Ipsen S.A. (IPN) Earnings Call Transcript & Summary

Hello, and welcome to Ipsen's Investor Science call at AASLD. I'd now like to turn over to Craig Marks of Ipsen.

Hello, everyone. As you just heard, I'm Craig Marks, Vice President of Investor Relations at Ipsen. We're live in Boston, and it's a real pleasure to welcome you at Ipsen's Investor Science Conference Call here at the 2023 AASLD meeting. The plan for this call is to focus on the results from the elafibranor ELATIVE Phase III trial presented yesterday at the late-breaker session. We plan to comment today only on the results of the trial. Commercial questions will be answered at next month's Capital Markets Day. Next slide, please. This is our usual safe harbor statement. Next slide, please. I'd now like to introduce you to our 3 speakers today. Jennifer Schranz, Global Head of Rare Disease R&D, Ipsen will summarize our focus in rare disease and our extensive presence at AASLD over the past few days. Dr. Christopher Bowlus, Professor and Chief of the Division of Gastroenterology and Hepatology at the University of California Davis, will recap on yesterday's late-breaker session while David Loew, Chief Executive Officer of Ipsen, will conclude our presentation. We'll be happy to then take your questions. I'll now hand over to Jennifer. Next slide, please.

Thanks, Craig. Hello, everyone, this is Jennifer Schranz, Global Head of Rare Disease R&D at Ipsen. I'm truly thrilled in my role to have the opportunity to help grow Ipsen's presence in rare disease and I'm proud to lead a team of dedicated and passionate healthcare professionals as we support our voted endocrine franchises and build a strong platform in rare cholestatic liver disease. Next slide, please. We have a clear strategy to bring transformative first or best-in-class medicines to patients across our 3 therapy areas, expanding our scope within rare disease is central to the strategy. Unfortunately, despite 1 in 10 people living with 1 of the 7,000 known rare diseases, 94% of those rare diseases have no effective treatment. So within rare cholestatic liver disease, we are committed to expanding the number of available treatment options, and it was this commitment that led to our partnership with GENFIT in 2021 and the acquisition of Albireo this year. We're currently focused on 5 potential rare cholestatic liver disease indications across 3 pipeline and on-market assets. Based on our external-innovation success, we are increasingly being seen as a partner of choice to discuss academic collaborations and development partnerships, giving us great access to innovation and scientific expertise. We like to call ourselves the rare team. We have the experience, expertise and agility to be well positioned to potentially launch a next generation treatment for patients suffering with PBC and it's this on which I'll now focus. Next slide, please. At AASLD, we've demonstrated our growing presence in rare disease with 2 late-breaking presentations and 9 additional abstracts. 5 abstracts were presented on Bylvay or iBAT inhibitor. The data highlighted our deeper understanding of its efficacy and safety profile in various PFIC types reporting on long-term clinical outcomes such as event-free survival, reduction in biomarkers here in bile acids, improve pruritus and other quality of life measures. We also presented further pool data from the Phase III ASSERT trial and the open-label extension in Alagille syndrome, where we interrogated outcomes of pruritus and serum bile acids, sleep disturbances and response based on changes in several hepatic parameters. In addition, we have strengthened the understanding of Bylvay safety profile in patients living with Alagille syndrome. Finally, preclinical and clinical data were shared on 2 pipeline assets investigating potential further treatments for additional liver diseases. Our headline data presentation, however, was on the efficacy and tolerability profile of elafibranor in PBC. And with that, I'm glad to hand over to Dr. Bowlus. Next slide, please.

