Hello everyone, and welcome to this webinar focused on Poxel 2022 half-year results and the overview of DESTINY-1 histology results. Before giving the floor to Thomas Kuhn, CEO of Poxel, I would like to remind you that you can ask a question by clicking on the Q&A button at the bottom of your screen. Now I give the floor to Thomas Kuhn. Thank you very much, Nicolas. Hello, everyone. Welcome to this call. Thank you for joining us today. I'm Thomas Kuhn, the CEO of Poxel. Going to the disclaimer. Before we begin, this is our forward-looking statement. Forward-looking statements are subject to inherent risks and uncertainties beyond the company's control that could cause the company's actual results or performance to be materially different from the expected results or performance expressed or implied by such forward-looking statements. Further information can be found in our most recent regulatory filings. Going to the agenda for today's call. I will start by reviewing recent developments and corporate highlights. Following my introductory comment, I will hand the call to Anne Renevot, our CFO, to review our half year 2022 financial results. David Moller, our CSO, will briefly summarize our rare disease efforts, and then we'll share exciting results from our phase II DESTINY-1 NASH trial with PXL065 in greater detail following this morning announcement regarding histology findings. I like to welcome as well Dr. Stephen Harrison, who was the principal investigator on the trial, President of Summit Clinical Research, who will take you through the data. Thank you very much, Stephen, for taking the time, and welcome to the call. Following my closing comments, we'll then take all your questions. Going first to our recent strategic developments. We are thrilled today to be able to take you through the positive results from the phase II NASH trial for PXL065, our novel proprietary deuterium-stabilized R-stereoisomer of pioglitazone. As you may recall, at the end of August, we announced the primary efficacy endpoint of the trial, which was met. Indeed, all of the three doses tested demonstrated statistically significant improvements in the relative decrease in liver fat content measured by magnetic resonance imaging, estimated proton density fat fraction, MRI-PDFF, after 36 weeks of treatment. PXL065 was also observed to be safe and well-tolerated with no disease-dependent increase in body weight and no increase of edema versus placebo. Today, we are really pleased to announce histology findings that are really consistent with our initial results. Favorable and robust changes in fibrosis were observed with an effect size comparable to the best competitor's results. We'll get back to this. Positive trends in other NASH histology components were also observed. These results have really reinforced our strategic focus on NASH, but also on rare metabolic indications. In detail, PXL065 will be prioritized for further development in NASH with the initiation of discussion to enable the launch of a pivotal trial. The future for the treatment of NASH is looking much brighter. Recent positive results in the NASH space are promising to address this large patient population of high unmet medical need with more than one treatment modality. PXL770 development will exclusively focus on rare metabolic diseases based on a strong potential in multiple rare metabolic indication. David will get back to this. Now that this trial has validated the hypothesis that the deuterated TZD platform reduced PPAR gamma side effect while retaining the efficacy benefit of thiazolidinediones, exploration in other rare diseases such as adrenoleukodystrophy, ALD, is also warranted. During the year, we also continued to successfully enhance the value of our two mid-stage development compounds, PXL065 and PXL770. To start with, for PXL065, a new U.S. patent was issued, which describes a specific form of the molecule with unique properties. Importantly, this patent provides additional protection through 2041 and could expand protection worldwide with the potential for an additional five years through patent term extension. Both compounds, 65 and 770, were granted FDA Fast Track and Orphan Drug Designation for the treatment of ALD. The purpose of Fast Track is to expedite development of pharmaceutical products which demonstrate the potential to address unmet medical needs in serious or life-threatening conditions. For PXL770, we also generated strong preclinical data in ADPKD. We have a phase two-ready asset in this indication that is generating significant interest amongst potential partners. In early August, we completed a debt restructuring agreement with IPF Partners, as well as an equity link financing facility with IRIS Capital Investment. As a result of these two agreements, our cash runway extend through at least February 2023. This accomplishment provides further flexibility to finalize additional financing solutions, including ongoing active partnership discussions related to our program. To execute our rare disease strategy. Finally, royalties from TWYMEEG imeglimin sales in Japan are progressing. We are confident that the sales will increase further since first year prescribing restrictions have been lifted as of September 1st, 2022. Due to Sumitomo Pharma promotional activities and efforts since the launch in September 2021, TWYMEEG is very well known among prescriber. Sumitomo Pharma commercial efforts continue to leverage TWYMEEG potential to be used both in combination with other treatments, starting with DPP-4 inhibitors, which are the most prescribed treatment for Japanese type 2 diabetic patients as well as monotherapies. We are also in discussion for selected regional partnerships outside Sumitomo Pharma territories. All this is represented in our updated pipeline that we can see on this chart. As a reminder, Poxel mission and vision remains to discover, develop and commercialize innovative therapies for patients suffering from serious chronic and rare diseases with underlying metabolic pathophysiology. To fulfill our mission, our goals following with this positive phase II results is to advance PXL065 into pivotal trials in NASH. Based on strong potential in multiple rare disease, we have also decided to focus PXL770 development exclusively on rare metabolic disorder, starting with ALD and also ADPKD. Rare metabolic diseases represent the intersection of high unmet medical need, promising preclinical and clinical data, opinion leader enthusiasm, and significant commercial opportunity as well as attractive timelines. Before we review with Stephen the DESTINY phase II results, David will briefly update our progress in these rare diseases. I will now hand over to Anne, our CFO, to present our financial results. Anne? Thank you, Thomas. Good