Celcuity Inc. ($CELC)

Good day, and thank you for standing by. Welcome to the Celcuity VIKTORIA-1 trial Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Brian Sullivan, Chief Executive Officer and Co-Founder of Celcuity. Please go ahead.

Good morning. Thank you for joining us today. I'm Brian Sullivan, CEO and Co-Founder of Celcuity. Before we begin, I must point out, and let's turn now to Slide 2, that some of the comments today contain forward-looking statements that are subject to risks, uncertainties and assumptions. In particular, our expectations around gedatolisib are uncertain and subject to change. Should our expectations fail to materialize, should our assumptions prove to be incorrect, actual company results could differ materially from these forward-looking statements. A description of these risks and uncertainties and assumptions is included in our SEC filings. Let's now turn to Slide 3. Joining us today is Dr. Sarah Hurvitz, the co-principal investigator of the VIKTORIA-1 study and the Senior Vice President of the Clinical Research Division of the Fred Hutch Cancer Center and President and Head of Hematology and Oncology at the University of Washington School of Medicine. Dr. Hurvitz will present the detailed results from the PIK3CA mutant cohort of the trial. Dr. Sara Tolaney, Chief of Breast Oncology at Dana-Farber, will then join for a discussion about the treatment landscape in the second-line setting for patients with HR-positive HER2-negative PIK3CA mutant advanced breast cancer. Dr. Igor Gorbatchevsky, our Chief Medical Officer, will provide a few additional observations about these results, and we'll finish up with an update from Eldon Mayer, our Chief Commercial Officer, who will provide a brief update on our preparations for a potential launch of gedatolisib. Despite the importance of the PIK3CA or PI3/AKT mTOR pathway as a cancer driver, inhibitors targeting this pathway have had more limited impact than would have been expected when its importance was first discovered over 20 years ago. And this reflects the PAM pathway complex structure, which requires multiple components to be inhibited to comprehensively blockade the PAM pathway activity, when only a single component of this target, adaptive resistance arises and pathway shutdown is limited. Further complicating the challenge of drugging this pathway is the narrow therapeutic window that exists. There's a graveyard of drugs attempting to inhibit all of these components that were not efficacious, due toxic or both. Gedatolisib overcomes these challenges by over inhibiting all 4 Class I isoforms of PI3K and both mTORC1 and 2 with a potency and PK profile that patients can tolerate well. Let's now turn to Slide 5. Today is an important day for patients with HR-positive/HER2-negative advanced breast cancer. Both gedatolisib regimens doubled the likelihood of a patient survival without disease progression or death compared to alpelisib plus fulvestrant. The clinically meaningful improvement in progression-free survival showed by both the gedatolisib triplet and doublet from the PIK3CA mutant cohort of our VIKTORIA-1 trial is now the second positive Phase III readout for gedatolisib, provides further demonstration of the clinical benefit comprehensive inhibition of the PAM pathway. With positive Phase III results now in both the PIK3CA wild-type and mutant cohorts of VIKTORIA-1, we're well positioned to offer potential standard of care therapeutic combinations for all patients in the second-line setting. We believe these results also augur well for our two ongoing Phase III trials evaluating patients with HR-positive HER2-negative advanced breast cancer in the first-line setting. Let's now turn to Slide 6. As was the case with the data reported for the wild-type cohort of the VIKTORIA-1 trial, these results established several new milestones in the history of drug development for HR-positive/HER2-negative advanced breast cancer. First, VIKTORIA-1 is the first Phase III trial to demonstrate superiority of one PAM inhibitor versus another. And second, the greater than 11 months median progression-free survival for the gedatolisib triplet and doublet are the highest reported by any Phase III trial for a regimen, including endocrine therapy in the second-line setting. And third, the 49% objective response rate for the gedatolisib triplet is the highest reported by any Phase III trial for a regimen, including endocrine therapy in the second-line setting. Now let's turn to Igor Gorbatchevsky, our Chief Medical Officer.

Thank you, Brian. I'm very happy to introduce Dr. Sara Hurvitz with whom we are very happy to work for the last 5 years as a co-principal investigator for VIKTORIA-1 study. As Brian mentioned, Dr. Hurvitz is currently serving as the Senior Vice President of Clinical Research Division of Fred Hutch Cancer Center and Professor Head of Hematology and Oncology at University of Washington School of Medicine. So I will turn to Dr. Hurvitz to review results of VIKTORIA-1 Study 2 in patients with 638 mutation-positive disease.

