Good day, and welcome to the Genfit conference call. Today's call is being recorded. At this time, I would like to turn the conference over to Stefanie Magner. Please go ahead.
Hello, everyone. Thank you for joining us on our 2023 half year earnings call and corporate update, following publication of our half year results press release. Press release can be accessed via our website at ir.genfit.com in the News tab. Joining me on this call today are Pascal Prigent, CEO, and members of the management team. Before we begin, I'd like to remind everyone that statements made during this conference call, including the Q&A session relating to Genfit's expected future performance, business prospects, events, or plans, including ability to meet and obtain milestones through our licensing agreements, obtain regulatory approvals, anticipated timelines for clinical development, study enrollment, and data release dates, as well as expected cash used in our operational activities and cash runway, are forward-looking statements as defined under the U.S. Private Securities Litigation Reform Act of 1995.
They're based on our management's current assumptions and estimates, which, although believed to be reasonable, are subject to numerous known and unknown risks and uncertainties, which cause actual results to differ materially from those expressed in or implied or projected by the forward-looking statements. For further discussion of the material risks and other important factors that could affect our business operations and financial results, please refer to those contained in our most recent filings with the SEC and AMF. These forward-looking statements speak only as of the date of this webcast. Other than is required by applicable law, the company does not undertake any obligation to update or revise any forward-looking information or statements, whether as a result of new information, future events, or otherwise. Following the prepared remarks, we'll open the call up for questions that will be addressed by Genfit management.
Please limit yourself to one initial question to allow time for others. I now turn the call over to our CEO, Pascal Prigent.
Thank you, Stefanie. Well, this is an exciting time for Genfit, as we are now entering a new era for the company. Indeed, we are now pivoting from a model that was centered on elafibranor to one where we will be focusing on the development of a promising portfolio of drug candidates targeting primarily ACLF. Elafibranor was discovered at Genfit, and the company took it all the way from drug discovery to phase III. These years of development culminated earlier this year when, at the end of June, we announced positive data from the 52-week double-blind treatment period of the pivotal ELATIVE phase III trial of elafibranor in PBC. As a reminder, the trial met its primary endpoint with a statistically significant higher percentage of patients achieving a clinically meaningful cholestasis response compared to placebo.
Indeed, 51% of patients on elafibranor 80 milligrams achieved a cholestasis response, compared with 4% on placebo. It means that we saw a strong treatment effect, with approximately thirteen times more responders on the active arm compared to placebo. We hit the first key secondary endpoint, normalization of ALP at week 52, which was also highly statistically significant. Although the other key secondary endpoint did not reach statistical significance, we observed a trend for pruritus improvement. The study showed that elafibranor was generally well-tolerated, with a safety profile consistent with that observed in previously reported studies. We believe these findings already demonstrate that elafibranor can be a very valuable option for patients with PBC. We have seen some analysis speculating about the competitiveness of elafibranor ELATIVE to other alternatives in development, but we believe it is an exercise of limited value at this stage.
Comparing partial high-level results across different studies without a full understanding of potential design differences or population differences is not scientifically sound. Much more meaningful conclusions might be possible after more data is released at upcoming scientific conferences. As far as Genfit is concerned, we are now finalizing the transfer of the elafibranor program to Ipsen. Ipsen is now fully responsible for the next steps, including scientific communication, regulatory filing, commercialization, and potential additional developments. We are very pleased by Ipsen's continued commitment to the program. We believe that their strong commercial track record and international footprint will enable them to make the most of the opportunity and achieve significant commercial success. As elafibranor becomes an Ipsen program, it essentially turns into a potential source of revenue for Genfit.
As per our agreement with Ipsen, we are eligible for up to EUR 360 million of milestone payments, and the first payment could start as early as later this year. Of course, the potential approval and successful launch would trigger additional milestones and a regular stream of revenues through the royalties. As I was alluding to earlier in this call, we are now shifting our strategic focus from a single program to a diversified portfolio of programs. The development of elafibranor brought us two things. First, over the years, we built R&D knowledge, capabilities, networks, and strong partnerships in the field of liver disease. Second, the successful PBC program and subsequent partnership with Ipsen brought us the funding to build and now to develop a diversified pipeline that we have strategically put together over the last 18 months.