morning, everyone. I will now review our financials for the half year 2022, starting with the revenue. Poxel reported revenues of EUR 83 thousand for the six months ended June 30, 2022. As a reminder, as part of its agreement with Sumitomo Pharma, Poxel is entitled to receive escalating royalties on TWYMEEG net sales in Japan. At June 30, 2022, the revenue mostly reflects these royalties, representing 8% of TWYMEEG net sales as stated. Also as a reminder, revenue amounted to EUR 13.3 million for the same period in 2021, reflecting TWYMEEG marketing approval milestone payment received from Sumitomo Pharma. Moving to the next slide with the statement of comprehensive income. I just commented the revenue. As part of the Merck Serono licensing agreement, Poxel will pay a fixed 8% royalty based on the net sales of imeglimin. This payment is reported in cost of sales, which explains the gross margin, which is now at the end of June. In the first half of the year, R&D expenses amounted to EUR 8.8 million as compared to EUR 16.2 million in the same period of last year. They mostly reflect the clinical study cost incurred for the phase II DESTINY study evaluating PXL065 in NASH. This study is now finalized. General and administrative expenses amounted to EUR 4.3 million in the first half of 2022, as compared to EUR 5.4 million in the same period of 2021. The financial loss amounted to EUR 1.4 million in the first half of the year, which is the same as for the same period of last year. This amount mostly reflected the interest attached to the company indebtedness. The net result for the period ending June 30, 2022, was a net loss of EUR 13.4 million, as compared to a net loss of EUR 8 million in the same period of 2021. Moving to the next slide with the assets. I will just have two comments. The first one is on intangible assets, which amounted to EUR 16.6 million at June 30, 2022, which is a similar level to December 31st, 2021. This amount mostly reflects DeuteRx portfolio acquisition in 2018. Second comment is on cash and cash equivalents, which amounted to EUR 16.1 million at June 30, 2022, as compared to EUR 32.3 million at December 31st, 2021. As a reminder, as mentioned by Thomas, the company announced in August its debt restructuring with IPF Partners, resulting in a postponement of the Q3 and Q4 2022 repayments and lowering certain financial covenants until the end of January 2023. Concurrently, we entered into an equity-linked financing arrangement for an initial gross amount of EUR 4 million. Please note that we have the option to draw two additional tranches of EUR 1 million each at the latest on December 31st this year. As a consequence, we anticipate that our cash runway extends to at least February 2023. Moving to the next slide, which holds equity and liabilities. Two comments on this slide as well. First comment is on shareholders equity, which amounted to EUR 3.6 million at June 30, 2022, compared to EUR 8.2 million at December 31st, 2021. This mostly reflects the net loss of the first half 2022. Second comment is on total financial liabilities, which amounted to EUR 33 million at June 30, 2022, if we exclude IFRS 16 impacts and derivative debts, as compared to EUR 35 million at December 31st, 2021. Moving to the next slide on statements of cash flow. The cash burn for the first half of 2022 amounted to EUR 16 million. It reflects a EUR 13 million cash burn from operations and EUR 3 million cash burn coming from financing activities. Finally, moving to the last slide. On this slide, you can find a summary of the key information related to our capitalization and on our analyst coverage. I will now hand the call to David Moller, our CSO. Thank you very much, Anne. Before we review the DESTINY-1 phase II results, I'll briefly update our progress in rare diseases. PXL770 is our novel direct AMPK activator, the first such molecule to be studied in any human disease. As this slide depicts, AMPK has the potential to ameliorate many disease processes, and 770 produced substantial efficacy in multiple disease models, including for NASH, diabetes, diabetic nephropathy, and adrenoleukodystrophy. Most recently, we've seen compelling results in polycystic kidney disease models, which I'll share with you in a minute. Clinical development to date has demonstrated target engagement and translation of several disease-related efficacy parameters, suggesting the likelihood of broader translation for this mechanism. Preclinical and clinical safety has also been very favorable, with more than 200 humans exposed for up to 12 weeks. We remain committed to targeting X-linked adrenoleukodystrophy, or ALD, which is a serious disorder with no approved pharmaceutical therapy. ALD is a monogenic neurometabolic disease due to mutations in the ABCD1 fatty acid transporter, this defect resulting in the accumulation of toxic very long-chain fatty acids, or VLCFA, in cells, in particular in neurons. There's a strong rationale for AMPK in ALD, and our preclinical data for PXL770 demonstrates substantial efficacy potential both in patient-derived cells and in the classic animal model, the ABCD1 null mouse. These data were also published last month. Our team has been preparing for the initiation of a phase IIA study, which would enroll adult male patients with adrenomyeloneuropathy, the most common form of ALD. As a reminder, PXL065 also shows substantial efficacy in models of ALD. Therefore, we will also continue to plan for an identical study with PXL065 using a deuterium-modified TZD approach in this disease. Let's turn to newer developments in ADPKD. It's an orphan inherited form of chronic kidney disease with a prevalence of about 140,000 in the U.S. There's a very high unmet medical need, and only one drug, tolvaptan, is approved, which is associated with significant safety and tolerability challenges. The pathophysiology involves altered kidney metabolism, and several publications cited here provide a strong rationale for AMPK activation as a therapeutic approach. We recently completed the preclinical assessment of PXL770 in ADPKD, and here we've seen compelling benefits, and this phase II-ready asset has garnered significant interest from potential partners. PXL770 produced strong suppression of cyst formation in 3D in vitro assays, as shown on the left panel, and in an established in vivo rodent model with inactivation of PKD1, the causative gene, we saw robust reductions in kidney size and cyst area, middle and right panels, along with improved kidney histology and normalized kidney function. These new results add value and create optionality for our AMPK platform, and we've initiated development program planning and regulatory interactions. Let's turn to the review of results from our phase II DESTINY-1 trial in NASH