Thank you so much. It's my pleasure to be here. Good morning. By way of background, currently available therapies target a single component of the PI3-kinase AKT mTOR signaling pathway, which is a complex multicomponent signaling pathway that drives breast cancer growth and contributes to endocrine and CDK4/6 inhibitor resistance. These agents have modest efficacy and tend to be limited to biomarker selected patient subsets. These agents also as well as earlier therapeutic attempts to completely block the PAM pathway can produce significant toxicity. And so there is an unmet need for safer and effective PAM inhibitors. As Brian told you, gedatolisib is a highly potent multi-target PAM inhibitor that targets all Class I PI3-kinase isoforms as well as mTORC1 and mTORC2 for comprehensive blockade of this important pathway. VIKTORIA-1 is a randomized open-label two-part study designed to evaluate gedatolisib-based therapy in patients with hormone receptor positive HER2-negative advanced breast cancer after progression on a CDK4/6 inhibitor and nonsteroidal aromatase inhibitor. Study 1, which was just published and was presented at the end of last year, enrolled patients with PIK3CA wild-type disease and demonstrated a statistically significant and clinically meaningful benefit compared to fulvestrant in patients with PIK3CA wild-type advanced breast cancer. For the triplet, the median progression-free survival was 9.3 months versus 2 months for fulvestrant with a hazard ratio of 0.24, and the doublet had a median PFS of 7.4 months versus 2 months with a hazard ratio of 0.33. The safety profiles were generally consistent with the individual agents. So today, we present the first results for Study 2, which evaluated gedatolisib-based therapy in patients with PIK3CA mutated disease. Next slide. VIKTORIA-1 is a Phase III global open-label randomized two-part clinical trial that assigned patients to Study 1 or Study 2, as I said, based on tumor PIK3CA status. Eligible patients had received prior CDK4/6 inhibitor and an aromatase inhibitor and experienced disease progression. Up to two prior lines of endocrine therapy were allowed, but no prior chemotherapy and no prior PI3-kinase pathway inhibitor was allowed. Our cutoff for HbA1c was 6.4%. Study 2 enrolled patients with a tumor PIK3CA mutation and randomly assigned patients in a 3:3:1 ratio to the triplet of gedatolisib palbociclib fulvestrant or alpelisib fulvestrant or gedatolisib fulvestrant. The primary endpoint was progression-free survival comparing the triplet arm D to alpelisib fulvestrant, which is standard of care for PIK3CA mutated breast cancer. Next slide. The primary efficacy analysis progression-free survival by blinded independent central review was performed on the intent-to-treat population of the gedatolisib triplet versus the alpelisib fulvestrant control arm. Key secondary endpoints were to be tested in hierarchical order. Although the overall survival data are not yet mature, an interim analysis was planned to coincide with the primary efficacy analysis, and those results will be reported today. Additional secondary endpoints comparing the gedatolisib doublet to alpelisib fulvestrant as well as objective response rates for all three treatment arms will also be presented. Next slide. At the data cutoff, 362 patients had been assigned in a 3:1:3 ratio, and most patients in each arm received their allocated treatment. There were more patients who discontinued treatment with the standard alpelisib fulvestrant than with the gedatolisib triplet, and this was mainly due to disease progression. Moreover, there were more adverse events and treatment-related adverse events that led to treatment discontinuation as well as deaths in the alpelisib fulvestrant arm compared to the gedatolisib arms. At the data cutoff, the median follow-up was 12.8 months. Next slide. Baseline demographics and characteristics of the patients were generally well balanced across treatment arms. A large proportion of patients had liver and lung mets over approximately 3/4 of patients and about 15% of patients had endocrine-resistant disease as indicated by a short time to progression of 6 months or less. Consistent with real-world usage patterns, there were significantly more prior ribociclib and palbociclib treated patients relative to abemaciclib overall, and usage was similar for the gedatolisib triplet and alpelisib fulvestrant arms. Next slide. Here are the progression-free survival data. VIKTORIA-1 study 2 met its primary endpoint. The gedatolisib triplet produced a statistically significant and clinically meaningful reduction in the risk of disease progression or death relative to alpelisib fulvestrant. The hazard ratio was 0.50, meaning that we saw a 50% reduction in the risk of progression or death. To our knowledge, the 11.1 month median progression-free survival is the highest reported by any Phase III trial for a regimen, including endocrine therapy in second-line hormone receptor positive HER2-negative advanced breast cancer following treatment with the CDK4/6 inhibitor. It is also notable that separation of the curves occurred early around the time of the first scan being performed. Next slide. Subgroup analyses demonstrate that the clinical benefit of the gedatolisib triplet was generally maintained across all subgroups. All hazard ratios were less than 1.0, although some of the confidence intervals at upper limits include 1.0. And as was seen in the wild-type cohort in Study 1, results were consistent across the different CDK4/6 inhibitor subgroups. Next slide. The gedatolisib doublet also produced a clinically meaningful reduction in the risk of progression or death. Although not part of the primary efficacy analysis, the hazard ratio was similar to that with the gedatolisib triplet, so 0.51 versus 0.50, respectively, as was the median progression-free survival, 11.1 months here. The descriptive p-value of 0.0013 indicates the results are robust. These results suggest that when PIK3CA is mutated, the PAM pathway may play a more important role in tumor cell proliferation than in tumors lacking a PIK3CA mutation. Next slide. Similar trends are seen in the subgroup analysis for the gedatolisib doublet versus alpelisib fulvestrant. Next slide. Looking at overall survival, we see encouraging trends in the interim analysis with separation of the curves occurring at the outset. With 110 deaths total among 362 patients, the interim boundary for statistical significance was not yet met. Next slide. The overall response rates, clinical benefit rate and disease control rates were all higher for the gedatolisib-based regimen than for alpelisib fulvestrant. To our knowledge, the 49% objective response rate for the gedatolisib triplet was higher than has been previously reported by any Phase III trial for a regimen, including endocrine therapy in second-line hormone receptor positive HER2-negative advanced breast cancer. Additionally, nearly 3x as many patients in the alpelisib fulvestrant group experienced disease progression compared to the gedatolisib arms. Next slide. Gedatolisib-based treatments also produced a clinically meaningful duration of response as seen here for the gedatolisib triplet on the left and the gedatolisib doublet on the right, both compared to alpelisib fulvestrant. The median duration of response was doubled with the gedatolisib triplet, 15.7 months versus 7.5 months and triple with. Next slide. The safety profiles of each regimen were generally consistent with the individual agents within the regimen and no new safety signals emerged. Similar to the Study 1 wild-type data, there was a low rate of treatment discontinuation due to adverse events in the gedatolisib arms, 2.6% for the triplet and 3.8% for the doublet. In contrast, 7.1% of patients in the alpelisib fulvestrant arm discontinued treatment due to AEs. There were three Grade 5 events seen related to treatment by the investigator, in the gedatolisib triplet and two in the alpelisib fulvestrant. The safety profile of gedatolisib was generally consistent with that reported for Study 1 with the most common treatment-related AEs, including neutropenia in the triplet arm, which is likely or most likely related to the palbociclib and stomatitis in both arms, 61.4% and grade and 16.3% grade 3 with the triplet and 5.8% grade 3 with the doublet. Notably, rates of diarrhea and hyperglycemia, both considered class effects with PI3 kinase inhibition were much lower in the gedatolisib arm than in the alpelisib patient group. In summary, gedatolisib, next slide, plus fulvestrant with or without palbociclib significantly improved progression-free survival compared with alpelisib fulvestrant in patients with hormone receptor positive HER2-negative PIK3CA mutated advanced breast cancer in VIKTORIA-1 study 2. Patients in the gedatolisib triplet and doublet groups or 2x as likely to survive without disease progression or death compared to alpelisib plus fulvestrant. Adverse events associated with the gedatolisib-based treatment were mainly Grade 1 or 2 in severity. Notably, hyperglycemia was low as was diarrhea, which is unexpected for a drug targeting the PAM pathway. For alpelisib and fulvestrant, hyperglycemia was 58% and diarrhea was 40%. Stomatitis was the second and most -- and first most commonly reported treatment-related adverse event for the gedatolisib triplet and doublet, respectively, but study treatment discontinuation due to these adverse events was 2.6% for the triplet, 3.8% for the doublet and higher in the alpelisib arm at 7.1%: Gedatolisib with or without palbo represents a potential new standard of care for patients with hormone receptor positive HER2-negative PIK3CA mutated advanced breast cancer after progression on or after treatment with the CDK4/6 inhibitors. The combined results of VIKTORIA-1 Study 1 and 2 validate the PAM pathway as a molecular driver in hormone receptor positive HER2-negative advanced breast cancer regardless of PIK3CA mutation status. And with that, I will close.