Genfit's focus now fully turns to our expanded pipeline in rare and severe liver diseases with a high, unmet medical need, with a primary focus on ACLF syndrome, also known as acute and chronic liver failure, where we are running multiple programs with several key inflection milestones to look forward to. Our ACLF franchise now comprises five assets, all based on differentiated mechanism of action, leveraging complementary pathways through different modes of administration. So we have VS-01, NTZ, as well as a newly in-licensed SRT-015, that we licensed from Seal Rock Therapeutics, in Seattle, and CLM-022, that we licensed in from Celloram, in Cleveland, as well as VS-02, in hepatic encephalopathy, which is a condition closely associated with ACLF. Development stages of these different programs range from preclinical to phase II.
So let's start with VS-01, our potential first-in-class liposomal-based therapeutic. It's currently being evaluated in the international UNVEIL- IT phase II, open label, randomized, controlled multicenter proof of concept study to assess its efficacy, safety, and tolerability, in addition to standard of care, compared to standard of care alone in adult patients with ACLF grade one and two with ascites. The first patient was randomized in early July, and we expect interim data to be available in the first half of 2024. Given the high unmet need in this indication and the orphan drug designation obtained from the U.S. FDA for VS-01, it is expected that the program may qualify for some of the expedited regulatory pathways provided by health authorities.
In May 2023, we presented positive data at the Digestive Disease Week, 2023, from an NTZ phase I study, demonstrating that it was generally well-tolerated with a favorable safety profile in subjects with moderate and severe hepatic impairment. Preliminary data from a similar phase I study conducted in subjects with renal impairment also support a favorable safety and tolerability profile. So those studies enable us to move forward, but for NTZ in ACLF, Genfit has decided to pursue the development of a new nitazoxanide formulation, which will permit greater dosing flexibility. We have therefore revised the expected launch date of a phase II clinical trial to the first half of 2025. In the first half of this year, we further expanded our ACLF franchise by in-licensing two additional exciting programs.
In May, it was SRT-015, an ASK1 inhibitor, in an injectable formulation, and more recently, in July, CLM-022, which is a first-in-class inflammasome inhibitor, that we licensed, as I was saying, from Celloram. So ASK1 inhibition has shown several potentially beneficial effects that may be relevant in ACLF, such as blocking LPS-associated impaired inflammatory response, reducing the ROS-related immune response, reducing apoptosis, reducing release of a pro-inflammatory cytokines, reducing fibrosis, and protecting macrophage mitochondrial function. A first-in-human study is planned for SRT-015 in the second half of 2024 to support a proof of concept study in ACLF patients as early as 2025. CLM-022 enabled Genfit to develop a potential of an inflammasome inhibitor into a liver disease indication for the first time.
We will provide updates on this program as it moves closer to an IND. The last asset in this franchise is VS-02, which is a urease inhibitor, which is being developed in hepatic encephalopathy, which is one of the major complications of advanced liver disease and portal hypertension and is closely associated to ACLF. IND enabling studies are targeted to be completed in 2025. We are very pleased to have created a unique portfolio in ACLF. There is a very high unmet medical need, and we believe our deep pipeline provides us with a unique opportunity to drive value rapidly and potentially bring new hope for these patients. Besides ACLF, we are running our phase Ib/2a program for the treatment of advanced KRAS-mutated cholangiocarcinoma, evaluating our novel clinical-stage autophagy inhibitor called GNS561.
The first patient is expected to be screened in the last quarter of 2023, and the first biomarker data, expected to be available as early as first half of 2024, should support preparation of further evaluation of efficacy with the optimal doses of GNS561 and trametinib in the phase IIA part of the study. Other than ACLF and CCA, we have an earlier stage program underway with VS-01, this time developed for acute hyperammonemic crisis associated with inborn errors of metabolism in urea cycle disorders and organic acidemia, or OA, where IND enabling studies are targeted to be completed in 2024.
