ABIVAX Société Anonyme (ABVX) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the ABIVAX ABTECT Part 2 results webcast and conference call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Patrick Malloy, Senior Vice President, Investor Relations. Please go ahead.

Great. Thank you, operator, and good afternoon, and good evening, everyone. We hope you've had the chance to review the press release we issued after market close in the U.S. today, announcing the ABTECT maintenance Part 2 results, strengthening the Obefazimod safety dataset and demonstrating continued clinical benefit in refractory ulcerative colitis patients. Joining me on today's call are our Chief Executive Officer, Marc de Garidel; our Chief Medical Officer, Fabio Cataldi our Head of Global Medical Affairs, Chris Rabbat, and our Head of Regulatory Affairs, Keith Fournier. In a few moments, Marc will provide some opening remarks. And following that, Fabio will present the efficacy results. Chris will then present the safety review and exposure-adjusted incidence analysis with Keith providing a regulatory assessment. Following their prepared remarks, we will hold a KOL panel where we are honored to be joined by Dr. Jordan Axelrad and Dr. Remo Panaccione, who will provide their perspectives on the totality of the Obefazimod data presented today. We'll then open the floor to a Q&A session with ABIVAX management and our KOL panel. Dr. Axelrad serves as Professor at the New York University Grossman School of Medicine and serves as the Co-Director of the Inflammatory Bowel Disease Center at NYU. Dr. Panaccione serves as Professor of Medicine and Director of the Inflammatory Bowel Disease Clinic at the University of Calgary. Before I hand the call over to Marc, I'd like to remind you that during today's call, we will be making forward-looking statements. A summary of the forward-looking statements are included on Slide 4 of this deck and can be referenced in our 6-K filing. Now I'd like to hand the call over to our CEO, Marc de Garidel. Marc?

Thank you, Pat. Today, we are pleased to present the ABTECT maintenance Part 2 results. which we believe further strengthens the overall profile of Obefazimod in ulcerative colitis. These efficacy data reinforce a meaningful clinical benefit of Obefazimod even in the highly refractory patient population. It has demonstrated best in disease efficacy, unmatched by the most efficacious treatments available today in a hard-to-treat population. Part 2, also expands our long-term safety experience with malignancy and non-melanoma skin cancer rates remaining within the expected background range of patients with ulcerative colitis. As a result, the larger safety database further increases our confidence in the long-term safety profile of Obefazimod, and we believe further derisks the regulatory pathway. Before we take you through the results in detail, I want to emphasize that this is a very unique data disclosure, sharing this level of detail at each phase of our development is unprecedented. However, we have chosen to accelerate this Part 2 readout because we believe it is important to be transparent and provide the market with a complete picture of Obefazimod benefit risk profile. First, our efficacy story continues to strengthen. We continue to see best-in-disease efficacy in difficult-to-treat patients, including induction nonresponders. In fact, 37.2% of 50-milligram induction nonresponders went on to achieve clinical remission, and 34.5% achieved endoscopic remission at week 44 of maintenance. Those are remarkable results. Additionally, for patients who relapsed on 25-milligram in Part 1 of the study, we can now report that nearly half of them were able to achieve clinical remission at week 44 once they dose escalated to 50-milligram in Part 2. Second, the expanded safety database gives us even greater confidence in the overall safety profile of Obefazimod. We have now accumulated more than 1,700 patient years of exposure across Phase II and Phase III. And when the data are viewed in context, malignancy and non-melanoma skin cancer incidents remain within or below the expected background rates for patients with ulcerative colitis. We also carefully evaluated the individual safety events and found no evidence of a new or unexpected safety pattern. Importantly, these findings are consistent with Obefazimod mechanism of action by enhancing miR-124, Obefazimod helps to rebalance a dysregulated immune system rather than broadly suppressing immune function. We believe this differentiated non-immunosuppressive mechanism contributes to the favorable safety profile observed across the clinical program. Finally, we have independently reviewed the Part 1 and Part 2 maintenance safety data with multiple experts and regulatory consultants. Their conclusions have been consistent based on the data that's available today, they do not expect a boxed warning for Obefazimod. They support filing both the 25- and 50-milligram maintenance doses to address the needs of different UC patient population and believe Obefazimod has a clear regulatory path forward. Now I would like to hand the call over to our Chief Medical Officer, Fabio Cataldi, who will walk through the Part 2 efficacy results in detail. Fabio?