with PXL065. I'll first briefly summarize the rationale and background before handing it off to Dr. Harrison. As our molecule is related to pioglitazone, our interest in studying PXL065 in NASH was motivated by the history of positive effects with pio. Pio is an approved drug for type 2 diabetes, and it's been extensively studied in NASH, including six trials where positive biopsy data were reported. Of note, three meta-analyses also support pio's efficacy in NASH, including a prominent effect on fibrosis, as illustrated by Musso et al. in the lower right figure. Based on strong efficacy, off-label pio use in NASH is actually recommended by AASLD and EASL. However, given adverse effects, principally excessive weight gain and edema, pio is not often prescribed. PXL065 is a new chemical entity derived from pio. Pio is a mixture of two stereoisomers or enantiomers that rapidly interconvert in vivo. The Poxel team discovered that only the S isomer has PPAR gamma activity, which accounts for the weight gain and edema. Both isomers have similar effects on two non-genomic pathway targets that have both been independently implicated in NASH. PXL065 is a deuterium-modified form of the non-PPAR active R isomer, which is designed to retard interconversion, leading to a substantial change in the R to S ratio, which favors R in vivo and including in humans. In preclinical NASH models, PXL065 retains pio-like efficacy without significant PPAR gamma-mediated weight gain or fluid retention. Now it's my great pleasure to introduce Stephen Harrison, President of Summit Clinical Research and the PI of our trial, who will walk you through the summary of the results. Thank you, David. Can you hear me okay? Yeah. Okay, perfect. I'm not going to be advancing the slides myself, so I think Pascale will do that. It is my honor to be here today to talk to you about the DESTINY-I trial and the primary endpoint as well as key secondary endpoints from the study. It's an exciting time to be in the NASH space. We have seen some great data come out already. As we lead up to AASLD, there's a lot of positive momentum that we're picking up. Let me walk you through the phase II trial design. DESTINY-I is a phase II study in biopsy-proven NASH subjects. It's a phase IIB trial, so there's a biopsy to get in and a biopsy to get out. Three different doses of PXL065 versus placebo were studied. As you can see from the study schema, it was planned to recruit 120 subjects. Essentially 30 subjects per group with a treatment period of 36 weeks. The primary endpoint was relative change in liver fat content assessed by the gold standard MRI-PDFF. In addition, several key secondary endpoints were evaluated, including liver histology at 36 weeks and key non-invasive NASH-related test, metabolic parameters, PK profile, and safety and tolerability. Next slide. Let's look next at the summary of the subject disposition. At the top, you see 117 subjects were randomized. There were roughly 25 subjects-32 subjects per group, and they were included in the intent-to-treat set. Importantly, 72%-90% of the subjects completed the double-blind treatment period. The main reasons for discontinuation were loss to follow-up, a total of eight subjects, and withdrawal of consent, eight additional subjects. Only two subjects discontinued for safety reasons, one in the placebo group and one in the high-dose PXL065 22.5 mg dose group. Next slide. Now let's look at the demographics and baseline characteristics of this intent-to-treat set. The demographics and baseline characteristics appear to be well-balanced across the groups. There's a mean age of 53 years, a mean BMI of 36. Subjects with fibrosis stage F1 versus F2 and F3 and with diabetes versus non-diabetes were stratified at randomization. As you can see, the percentage of subjects with F1 disease was 35% versus 65% F2/3, and 41% of the cohort was diabetic. The mean liver fat content was robust at 20%, and the mean liver enzyme ALT was 61, indicating again a significant activity in the setting of liver disease due to NASH. Most of the diabetic subjects were previously treated and very well controlled, with an overall hemoglobin A1c of 6.2%. Next slide. Turning to the primary endpoint, which was relative change in liver fat content from baseline to week 36. And again, the intent to treat population. The primary endpoint was achieved and statistically significant in all the PXL065 dose groups, with a mean decrease of 21%-25%. Although the mean effects were not dose responsive, the percent of subjects who achieved a relative decrease of at least 30% in liver fat content was dose-related and reached 40% at the top dose of PXL065 versus 17% in the placebo group. Based on historical data, this does have read-through potential for histopathologic benefit based on work previously done by myself and others. These effects on liver fat were within the range of effects previously published with pioglitazone in patients with NASH. Next slide. Now looking at liver chemistry tests, there was a positive trend to decrease each of the four liver chemistry tests tested to include ALT, AST, GGT, and alkaline phosphatase. It's important to note that several COVID cases plus a placebo effect may have contributed to the lesser effects with the high dose 22.5 mg group. When we pool the data from all dosing arms, the time course of lower mean ALT value versus placebo can be seen as illustrated in the graph on the right. The gray area highlighted illustrates the treatment period. Next slide. Now when we look at these waterfall plots of individual patient ALT change from baseline in international units per liter, you can see the% of ALT responders based on a cut point of 17 international units per liter was substantially greater in the PXL065 treated arms versus placebo. Again, it's important to note that COVID cases near the study end in the high dose group may have also contributed to the higher ALT levels in a couple of patients, as illustrated by the arrows in the high dose graph. Next slide. Now it's important to also look at additional biomarkers done and obtained during the study to include markers of fibrogenesis. You see several listed here. Three biomarkers of fibrogenesis were measured to include PRO-C3, P3NP, and ELF. All three showed dose responsive decreases as noted in the upper three panels. Importantly, P3NP, a component of the ELF score and a relative of PRO-C3, has also been shown to better predict fibrosis improvement over ELF, as illustrated in a recent publication by Professor Naga Chalasani. In addition, two scores, the NAFLD fibrosis score and the FIB-4 score that have been reported to be associated with fibrosis risk, were also favorably impacted, and these are noted in the lower panels. Next slide. Now turning to histology. We'll first look at fibrosis. Again, this is an exploratory efficacy endpoint. 