Last but not least, we will continue to explore partnerships opportunity for our NIS2+ technology, with a goal to release an IVD test powered by NIS2+ on the U.S. and European markets. We believe this market is bound to grow now that approval of NASH drugs seem to be on the horizon. In 2023, we've continued to have scientific publication and presentation at scientific events on NIS2+. In conclusion, I'd like to say just a few words about Genfit's corporate social responsibility. As this was recognized by three independent stakeholders. In January, we were granted a Prime status by ISS. In June, Genfit was classified by Oddo BHF research as best in class for ESG, based on two main criteria, activity impact and ESG maturity.
In July, Genfit was awarded a gold medal by EthiFinance and ranked 2 out of 75 companies in the biopharmaceutical sector in France. These recognition are a testament to a company-wide effort in implementing CSR initiatives and ensuring transparent communication about them. In the second half of 2023, Genfit will continue to reaffirm its commitment to associate all its social responsibility and sustainable development. I will now highlight a few key financial elements from today's press release, but I won't get into details since all numbers were already described in the documentation provided. As of June 30, 2023, Genfit had EUR 111.8 million in cash and cash equivalents, compared to EUR 140.2 million as of December 31, 2022.
The decrease in cash, cash equivalents, and current financial instruments between December 31, 2022, and June 30, 2023, is largely the result of our research and development efforts, notably for ELFIDENCE phase III clinical trial with elafibranor in PBC, UNVEIL-IT of phase II clinical trial for VS-01 in ACLF, the study for GNS561 as part of our cholangiocarcinoma program, as well as the continued development of nitazoxanide in ACLF. As we continue to advance our current product candidates, conduct preclinical studies, as well as clinical trials, we expect that our cash use in operational activities will amount to about EUR 60 million in 2023. This amount does not include potential expenses we may incur in future business development activities, such as in licensing.
Genfit's finances remain secure until the Q4 of 2024, based on current assumption, excluding exceptional events and in particular, excluding potential milestone payments, which Genfit can expect to receive following the positive interim readout of ELATIVE. If Genfit were to receive milestones related to a successful ELATIVE study, according to potential regulatory submission and approval, as well as potential commercialization, we expect that company funding may be secured far beyond 2024, obviously, assuming that all planned outcomes are favorable. I guess we are now ready to take questions. Operator, I'll let you give the instructions to the audience. Thank you.
Thank you. If you would like to ask a question, please signal by pressing star one on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, please press star one to ask a question. Our first question will come from the line of Evan Wang with Guggenheim Securities. Please go ahead.
Hi, guys. Thanks for taking the question. Just have a question on elafibranor. It seems like both Genfit and Ipsen are pretty confident in, you know, some nuance heading into AASLD. So just, you know, interested to hear, you know, what kind of analysis we could look forward to at AASLD, whether it be on baseline characteristics, different measures of biochemical response or different cuts in seladelpar. Thanks.
Hi, Evan. Well, you know, at this point, we can't really comment further. I think both CymaBay as well as Ipsen are going to present more data at upcoming conferences. And as the sort of full data is made available, people will have a better idea about, you know, how the two products profile are. I think at this point, we just can't comment on what Ipsen is going to present, but AASLD is not too far out, so there's not much time to wait.
Got it. And if I could ask one follow-up. You know, great to see the ELFIDENCE confirmatory trial is underway. Does that trial provide an opportunity to look at pruritus in a larger patient population?
So this trial is primarily designed to show the impact of the treatment on the hard clinical endpoint to demonstrate that the target that are in the phase III are indeed productive of hard clinical endpoint. That being said, it is also an opportunity to gather much more data from a larger group of patients. So I fully expect Ipsen to be communicating on various elements for this study.
Thanks. I'll just thank you.
We will take our next question from the line of Sushila Hernandez with Van Lanschot Kempen. Please go ahead.
Yes, thank you for taking my question. First of all, could you just repeat when you expect the first milestone to come in from Ipsen and what triggers them? And as a second question, are you expecting to further build out your ACLF franchise? Thank you.
Hi, Sushila. Well, actually, we hope to get the first milestone, or we hope to meet the first milestone before the end of the year, and the first milestone linked to regulatory filing in the U.S. and in Europe. As your second question is concerned, no, I think we now have a pretty deep portfolio in ACLF. As far as I know, no other company has more than one program in ACLF, and we have now five. The idea is not to continue to build that, but really to execute on the development of the first program.