Thank you, Marc. Before reviewing the Part 2 data, it is important to highlight 4 key design features. First, Part 2 serves as a supplemental data set to the Part 1 registrational cohort shown on the left-hand side of the slide. Second, Part 2 includes 2 distinct patient populations. Part 1 relapse, we were rescued with open label of Obefazimod 50-milligrams and induction non-responders who either continue their assigned Obefazimod dose or if previously on placebo were randomized to an active dose. Together, the two 50-milligram groups account for 447 or 633 Part 2 patients or about 71%. Third, these patients represent a more refractory and difficult to treat population either because they relapsed after response or did not respond during induction. Finally, Part 2 did not include a placebo arm. All patients received Obefazimod. So efficacy and safety results should be interpreted in that context. Today, we will focus on the key efficacy and safety findings for Part 2, with additional analysis to be presented at upcoming congresses. This slide highlights the Part 2 patients were a more difficult to treat population. Over 55% have previously failed at least one advanced therapy compared with approximately 38% to 46% in Part 1. Despite this, 44-week completion rates remain high ranging from about 70% to 86% across the Part 2 groups. This context is important when interpreting the efficacy results because clinical benefit in induction respond and relapse represent a higher bar than a traditional maintenance population. It is also important to recognize that induction nonresponders that ended Part 2 had only been treated for 8 weeks without achieving clinical response. This means that they're carrying a substantially higher inflammatory burden of the start of maintenance treatment, than induction responsers, that entered Part 1. This is reflecting the baseline characteristics at the start of maintenance. Mean Modified Mayo Score was more than twice as high in induction responders in Part 2 compared with induction responders that enter Part 1. While over 80% of induction nonresponders in Part 2 have fecal calprotectin levels above the clinically meaningful threshold of 150 micrograms per gram compared with approximately 50% in Part 1. As a reminder, we enrolled the highest percentage of JAK failures of any Phase III UC trial to date. 19% to 22% of the prior advanced therapy patients failed JAK inhibitor in Part 1 and Part 2 respectively. Now let's focus on the Part 2 induction responders. These are patients would not achieve clinical response after 8 weeks but continued Obefazimod treatment. These 3-through design allowed us to evaluate whether longer-term therapy will provide benefit in patients who will discontinue in other Phase III programs, did not allow drug nonresponders to enter maintenance or long-term expansion. By week 44 of maintenance, efficacy was observed across all exploratory end points with numerically stronger results seen in the 50-milligram arm. In this group, 37% achieved clinical remission, 62% achieved clinical response and perhaps most impressively, approximately 1/3 achieved endoscopic remission, which is the most difficult and objective endpoint. Although these analysis are exploratory and uncontrolled, the consistency across symptomatic and objective endpoints suggest that a meaningful proportion of initial responders benefit from continued Obefazimod treatment. The second part population we will discuss consists of patients who initially responded to Obefazimod during treatment and were randomized to 25 milligrams in Part 1 of the maintenance study, but subsequently relapsed and received open-label rescue treatment with a higher 50-milligram dose. Importantly, 45.5% of these patients who relapse on 25 milligrams were able to achieve clinical remission and 2/3 reestablished clinical response after dose escalation. We believe these findings are particularly meaningful because they mirror what physician encounter in clinical practice. Patients who lose response on maintenance dose often require treatment optimization rather than switching to an entirely new therapy. This data demonstrated increasing the dose from 25 milligrams to 50 milligrams can reestablish disease control in a meaningful proportion of patients. In early June, we reported that Obefazimod delivered potential best-in-disease endoscopic remission among induction responders. Today, data showed that this efficacy stand to an even more challenging population. Patients will not respond after initial 8 weeks induction period. Remarkably, the endoscopic remission rates achieving this induction nonresponder are as high or even higher than rates reported for induction responders for other approved therapy, including Rinvoq. Endoscopic remission is an especially important endpoint as associated with lower relapse rates and improved long-term outcomes in ulcerative colitis. I'll now turn it over to Chris Rabbat, our Head of Global Medical Affairs to walk through the safety review.