Thank you, Jennifer. It's a pleasure to be here today. This is a point of introduction. I am a hepatologist and I've been practicing in the field of cholestatic liver diseases, including PBC for the last 20 years, and it's a pleasure to be here and present the results of the ELATIVE trial, which was presented at the late-breaker session yesterday. In addition, for those of you that aren't aware, the results of this trial have been accepted for publication at the New England Journal of Medicine and are available online for your review. Also yesterday, we heard a presentation related to the RESPONSE trial and seladelpar. And so I will be making some comments, which are important in terms of consideration of the results of the ELATIVE trial. As you know, the ELATIVE trial was a double-blind, randomized, placebo-controlled Phase III trial that studied the efficacy and safety of elafibranor in primary biliary cholangitis. Next slide. So primary biliary cholangitis or PBC is a rare autoimmune cholestatic liver disease that predominantly affects women over the age of 40 years. In fact, 90% of the patients affected by PBC are women, and it can lead to cirrhosis and the need for liver transplant. In addition, PBC causes a symptom burden that includes pruritus or itching. Currently, there are only 2 licensed therapies for PBC, for first-line therapy, we have ursodeoxycholic acid or UDCA. And it works, but up to 40% of patients have an inadequate response. And those that have an inadequate response, we know are at risk of disease progression. In addition, 3% to 5% can't tolerate UDCA. And UDCA does nothing to treat the symptoms of PBC. For those patients, obeticholic acid is indicated as second-line therapy. But again, more than half of the patients have an inadequate response and obeticholic acid can exacerbate the pruritus that patients have. And so elafibranor is an investigational dual PPAR alpha/delta agonist. And elafibranor works through activating PPAR alpha and delta to affect transcriptional regulation of genes, which leads to reduce bile acid toxicity and inflammation. In a prior Phase II trial in PBC, elafibranor showed significant improvements in biochemical markers of cholestasis, improved symptoms of pruritus and was well tolerated. Next slide. So based on those results as well as the unmet need in PBC, the ELATIVE trial was conducted and aimed to evaluate the efficacy and safety of elafibranor in patients with PBC who had an inadequate response or intolerant to UDCA. 161 patients were enrolled in the trial in a 2:1 fashion to receive elafibranor 80 milligrams once daily or placebo. Randomization was stratified by an alkaline phosphatase greater than 3x the upper limit of normal or total bilirubin greater than the upper limit of normal and by a PBC Worst Itch Numeric Rating Scale or NRS score greater than or equal to 4. All patients that completed the double-blind treatment phase were offered enrollment in the ongoing open-label extension study. The primary analysis occurred at 52 weeks, but patients remained in the double-blind treatment phase for up to 104 weeks or until all patients completed their 52-week assessment. Importantly, safety data was collected during the entire double-blind treatment period. Next slide. The primary endpoint of the study was a proportion of patients with a biochemical response at week 52 and a biochemical response was defined as an alkaline phosphatase less than 1.67x the upper limit of normal with at least a 15% reduction from baseline and the total bilirubin less than or equal to the upper limit of normal. Secondary endpoints included the proportion of patients with normalization of alkaline phosphatase at week 52. The change in pruritus based on the PBC Worst Itch NRS scores in patients with moderate-to-severe pruritus, which was defined as a baseline PBC Worst Itch NRS score greater than or equal to 4 from baseline through week 52 and through week 24. Other secondary endpoints included the change in alkaline phosphatase levels from baseline to week 52, as well as the change in more comprehensive measures of itch including the PBC-40 Itch and the 5-D Itch scores also assessed in patients with moderate-to-severe pruritus from baseline to week 52. Next slide. The baseline demographics and disease characteristics were well balanced between the 2 groups and were typical of the patient population with PBC who are refractory to therapy. Some of the features I'd like to highlight are the mean alkaline phosphatase at baseline, which were 321 and 323 in both groups. Now just for comparison in the RESPONSE trial, the baseline alkaline phosphatase levels were a mean of 314 and 315. Almost 40% of patients in the ELATIVE trial had an alkaline phosphatase greater than 3x the upper limit of normal at baseline. The vast majority were on concurrent UDCA treatment, and roughly 40% had moderate-to-severe pruritus again, defined as a PBC Worst Itch NRS score greater than or equal to 4. About 1/3 of patients had advanced liver disease defined as the liver stiffness of greater than 10 kilopascals and/or bridging fibrosis or cirrhosis on histology. Next slide. And now for the results. The primary endpoint of