92 of 95 study completers received biopsies at both beginning and end of study, again over a 36-week time period. Analysis of the histology shows that the percentage of patients in the PXL065 groups who achieved at least one stage improvement in fibrosis score was greater compared to the placebo, reaching 50% at the dose of 15 mg versus 17% in placebo. It's important to note that the study was not powered for histology as this was not the primary endpoint. However, this value was nearly significant with a P value of 0.0562. This effect was roughly similar to the overall percentage of patients achieving fibrosis improvement without worsening of NASH, which is an FDA agreed pivotal trial endpoint. Next slide. I think it's important to also put this in perspective. I'm not a big fan of comparing apples to oranges, but I do think this slide puts these data into context by comparing fibrosis improvement without worsening of NASH against several other potential medications in investigation currently for NASH. Again, this is looking at the fibrosis component only. It's important to note here on the left, highlighted by the red in the bar graph, that's the treatment effect delta relative to placebo, that Poxel or at least Poxel PXL065 efficacy appears comparable or better with other oral agents. In addition, the results also appear similar to those reported with efruxifermin in the recently released phase IIB data for this injectable agent. Next slide. Now let's turn to NASH. We first talked about fibrosis. Now we'll look at this exploratory efficacy endpoint. Looking at other histologically derived parameters, we also see a numerically greater percentage of patients who improved by at least two points in the NAFLD activity score, including steatosis, inflammation, and ballooning without worsening of NASH. Although the effect on NASH resolution, defined by an inflammation score of zero or one and ballooning of zero, was modest, as noted in the middle panel, there was a numerically greater percentage of subjects who achieved both regulatory endpoints, improvement of fibrosis by at least one stage and NASH resolution, as seen in the right-hand panel. Next slide. Now let's look at pooled PXL065 dosing arms. When we evaluate this pooled data from all three treatment groups, this slide shows the improvement or worsening in each individual component of NASH to include steatosis, inflammation, and ballooning, as well as fibrosis. 69 PXL065 patients are compared to 23 placebo patients. The effective observed on liver fat content with MRI-PDFF was confirmed on histology, with steatosis's improvement seen in 42% versus 17% in the placebo group. Overall, PXL065 improved fibrosis, as already noted, in 42% of patients versus 17% in the placebo group. Importantly, it also prevented worsening of fibrosis, which occurred in 26% of subjects in the placebo group versus 10% in the PXL065 patients. PXL065 improved both inflammation and ballooning by at least 50%, but there was an unexpectedly high placebo response for inflammation, which seems to explain the modest effect on NASH resolution versus placebo that we showed in the previous slide. Next slide. Now turning to metabolic parameters, specifically hemoglobin A1c and insulin sensitivity. The metabolic profile was consistent with the well-known effects of pioglitazone. There was a dose-dependent decrease in hemoglobin A1c by 0.41% versus placebo, with low baseline values ranging from 6.1%-6.3%. This effect that was reached was 0.5% in the diabetic subpopulation. Serum C-peptide is decreased at all doses, indicating less demand for insulin secretion. In other words, improvement in insulin sensitization. Both A1c and C-peptide decreases are significant at the top doses of PXL065. Additional dose-dependent and statistically significant improvement in two indices of insulin sensitivity, HOMA-IR and Adipo-IR, were noted. Next slide. Now let's look at adiponectin and serum lipids. As you can see from this slide, dose-dependent and statistically significant increases in adiponectin were noted. There was also, these beneficial effects appear to be attributed to the PPARγ action of PXL065 in line with improvement in insulin sensitivity that was seen previously. Relative to previous pio-reported data, the increase in adiponectin is also modest. 2x the baseline values at the top dose, up to 9 μg/mL. In contrast to pioglitazone increases by 3x-4x the baseline values, reaching 15-20 μg/mL. These modest adiponectin increases are consistent with dose-dependent increases in drug exposure and more limited exposure to the PPARγ active S enantiomer. Additionally, circulating lipids were unchanged except for potentially beneficial HDL increases, and there was a trend for this. Next slide. Now let's shift to body weight, and here you see a graph illustrating body weight to week 36. Body weight analysis shows no dose-dependent increase in weight gain, with a roughly similar profile for both the 7.5 and the 22.5 mg dose versus placebo. At 15 mg, there was a limited degree of weight gain, roughly around 2 kg. The majority of patients gaining weight in this group were also low or non-responders. Next slide. Another way to look at this is placebo-adjusted change in body weight. This profile appears to be substantially improved compared to body weight increases typically observed in clinical trials with pioglitazone treatment for six or more months, 3.4% with dietary restrictions and 4.5%-5% without. Next slide. Now we'll look at the time course of body weight change in kilograms and the incidence of underlying edema or additional findings of edema. In addition, the small weight gain effect at 15 mg is not typical for pioglitazone, as it only appears late in the course of the study between 18 weeks and 24 weeks. There is no change in the time course of body weight in the two other groups, despite a PK profile and adiponectin levels which showed a clear dose response. The incidence of peripheral or specifically pitting edema was low and similar across the groups, including placebo, with no case of pitting edema in the dose of 15 mg PXL065. Next slide. When we look at overall frequency of treatment-emergent adverse events, the safety tolerability profile was good. Mainly grade one or grade two treatment-emergent adverse events were noted. The incidence of subjects presenting with related treatment adverse events was low and comparable across the group. Only one subject discontinued for a treatment emergent adverse event, which was an episode of agranulocytosis. One subject died in the placebo group. There was nothing remarkable in the profile of the serious treatment emergent adverse events. There were no SUSARs and no