Thank you very much, Sara, for this presentation and your leadership you provided for this program. I would like to provide a brief review of the results in comparison to the current treatment landscape in a second-line setting for hormone-positive HER2-negative advanced breast cancer. Let's move to the next slide. As the results presented by Dr. Hurvitz confirm that gedatolisib regimen showed the strongest efficacy results, we compare them to reported results from other studies. And as you can see, both median progression-free survival and objective response rate high with a triplet reported 11.3 months, doublet reporting 11.3 triplet reporting 11.1 and objective response rate of almost 50% for the triplet, 36% for the doublet. When it compared to other agents in this class with the median progression-free survival, very similar between alpelisib and fulvestrant of 5.6 and 5.5 months and objective response rate of 26% in alpelisib fulvetrant 23% in previously reported studies in patients who previously received CDK treatment. Let's move to the next slide. I would like to remind showing again the data that we presented last year, Dr. Hurvitz presented at ESMO in 2025 as the study met its primary endpoint, which was very statistically significant and the lowest hazard ratio ever reported in randomized Phase III study in advanced breast cancer for the triplet of 0.24 and for doublet of 0.33. Both regimens showed meaningful improvement in progression-free survival compared to standard of care. Let's move to the next slide. When we look at the current landscape for treatment in patients with wild-type disease, we can see that changes in results when we compare to standard of care are very significant in gedatolisib treatment regimen. Median progression-free survival was improved by almost 5x with a triplet agent and almost 4x with a doublet agent in this disease. And as you can see, some of the products are already approved, some of them not yet approved and comparison is obvious. Let's move to the next slide. Another way to compare efficacy and improvement for gedatolisib, as I already mentioned, triplet regimen in wild-type reported the lowest hazard ratio reported to date of 0.24% and the double 0.23%, which compares favorably to other studies reported in recent years. Let's move to the next slide. Right now, I'm very happy to introduce Dr. Sara Tolani, who is the Chief of Division of Breast Oncology at Dan at Harvard Cancer Institute and Professor of Medicine at Harvard Medical School. Dr. Tolani kindly agreed to talk with us to provide her impression of the data that was shared with Dr. Hurvitz.

So Dr. Tolani, in the first question, I would like to hear your initial impression of the results from Study 2 evaluating gedatolisib regimen in mutated disease, especially when we compare to other agents in this class. What would be your initial impression?