the trial was met. Treatment with elafibranor led to a significant improvement in biochemical response at week 52, with 51% of patients treated with elafibranor achieving a biochemical response compared to only 4% who received placebo. This translates into a treatment benefit of 47%. I'd like to highlight that the 4% placebo rate in this trial is consistent with prior trials in this patient population. And the treatment benefit here of 47% is aligned with the response trial in which the treatment benefit was 42%. Despite the high levels of alkaline phosphatase at baseline, 15% of patients treated with elafibranor achieved complete normalization of alkaline phosphatase at week 52, while no patients treated with placebo achieved this milestone. Next slide. Treatment with elafibranor resulted in a rapid and sustained reduction in alkaline phosphatase throughout the 52 weeks of therapy. In contrast, alkaline phosphatase in patients treated with placebo remains stable throughout the treatment period. At week 52, there was a 41% improvement in patients treated with elafibranor compared to those treated with placebo. Again, this effect was seen -- this effect similar to that seen in the RESPONSE trial. I'd also like to note that this response was seen in patients with a baseline alkaline phosphatase greater than 3x the upper limit of normal as well as those with an alkaline phosphatase of less than 3x the upper limit of normal. So now moving on to pruritus. I'd like to highlight that 3 scales were used to measure pruritus in ELATIVE trial. The PBC Worst Itch NRS is a unidimensional scale that quantitatively measures the intensity of itch. It's an 11-point scale ranging from 0 meaning no itch to 10 being the worst-itch imaginable. It was assessed daily and has a recall period of 24 hours. And while this is an excellent tool for quantifying the intensity of itch, it lacks other features that measure the impact of itch on patients' daily quality of life. For that, we used the PBC-40 Itch domain. The PBC-40 is a multidimensional tool specifically designed and validated for PBC. The itch domain consists of 3 questions that capture the impact of itch on quality of life. It was assessed at each study visit with the recall period of 4 weeks. Similarly, the 5-D Itch is also a multidimensional tool that assesses the impact of itch on patient lives. It includes domains to capture the duration, degree, direction, disability and distribution of itch. It was assessed at each study visit with a recall period of 2 weeks. Next slide. A trend for improvement was observed in the PBC worst-itch NRS score, but did not reach statistical significance through week 52. Next slide. However, treatment with elafibranor improved pruritus based on the PBC itch score as well as the 5-D itch total score. Here on the left, we see that treatment with elafibranor resulted in a rapid and sustained improvement in the PBC-40 Itch score from baseline through week 52, where there is little change in the score in patients treated with placebo. At week 52, patients treated with elafibranor had a reduction in their PBC-40 Itch score of 2.5 compared to 0.1 in patients treated with placebo. Next slide. Similarly, there are greater reductions in the 5-D Itch total score in patients treated with elafibranor. At week 52, patients treated with elafibranor had a reduction in their 5-D Itch score of 4.2 compared to 1.2 in patients treated with placebo. Next slide. elafibranor was generally well tolerated, and no new safety signals were observed. The percentage of patients who experienced any adverse event were similar between the 2 groups. The only adverse event seen more frequently in elafibranor were mild-to-moderate in severity and generally GI in nature. The percentage of patients experiencing treatment-related adverse events, serious adverse events, severe adverse events or adverse events leading to treatment discontinuation were similar between the 2 groups. There were 2 deaths in the trial, but neither was deemed to be related to treatment by either the investigator or a blinded and Independent Clinical Events Committee. One death was due to complications following an elective abdominal hernia repair. The other occurred in a patient -- excuse me, the other occurred in a patient with cirrhosis who developed sepsis and acute kidney injury. So in summary, treatment with elafibranor led to a significant improvement in biochemical response compared to placebo at week 52, with a treatment benefit of 47%. Reductions in alkaline phosphatase were rapid and sustained through week 52 and only patients treated with elafibranor achieved alkaline phosphatase normalization. The greater reductions we observed in the PBC-40 and 5-D Itch scores suggest that elafibranor may improve moderate-to-severe pruritus in patients with PBC and elafibranor was generally well tolerated with an acceptable safety profile. So in conclusion, treatment with elafibranor led to significant improvement in biochemical response along with potential antipruritic benefits and was generally well tolerated. Thus elafibranor may provide an effective treatment for patients with PBC. And let me now pass it over to David.