drug-related SAE in any group. Two subjects had severe COVID, as previously noted. One subject with gastroenteritis and associated metabolic disorder of acidosis and hypokalemia. One subject with procedural pain after surgery for biliary dyskinesia. Adverse events of specific interest, including edema. One increase in liver enzyme occurred in the placebo group, considered as not related. Next slide. Now let's look at the dose proportionality in exposure. PK profile is consistent with previous phase I results. Dose-dependent increases in PXL065 exposure were noted. There was a similar ratio of the R enantiomer, as noted in the black boxes, greater than PPAR gamma active S enantiomer, as noted in the red boxes at each dose. Very different from prior pio results, showing a ratio closer to 1:1. This was stable over the study duration. Next slide. In conclusion, this study, DESTINY-1, achieved its primary endpoint in liver fat content reduction at all three doses at 36 weeks. Non-invasive NASH test showed positive impacts. There was a strong effect to reduce fibrosis as well as prevent worsening. Favorable trends in other histology endpoints, including increasing number of patients who reached both endpoints of fibrosis improvement and NASH resolution versus placebo. There was improved glucose control as well as insulin sensitivity. A good safety tolerability profile with no dose-dependent weight gain and no increase in edema. The PK was consistent with the phase I results. A dose-dependent increase in the R enantiomer limited exposure to the S enantiomer. There was modest adiponectin increases also consistent with lower PPAR gamma target activity versus pioglitazone. It appears that PXL065 is a differentiated NASH development candidate. Results confirm potential to retain beneficial hepatic and metabolic effects with reduced PPAR gamma-driven side effects. These results are very promising, and next steps for the company include a pivotal trial design and dose selection, including external input here, and then to pursue regulatory interactions leading to the end of phase two meeting. With that, I'll turn it back over to Thomas. Thank you very much, Stephen, for reviewing these, very important results. This year has been marked by important achievement for Poxel. On the clinical front, of course, as just discussed. Thanks again, Stephen, for your presentation. Our phase II NASH DESTINY-1 trial for PXL065 met its objective and demonstrating a statistically significant effect, with a favorable safety profile. Based on these positive results, as you have understood, PXL065 will be prioritized for further development in NASH and will of course, initiate discussions for potential pivotal program in NASH. In parallel, we focus PXL770 development efforts exclusively in rare disease on the basis of our promising data which demonstrated strong potential in multiple rare metabolic indications. In addition, these results from DESTINY-1 have validated our hypothesis that the deuterated TZD platform reduces PPARγ side effect while retaining the efficacy benefit of TZDs and thus warrants exploration in other diseases such as ALD. In parallel of this, we are actively pursuing a number of funding initiatives to extend our cash runway, including dilutive and non-dilutive sources, and we are confident that we'll close at least one transaction in a reasonable tim.frame to execute our strategic plan. In closing, I really like to express my deepest gratitude to the patients, such as Stephen, who participated in our NASH trial during very challenging times over the past two years that made this result possible. I also like to thank our talented and dedicated staff. All of the work and success we accomplished so far this year would have not been possible without their incredible energy. Lastly, I appreciate your continuous support as a shareholder. Thank you very much all for your attention. We look forward to updating you on our progress. I suggest now to move to the Q&A session. Participants to the call can now submit questions in the chat. Thank you. Thank you very much, everyone. Before starting the Q&A session, I would like to remind you that you can ask your question by clicking on the Q&A button at the bottom of your screen. First, we have a question from Andy from William Blair. Normally now your microphone is on. Andy, you have the floor. Hi. Can you hear me? I'm sorry for the bad Wi-Fi. I'm curious. Dr. Harrison, you're one of the preeminent leaders in the field of NASH. I'm curious about your take on several things in the trial. One is really kind of the 36-week duration. Obviously this is a progressive disease. Just kind of put in perspective the duration of the trial and your expectation for efficacy endpoint. Also, your views on kind of the proportion of the fibrosis stage one that's kind of a little bit high. Would that be an impediment to see fibrosis reduction based on the baseline characteristics? Thanks. Thank you for your questions. It was a little bit challenging to understand what you were asking, but I think what you were asking is comments about the duration of the trial and putting things in perspective relative to this 36-week duration. You know, the second question was kind of where we are with reflecting on the response in the different F classes or different stages, particularly the F1. Let me just kind of break this down a little bit. When thinking about kind of NASH clinical trials in general, I do think it's important to put it in perspective. What we know is that steatosis can move very quickly, and we know that when you are able to move steatosis as measured by PDFF, that has been shown with very specific detail to improve histology. Not only the NAFLD Activity Score, but also NASH resolution, and if you're able to achieve a high enough amount of liver fat content reduction, potentially even fibrosis. We have historically used a 30% relative drop to predict histologic response. I think there was another online question about that. That data has been supported again across several different mechanisms. The more fat you lose, the better the probability of histologic response. We look at 30% as kind of that initial cut point. Now, the time course at which these non-invasive tests reach significance is unknown as to whether or not that correlates with histopathologic benefit. In other words, if you achieve your liver fat content reduction at 12 weeks, does that improve your probability of histologic response at, say, 36 weeks or a year? We don't know that yet. We just simply know if you achieve the drop that that has historically been linked to improvement. Now, the 36-week time point we've seen in a couple trials, specifically the Madrigal phase II trial was 36 weeks in duration as well. The primary