Thank you, Fabio. Now we will dive into contextualizing the safety results of the full Obefazimod clinical program. First, we'll provide a high-level recap of the key findings from the June 1 data release. Next, we'll review the Part 2 safety data with a particular focus on malignancies excluding non-melanoma skin cancers and separately non-melanoma skin cancers. Finally, we will put these findings into context by reviewing the exposure-adjusted incidence rates for these rare events across the Obefazimod program. This slide provides important context from safety observed in Part 1 of maintenance. Overall, Obefazimod showed a favorable safety profile with infrequent serious treatment emergent adverse events, no signal for serious infections, low incidence of headache with strong treatment persistence. Before we review the Part 2 safety data, I want to level set on one important point regarding the difference between malignancies excluding NMSCs and NMSCs. Malignancies, excluding NMSCs are the primary focus of regulatory and clinical safety assessments for malignancies. They have been associated with box warning language for JAK inhibitors and TNF inhibitors because they can result in significant impact on patients' well-being. NMSCs on the other hand, are typically evaluated separately. They have not been associated with box warning language in IBD therapies or other therapeutic areas and are generally managed through routine dermatologic surveillance, which is part of standard IBD clinical practice. When identified early, they are typically treated with local excision and have low impact on patients. Keeping this distinction in mind is important as we review the Part 2 safety findings and the exposure-adjusted incidence rates on the following slides. Now let's put Part 1 malignancy, excluding NMSC findings in context with other Phase III placebo-controlled maintenance cohorts in UC. This comparison focuses only on the placebo-controlled maintenance period since that is the common registrational data set across programs. This table shows the percentage of patients in any active treatment arm who experienced a malignancy excluding NMSCs, or all approved UC treatments since Entyvio was approved in 2014. In ABTECT, Maintenance Part 1, there were 2 events or 0.52%, placing Obefazimod in the middle of the range. Both events occurred in the 50-milligram arm with no events in the 25-milligram or placebo arms. While this is a numerical imbalance for rare events, similar patterns have been seen in other UC programs, including Skyrizi, one of the most utilized agents available, which had the same number and event distribution with 2 events in the high dose and no events in the low dose or placebo. Overall, the Part 1 malignancy findings are consistent with the experience reported for approved UC therapies. Before reviewing the Part 2 safety summary, it is important to consider the imbalance between dose groups, both in number of patients exposed to each dosing group, but also the cumulative duration of exposure. One way this is typically done is by utilizing the relative proportion of patient years of exposure for each group. In Part 2, the 50-milligram group accounted for 288 of the 420 patient years of exposure or nearly 70% with approximately 30% for the 25-milligram and notably, as a reminder, 0 on placebo since there was no placebo comparator for Part 2. Because more exposure creates more opportunity to observe safety events, especially rare events, they are more likely to be observed in the group with the largest portion of exposure. In this case, the 50-milligram arm. This context is important as we review the overall Part 2 safety on the next slide. This slide summarizes the top line safety findings from Part 2. As a reminder, Part 2 did not include a placebo arm. So these results are descriptive and should be interpreted in the context of active Obefazimod treatment. Overall, TEAE rates were similar across dose group. TEAEs leading to study discontinuation were somewhat higher in the 25-milligram group, which was partially driven by a worsening of ulcerative colitis. One death occurred in the 25-milligram group and was assessed by the investigator as unrelated to treatment. The suspected cause was pulmonary embolism in a patient over 65 and with multiple pre-existing risk factors, including a prior pulmonary embolism, atrial fibrillation, type 2 diabetes, hypertension and recent prolonged immobility. Serious or severe infections and opportunistic infections were infrequent and did not suggest a dose-related pattern. There were 2 malignancies excluding NMSCs both deemed unrelated to treatment by study investigators in patients with pre-existing conditions and multiple other risk factors. Importantly, both occurred in patients who were previously on placebo in Part 1 and experienced relapse. Since the protocol indicated, all Part 1 relapsers would receive the 50-milligram dose in Part 2, both cases landed in the 50-milligram group. NMSCs were balanced by event count with 2 cases in each dose group, acute pancreatitis was also reported once in each dose group, and there were no cardiac abnormalities suggestive of cardiac fibrosis. Before we review exposure-adjusted incidence rates, it is important to look at how patient your exposure is distributed across the data sets we will analyze. For the integrated UC clinical program, which includes Phase II and Phase III, placebo represents only a small portion of total exposure, about 11%, while the 50-milligram dose accounts for the largest share at approximately 49%. As I mentioned earlier, this pattern is even more pronounced in maintenance Part 2 where there was no placebo arm and nearly 70% of exposure occurred in patients receiving the 50-milligram dose. Because exposure is not balanced across treatment groups, raw event counts can be misleading particularly for uncommon events. Groups with more patient years simply have more opportunity to observe rare safety events. For that reason, exposure-adjusted incidence rates relative to the expected background rate in the patient population being studied provide a more meaningful way to compare safety findings than across treatment groups with unequal exposures. Before discussing the exposure-adjusted incidence rates for malignancies excluding NMSCs, I want to briefly note the source and interpretation of the published reference range used here. The reference range was selected based on a careful review of literature describing incidence of background malignancy, excluding NMSCs and a broad UC population, including both treatment naive and advanced therapy experienced patients. Other high-quality publications report higher rates, in some cases, more than 1.0 per 100 patient years, particularly in more refractory or heavily pretreated cohorts. For that reason, this reference range should be viewed as a useful benchmark for context rather than a statistical test of treatment relatedness. This slide applies the exposure-adjusted approach to malignancies excluding NMSCs across 3 data sets, the full integrated UC clinical program, the combined maintenance population, and maintenance Part 2 alone at the bottom. The exposure-adjusted incidence rates for the combined active arms remained within the published UC reference range across all 3 analysis sets. Because malignancies excluding NMSCs are uncommon events, incidence rate estimates become more precise as cumulative exposure increases. The ABTECT maintenance data should be interpreted using the totality of the exposure-adjusted evidence, making the integrated UC clinical program analysis at the top of the slide the most relevant data set with 1,700 patient years of active drug exposure. The results in this table demonstrate that exposure-adjusted incidence rates in each individual dose and the active combined treatment arms are consistent with the UC background reference range, which again, were based on published UC studies. This supports the interpretation that when adjusted for exposure, the observed malignancy rate, excluding NMSCs that were observed in all 3 data sets is consistent with the expected range for this patient population. As noted on the prior slide, in Part 2 of the maintenance trial, there were 2 malignancies excluding NMSCs observed, both deemed unrelated to treatment by study investigators likely due to preexisting and confounding risk factors. The MPN patient had preexisting thrombocythemia at baseline with elevated platelets of 909,000 per microliter which remained elevated throughout the study until the diagnosis. And the second case was a 55-plus-year-old patient diagnosed with prostate cancer who was exposed to Obefazimod for just 3 months. Before discussing non-melanoma skin cancer, the key context is that this program used more intensive skin lesion surveillance than any of the UC Phase III protocols we benchmarked, which included all 3 trials completed since 2016. Skin lesions were first identified as an adverse event of special interest based on a modest numerical imbalance in Phase II. Following a nonclinical photosensitivity finding, regulatory feedback led to photosensitivity being incorporated into the existing skin lesion AESI framework. The Phase III and Phase II OLE protocols were strengthened to include dedicated reporting, lesion photography, central dermatologist review and lesion-specific adjudication. Features not included in the benchmark protocols. That matters for interpreting NMSC findings. Before enhanced surveillance, no NMSCs had been reported in the UC program. After enhanced protocol-driven surveillance was implemented, NMSCs were detected, consistent with increased ascertainment. Despite this intensive surveillance, exposure-adjusted incidence rates for the broader skin lesion AESI were similar between Obefazimod and placebo and ABTECT with no treatment imbalance. I'll detail this on the next slide. NMSCs remain rare and were detected in patients with multiple risk factors, limiting ability to infer a causal relationship with treatment. In Phase III, 60% were identified within the first 6 months of exposure with no increase over longer treatment duration, a finding consistent with detection of potentially preexisting or developing lesions. Taken together, the timing and pattern of events are more consistent with enhanced detection from protocol-driven surveillance than with a cumulative exposure-related NMSC signal. Because skin lesions were monitored as an AESI, we can compare overall skin lesion occurrence across treatment groups using exposure-adjusted rates. In the combined maintenance data set, rates were similar across groups, 10.2 per 100 patient years with placebo, 8.8 with 25 milligrams and 10.0 with 50 milligrams. So even with robust protocol-driven surveillance we did not observe an increase in overall skin lesion occurrence with Obefazimod. This provides important context for interpreting the NMSC findings on the next slide. If Obefazimod were increasing skin-related toxicity, we would expect to first see an imbalance in overall skin lesions. We simply do not observe that. This side applies the same exposure adjusted approach to NMSCs across the 3 data sets, the full integrated UC clinical program, the combined maintenance population and maintenance Part 2 alone. The exposure-adjusted incidence rates for the combined active arms remained within or slightly below the published UC reference range across all 3 analyses. As with the prior malignancy analysis, the largest data set is the most informative because it includes the greatest amount of patient years of exposure and provides the most stable estimate for uncommon events. In the integrated UC clinical program, which again includes approximately 1,700 patient years of active drug exposure, the active combined NMSC incidents was 0.59 for 100 patient years which is slightly below the published UC reference range of 0.7 to 1.4. Overall, the NMSC rates observed with Obefazimod were within or below the range reported in published UC studies. As discussed earlier, NMSC should be interpreted separately from non-NMSC malignancies given their different clinical and regulatory significance. In Part 2, there were 4 NMSCs reported 2 for each dose. All 4 cases occurred in patients with multiple established risk factors including 3 with advanced age, 3 with prior thiopurine use, 2 with prior history of skin cancer; and 3 with failure of multiple advanced therapies with an established increased risk for NMSC. With the addition of the Part 2 maintenance data, the observed safety database now includes more than 1,700 patient years of exposure. The key takeaway is the overall safety profile continues to remain favorable. Importantly, we continue to see low incidence of adverse events typically associated with broad immunosuppression, which is consistent with Obefazimod's mechanism of action and its role in restoring mucosal immune balance without evidence of broader immunosuppression. We also evaluated malignancies using exposure-adjusted incidence rates. Rates for both NMSC and malignancies excluding NMSCs were consistent with expected background rates in a UC population. Taken together, the expanded maintenance data set continues to support confidence in Obefazimod's long-term safety profile. Now I'll turn it over to Keith Fournier, our Head of Regulatory Affairs, to provide the regulatory assessment. Keith?