Thank you, Dr. Bowlus. As Jennifer was saying earlier, expanding our scope in rare disease is at the heart of our therapy area strategy, and elafibranor is key to this. We're building a nice platform with Bylvay already launched in the U.S. in PFIC and Alagille and in the European Union in PFIC. As we announced earlier, the Alagille indication will be resubmitted under a different brand name in Eurozone. Furthermore, we are conducting a Phase III trial to achieve an additional indication in biliary atresia. There is also a real possibility to extend our presence in rare cholestatic liver disease with elafibranor given the compelling data you saw a moment ago. To confirm, we plan to file PBC by the end of the year in both the U.S. and the European Union. Finally, outside of liver disease, we are happy to see the Sohonos approved in the United States this year, which was a real breakthrough for the FOP community, especially as Sohonos is the first and only treatment for patients with this disease. Next slide, please. So to conclude, we are pleased with the compelling Phase III trial results presented this week. Elafibranor clearly has the potential to be a transformative treatment option for patients suffering from PBC where there is certainly a significant unmet need, and it's an opportunity like this that is central to our strategy to expand our scope in rare disease. Next slide, please. So thanks for listening. We now have time for your questions. Operator, over to you.

[Operator Instructions] And your first question comes from the line of Xian Deng from UBS.

So I have 2 questions for Dr. Bowlus, please. The first one on ALP reduction and ALP normalization, please. So if I look at the data for elafibranor and seladelpar, it seems that the ALP reduction on the absolute term, it seems to be quite similar, but seladelpar has a much higher ALP normalization rate. So just wondering if you could help us understand the link between ALP reduction and normalization, please? I'm just wondering why do you think that was -- the difference could come from. And second question on the pruritus endpoint, please. So elafibranor missed one, but hit the 2 other endpoints and also note the quite a bit of difference in terms of P value because the NRS 1 is the P equals 0.2 whereas the other 2, the p-values are comfortably below 0.05. So just wondering why do you think that's the case? You missed one, but hit the other 2 and especially construing the other 2 are sort of multidimensional. And also I was just wondering, how do you think the other 2 could help you as a physician in terms of understanding the prices endpoint.

So regarding the biochemical improvements, particularly related to alkaline phosphatase normalization. So that's an interesting metric. And let me just first caution us regarding comparison across trials. And there were clearly differences in the patient population and the study designs that make strict comparisons between results somewhat difficult. However, alkaline phosphatase normalization depends both on where the patient starts at above the upper limit of normal as well as where we set the upper limit of normal. And in these 2 trials, those were both different. The mean alkaline phosphatase in the ELATIVE trial was greater than in the RESPONSE trial, and then if you look at the upper limit of normal, which the patient had to get under, it was lower in the ELATIVE trial compared to the RESPONSE trial, so the goalposts were not the same necessarily in terms of achieving alkaline phosphatase normalization. So I think it's really hard to compare these 2 trials, specifically in that outcome as well. Regarding pruritus, capturing the impact of pruritus on a patient is quite difficult and something we discussed at the session yesterday. The NRS is sort of like asking a patient to rate their pain but not asking them anything more about their pain. Not asking them where it hurts? How long it's hurt? Does it wake them up at night? Whereas the other metrics, the PBC-40 itch domain in the 5-D Itch domain capture more of the impact of the itch. And so I think as a practicing clinician, they all have their value. You want to know the intensity of course, but we also want to know more about the itch. And that's what the patients want also. If their itch intensity changes, but their quality of life doesn't, it doesn't mean as much. It's really about their quality of life that's more important. So how that plays out in clinic is really a very nuanced practice of medicine and hard to capture in these metrics necessarily.

And our next question comes from the line of Richard Parkes, BNP Paribas.