endpoint in that trial was very similar. It was liver fat content reduction with key secondary endpoints in histology. This trial, very similar in design to that trial. I think what we've seen here is an important improvement in fibrosis. Now, again, not powered to find a histopathologic benefit, but we look at the numerical differences. There it's impressive to see the numerical change in fibrosis relative to placebo. Two quick points on that. When we look at drug development in NASH, much of it hinges on the placebo response rate. What do we know historically about placebo response rates for fibrosis? Well, we know that this is kind of spot on what you would expect for fibrosis response. In fact, if you look across the board, kind of the number that I use for fibrosis response in a placebo group is around 20%. Again, not out of line with what we see here at 17%. In fact, if you look at the REGENERATE trial and the RESOLVE-IT trial, very close there with much larger cohorts of patients, and this placebo response rate is lower than, say, what you saw with lanifibranor and semaglutide. You know, I think this is a relatively appropriate placebo response rate of 72%. To see a treatment effect delta of 22%, I think speaks well for the potential implications of this drug on fibrosis. Then you combine that with a non-invasive test showing similar reductions or reductions that would imply a histologic response on fibrosis, I think are encouraging. I think that answered your question, the 36-week treatment duration. The other comment I would make about that is, historically, we have discussed that fibrosis sometimes takes a long time to resolve, and I think that's more a reflection of the drugs that haven't shown that big of a benefit in fibrosis than the actual physiology of fibrosis in liver disease patients. We have shown, I specifically have shown, that we can move fibrosis in as short as 12 weeks, 16 weeks, and 24 weeks. Others to include lanifibranor have shown that you can move fibrosis in as short as 24 weeks. Showing improvement at 36 weeks with this particular compound is not surprising, and in fact very welcomed relative to the treatment effect delta that's seen. I hope that answered your question. Thank you very much. Hey, Stephen, I just wanted to interject one additional comment related to liver fat content, and maybe feel free to disagree with this, but. My suspicion is that different mechanisms may have a different relationship in terms of liver fat content versus histologic benefits. For example, if it's a pure weight loss mechanism like semaglutide, you might have a different degree of liver fat content reduction that's required to see that translate to an improved fibrosis versus the mechanisms like PXL065 has, which go beyond steatosis and may more directly affect fibrogenesis and inflammation. Kenneth Cusi has shown with pioglitazone that there's not a good correlation between liver fat content reduction and other benefits histologically. I don't know if you wanna comment on that. Yeah, I think that's a fair comment, David. You know, what are we measuring? We're not measuring inert triglyceride content, which really doesn't have anything to do with underlying pathophysiology of the disease. I think what we're really measuring when we show a drop in liver fat content as measured by PDFF is that in addition to dropping inert triglyceride, we're having an effect on toxic lipid species that just happen to be occurring in a collinear fashion. You're improving liver fat content, you're also improving toxic lipids. It doesn't mean necessarily that they're happening at the same rate, right? I think that's what you're alluding to, that the drop in liver fat content may not truly reflect what's happening with toxic lipid species within the liver, and PXL065 might be having a more specific effect there than what is noted relative to the liver fat content reduction. For sure, I agree with you. Also, it's important to note that you can have a histopathologic benefit without moving liver fat content at all. seladelpar, a PPAR-delta agonist, has shown us that. You know, I think we have to take it at face value, but understand that you know, the movements that we've seen in liver fat content when you are able to move it, that we do historically see improvement in underlying pathology. Thanks. Thank you very much. Next question is from David from Kepler Cheuvreux. Normally, your microphone is on now. Yes. Good afternoon. Thank you very much. Regarding the strategy for PXL065 in NASH, assuming you will partner, at what stage do you plan to enter into a partnership and how confident are you basically that you'll secure said partnership given that you like this dose responsive or dose response relationship for the fibrosis readout? Yeah. Thank you. Thank you, David. Maybe I can start and I'm sure David, Pascale or and others, you know, can add on this. We're definitely, you know, considering partnership, you know, for PXL065 in NASH. Of course, now we need to work further on the phase III development, but we know it's gonna involve several hundreds of patients, as you know, others, you know, perform phase III with 1,500 patients. We discuss that further because we aim of course to leverage the 505(b)(2) pathway. It's gonna be, you know, a significant number of patients treated for pretty significant duration as well. More than that, of course, the commercialization will require really a lot of expertise there. As you know, it's a field with a lot of unmet medical needs that will require a lot of education from really all the people involved in the value chain of commercialization, of commercializing a product in this field there. Definitely, you know, having a partner, having the experience on that would be great, and so like we did for hemophilia and diabetes and having a partner in phase III, you know, is even better to really perform really the phase III and prepare to run commercialization there. That's definitely, you know, part of our strategy. One of the points is of course, as you said, to really prepare well with the next steps. We'll be discussing this, as Stephen mentioned, with experts in the field, with regulatory bodies. We have couple of options there. One of it, which could maybe answer really your second question is, can we also, you know, include in this product program an adaptive design, so that basically, you know, we could test, you know, maybe two doses to begin with and, based on pre-specified analysis then select one dose to then, you know, move forward, you know, with the approval endpoints. We have couple of options down the road to further, you know, strengthen the optimal dose to be used. Of course, now we need to one, analyze further the data, two, discuss with expert in the field, and