Thank you, Chris. So let me now turn to the feedback we received from 4 independent former FDA senior leaders who reviewed both the complete ABTECT maintenance Part 1 and Part 2 data sets. While these are independent expert opinions rather than formal FDA guidance, the feedback was remarkably consistent across 3 key areas: first, on safety and labeling, the consultants view that the overall safety profile supports advancement without major regulatory concerns. They considered it highly unlikely that a box warning would be required and did not anticipate significant additional testing or referral requirements. Importantly, they noted that potential safety considerations could be addressed through established clinical practice measures such as routine skinning examinations and standard patient counseling around sun protection. Second, regarding dose strategy, there was strong consensus that both the 25-milligram and 50-milligram maintenance doses should be advanced. Maintaining both doses provides flexibility for physicians to tailor treatment based on individual patient needs while preserving optionality in the product label. Third, when looking at the totality of evidence, the consultants believe that the maintenance data meaningfully strengthens the overall regulatory package. They viewed Obefazimod as having a compelling efficacy and safety profile when considering the combined Phase II and Phase III experience. They also felt that the maintenance data provide important context showing that observed adverse events remain within expected ranges and support a favorable overall benefit risk assessment. Building on that regulatory feedback, our strategy then is to pursue a label with 50 milligrams for induction and both 25-milligram and 50-milligram for maintenance. Both the 25-milligram and 50-milligram doses deliver exceptional efficacy with best in disease endoscopic remission rates. The 50-milligram dose offers additional value for patients with more refractory severe or extensive disease, supporting our strategy to file both maintenance doses. Importantly, including both maintenance doses gives physicians the flexibility to tailor treatment based on individual patient needs. Now I will hand it back to Marc to summarize today's presentation.