I've got 2 as well for Professor Bowlus. Firstly, when I look at the prevalence incidence of patients with PBC and then correlate it and look at Ocaliva sales, it looks like only a small minority of patients are actually taking second-line therapy. So I just wondered if you could talk us through what the main reasons in your experience are for patients not being on second-line therapy currently? Is it just due to the exacerbation of itch with Ocaliva and loss of efficacy? Or is there other reasons like misdiagnosis or access to treatment or just less severe disease. So that's the first question. And then secondly, on the data. Looking forward, it looks like we could have 2 new options for PBC patients, but maybe there's a possibility that seladelpar might include a labeled claim for pruritus reduction, which might be more challenging for elafibranor. So can you talk about how you'd go about discussing that with the patient and making treatment selection if you have 2 new therapies available.

So the first question regarding the uptake of Ocaliva and how that might compare with elafibranor. I think somewhat speculative on my point, but from my clinical experience, my own experience, I will say that the reasons for the low uptake are multifactorial. There clearly are patients that are hesitant to take Ocaliva because of the reported itch issue. That's been my personal experience, even if it's only a temporary exacerbation. Once they read about that or hear about that, they're hesitant to take it. I think on the physician side, there has been hesitancy to use it based on some concerns about safety, particularly in those with the advanced disease. And it was a new mechanism of action that the Board comfortable with. And then there is probably the biggest issue though is access and education of both physicians and patients of the need to treat patients who have inadequate response in getting therapy to those patients. I don't think those -- some of those issues, obviously, are not going to be present with elafibranor and that, obviously, the itch is not an issue. I think that physicians and patients will be much more comfortable with the mechanism of action, less of safety concerns. So I think the uptake will be better. There will be challenges in terms of reaching out to get to these patients that weren't being offered treated currently. So there's still work to be done there. Regarding whether an indication for itch is included for one versus the other of these therapies. I'm not through in the clinic that's going to make a whole lot of difference in terms of what's on the label as a physician. We use what we think is [ one ] for our patients and also within the confines of what's available for patients. If we have 2 highly effective therapies that are available, some of our decision-making is driven by payers and other issues related to access and support for patients. So I'm not sure that what the label indicates that are going to impact our practice.

And your next question comes from the line of Richard Vosser from JPMorgan.

First question, just thinking on the -- some of the side effects that were disclosed for elafibranor. So just ask Dr. Bowlus, what he thinks about the muscle injury, which I think was mentioned in the New England Journal paper? How significant are those for him and also blood creatinine phosphokinase increases? Is that anything we should be concerned about? And then the second question maybe for Dr. Bowlus, but also the company. On the basis of this sort of second line study, would -- what's the thoughts on moving into earlier lines of therapy or patients with lower levels of ALP. Just thoughts there from both Ipsen and the doctor on the basis of these data.

So I think in terms of the safety data with muscle injury you're referring to 4 patients that had elevated CPKs. And so 2 of those patients who are on concomitant statins. One had chronic kidney disease and one had autoimmune thyroiditis. So I think that the concern there is, I would say, minimal in terms of risk of those sorts of safety issues. And was there another issue you would discuss, you brought up [indiscernible] creatinine was relatively stable, and I didn't see any particularly concerns related to renal toxicity.

This is Jennifer Schranz. Thank you for the question. And clearly, your question is relevant to ensuring that we most appropriately and adequately and effectively treat patients. So I think historically, as you heard from Dr. Bowlus many patients are on UDCA therapy as first-line therapy, and not all of them actually are followed very closely to see what's happening back to their liver function related to, obviously, the alk phos is one the surrogate markers. So I think, in general, what I'm understanding from Dr. Bowlus is that between month 6 and 12 are starting UDCA and there may be -- need to be some decisions made and perhaps even education of some of other community physicians on whether that patient is responding or not and that's obviously critical. Given the really compelling results, you heard from the ELATIVE study today with our reduction in alk phos, our impact also on quality of life parameters with pruritus. It does kind of beg the question and makes sense. So now that we've demonstrated this in this population or perhaps more advanced, is there a reason to go more to the left of the treatment paradigm and to see whether we can have a more prolonged effect on patients long term. If we start with -- starting early in the treatment paradigm or with an alk phos that perhaps is already not over 1.67x upper limits of normal but heading there or perhaps certain patients that are high risk with younger age, higher alk phos. We think some of those parameters. So yes, I can say our team is very interested and in fact, are working on perhaps a protocol that will address some of those important questions that I know physicians will start to ask us. And so I think your comment on that is appropriate.