three, with regulators there. Of course, as soon as we have more clarity, we get back to the market. Okay. Thank you. Thank you very much. Next question is from Khalid from Bryan, Garnier & Co. Congrats on these results. Data looks very exciting. Could you give some information about possible explanation why there was no dose-dependent effect on prior duration and the dosage which will potentially be used in the pivotal study, expected cost of this trial. Maybe I can start with a brief intro and maybe, Pascale and David or Stephen, you can add on this, to answer the question. We need to continue looking at the data. We got you know, the liver fat contents data, you know, a few weeks ago. As Pascal and David and Stephen presented, we could see, you know, the waterfall plot, for instance, really looking at individual response there. Of course, we need to continue doing that, you know, with this new histology data, specifically assessing the consistency, you know, on an individual basis. This will help, you know, having a better understanding of what, you know, the placebo behavior and each dose behavior. That's ongoing. Maybe, Pascal, you want to say a word on this? I would say that, well, it's the. It appears that there is no real dose effect, mainly in the liver assessment and the liver fat content and the biopsy. For other parameter like the glycemic parameter, the insulin sensitivity or the, adiponectin, for instance, we see. Or even the biomarker of fibrogenesis. We see like, well, a good dose response with the top dose of 22.5 mg is the best, give the best effect. I think we need to go now in data and make also correlation between the PK and the data and analyze the response for a given patient with many different response. To better, you know, investigate this dose effect. The placebo effect. The placebo effect. David, anything you want to add on this? No, I would just add that I think I would agree with Pascale. It seems like 15 mg-22.5 mg is the sweet spot for if you look at all of the efficacy data in aggregate, and certainly there's no safety liability at the top dose. If you look at the PK, these doses are really very closely related in terms of the PK. There's a big overlap. You know, we're thinking that something in the range of 15 mg -22.5 mg would be optimal, but, you know, one could potentially choose both doses as well as Thomas previously mentioned. We have to do more work to really nail that down, but it looks pretty good. Thank you very much, everyone. What is a clinically relevant decrease in liver fat? Are you going to leverage 505(b)(2) to try and get agreement to conduct one pivotal trial? Given finances, have you considered investment from a royalty pharmaceutical investment company? Okay. Couple of questions. Maybe we can start with the first one, and I'm sure Stephen will have a lot to say on the threshold really for a relevant liver fat content reductions there. You discussed, you know, the 30% threshold. Stephen, maybe you want to add on this. Yeah, I think we've kind of covered this one, but just to kind of reiterate that different thresholds of liver fat content reduction, looking at different mechanisms of drug that are metabolic and can move liver fat have been linked to increasing grades of both NAS improvement as well as NASH resolution improvement. The threshold that we have historically used as the target is 30% relative fat content reduction. That's based on work done with resmetirom. It's also been shown to be a true link with aldafermin and FGF19 agonist, as well as efruxifermin and FGF21 agonist, and a few others I'm missing. Ultimately, that's the cut point that we look at in clinical trials. That cut point has been used as a primary endpoint in studies to include this one. You know, I think there's important caveats to that, as David and I also discussed, that we're just here moving inert liver fat content, liver triglyceride. Likely what this is really a reflection of is the collinear movement of toxic lipid species like ceramides, diacylglycerols, et cetera. Thank you, Stephen, for this answer. On the second part of the question, 505(b)(2), indeed, I think this is a really significant benefit of the product to that we've already, you know, discussed with the FDA. That we have already, you know, leveraged, because as we've communicated before, this has helped. We need to have a streamlined development, as an example, you know, we didn't have to perform a significant portion of some, you know, regulatory preclinical activities like tox activity, long-term tox studies there. Our goal will be to continue leveraging, you know, this 505(b)(2) process there, utilizing the pioglitazone data, and we know how extensive this data is, of course in diabetes, but also in NASH, and also adding our own data. We need to discuss that further, you know, with the FDA and other regulatory bodies, because in Europe you have, you know, not completely the equivalent of this, but roughly to help us, you know, define how we can leverage as best really this history of the product versus the pioglitazone. More to come on this. That's what, you know, we alluded to before is that this discussion with regulators will be very important. Of course, our aim here is really to streamline, you know, the development as much as possible. That's why before answering more clearly about, you know, the number of patients, the cost, we like really, you know, to discuss that, you know, with regulators because we have this benefit. We'd like to leverage it, but it's more, you know, the magnitude that, you know, needs to be discussed with the regulators. Anything to add, Pascal or David on the 505(b)(2) pathway? No. No. Our point on the royalty monetization to get to further financing. Indeed, this is you know something that we've also communicated in the past. We are looking at you know multiple options to strengthen our financing and specifically non-dilutive options of course. Royalty monetization is definitely you know something we're looking at. This is having TWYMEEG commercialized in Japan by a strong partner like Sumitomo Pharma, a well-known company, number one in diabetes in Japan. That's interesting. We've you know engaged in a discussion in this field with specific investors there. More to come on this at a later point. Thank you very much. We have another question from Andy, from William Blair. Given the overall metabolic improvement shown by PXL065, how important is it to show liver health improvement as evidenced by significant liver enzyme reduction? Yeah. I don't know, David or Stephen, whether you want to answer this one. I'm not sure I understand the question. Well, maybe Stephen can comment. I mean, my impression is that ALT levels are more of a direct measure of liver fat and not