Well, I was very impressed with the data. I think this is a very challenging to treat patient population. These are patients post CDK4/6 inhibition who have an underlying PI3K mutation. And traditionally, we've been previously using fulvestrant alpelisib. And in the U.S., we're often using fulvestrant capasertib. And what we're seeing with fulvestrant and capivasertib in a post-CDK population is a PFS of around 5.5 months. And so this, in essence, is doubling compared to control therapy, what we're able to achieve in terms of disease control. And so I think this is a very meaningful improvement for our patients.

Thank you, Dr. Tolani. Another question, one follow-up as we presented previously last year in Study 1 and as Dr. Hurvitz mentioned and we presented results from Study 2, treatment discontinuation due to adverse events was low in this study below 4% for both triplet and doublet regimen across both studies. When we look at your already mentioned currently used agents in this disease, what's your initial impression about safety profile, low discontinuation rate and especially those side effects, as Dr. Hurvitz mentioned, related to PAM inhibitors, diarrhea, colitis and hyperglycemia. What's your initial impression of those results?

Well, I'll say we never get a discontinuation rate as low with the PI3K inhibitor. So it is very impressive. I mean I think we are challenged right now in the clinic with using the current treatment. While [indiscernible] was certainly a step forward, I think, compared to alpelisib in terms of tolerability, it still requires monitoring. I have to do glucometer teaching with my patients, have them do finger sticks, which is challenging. The rate of diarrhea is over 70%. Patients are often using loperamide. So these drugs are not easy for us in the clinic and patients can often need to discontinue therapy due to rash. And so it has been a challenge. So again, to see a discontinuation rate under 5% is not something I've ever seen with the PI3 kinase inhibitor, so very impressive.

Thank you very much. And the last question, with this result that you saw, how do you think gedatolisib combination regimens will be positioned in a second-line advanced breast cancer following potential approval. What's your opinion?

Well here, I think combining the totality of the data across both studies within VIKTORIA-1, it does suggest that there's benefit for gedatolisib honesty irrespective of PI3K mutation. I do think in the PI3K mutant pathway, this is really an important step forward because, again, we're very challenged with our current treatment regimens. I think the PI3K wild-type population, as you pointed out, reviewing the current landscape is a bit more complex in terms of thinking about various treatment options. But I think, again, this gives a very broad utilization in a post-CDK population, which is really nice for patients.

Thank you so much for your time. We really appreciate it.

So let's turn to the next slide. I will finish my part of discussions with a general summary of overall observations for this results. First, [indiscernible] evaluating patients in mutation positive disease did exceed statistical assumptions that we were set up before. As you see in both hazard ratio and based on assumed expected median progression-free survival, statistically significant improvement with hazard ratio of 0.5 and 0.51. The next important point is that control arm in this study, alpelisib fulvestrant actually represents today's most realistic real-world results for this therapy based on the number of points I would like to bring. The first, this is the largest randomized study comparing the study arm to alpelisib fulvestrant when we look at the previously reported study with alpelisib. The higher number of sites participating and enrolling patients and a significant proportion of patients with a significant tumor burden and a higher proportion of those who were endocrine resistant compared to previously reported results. And the last point with that is that event rate resulting in treatment discontinuation for alpelisib actually indicates that the efficacy outcomes are not associated with drug exposure and provide very realistic efficacy for alpelisib fulvestrant combination in real world for patients with advanced breast cancer who were previously treated with cell cycle inhibitors. And the last point to summarize the efficacy and safety profile of gedatolisib is explained by gedatolisib mechanism of action, PK profile and route of administration. All of those are responsible for significantly improved efficacy and safety compared to oral agent targeting a single component of the PAM pathway. With 300x more potent activity, gedatolisib can be dosed infrequently, which results in significantly less frequent exposures of Cmax and lower systemic AUC. Also by passing initial GI tract metabolism, gedatolisib intravenous administration results in significantly lower number of immune-mediated and metabolic side effects such as diarrhea, rush and hyperglycemia. I will be concluded with my part of presentation and turning back to Brian.

Great. Well, thank you, Igor. I'd like to now turn to Eldon Mayer, our Chief Commercial Officer. Eldon will provide a quick overview of the progress we've made establishing the commercial infrastructure for a potential launch of gedatolisib.