That's clear. Thank you.
Our next question comes from the line of Ed Arce with H.C. Wainwright. Please go ahead.
Great. Thanks for taking my questions, and congratulations on the data earlier in the quarter. I wanted to ask about your growing ACLF portfolio. You know, you have this a new ASK1 inhibitor with data potentially in 2025. I'm just curious, you just brought this in. I'm wondering if you can explain to us what specific aspects to the profile of this asset gives you confidence in ACLF? And how does this sort of inconclusive data previously with this target in NASH have anything to do, if at all, in ACLF? And then I have a follow-up.
Yes. Hi, Ed. So I'll let Dean comment on this specific ASK1 inhibitor and how it differed from the one that was tested in NASH. I just want to maybe preface Dean's comment by talking just a little bit about the importance of unmet medical need in ACLF. I mean, as we know, all liver disease sort of, you know, lead to cirrhosis, regardless of the etiology, right? It could be NASH, it could be alcoholic hepatitis. It could be viral hepatitis. They all lead to cirrhosis, first compensated and then decompensated cirrhosis. In the U.S., it's about 300,000 hospitalized decompensated cirrhosis per year.
About a third of those, or 100,000, go to ACLF at that stage three. If you just look at ACLF one and two, it's about 80,000 ACLF episodes every year in the U.S., and probably about 150,000 in Europe. The mortality is really high, 25% fatalities at 28 days for ACLF one, 50% for ACLF two, and currently there is no approved product for this condition. The unmet need is really high. The cost to public health is also really high since it obviously mobilizes a lot of ICU resources. It's really important to try and address this.
Yes, one is underway, and then we brought those two assets, and I let Dean comment on, on specifically on SRT-015 and ASK1 inhibition.
Hi, Ed, thank you for the, question. So the SRT-015, as, as you just mentioned, is an inhibitor of ASK1. I think the audience probably know ASK1 inhibitor is best at the position in NASH. And when it's positioned in NASH, I think, most of the focus was looking at, the inhibitors to be able to impact on fibrosis. However, I think when, when you look at the mechanism of ASK1 pathway, we know that when ASK1 is activated, it leads to activation of downstream pathways like p38 JNK. And that pathway, when it is chronically activated, which is what you have in, in chronic liver diseases, including cirrhosis and late-stage cirrhosis, decompensated cirrhosis.
Beyond the fibrosis, there's going to be benefits because this pathway impacts on inflammation, and we know that systemic, high systemic inflammation is a real hallmark of ACLF patients. And the other important activity of an ASK1 inhibitor is that it impacts on cell death. And as we realize that ACLF hallmarks of which is, as I mentioned, systemic inflammation, but also organ failures, multiple organ failures. So that combination of activities on fibrosis, inflammation, as well as cell death, is, I think, going to be a potent combination to be used to address for the treatment of ACLF patients. The SRT-015 molecule itself, I think, has a wider therapeutic window than the molecules which and I'm talking about selonsertib than what was used in NASH.
I think also, Seal Rock also has done a lot of work looking at the activity of, of this molecule in different disease models, things like acute liver failure, drug-induced liver failure, and so on. There is some very nice positive data looking at that, which of course, is aligned with some data looking at specifically at, at the ability of inhibiting ASK1 with SRT-015, impact on key steps within the, the pathway. I hope that answers your question, Ed.
I think maybe we can add that. I think generally what people think happened with selonsertib is that the drug dose was too low, maybe, to show efficacy. And that was because at a higher dose there was some safety concern. And I think the folks at Seal Rock have really made a convincing case that this issue does not exist with SRT-015, which enables them to dose it at the right level for efficacy.
Great. That's very helpful. Thank you. One follow-up, if I may, before I get back in the queue. This is sticking with your proprietary pipeline, beyond elafibranor. Given that the first biomarker data out of the CCA program is probably the nearest coming up here in the first half of 2024, I'm wondering if you could give a little more detail about what exactly we can expect with that data readout. Thanks so much.