necessarily a measure of, you know, other not necessarily a very good predictor or a correlate with other histologic findings as much as some of the other non-invasive tests where we have a more dose responsive and significant effect. Comment on that, Stephen? I mean, I think, look, ALT is a marker of disease activity. We see that in every liver disease that we assess. It's also a marker of other. Like, it's not specific for a particular mechanism. I think what we have highlighted in this data is the contribution of COVID and how it's impacted this study, particularly as it pertains to serum liver chemistry tests. I don't think that can be overlooked, the importance of that. We've seen it in multiple trials. We've seen it across the board for the past two years. I think it's important to look at the totality of the data. The totality of the data speaks to improvement in liver fat content, improvement in fibrosis biomarkers, improvement in histology, not only in fibrosis and steatosis and ballooning. Yes, there was some inconsistencies relative to inflammation, but again, there was a high placebo response rate there as well. You know, understand this is a phase IIB. The power of the trial to look at histology was not there. The overall numbers were relatively low, and so there's innate variability with ALT that goes along with that. I think it's more important to look at the totality of the data rather than a specific single biomarker. But when you want to look at ALT, it's better to look at the 17 unit per liter reduction. We showed the slide where there does appear to be a nice responder analysis with 17 units per liter at the different doses relative to placebo. Maybe I'll just end there to say that you know that don't look at that number in isolation. Thank you very much. Next question is, what were the serious adverse events in the drug-treated group? Pascale, do you wanna take this one? Yeah. We had two serious COVID, one in the placebo and one in the top dose. We had, I think it was in the top dose, we had one subject who had febrile gastroenteritis with two metabolic complications. That's one subject, three different serious adverse event like hypokalemia and metabolic acidosis, which recovered. We had, I think it was in the 7.5, we had one subject who had biliary dyskinesia, got surgery and had post-surgery pain. This was two serious adverse event in one patient as well. We had also, I think in the 15, one subject who had muscular chest pain, and that's it. I think nothing remarkable. Yeah. On those adverse events and none of them were considered related to the drug and I think they are not somehow worrying. Yeah, yeah. Mm-hmm. Very clean profile, absolutely. Yeah. Thank you very much. Next question is, as noted, pio can decrease A1C and is sometimes used as adjunct treatment for diabetes. Might pio be used in diabetes treatment more often if the weight gain side effect was removed? Okay. Basically the question is around whether we could use PXL065 for the treatment of type 2 diabetes, given the low incidence of side effects. David, you wanna- Yeah. I think I'll take a shot at that 'cause I think it's a very interesting question. Pio is the only approved drug right now that is an insulin sensitizer, and there's a big demand, I think, in the diabetes field for something else that might improve insulin sensitivity. It is not used even in diabetes very frequently because of the weight gain and the edema liabilities. For sure it would be nice if there were another drug that improved insulin sensitivity, and it would be used much more frequently than pio is. Our goal is to develop PXL065 for NASH because the diabetes field is quite saturated with multiple products and pio is generic, and other drugs are going generic as well. There's an additional benefit that we can derive by having a product that not only is good on fibrosis and other endpoints in the liver, but also has these metabolic benefits that you've seen here in terms of insulin sensitization and glucose-lowering activity. Because up to close to 50% of patients with NASH do have type 2 diabetes, and many of them are not that well controlled. We think that's an additional benefit that would be specifically helpful for the patients that have both conditions. Maybe to elaborate on one point there, yeah. pio, you know, is still available in multiple countries for the treatment of type 2 diabetes. Not for NASH. There is no product on NASH. Definitely as David mentioned on the opportunity, the commercial opportunity is very different. Pio is, you know, used as a generic product in many countries for diabetes. Very different, you know, very strong commercial opportunity. Given the data that we just released, we believe the positioning of the drug in NASH is definitely, you know, the way to move forward. Knowing that, as David mentioned, we could also leverage this beneficial effect on metabolic parameter, as we know it's very important, you know, for these patients also to benefit from that. Yeah. Thank you very much. We have a final question, and maybe we can end the call after that. Could you please provide weight gain data after 36 weeks in per protocol data set? We haven't looked at this in this per protocol. The per protocol was only for the primary endpoint, so this is something that we can look at, but we don't have the data right now. I'm sorry. This is part of basically. Yeah. the further analysis that we need to do. When we say that we want to look also at individual data Yeah. Mm-hmm. is also, as Pascale mentioned, to understand, you know, the behavior of the placebo group, but also the verum group, you know, on a couple of endpoints, including, you know, the mid-dose, you know, with the weight assessment there. All this, you know, will be done in the next couple of weeks and happy to Yeah. to discuss that further. Okay. I think it was the last question we had. If you're ready, we can end the call. Okay. If there is no other questions, well, I'd like to thanks everyone really for attending the call and asking all these questions. A big thank you to you, Stephen, really for attending as well this and sharing your thoughts and on these results there. Thanks again, really for everything that you did really for this trial. We'll continue, as we said, analyzing the data. There will be, you know, more to come on this, with, you know, a publication or communication on scientific congress, further publications there. Of course, we'll keep, you know, everyone posted. We'll also keep everyone posted on our next set of results that will come and in the year of information. Again, thanks very much all for your attendance and strong support there. With that, we can now end the call, and I wish everyone a good rest of the day. We'll talk soon. Bye-bye.