Thank you, Brian. Let's turn now to Slide 30. I'm pleased to provide an update on our commercial strategy and launch preparation. We're very enthusiastic about the opportunity ahead. We believe our data in both PIK3CA wild-type and mutant patient populations can position gedatolisib to become a best-in-class treatment option in the second-line setting, and our commercial and medical affairs teams have been executing with urgency to ensure we're ready for launch. First, I'd like to take a moment to briefly review the exceptional leadership team that will drive the execution of this launch. Every individual here that is leading core functions of medical affairs, marketing, market access, commercial operations and sales has extensive industry and oncology experience. Over the past 2 years, they have each built highly experienced and deeply skilled teams designed to meet the specific market needs for launching gedatolisib. These leaders and their teams are seasoned, high-caliber people with a strong blend of industry know-how, commercial and clinical credibility and successful launch experience in both emerging biotech as well as large full-scale commercial stage organizations. And we're confident that together, we will deliver a successful launch that will create value for health care practitioners, for patients and for shareholders. Let's turn now to Slide 31. Moving on to the market opportunity. Within the U.S., approximately 37,000 patients with HR-positive/HER2-negative advanced breast cancer receive second-line treatment each year following progression on CDK4/6 inhibitors. Of these, roughly 60% are PIK3CA wild-type and 40% are PIK3CA mutant. And importantly, approval for both indications would allow gedatolisib to address 100% of this market with the simplicity of a single PIK3CA agnostic treatment approach. This would be a major differentiator versus currently available drugs that are restricted to either wild-type or mutant patients. There remains a significant unmet need in this market for therapies that deliver better efficacy without compromising safety. Gedatolisib's unique mechanism of action as a potent pan-PI3K/mTOR inhibitor, combined with its pharmacokinetic profile and IV route of administration provide a distinct efficacy safety profile relative to existing oral agents. Taken together, we believe gedatolisib will offer a compelling value proposition, a unique combination of efficacy and safety that has the potential to become a new standard of care in this setting. And finally, we estimate a $6 billion total served market opportunity across both PIK3CA wild-type and mutant patient populations. Let's turn now to Slide 32. Moving on to the launch readiness and preparations for the PIK3CA wild-type launch. For market access and reimbursement, we have completed payer engagements covering 90% of U.S. medical benefit lives. We've had multiple productive discussions with nearly all major payer and provider pathway organizations as well as 90% of 36 key strategic accounts and more than 50 local and regional accounts. Our NCCN submission pathway and compendia packets and AMCP dossier will be ready for submission within 72 hours of approval. And with regard to reimbursement, we expect prior authorization to label payer coverage, which is very important for a buy-and-bill IV therapy. Let's turn now to Slide 33. Our sales force, field marketing and medical affairs teams are fully built and prepared. We have created a tenured sales organization that has an average of 24 years in pharma and 17 years in oncology experience, and every sales specialist has IV and buy-and-bill experience. Our medical science liaison team and field-based marketing team have been actively engaged with the breast cancer and oncology community. We began key opinion leader engagement and advisory boards in 2024 and have now reached a combined total of 1,000 community breast cancer experts, physicians that treat a high volume of breast cancer patients and key opinion leaders. Let's turn now to Slide 34. On the broader marketing front, we launched the unbranded campaign, panpathway.com, which has already generated over 4 million digital impressions that highlight the importance of comprehensive PAM pathway inhibition. We've maintained a strong presence at all major oncology and breast cancer congresses and have developed a full array of promotional and educational materials and programs along with a digital media campaign that is ready to deploy immediately upon approval and launch. Let's turn now to Slide 35. And finally, our distribution and patient support infrastructure is in place. We have secured our 3PL partner, our specialty distribution network, GPO contracts, specialty pharmacies and comprehensive patient and reimbursement support programs that are all ready to go live at approval. We have also built strong partnerships with breast cancer patient advocacy groups. In summary, we've built a strong launch team that is fully prepared to drive rapid adoption and establish gedatolisib as a new standard of care in the PIK3CA wild-type market and if approved for both indications across the entire HR-positive/HER2-negative second-line treatment patient population. We're confident that gedatolisib's differentiated clinical profile, combined with a high level of commercial readiness positions us for a strong and successful launch. I look forward to sharing more updates as we approach potential approval and launch. Back to you, Brian.

Thank you, Eldon. And let's now turn to Slide 37. We're obviously very encouraged by these results and the implications for our two new Phase III first-line clinical trials and other potential future clinical development plans. And since gedatolisib has the potential to address a number of additional unmet needs in a variety of additional settings, we're thankful that our intellectual property position is very strong. We expect to have patent exclusivity with gedatolisib at least until 2042 with the potential to extend it further with the subcutaneous formulations we're developing. And this gives us a long runway to develop new potential indications and to expand the patient population we can treat with gedatolisib. Let's now turn to the next slide. We have a number of several important milestones coming up in the back half of this year. First, we're expecting an approval decision from the FDA by our PDUFA date of July 17, 2026, for the VIKTORIA-1 PIK3CA wild-type cohort. Second, we have several data updates later this year. We expect to update data from our Phase Ib metastatic castration-resistant prostate cancer study in the fourth quarter and to provide updates from our VIKTORIA-1 wild-type and mutant studies later in the year as well. And then finally, we have some important regulatory submissions we expect to file. First, we're targeting submission of a supplemental NDA to the U.S. FDA in the third quarter of this year. And secondly, we expect to submit the marketing authorization application or MAA to the European Medicines Agency in the fourth quarter of this year. Let's now turn to Slide [ 30. ] So this concludes our presentation portion of the day. We'll now turn to a Q&A session. Thank you to those who have submitted questions, and we'll go from there. So operator, if you could open up questions, please.

[Operator Instructions] Our first question comes from the line of Maury Raycroft with Jefferies.

Congrats on the data and the strong PFS HRs in both the triplet and doublet. Given the similar PFS curves in the doublet versus triplet regimen, but differences in OS curves, how are you thinking about the potential labeling and commercial use? Will the triplet still be the predominant therapy across wild-type and mutant if CDK4/6 is not needed in the mutant setting? And can the doctors comment on whether they'll still test for PIK3CA mutations and whether they would use the triplet or the doublet...