And on the lower level of ALP, the 1.6.

Yes. To that point, that [indiscernible] met, but perhaps there's enable -- ability to see that if you treat before it gets above 1.67, especially in those patients, are they predicted that of having perhaps longer term or worse outcomes over time, it would be more appropriate to try to intervene earlier. We're really kind of at the, I'd say, infancy of starting to do precision medicine. And as we gain more information on how patients are responding and understanding more about alk phos as a surrogate marker among other things, I think as you would with any patient, you want to treat as aggressively and as early as possible to prevent harm to the liver.

Your next question comes from the line of Evan Wang from Guggenheim Securities.

Great to see some of the effects on other measures at 12 months. Can you talk to whether you expect to see that each data within the label such as within the clinical study section? And then just following up on some of the CPK elevation, I guess how -- was there any specific time course that these occurred at? Were they relatively early on? Or were they kind of spread out?

Yes, I will take the first one. Thank you. So certainly, we believe that the impact on the patients with respect to the quality of life with parameters of the PBC-40, impact on the itch as well as the 5-D Itch score are really critical. So from our perspective, we would certainly try to get that information in the label. But clearly, that will be a regulatory review issue to labeling negotiations. And related to the next point about CPK elevation, just -- yes, there's no time course that we could predict that would -- we would see CPK elevation. And in the protocol -- per protocol, they were just continued just based on the level of CPK elevation and whether or not they had any myositis. So it was a protocol-defined requirement to stop the study. And I think our guidance to clinicians would be the important, very carefully watching patients who on concomitant statins, which a lot of these patients are on. So I think it's required to your point earlier, is just the importance of education of physicians.

I have 1 follow-up. If I could ask one follow-up with respect to the PBC-40 and 5-D Itch score. I guess, were those kind of predefined endpoints? Just wondering, I guess, how they're kind of incorporated with the study design.

Yes, those were predefined as a secondary endpoint.

Your next question comes from the line of Manos Mastorakis from Deutsche Bank.

Two quick ones, please. So given your experience with Ocaliva in the real world and your clinical study experience with elafibranor processes, how would you compare your confidence in the safety profile of these 2 drugs? And just a quick follow-up on the quality of life and the standard fatigue is perhaps the most common symptom. But how would you, again, compare how elafibranor helps with that aspect since we didn't get to see much data other than some reference into the fatigue element in the adverse event table. So yes, we'll be keen to get that coming from you?

Yes. So related to obeticholic acid and elafibranor just in terms of clinical -- my clinical experience with obeticholic acid. I think in terms of safety, I think that particularly in those patients that are more advanced, elafibranor would be definitely preferable as well as being more tolerated and honestly, probably more effective. So I think there's probably, in my opinion, elafibranor would be the preferred agent moving forward. In terms of quality of life and fatigue, you're absolutely right that fatigue is one of the more common, if not the most common symptoms in our patients with PBC. And it's been very hard to address. And it's probably multifactorial, some of which is related to the inflammation that we see not only PBC but similar fatigue related to rheumatoid arthritis or any inflammatory condition. But in addition to that sort of fatigue, patients with itch also don't sleep well. And so there is probably a component of fatigue related to itch and lack of sleep. And we did see an effect on the PBC-40 fatigue domain, which would suggest there may be some impact there. So probably it's a difficult symptom to address as difficult to measure as itch is, but an important one for sure.

Your next question comes from the line of Delphine Le Louet from Societe Generale.