Thank you, Keith. In conclusion, we are excited to report today the remarkable efficacy of Obefazimod demonstrating in a highly refractory ulcerative colitis population. Equally important, our expanded safety database now includes more than 1,700 patient years of exposure across the Phase II and Phase III studies with patients treated for up to 7 years. The addition of the Part II data presented today, further strengthened the benefit risk profile of Obefazimod. With this in mind, we'll meet with the FDA on July 30 for our pre-NDA meeting as we continue to work towards an NDA submission by the end of this year. Looking ahead, we are very enthusiastic about the readout of the Phase IIb Crohn's program, mid '27, particularly in light of the remarkable efficacy in this highly refractory ulcerative colitis population. With that, I'll turn the program over to Chris to introduce our 2 distinguished key opinion leaders. Chris?

Dr. Axelrad serves as an associate professor at the NYU Grossman School of Medicine and serves as the Co-Director of the Inflammatory Bowel Disease Center at NYU. Dr. Axelrad's clinical and research focus includes malignancy risk, cancer surveillance and the management of IBD patients with current or prior cancer. He will provide clinical context for interpreting the observed malignancy and NMSC findings in ABTECT relative to expected background risk in patients with ulcerative colitis. Dr. Panaccione serves as a Professor of Medicine and Director of the Inflammatory Bowel Disease Clinic at the University of Calgary. Dr. Panaccione is an internationally recognized IBD clinical trialist with extensive experience evaluating the efficacy and safety of new therapies in ulcerative colitis and Crohn's disease. He will provide his perspective on the clinical relevance of the ABTECT maintenance Part 2 efficacy findings and the overall benefit risk profile of Obefazimod. All right. So first, welcome to the call. I'd like to start by asking you each the same question, if you could both comment on it, that would be great. And that is, taking a step back and looking at both the safety and efficacy from the Part 2 data that we just presented, has anything changed with regards to how you view the overall benefit risk profile of Obefazimod or its potential place in the treatment paradigm? Maybe we can start with Dr. Panaccione.

Yes. Thanks, Chris, and thanks for the presentation. I guess from an efficacy standpoint, what stands out is that these were not easy to treat patients. And Part 2 did include those nonresponders in patients who had relapsed during maintenance. And those are precisely the types of patients who often challenge us in clinical practice. Yet despite that, we continue to see those meaningful rates of clinical remission endoscopic improvement and endoscopic remission in that more refractory population. And that suggests that the efficacy signal is both durable and clinically relevant beyond the original registrational data set. I think more importantly is, in addition, if you combine this with the efficacy and the registrational data set, the proportion of patients who are benefiting from Obefazimod is amongst the highest we've ever seen in ulcerative colitis. In fact, it is the highest we've ever seen in ulcerative colitis. Having done this for over 25 years, this is the most robust efficacy data set that I've ever seen. From a safety perspective, I think we have more than 1,700 patient years of experience across the integrated program and importantly, the safety profile remains remarkably consistent with what we've seen previously. And I think that we need to remember that the data reinforce what I think clinicians are increasingly looking for a therapy that combines deep, best-in-class -- I mean, best-in-disease efficacy with a safety profile that supports long-term use. So to succinctly answer your question, yes, it's viewed, it has changed in my view, but in a positive direction. The Part 2 data really increased my confidence in both the benefit risk profile and the potential role of Obefazimod as an important future treatment in moderate to severe ulcerative colitis.

Thank you, Dr. Panaccione. Dr. Axelrad, any additional comments on that?

Yes. Thanks, Chris. No, I agree with everything Remo said. As you know, in IBD, we're really desperate for more effective therapies, particularly for our most refractory patients. And so as underscored, this is really one of the most effective data sets we've seen and something that we're really looking forward to having access in the clinic for our sickest patients. I think what's also really important of the data set you showed is that we're still capturing a large number of delayed responders. We're still capturing patients who relapse on lower dose. And so there's already pathways to getting more patients into some of these higher remission rates that you've demonstrated. And I think that, that's really important. As far as reflecting on the safety data, and I'm happy to talk more about that. I think that these data also really underscore very good safety. And particularly in a more refractory population where our risk tolerance changes. I feel very reassured with these data that there's not really a sacrifice of safety with a more effective drug, which we have experienced doing with other advanced and conventional therapies. So I think that this is a really nice data set and look forward to having its access in the clinic.

Thank you for that Dr. Axelrad. So maybe I'll follow up with a specific question for you on the safety. So in the new Part 2 data we presented today, we observed 2 malignancies excluding non-melanoma skin cancer, both in the 50-milligram arm. And then 4 non-melanoma skin cancers, 2 in each arm of the 25 and the 50 milligram. So based on the incidence rate and the background for the individual cases, how should investors think about this?

Yes. So I think the most important considerations here, which especially when we're talking about so few overall events is whether these exposure-adjusted incidence rates really differ from either the general IBD population or the general population of IBD patients who are exposed to other therapies. And then, of course, within the context, which you provided really nicely, the sort of the individual case characteristics that may help us contextualize some of these findings. So I think the way I really think about it is, are there red flags or are there more reassuring factors? And I think there are substantially more reassuring factors from a malignancy standpoint. I mean we're talking about very low event counts, a very common, generally experienced tumor types in the general population and in particular, the IBD population. And then, of course, as you demonstrated in a heavily pretreated otherwise higher-risk population. And then you went through the data very nicely demonstrating there really was not an imbalance year after exposure adjustment as it compares with general data that we have from other data sets and from other Phase III programs. So I feel very confident there. Things that may make me think about a red flag, which again, just underscoring, I'm not seeing that in a handful of these cases, is that if there were high rates exceeding comparable populations or a clustering around a rare malignancy, and we're really not seeing anything like that. And so from a cancer standpoint of which I feel really confident speaking on, there's really not something that causes concern at least from my end.