Ed, I'll let Dean comment on what we can expect to see. I would just say that the first data we'll have is likely to be VS-01. Of course, it will depend on the rhythm of enrollment, but then I think the two will be really close next year. So Dean, I'll let you comment on GNS561.
Yeah. Ed, as you probably remember, GNS561 is an inhibitor of autophagy. As an inhibitor of autophagy, it specifically inhibits PPT1, which is an enzyme towards the later stage of the whole autophagy pathway. I think some key markers, which we'll be assessing, is the ability of this molecule to decrease the expression of PPT1, for example. There are different steps throughout the autophagy pathway downstream of PPT1 we'll be looking at, but I think that is a particular one, which will be of high interest.
Thanks again.
Our next question comes from the line of Evan Wang with Guggenheim Securities. Please go ahead.
Hey, guys, just wanted to, you know, ask a follow-up specific to the VS-01 program. Great to see some of the progress there, and, you know, sounds like we're on track for a first half 2024 interim read. So just, you know, just wanted to get a sense, you know, on how enrollment is tracking, and can you talk through some scenarios that would allow for expedited pathways? Is the trial size sufficient for a potential accelerated approval, you know? Thanks.
Hi, Evan. So in terms of enrollment, I mean, it's still early days. I mean, right now, we still, we're still on track. We hope to open more sites in the U.S. that are going to come online later this year, and that obviously help with accelerating enrollment. So we're hopeful. Obviously, we're breaking a little bit new ground here because there have not been a lot of ACLF trial up until now. But we're confident and we'll update you as we go along. In terms of accelerated approval, it will obviously depend on what we're able to show.
I think the view is that if we can make a case that there is efficacy, there will be openness from the authorities because of the very high unmet medical need and the fact that we got the orphan drug designation. Right now, we have, and I'll let Dean comment about the design, but we have an adaptive design, where the primary is the CLIF-ACLF score, which is a score developed by EASL, and look at organ function. But we're also obviously looking at survival, and obviously, if we can show something here, that would be a very strong argument to get accelerated approval.
Dean, do you want to comment on the, on the design of the, of the,
Yeah.
- study?
Sure. Yeah, before I get into that, I think another important point, and this is what we're seeing as we engage with different investigation centers as well as the investigators themselves, I think there's a lot of excitement and motivation from the different investigators with whom we have met and with whom we're reaching out to. I think, as you know, you know, that's gonna be a key point to be able to drive recruitment of any trial. This trial is not an easy trial, but I think it's viewed as technology, as a engineered liposome and the mode of administration and all of that, I think is seen as a technology that really has potential to be groundbreaking and real, and be a real game changer.
I think, you know, all these different things taken together, also based on what has been seen in terms of results in the first human trial, with some very compelling results, I think drives a lot of excitement. Right now, the study is in phase II. We have different centers open in Europe, and the design is to recruit a total of 60 patients. We'll have 30 patients on treatment with VS-01 on top of standard of care, versus the control group, which is standard of care. Pascal mentioned the primary endpoint with the CLIF-ACLF score. The CLIF-ACLF score is something that was developed by the CLIF consortium, and this was published, I think, back in, like, 2014. I invite anyone who's interested to really look at that paper.
I think it's published in a journal, Hepatology. Really describing the development of the CLIF score, the strength of the CLIF score, and also the ability of the CLIF score to be prognostic and inform on, you know, risk of mortality of these different patients. The CLIF score is basically a score comp, you know, it's an algorithm which looks at organ system function, which is composed of liver, the kidney, the brain, coagulation, circulatory, as well as respiratory. The two other components, which it captures, is age and white blood cell count, to inform on inflammation. Again, you know, it's a score which has been developed and tested quite extensively, and you'll see it in the publication, that it does have a lot of evidence supporting it.
So that's the primary endpoint. And of course, the secondary endpoint, which is equally important, concerns mortality. In terms of the timing of this, so the protocol itself is that we will introduce the VS-01 technology into the intraperitoneal space, and leave it in there up for 4 hours. So it's a 4-hour dwelling time. We then drain it back out, and we do this once a day for 4 consecutive days. And then, we follow up the patients. We look, we keep them in the hospital up to 7 days, and then, we follow up at day 14, 20, and 90. And at day 90, at the end of study.