A different type of question on my side. It sounds to me that when I look at the efficacy, there is no brain in a way that the 2 drugs may be approved. Do you think that could be different? It's the first question. In that case, we have an approval or now we're going to go for a PBC molecules addressed by 3 drugs. What could be the backbone treatment in that PBC, let's say, like that. Do you see a major change or do you think people will continue on Ocaliva and that the switch is going to be very light and then probably elafibranor and then probably seladelpar, what would be your pick yourself? And thirdly, I was wondering regarding this multidimensional scoring system or achievement that you get into the pruritus. Do you think that should be part of, let's say, the package to be submitted and so to the regulatory catch to be submitted in the future? Or is it still too preliminary into the approach? And finally, just wondering, when I look back on the Slide 17. So can you explain -- so this is the slide where you have the change in PBC was Itch NRS. Can you explain in the deep that you had observed in week 24? Is it really a patient-related or anything specific that very much appreciated.

So I'll address the first question. I think you're asking sort of what would the treatment paradigm be for new patients with PBC if we have traditional therapies approved. So we're going to continue with first-line therapy being UDCA. I think that's likely to continue or will continue. Second-line therapy, in my opinion, will be a PPAR agonist. And then those that we don't have an adequate response likely would be adding on obeticholic acid. I doubt switching to obeticholic acid is going to be part of that. But there's still some information that's still an unknown for us right now. There's not a lot of data in terms of combination therapies when we talk about fibrates. So -- and then there's the patients that are intolerant and those likely also will go to one of the PPAR agonists directly. And in terms of selection, again, as I mentioned earlier, with 2 highly effective therapies, these are going to be case-by-case decisions and driven largely by access and payer decisions rather than necessarily decisions by clinicians. Then the question related to the dip in the placebo group and which of the...

Yes, that was in the placebo, on the Slide 17.

PBC-40 or in the NRS what you're saying?

NRS.

In the NRS. Okay. Yes. it's likely just due to the variability in pruritus over time. There's no definite explanation in terms of particular individual patients or other effects that we could sort out at this time.

And just a follow-up to this one. Do you think that both the placebo group and elafibranor group was large enough or it should have been a bit larger.

Well, that's a difficult one to say. I guess being large is always better. And if I guess the point is if it was larger, the difference might have become statistically significant, that's obviously possible.

With some of the multidimensional scoring on pruritus as part of the package. Jennifer, do you want to take this?

Yes, of course. So for our regulatory submission packages, it would include all scoring systems. There's also all the background material for the agencies to look at related to the importance of the PBC-40 and the 5-D Itch and so yes, that definitely would be part of the core package.

Your next question comes from the line of Brian Balchin from Jefferies.

Just a clarification, I think, on the last answer that you gave about goalposts being different. Just clarify, did you say that your ALP normalization criteria was stricter than seladelpar. I thought both were less than 1x upper level limit of normal. So can you just clarify that? And then just secondly, on the disparity between the primary which is less than 1.67x than on normalization. Did you attribute that to having a greater proportion of patients with greater than 3x ULN baseline at 40%. I'm not entirely sure what sort of delta had, but is that potentially a contributing factor there?

Yes. So this is, I think, a point of confusion. And in terms of the upper limit of normal, is not always the same. It's dependent on the laboratory in which it's being tested. And so for the ELATIVE trial, the upper limit of normal was 104 in females and 129 in males. And essentially 90% of the patients in the trial are female, so essentially the upper limit of normal was 104. So with elafibranor, patients had to get under that 104 with the [indiscernible] study, the upper limit of normal was 116 for the whole population. And so with some of these responder criteria, a few points can make a difference in a few patients and make significant changes in terms of what the response rate is or normalization rate is. And then yes, I think in terms of the 3x the upper limit of normal, that was not reported by [indiscernible] so we don't know. But we do know that in the ELATIVE trial, the mean alkaline phosphatase was higher than in the RESPONSE trial. So again, patients were starting at a higher level and had to get to a lower level in order to meet that complete normalization.

Great. I've just got one follow-up. Just on the other liver enzymes and ALT reduction. How important do you think clinicians would view that? Just because I think seladelpar showed reduction, 15% to see about month 12, I'm not seeing that data. I think it might be in [indiscernible] not yet taken a look, so if you could just...