Thank you for that Dr. Axelrad. So maybe one more question for Dr. Panaccione before we turn it back over to the operator for investor questions. So today, we presented rare event data in the context of exposure-adjusted incidence rates and compared them to incidence rates from published studies to try to understand whether the overall incidence rate for patients on Obefazimod was elevated. Can you comment on whether you see this as the right methodology. So why shouldn't investors expect these rare events to balance across treatment arms versus doing the exposure adjusted analysis that we did.

Yes, I'm happy to comment on that. Maybe before I comment -- I'll make a general comment. I think first, whenever safety is discussed, the initial response is often emotional rather than analytical. And this is entirely understandable, whether you're a patient, physician or investors alike, you're naturally more sensitive to potential harms and benefits. And really, the key is to move beyond that initial reaction and evaluate the totality of the evidence through a rigorous scientific lens. And clinically, I think this is exactly the right way to look at rare events. When events are uncommon, the crude percentages can be really misleading, particularly when exposure is not balanced across the groups. And what matters is not only how many events occur, but how much time patients were actually exposed to treatment. And that is why exposure-adjusted incidence rates are so important. They allow us to take that into account by correcting for exposure. I would also not expect rare events to balance perfectly across treatment arms in a trial of this size. By definition, those rare events occur infrequently and small numerical imbalances can happen by chance. One of the prime examples in this data set, if you go back to the registrational data set is there were 2 pregnancies, a good event when we think about IBD in the 50-milligram group, none in the 25 and none in placebo. And scientifically, we wouldn't interpret that because there's a numerical imbalance that this drug is a fertility drug or is responsible for those pregnancies. And those are the exact same numbers that we were seeing for some of the malignancies. So it's really important to take into account. So the methodology is appropriate. And I think Jordan really summarized it beautifully is that we look for patterns. Are there events increasing over time? We can look at the Phase II? Are they above the expected background rates? Is there organ-specific clustering? None of which we see with this data set. So from my perspective, the methodology is completely appropriate and the current data support continued confidence in the overall safety profile.

Thank you so much, Dr. Panaccione and Dr. Axelrad. With that, I'm going to hand it back over to the operator.

[Operator Instructions] We will now go to the first phone question. One moment please.

Maybe before we get to the first question. We are a little bit short on time. I want to get through as many of the questions from the analysts as possible. So please one question per analyst.

Your first question comes from the line of Thomas Smith from Leerink Partners.

Congrats on this update. For the clinicians, now that we have the Part 2 maintenance data, can you just comment on how you intend to use Obe in your clinical practice? What proportion of your advanced therapy naive patients and experienced patients would you see as ideal candidates for Obe given the balance of the efficacy and safety that we've now seen across substantial data set.

I'm happy to start, Jordan, if that's okay with you.

Yes, please.

When I tend to answer this question when we have new therapies, especially with a therapy that has the efficacy that we've seen with Obe is you need to ask yourself why or where wouldn't you use Obefazimod. And so efficacy in IBD is, I always say, is always king or queen. And you can't really discount the efficacy that we've seen, especially when you look at the endoscopic remission differences compared to other existing therapies. So because the -- I don't believe that there's a safety signal here, I think that this could easily find itself as a frontline therapy in moderate to severe ulcerative colitis. But we also have the benefit that in the patient population because of drug exposure, it's shown to be very highly effective in advanced therapy exposed patients. So in that situation, it would also be a prime drug that we would use after the failure of first advanced therapy. So I can see this being used very broadly. And if you layer on the fact that it's a once-a-day oral therapy, it's going to be a very, very attractive therapy to offer patients.

I think I'll have very little to add other than to really echo that there is very limited therapies that we have at our disposal that work in our sickest patients. And so there's really nice data presented here in a largely refractory population that this drug is very effective. And so yes, I agree with Remo that I think that there is a pathway to use in the first line and a pathway to use in our sickest most refractory patients. And that's not something that we commonly see in a data set. So I think that really could find a place in many segments of the population. And particularly refractory sick group, I think that there's a great place for this drug. But yes, I can see it being used in many segments.

The other thing that we may want to add briefly is the fact that if the drug is approved at both the 25 and 50 milligrams, it also gives that flexibility that clinicians are looking for. So you could rescue patients if you had 25 milligrams or loss of response, which is another attractive attribute of the therapy.

Great. Thank you, Remo. Thank you, Jordan. Operator, let's move to the next question.

Your next question comes from the line of Jason Butler from Citizens.

I appreciate all of the details you guys have gone into today. Again, a question for the physicians. The company has spoken to regulatory experts that suggest the malignancies and non-malignancies would not show up in meaningful warning language in the label. Do you agree with that? And to what extent would the inclusion or exclusion of that language impacts your view on how the drug will be used.