Okay. Well, thank you, Maury. Both Sara, as it turns out, have commitments to present in other settings right now. So we were basically very lucky to get them at the beginning of this trial. So we'll be answering these questions, and you will be participating. As far as the going-forward label, in the wild-type setting, we think there's a clear obvious distinction and benefit for the triplet versus the doublet. Research we've done, both quantitative and qualitative indicates that physicians will likely prefer probably 5:1, the triplet versus the doublet. And part of that is related to the idea that with these patients in the second-line setting, providing complete coverage of the disease pathways is very appealing. And also knowing that if for whatever reason, palbociclib is no longer appropriate for a patient or if it's not appropriate at the get-go, that they can use to get a doublet with confidence that patients will receive an important benefit. Now in the mutant setting, it is a little bit different. We, to be frank, I mean, surprised that I think that doublet outperformed our expectations, and we think that's very encouraging because it basically indicates that in the mutant population, this pathway is playing more of a driver role. And you can think of the CDK4/6 pathway potentially as being more of a passenger. You do see differences in activity when you look at the objective response rate, 50%, 49% versus 37%. And you also see OS curves that might be a little more separated, but that's obviously early and not conclusive. And so in the mutant setting, we think there'll be a similar perspective that controlling all pathways provides the potential most coverage of the tumor drivers. But certainly, we think there'll probably be maybe a higher preference for the doublet than in the wild-type setting. Overall, what we think this demonstrates is that both regimens are appropriate options for patients. And by having both regimens, we're providing flexibility to doctors. It's a very heterogeneous population. And so we think having options and having strong data for both potentially provides a lot of flexibility and optimization for the doctors to tailor the treatment that best reflects the patient's characteristics.

Our next question comes from the line of Tara Bancroft with TD Cowen.

So I guess with the doctors not here, Brian, my question is for you. So maybe thinking about the relative potencies and activity of hitting the single node like mutant specific versus the PAM pathway, does this at all change your expectations for future competition from the oral PI3Ks and where those can end up in Phase III?

Well, again, our view has been based on the underlying biology of these tumors and the role of this pathway. And ultimately, it's a complex pathway, multiple components that essentially allow cross activation to occur if one of the components is not inhibited. And I think if we go back 20 years, we see that this general biological imperative was well understood by every major pharmaceutical company. All the programs that were launched initially when this pathway was discovered as an important driver were pan-PIK/MT4R inhibitors. And they took that approach for a reason that was understood and nonclinical work certainly reflected that, that comprehensive inhibition is required to optimize control this pathway and maximize potential antitumor control. The switch or the shift towards single target inhibition really was just a reflection of the challenges of drugging and hitting these multiple targets, not necessarily an approach that was optimized according to the tumor biology. So our view is that single target inhibition is just fundamentally limited in the level of antitumor control that will be available just because of the structure and function of this pathway. We -- I think the results for the alpelisib arm probably represent real-world experience. Our nonclinical work and I think others nonclinical work have shown that alpelisib and [ capivasertib ] in in vitro models, and we've tested a lot of different tumor cell line models as well as in animal models show that the results for these two drugs are very, very similar. And so the results that we saw today actually don't surprise us. And the fact that they're very consistent with [ capivasertib ] is kind of very consistent with the other data that we've seen. Igor explained some of the -- what we think the reason why in this robust Phase III setting, we probably got the best look at what alpelisib does in the real-world setting. And so again, I think single target inhibitors, particularly those that are focused on this alpha isoform. Again, are just going to be limited and probably alpelpib provides a very good demonstration of that. The fact that alpelisib's discontinuation rate is very low and that these patients were largely exposed to alpelisib continuously suggests that there was not a dose exposure. I think there's been some question about the limitations of alpelisib because of its safety profile to provide a consistent treatment or exposure. 7% discontinuation rate is 1/4 of the level that had been reported previously. And so again, in this setting, seeing alpelisib utilized consistently kind of we think, provides a demonstration of what its real potential or rather what its real efficacy is and the potential of inhibiting this alpha target.

Our next question comes from the line of Oliver McCannon with LifeSci Capital.

Congratulations on the data. Two questions here. Just given where the alpelisib plus fulvestrant comparator arm landed, can you remind us of why it may be important to really look closely at the hazard ratios here? And then on the second question, I'm curious if you can describe a little bit of how you see the read-through to the frontline endocrine-sensitive study plan as well.

Well, ultimately, we conduct randomized Phase III studies to compare the results from one regimen to another in a setting that ensures that all variables that could be related to differences in patient composition or the prior treatments are eliminated. And so a head-to-head comparison in a randomized setting really provides the best understanding of how one drug stacks up against another. And it's unusual to be frank, in a study that is comparing head-to-head drug from the same class to show this level of differentiation. And I think it again, provides further demonstration of the importance of multi-target inhibition. So the hazard ratio of 0.5, be frank, that's a fantastic result. I think it's the most relevant finding from the study. The fact that gedatolisib as a doublet was able to deliver that level of differentiation. I think, again, it's almost as good as it gets to show that differentiation, better than what we expected, to be frank. Our statistical assumptions were conservative. And so to exceed those statistical assumptions and then to see this over performance of the doublet really highlights just how effective and how important it is to shut down this pathway. And the hazard ratio really provides the most informed metric to establish that. As far as how that reads to the endocrine-sensitive population, again, I think what we've shown is independent of the status of PIK3CA, this pathway, the PAM pathway is relevant. We've reported very encouraging results, preliminary results from our Phase Ib study, small sample size of 41 patients at least, 48 months median PFS, which compares very favorably to what's been reported previously of 24 months for other [ CDK4/6leprozole ] combinations. And so again, showing in both settings, very, very, very strong efficacy, we think augurs well, and we think significantly decreases or increases rather the probability of success for that study as well as the endocrine-resistant study that we're fielding.

