been already started. We need to be successful in terms of strategic partnership with the major pharmaceutical diagnostic players, but all those discussions have been already started. Many activities have been already partnered with pharma companies. It is, of course, I am considering the clinical studies, I am considering all the meetings to be included in the guidelines. Even if we did not discuss yet any partnership, activities and discussion have been started and some activities have been already achieved.
In terms of deployment and development of the IVD kit, again, I told you already, quite confident because the action plan has been started few months ago, and part of this dossier will be mainly based on what has been already performed for the LDT development. Again, 2028 will be a key year for us. If we go to the next slide. Next slide, please. Yeah. We can go directly to the next one because it is just a summary in terms of volume that we have said. The next slide. If we combine again the scale of the opportunity, the clinical evidences and the market need from a physician perspective and how differentiated we are, we would be, and we are already. Here you can see we plan for a peak sales annual laboratory market opportunity around EUR 1.5 billion in 2033.
With an uptake, we plan to be above EUR 1 billion in 2031. It means definitively we can see, and here we are really talking about the estimated revenue to be part in our lab, meaning the LDT partner or the IVD partner, not the private labs. Of course, the royalties that we do expect at GENFIT will be based on this peak annual laboratory market opportunity. Again, the big number, EUR 1.5 billion. If we go to the next slide. The third message, and we will try to summarize the main assumptions that we have used to build this forecast. I would like just to make sure that at the end you will understand our approach aims to be as much as fact-based.
By example, of course, when it is about the prevalence, it is quite easy because all the data are published data in terms of official numbers that we have seen, figures that we have seen in terms of prevalence. But we have now conservative and we took also a conservative approach. One is about the differentiation, because we have seen the big majority of the prescribers where they get a presentation and information that means NIS2+. They see clearly the differentiation and the value created by the NIS2+. Nevertheless, we took only one-third, 35% of frontline doctors testing will be done via NIS2+ at peak sales. So it is a conservative approach in terms of differentiation. In terms of market access, we took again a conservative approach. I mean, in terms of payer coverage, we took only, we take only 60% after four years.
We know, and especially in the U.S., as soon as you get the Medicare coverage, normally in the next, the following two years, you should reach, you should at least target 80% of coverage. So taking 60% of reimbursement coverage at year four is definitely for us a conservative approach in terms of market success. We included the monitoring aspect in the forecast and we explained why. In 2028 will be definitively a year, the critical year for the commercialization of the IVD kit. So they are the main assumptions here. The last comment, maybe you have seen at the start of the forecast, in 2026 and 2027, we have a low and slow start.
The main reason for that being we need to be successful via the action plan that we have just shared through the partnership with pharma companies, with IVD players to transform this market. To do so, we will focus mainly on qualitative objectives in 2026 and 2027. Nevertheless, we do expect to get EUR 10 million laboratory revenues in 2027. Then based on the kit commercialization, a huge acceleration starting in 2028. Next slide, please.
Thank you so much for your time and your attention. We are at the end of the presentation. I am more than welcome to your questions now.
Great. Big thank you to our speakers. At this time, we will be conducting a question and answer session. If you would like to submit a question, please use the Q&A text box at the bottom of the webcast player. We are a bit over, but I think we have about 10 minutes left for questions. Our first question comes from Thomas Smith at Leerink. Thomas Smith says, "Hi, team. Congrats on the progress and thanks for putting together this event. For Dr. Ratziu and the GENFIT team, can you elaborate a bit on the history of NIS4, the level of adoption of this blood-based test in the U.S., and some of the learnings from this experience, and what gives you the confidence that NIS2+ adoption will be better in comparison?
I can start. The issue I think, as was alluded to by Esther with NIS4, is that we had a great product on the market that did not exist. Because at the time of the invention of NIS4, if you want, there was no drug in the market. With no drug in the market, there was little incentive to find those patients, especially those at-risk MASH patients, because what would you do with that information, except say, you need to sort of watch your diet and exercise a little bit more, which was what you would have said to all patients anyway. So very little incentive. Nevertheless, where Labcorp was very successful is in talking to the only folks that had a very strong interest in finding those patients. Vlad actually alluded to that group, and that is the pharma companies.