Yes. So maybe I'll take that. So I think that with a handful of very common malignancies, I don't really see that there's a clear pathway to having any sort of language around the label or restrictions. And remember that we have a lot of experience using drugs that do have labels that have concerns about adverse events and whatnot. So we already have a lot of comfort with that. So one is that at least from a malignancy standpoint of these common malignancies in a higher-risk population that don't differ from incidence rates that would be expected in the otherwise IBD population and otherwise treated IBD population. I don't really see a pathway to anything on the label. But even if there were, I don't think that would have a major impact on our utilization, particularly from the standpoint of skin cancers, which again is the only thing really to be discussing and that's something we encounter with other drugs, and it's something that through health maintenance recommendations, our population should be receiving annual skin cancer exams anyway. So it's not really outside of our practice as it stands today.

Great. Thank you very much, Jordan. Operator, let's move to the next question.

Your next question today comes from the line of Judah Frommer from Morgan Stanley.

Thanks for the update, all the data here. Just real quick. Can you remind us what happened with the classification of the colonic dysplasia patient in Part 1? And can you help us with what role the Part 2 data play within the regulatory submission process in the pre-NDA meeting? Did that change at all? Or is this always contemplated within that package?

So maybe we'll start with Chris and then perhaps Remo or Jordan, if you want to weigh in on any of those topics around the colonic dysplasia, they probably have great perspective.

Yes. Let me just say that the company took a look at the case and realized that it wasn't a true malignancy, and we removed it from that category. It's sort of a MedDRA coding thing where it came up in the table. But yes, I'd like to invite maybe Dr. Axelrad to comment on whether or not colonic dysplasia should be categorized as malignancy or not?

Yes. So dysplasia is a colon polyp. These are precancerous lesions that are exceptionally common in the general population. That's why patients are required to have colon cancer screening and surveillance in the general population and in those with inflammatory bowel disease it's akin to a precancerous mold, for example, or it's not a cancer. It's a finding, and it's something that's completely removed and that obviously prevents the development of cancer down the line. But this is not a malignancy. It's not a cancer. It is a colon polyp that is extremely common. So really not ought to be considered a malignancy.

Great. Thank you, Jordan. And operator, let's move to the next caller.

Your next question comes from the line of Faisal Khurshid from Jefferies.

I wanted to ask, in the Phase II study that you're pulling in with the Phase III results here, was the surveillance for non-melanoma skin cancer similar to what you did in the Phase III?

Yes. Maybe, Chris, do you want to take that one?

Yes, I can take that. Yes. So it depends on when you look at the study. So for most of the study, it was different, right? So we still had the AESI for skin lesions, but not for photosensitivity. So the whole protocol and surveillance program was not applied to, I would say, the majority of the Phase II experience, but we did apply to the Phase III experience. And as you saw the number of discovered cases went up but I'd point out that even in the Phase III data set, we're still within the reference range that we provided.

Great. Thanks, Faisal. Operator, let's move to the next question.

Your next question comes from the line of Yatin Suneja from Guggenheim.

Two for me, if I may. Number one, how does FDA review the -- like what do they care more about? Do they care about NMSCs? Do they care about non-NMSCs? And especially with regard to the non-NMSCs, it seems like this is the best case scenario where you're seeing these 2 cases, they basically came from placebo and had some sort of an underlying issue. So can you maybe just confirm about these 2 particular cases for non-NMSCs -- they were at baseline?

Yes. So Chris, do you want to touch on that one and then perhaps throw it over to Jordan and Remo for their perspective.

Yes. So as I described in the presentation, some malignancies, excluding NMSCs are really evaluated differently by the agency and by clinicians because they're more serious. They have a larger impact on patients than NMSCs, which are typically resected and caught early or have a low impact on patients. In terms of the 2 malignancies, excluding NMSCs that we saw in Part 2 in the new data set, yes, I mean, as I mentioned, one of them seem to be arguably preexisting with the thrombocythemia. And the other one was a prostate cancer with only 3 months of exposure which seems to be unlikely to be related given that short-term exposure. But I think Dr. Axelrad is the expert here on this call. So maybe I can invite him to comment.

Yes. I think, of course, the FDA cares about malignancies. Nonmelanoma skin cancer is definitely low on that list. Keep in mind that, for example, nationwide SEER data does not even capture nonmelanoma skin cancers. And as far as cancers go, it's really more of an annoyance for patients when it is associated with medical treatment rather than something that is generally life-threatening or terribly concerning. Certainly, for the other malignancies that were detected here, I really think essentially nothing of them right, things like breast, prostate, these are incredibly common cancers. And it looks like based on the case characteristics that Chris provided, the patient with myeloproliferative disease really was something that predated. This is someone who had profoundly high platelet counts prior to enrollment in this trial. So I think that's, in my view, kind of completely unrelated. And the other 2 cancers are extremely common cancers in the general population, and those didn't feel terribly imbalanced from what we see. So I really don't think there's a signal here at all and particularly from the nonmelanoma skin cancer standpoint, the FDA, certainly they care about malignancies, but that's certainly lower down on the list of something that tends to be concerning.

And specifically to the regulatory authorities, we've gone to the regulatory authorities with similar data sets in the last 4, 5 years with Phase III trials. And certainly, that has not led to any language within the prescribing information. So I would be shocked if any regulatory authority, whether it be the FDA or EMA, looks at this any differently.