Our next question comes from the line of Andrew Berens with Leerink.

Just wondering, I think in the doublet arm, you saw much improved rates of mucositis. Wondering if there was anything in that arm that would explain it or it's just simply the low sample size.

Right. So palbociclib induces some level of stomatitis. There's a little -- yes. And so the fact that was a doublet didn't have palbo explains the difference in the stomatitis overall. And so there was a bit of an additive effect there.

Okay. And the patients were given the same mouthwash profile.

Yes. In other regimens, the prophylaxis were the same and very consistent between the wild-type and mutant population. I would say just Igor alluded to this, but the populations, baseline characteristics, demographics across the wild-type and mutant populations were very similar. Obviously, the major differentiation between the 2 was the status of PIK3CA. So we saw a very consistent population, roughly distributed in a similar fashion across geographies. And certainly, all the study procedures were the same, essentially as one protocol, screening patients and then just assigning them to different study arms. So there's really nothing different between the 2 studies in terms of how patients were treated and monitored.

Congrats on the progress, Brian.

Thank you.

Our next question comes from the line of Stephen Willey with Stifel.

Congratulations. Just curious as to why you think -- I know you talked about the alpelisib exposure, but why do you think there were much lower rates of hyperglycemia in this trial relative to EPIC P5, just given that I believe it was the same HbA1c cutoff.

That's hard to explain. I mean there's always some variety from one trial to another. And so it's really not possible to provide a definitive explanation. And to the extent that the population we enrolled was able to stay on alpelisib, and I suggest that they may not have been as sensitive to hypoglycemia as the other studies. I mean you just have to draw that conclusion from the data. But the fact that the patients were able to stay on the drug and receive essentially for the most part, high proportion of the available dose indicates that patients were fully appropriately treated. We didn't get the distortion that can occur when you have high dropout rates when 25-plus percent of the population drops out due to adverse events, that creates what can be characterized as a dropout bias or attrition bias. And essentially, you are not confident you're evaluating a representative population from the overall randomized pool. And so you eliminate that bias when you have patients who are able to stay on the drug without discontinuing. And so from our view, you get a real picture. Now what's interesting is that the EPICB-5 study reported, I think, around 0.5 hazard ratio relative to fulvestrant. And CAPI in its study, a similar population reported about a 0.5 hazard ratio. So those two drugs, when you look at them, even when you take into account potentially the different patient populations, reported very, very similar results. And so the fact that the study for CAI reported 5.5 results and study for GEA with VIKTORIA-1 for alpelisib reported essentially identical results is consistent with prior studies when you look at the hazard ratios that they both reported.

Okay. And maybe just a quick follow-up. As you think about the single node PIK3CA inhibitors following you into the frontline setting, how are you thinking about the need to prospectively generate some data to support sequencing opportunities in the second line?

I'm not sure I understand that question. I mean, obviously, to the extent that you can treat patients earlier, typically, that's found to be more favorable for the patients, prolong the progression and consequent morbidities that, that induces. So to the extent that we can offer an improvement in the progression-free survival period also creates an opportunity to potentially improve survival. I mean that's obviously the goal. And so to the extent patients don't receive, if we're looking into the future, get a solicit regimen in the frontline setting, certainly, then the data supports use of get in the second-line setting. And so we think long term that studies read out the way we hope that geda will be part of nearly all patients' treatment regimen, whether it's in the frontline setting or the second-line setting.

Our next question comes from the line of Bradley Canino with Guggenheim.

Congratulations. Now that we have the data, maybe some commercial questions. I guess with this profile, what do you think geda can achieve in the PIK3C mutant group? Annualized CAPI sales look to be about $700 million in the U.S. geography, if I've got that right. What do you think that can grow into? And then do you think the launch trajectories of prior oral therapies for second line are appropriate to think about for geda in the second half of this year. First quarter that was the full quarter for ELP and CAPI achieved $40 million to $50 million. Is there anything to think about for an IV launch relative to these precedents?