Because those pharma companies were actually conducting trial, and they had to identify those patients for inclusion in their studies. Because those were biopsy studies, they had to do biopsy to a large number of people just to identify those that could be randomized. Of course, we know and we have lived that in our own study. Sometimes you had a fail rate in excess of 70%-75%, which means you were doing a lot of unnecessary biopsies. Of course, it is an invasive procedure, so it is not good for a patient. It was also a waste of money because biopsies are quite expensive, especially in the context of a clinical trial. What Labcorp did was position NIS as a pre-screening tool.
Because the data was very clear and quite frankly, the evidence was overwhelming, we had a very large proportion, actually, almost all of them, that started to use NIS as a pre-screening mechanism just to avoid unnecessary biopsy and save money and sort of negative transfer of patients in the process. I would not say that those years with NIS4 were not important for us because what it did, it was not the cash generated, obviously, but it was the fact that all those pharma companies got exposed to a technology could see for themselves that it works. Of course, now that they are being approved, or on the verge of being approved, they can of course take that learning into their market building efforts.
What we may add to the success story during this NIS4 period, quite quickly we took the decision, and that is something we discussed with Labcorp, to focus a lot of the activities on the payer aspect. It is a huge achievement when they got this Medicare reimbursement sharing not only the NIS4 data but also a big part of the NIS2+ data because the discussion has been also started with Medicare NIS2+, and it is a big plus to why we are confident for the future, because it is always a long journey and sometimes a difficult journey. Now the baseline for the future commercial success based on this Medicare reimbursement of the NIS technology is for us a huge commercial achievement that now we have to translate in a successful sales with NIS2+.
The last thing I would say is for me, it all boils down to do you believe in the success of this market, therapy-wise? If you do, you have got to believe that pharma companies will be successful in their market building effort. I just do not see how you could build that market without leveraging heavily a diagnostic tool. Because at the end of the day, I think both speakers said it, you have to identify those patients, and the only sort of practical way to do it is to do it through those blood-based tests. Therefore, it comes down to I do not think there is any question that that market is going to be huge unless you do not believe that the MASH market itself will be big. But if you do believe it will be big, then the diagnostic/monitoring market has got to be big.
The question becomes which test is going to be used? The reason why we feel that pharma companies are going to push our solution is not because they like us, although we are likable, but it is more that this is the test that will allow them to get to the large mass of the market, which is the S2 patient. Because obviously you have a lot more S2s than S3 is the approved indication. If you are looking for patients with low fibrosis, those tests that were developed to look for fibrosis very clearly are not going to work as well. Hence, the test that will look also at that inflammation part, which is why those patients are in the approved indication in the first place, is going to be the preferred approach.
Great. Thank you. Our next question, also from Tom Smith at Leerink. For the GENFIT team, can you clarify the royalty rate that you receive from Labcorp and your expectations for revenue from the NIS2+ test to GENFIT?
Yes. We understand the question, obviously, from a modeling perspective. We've not disclosed the exact amount, and we will not disclose the exact amount with IVD either, because as you can imagine, those are business development activities. Usually our partner doesn't really want us to discuss those numbers because otherwise it will put us at a disadvantage in future negotiation with other potential partners. Likewise for us, for example, IVD would decide to work with several players and hence we don't want to give the exact terms. However, what I can say is that it's going to be within industry benchmark. Industry benchmark typically for IVD are between 7% and 15%, is not that different for LDT. That's where we are, and also where we will be.
Great. Thank you. Our next question comes from Sushila Hernandez at Kempen. Could you share color on the initial rollout via the Labcorp offering? How many tests have been sold? What income did it generate for GENFIT? Is Labcorp working on getting reimbursement in other geographies, and what efforts are they putting in to get private payers to pay for the rest?
I would say, first of all, it's way too early. We don't have a lot of those information. We need to realize that Labcorp got the official notification that it was active as of mid-August. But in fact, in terms of actual implementation, it's being rolled out as we speak. We know some centers have not received the official notification in the system, et cetera. When we were asking them, "Okay, how is it starting?" They were like, "Okay, you need to be a little bit patient because the implementation does take a little bit of time." It's too early to tell qualitatively what we've heard. It was very well received and that they are very excited. However, we don't have numbers to share at this point.