And actually, just if I could follow up on 1 second is that as Remo said, we act on emotion a lot. Remember that cancer is the most concerning side effect of any drug given for anything that we do. And so of course, this is something patients care about very deeply and putting that context into something that is so rare overall, especially from these data, I think it's just really actually reassuring.

Awesome. Thank you both. Operator, let's move to the next question.

Your next question comes from the line of Julian Harrison from BTIG.

I have one for the physicians on the call. When patients now receive Obefazimod and achieve remission following induction, are you expecting a categorical recommendation for those patients to step down to 25 mg? Or is there maybe a prevailing case for some of those patients to stay on 50 mg, if there -- even if they're in remission. Can you maybe walk us through your thought process there? And do you expect that it's generalizable to other gastroenterologists.

Yes. I think that I don't see that everyone would need to step down to 25 milligrams. Certainly, we need to see more of the post-hoc analysis in things that may affect overall efficacy. I think what we tend to know from previous agents that people who've been exposed to advanced therapies made you better on higher doses during maintenance than lower doses. And so I think once we have that data, it will probably be at the clinician and the patient's discretion on whether to go on to the 25 or 50 milligrams. But as we stated before, I think that this will be driven primarily by the efficacy that you could obtain in maintenance by the 25 or 50 based on some of the baseline characteristics that the patient may have.

Right. Awesome. Thanks, Remo. Operator, we're going to take 2 more questions and then we'll throw it over to Marc for some closing remarks. And I apologize in advance to everybody who's in the queue but we will try and make time tomorrow for follow-up calls with you.

Your next question comes from the line of Sam Slutsky from LifeSci Capital.

Great work on today's update. I guess for the data in induction nonresponders who became responders with longer treatment, is there a pattern for when they typically converted to a responder? And then maybe for the 2 physicians on the line to chime in, is it possible just given that data that physicians might try to keep patients on Obefazimod longer before considering another treatment versus historical? Just kind of curious that dynamic.

All right. Chris, do you want to take the first part and then yes, over to Remo and Jordan.

Yes. It's a really good question, Sam. And we're still analyzing the data. We want to see exactly when the majority of these patients start to respond and start to feel better after week 8. And it may depend. There might be some subgroup differences. So we've got some analysis to do before we can make any conclusions there. But what we do see is remarkable efficacy at week 44. But I'll hand it over to the clinicians here to see if they have anything to add.

Jordan do you want me to take that, and you can add or do you want to take it?

Maybe I'll start with just a really quick comment that I think Remo and I asked that specific question a couple of weeks ago on the call. I mean it's an important one for context because it helps us understand when we should keep patients on drug exactly like you're suggesting versus turn away to an alternative. And we know that from other drugs that yes, if you can have people stay on drug until week 16, maybe even week 24 that with certain therapies, you can capture another proportion of response. And so that data point is going to be helpful to us clinically for sure.

Yes. And just to highlight that is we probably want to see -- it's more about trajectory. So if patients are getting better. Remember, when we design these trials, we fix the induction endpoint semi-arbitrarily, which doesn't really connect to what we do in clinical practice. So based on this Phase II data, it's very encouraging. And certainly, if you had a patient who is trending towards better but didn't respond completely as defined in the trial, you would continue that patient on therapy because we know increased time of exposure will drive patients into better outcomes as was shown in Part 2, which is quite different than somebody who has -- you have them on 8 weeks of therapy and nothing happens either symptomatically or objectively. When we look at the totality of the data set, that's why it appears that you're going to have a high response rate in these patients. So I can see patients being exposed to 16 or 24 weeks before backing off.

Great. Thank's Remo. And operator, let's go to the last question before we go over to Marc.

Your final question today comes from the line of Allison Bratzel from Piper Sandler.

I think I've heard on our prepared remarks, July 20 -- or July 30, is the date for your meeting with FDA. Could you just talk to priority for that discussion? How much you'll be willing to communicate with investors following that? If malignancies are actually going to be an issue for the agency, would it be apparent from that meeting? Or just help us understand dynamics there.

Yes. Maybe I'll throw it over to Keith, who is our Head of Regulatory.

Yes. So thank you, Pat. Thank you, Allison, for the question. So obviously, as Marc referenced in the prepared remarks, July 30 is our pre-NDA meeting with the agency and really, this is the standard stop on the way to submission, as you all well know. And we have put in front of the agency, really the outline and plan for the content of the NDA, the format, the key elements and timing when we will be submitting and with what data. So to the question about if there is a concern, would it become evident there? We are in continuous contact with the agency through our clinical studies, through our reporting, et cetera. And just to reiterate, we have, of course, submitted all these events from our studies throughout the study periods and throughout the historic development. So we, of course, will continue to be fully transparent with them and continue to engage them in full discussions which is to bottom line at the full outline of what the NDA will contain and the questions of interest has been put in front of the FDA with the pre-NDA briefing document, and we look forward to continuing the dialogue with them.

Great. Thanks so much. And yes, operator, I think we're going to bring it over to Marc to a couple of words.

Yes. Thanks, Pat. So today's results significantly expand our long-term safety experience while demonstrating meaningful efficacy in one of the most difficult to treat patient population. So we believe the totality of the evidence strengthen our confidence on risk profile and positions us well for our planned NDA submission later this year. Thank you for your interest and good evening.

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