Our next question comes from the line of Thomas Smith with Leerink Partners. Please go ahead.
Hey, guys. Good afternoon. Thanks for taking the questions, and congrats on all the progress. Just a couple questions from our end. I guess first on elafibranor. We've seen a competitor post a study in patients who are above upper limit of normal, but below the 1.67 times upper limit of normal criteria. I guess, can you just remind us how the future elafibranor development plans are going to be implemented with Ipsen? You know, do they drive all of the clinical development decisions here, or are you working with them to help structure that? And how do you think about running a study in that patient population to perhaps expand- either expand the label or expand the addressable patient population? And then just a second question on overall strategy.
Can you just give us an update on sort of your latest thoughts on business development? Are you still out there evaluating some of these other rare liver disease programs and looking to bring in additional assets, or do you feel like you've kind of completed the pipeline build at this point, you're more in sort of an execution mode? Thanks.
Hi, Tom. Look, first of all, in terms of the development for elafibranor, Ipsen is now responsible for everything. That would include the open label part of the phase III, as well as the confirmatory study. Obviously, any new indication, either in PBC, similar to what CymaBay is doing to expand that market, or in other indication, I think Ipsen has communicated that they started a study in PSC, and also potentially in combination, for example. That's 100% Ipsen, Ipsen decision. The only sort of impact for us is, should it be successful, then state of elafibranor in overindication or-
W ill also give rights to royalties for Genfit. But whatever choice is made there is entirely up to Ipsen. That being said, I mean, obviously, we know the product very well. So if they have any question, we are 100% here to help, but that's their decision, how they want to pursue that. In terms of your second question, no, we feel that from a BD standpoint, we want to pause. We have, as I was saying earlier, built a portfolio in ACLF that's really unique.
Nobody else has anything close to that in terms of its depth and in terms of the company commitment to ACLF. But now, I mean, we can't, you know, keep adding... So first of all, we feel that we've covered the more sort of promising pathways. And also, we need to now really be focused on execution, and we don't have the bandwidth to do much more than that. So no, don't expect anything else from a BD standpoint. We'll obviously be continuing continuously monitoring the environment, and if there's something really promising, you know, we might change the vision.
But, in terms of strategy, we feel we have something that's really exciting, and we want to develop that.
Got it. That's super helpful. And maybe just one quick follow-up, if I could, on elafibranor. And I was just wondering if you could comment on, I guess whether there are any outstanding data sets that would potentially serve as a gating factor, you know, basically turning them over as opposed to Ipsen for the regulatory submission, or whether at this point, you know, essentially everything has been turned over, and it's just a matter of Ipsen preparing the NDA and submitting the NDA on their end?
Yeah, we have completed the transfer. So now it's really Ipsen in the driver's seat for the filing a nd also for the presentation of a much more complete data set in scientific conferences.
Got it. Okay, great. Yeah, super helpful. Looking forward to seeing the detailed data at AASLD, and congrats again on all the progress.
This does conclude today's question and answer session. I will now turn the call back to Pascal Prigent for any additional or closing remarks.
Thank you, and thank you all for joining. In conclusion, I'll just reiterate that the positive results for our ELATIVE phase III study in PBC means that Genfit is now entering a new era, and we pivot from a focus on a single program to the development of a robust portfolio of exciting programs with that focus on ACLF. Additional ELATIVE data will be released in the coming months, and we are confident that this data will further demonstrate that elafibranor has a very competitive profile and the potential to add significant value to patients with PBC. We are very pleased to see the commitment of our partner, Ipsen, and we believe that they will make the most of the opportunity. For Genfit, essentially, this means a potential first milestone met in 2023.
If elafibranor is approved in PBC, additional milestone and regular revenue stream for royalty payments. These potential revenues would be used to finance the development of our pipeline, with 7 different programs now ranging from preclinical to phase II. As I was saying, in particular, 5 distinct program in ACLF, where the medical need is really significant. Looking forward to our next corporate update at AASLD in mid-November. Thank you and goodbye.
This concludes today's call. Thank you for your participation, and you may now disconnect.