Again, as you have seen in the initial ramp up, we are a bit conservative for the coming months. We think it's going to take some time to start, which is why we're guiding that in terms of actual royalties to us, it's going to be single digit million next year, so not really that significant. However, it becomes double digit in 2028 and then accelerates quite quickly.
The payer's coverage, maybe do you want to-
Well, payer's coverage, yes. What we got, again, is more qualitative, but they are doing a lot of efforts to get additional payer coverage, and so far they've had some good success. There was also a question about ex-U.S., I think. So ex-U.S. is mostly IVD because the LDT model does not really exist in Europe. For the rest of the world, it's going to be IVD, which means it's not Labcorp doing it because they are focused on LDT.
Great. Thanks, Pascal. Another question from Sushila at Kempen. Could you elaborate on the next steps for the IVD kit until the launch in 2028, and does it require capital from GENFIT?
Yes, I can elaborate. As Pascal said, it's a program that we have started already a few months ago. I think it's important to realize that in the very early stages of the development of this technology, we were thinking about IVD. A lot of the things we did at the time, we did it with in mind the fact that we wanted to go IVD at some point. We started to work on the sort of technical feasibility a while back, which is why, A, we feel very confident about the 2028 sort of deadline that we've given. B, we think the sort of technical risk is very low. The fact that we've not yet announced who our partner or partners are in IVD is just that the commercial discussion is still ongoing, but the technical work is well underway.
The other point that is important is that a lot of the efforts that went into developing the LDT and a lot of the data that is in the LDT package can be repurposed for IVD. When you look at your typical sort of IVD development, those can be considerably shortened. It is not developing something de novo. It is actually taking something that is fairly developed already and adopting it for IVD.
Great. Thanks, Pascal Prigent. This is going to be our last question from Thomas Smith. A lot of questions here, and we are running over time. For the GENFIT team, with respect to the EUR 1.5 billion peak annual lab market opportunity, how much of this growth is dependent on the development of an NIS2+ IVD? What of the EUR 1.5 billion figure between IVD and LDT, and what is the path to developing and driving uptake/reimbursement for an IVD?
Yes. IVD, I would say roughly two-thirds. One-third, two-third LDT, IVD. Obviously IVD is really important. I think what is really key is to understand that that market is going to be developed not so much by our diagnostic partner, be it LDT or IVD, but by the pharma companies. In fact, when we discuss with pharma companies, they do not ask many questions about whether the test is doing what it is supposed to do or whether it is patentable because I think the data speaks for itself. Their only question is, can you make enough of it? Because they want to go big, and they need us to be able to respond for us or our partner, which is why the IVD is really important, because for those that are more sort of interested in the mass market development, especially the GLP-1 players, they need an IVD.
I think the development of that market is making sure that the kit is available, and making sure that it is in every lab, and that is where our partners of key competencies will play a role. But the demand itself is going to be coming from pharma. I do not think any of our sort of diagnostic partner is going to do DTC, for example, or any sort of TV campaign in the U.S. I very much think that the pharma companies will, and that they will encourage everybody with risk factor to get screened. Then the question is, if they do decide to get screened, will they have easy access to an efficient tool? And that is the role that our diagnostic partners will play, less so market building.
Great. Thanks, Pascal. This concludes our Q&A session from today. We know we didn't get to everyone's questions, but GENFIT will answer them at some point. But for now, I will turn it back to Pascal for some quick closing remarks.
Thank you very much, Tara. Thank you very much for everybody for sticking with us during this presentation. We are excited because we see a great opportunity ahead of us. It's not often that you have such a very important market that is burgeoning and at the same time, a tool that we believe is uniquely positioned to help that market develop. It's great to see the interest. We had a record attendance. Great to see the questions from Tom and Sushila. I'm sure there were more and we'll look at those and we'll try to come back to you with the answers. Stay tuned. We will have more coming in ways of partnership probably before the end of the year. Again, at your disposal to discuss this in more details as time passes. Thank you very much.