In the ELATIVE trial, there was a trend towards improvement in ALT, but it didn't reach statistical significance. But I will say that all the models that predict clinical outcomes, transplant-free survival or hepatic decompensation, none of them include ALT, it's never come up to be a significant predictor of clinical outcomes. So I think the relevance is not meaningful.

Your next question comes from the line of Simon Baker from Redburn Atlantic.

This is Qize Ding asking questions on behalf of Simon Baker. Two questions, if I may. So the first question is looking at the Slide #17. So why was the placebo response to Worst Itch [indiscernible] in contrast to the more smooth trend for the drug treatment arm? And the second question is that do you have the subgroup analysis to share with us? If so, was the response consistent across baseline enzyme levels and ages.

So the first question was the variability and the placebo-treated patients related to the NRS, is that correct?

Yes.

And do we have an explanation for the variability there?

That's the question.

So it's likely, as I said before, this is just the natural variation we would see in a patient population if we follow them through 52 weeks, while on placebo. We can see that there is a reduction in the first 6 months in the placebo group and then that placebo effect essentially waned later in the trial.

Can you repeat your second question, please?

Yes, sure. So do you have the subgroup analysis to share with us. If so, was the response consistent across baseline enzyme levels and age?

Yes. So in the supplementary material in the New England Journal article, are all the subgroup analyses that were performed. And essentially, all the criteria in terms of responses were similar in subgroups that analyzed that had sufficient numbers to actually look at. So regardless of baseline ALP being greater than or less than 3x the upper limit of normal, advanced liver disease, et cetera, responses were similar.

Your next question comes from the line of Alistair Campbell, Royal Bank of Canada.

I got 2 questions, please. First of all, just to go back to alkaline phosphatase and might be helping something, which I'm finding a bit confusing. If I look at the chart on reductions in ALP from baseline, obviously, very fast drop within about 4 weeks and then stayed very steady throughout the duration of the trial. But if I look at the percentage of patients achieving normalization, it actually was quite slow to begin with, but then sort of gathered pace during the trial hitting a peak of 15% in week 52. So I guess the question from that is, look, is 15 the peak? Or do you think it has tried to run longer, that could even be even higher? And might you actually pick something off that up from like the open-label extension. And then second question, just a quick one. Just looking at that subgroup analysis, it looks like you had too few patients with cirrhosis at baseline to break that out. But can you just confirm the directionally those data were numerically aligned with the headline results?

That's a great observation that the complete normalization increased over time. And it's quite possible that with longer duration of therapy, more patients might achieve normalization of alkaline phosphatase, so that will be interesting to see in the open-label extension, how that plays out. Regarding cirrhosis, you're correct, the numbers were quite low. And they're really too few to make any comment on cirrhosis, enough -- had advanced liver disease to say that the trend was -- there was an effect, and it was -- 95% confidence interval did show a benefit. But cirrhosis is still something we have to look at.

We will now take our final question for today. And your final question comes from the line of Richard Parkes, BNP Paribas.

And apologies for continuing to focus on the pruritus standpoint because it seems to be the only real difference between 2 drugs that seem to be very effective. But when I look at the pruritus data for seladelpar and elafibranor, I mean it just looks a bit more robust with seladelpar overall. So as a physician, I would have thought I'd be more -- maybe a little bit more tempted to maybe prefer that drug in patients that have more severe itch. So my question is, do you think that's a fair interpretation that the data is maybe just a little bit more robust on pruritus? Or can there be other differences to explain that? And I'm thinking about differences in statistical analysis or treatment of dropouts between the 2 studies, is there something else that could explain that difference?

So I think, again, we have to be careful in terms of comparing 2 trials that were run in different populations with different study designs, different inclusion criteria as well as the analysis of the endpoint. So we really are waiting, I think, to find out if the analyses were similar between the 2 trials, but even so, it would be quite hard to compare the 2 results, particularly in something like itch, which is hard to capture and has such a significant placebo effect. So I would be hesitant to read too much into a difference between the 2 trials in terms of its effect on price at this time.

Thank you, Richard. This concludes our call. Thank you, everyone, for joining us today, and we wish you a wonderful rest of the day. Goodbye.

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.