So really two questions. As far as the potential, I think CAPI, as you can see with the numbers, has relatively low duration of treatment. It has a reasonably high level of discontinuation. And so it may not fully represent what the full potential is, to be frank, in this setting. We would expect, and I guess our internal projections expect higher peak revenues than what [indiscernible] shown. And we think the overall safety profile, certainly the efficacy profile suggests that geda will become a new standard of care for these patients. As far as -- and then the implications for that will, we think, drive higher potential peak revenues as a result. As far as the launch trajectory, I mean, certainly, those are good analogs. I mean, I think the way we think of the trajectory in general and how to estimate it is that we start off with a peak revenue assumption or rather peak penetration assumption, what we think is reasonable. Then we estimate a time to achieve that. If you look at first-time launches for companies, you typically see a 36- to 42-month time to peak revenue. And then you work backwards from there and say, okay, if we can get to x penetration in 36 to 42 months, essentially, the round numbers, I'm just going to use round numbers, not a projection here. But if the round numbers, you said, okay, you've got 42-month time to peak, and you're assuming 42% -- 40% penetration. Essentially, you're assuming 1% a quarter penetration increase. And then -- so the question is what does a percent represent of this population. That's kind of internally how we think about those numbers. Certainly, you can look at comparable numbers or rather launches and draw some conclusions with that. But AZ launching a drug into a space where they already had a significant presence, maybe not representative of what we can do. But again, we think there'll be very, very significant demand for this drug given its efficacy and safety profile. We've received very, very encouraging feedback as we've essentially begun meeting with docs with our medical affairs teams, getting their perspectives. And so again, I think there's always a triangulation to figure out what's possible. But we start off with base assumptions and then work backwards from there.

Our next question comes from the line of Eva Fortea with Wells Fargo.

A quick one from us. Can you comment on the differences seen on duration of response between doublet and triplet?

Eva, I had a little trouble understanding you. Could you repeat that question, please?

Can you hear me?

Yes, it's your [indiscernible], sorry.

Oh, is it better now?

Yes.

Okay. Can you comment on the differences seen on duration of response between the doublet and triplet?

Well, I think it reflects the fact that CDK is still playing a role in this disease and that controlling it induces improvement in overall tumor response. And the extended duration of response, nearly 16 months versus alpelisib 7.5 is very encouraging. And so again, I think it's a question of which pathway is driving in the setting. I think the data for the doublet demonstrates that this PAM pathway is the primary driver. CDK is playing a role and that you got potential improved tumor control when you include that in the regimen. And survival data suggests there may be some differentiation and latency benefit. And it's too early to say. But clearly, the CDK4/6 pathway is still an important component of the disease process, but just potentially not as prominent and as important as it is in patients with wild-type disease.

Our next question comes from the line of Gil Blum with Needham & Company.

Congrats on the advancement here. So specifically on the median OS arms crossing in the doublet, do you think this is a powering artifact?

Yes. I mean essentially, our biostats team has looked at that. And just with that small sample size, we don't believe it's necessarily relevant. I mean we think it kind of creates a bit of a distortion bias. The hazard ratio that's below 1 is the most important stat there, showing essentially no decrement. But again, when you're doing an OS analysis with small sample sizes, you're vulnerable to just a few patients that can swing the results.

And from a technical perspective, could you walk us through the process or whether there is a way to get the doublet data onto the label?

No, we expect in the wild-type setting, we believe we will -- I mean, our approach will be to seek approval for both the doublet and triplet. Essentially, with our sNDA, we'll be seeking an expansion of the label, essentially saying that these regimens can be used irrespective of the status of PIK3CA. And we think the totality of this data supports that. We had a significant number of consultations at the beginning of -- prior to initiating the study, getting aligned with the agency. And so the study design reflects an alignment with the agency on what would be required to support an approval. Now -- it's early days. We haven't submitted the package. We haven't presented the data yet to the FDA. Those conversations will be coming soon. But we certainly think the data supports an approval of doublet or rather an expansion of the doublet to be used in patients irrespective of their PIK3CA status.

Our next question comes from the line of Kalpit Patel with Wolfe Research.

I have two. Number one, the duration of treatment, how should we think about the average duration of treatment in this mutant patient population versus your wild-type population? And then second, some individuals are going to make some cross-trial comparisons to some of the oral PIK3 inhibitors that are in development. So just curious on how you see the baseline patient population enrolled here versus competition?

Sure. As far as baseline duration of treatment, you don't get a full picture of duration of treatment with relatively short follow-up periods. And ultimately, the most relevant number is the average duration, and you don't get a full picture of that until you have a longer follow-up period. But typically, you'd expect that to mirror probably 90% of what you see, 85%, 90% of what you see from progression-free survival because you're netting out some discontinuation. But when you take into account the full persistence of the population over an extended period of time. As far as the kind of other studies that have been done, what's important, 2 things. When you have a randomized study, you're netting out any biases that could occur when you have different patient population. So you have the same population, and you're showing head-to-head how one -- in this case, class of drug, how one drug with different MOA compared to another drug targeting the same pathway. As far as how the single-arm studies that are done, it's always challenging to place much weight on those. They provide important signals. But in particular, with our study, you'd see that most of these patients had visceral mets, liver lung mets, very few patients had nonevaluable disease. In fact, they all were required to have a valuable disease as part of the screening process or eligibility process. When you start to get in early phase studies, there's a tendency to see a lot of patients with nonevaluable disease, and that's fine. you're trying to enroll patients, you're trying to get a signal. But that's not necessarily representative of a population you'd see in a Phase III, where typically regulators require to only enroll patients with evaluable disease because the progression-free survival requires measurable lesions to assess whether progression has occurred or not. But when you do incorporate a population with significant measurable nonmeasurable disease, you create an upward bias in the numbers. I mean we've seen in our study and the mutant around in the wild type that fulvestrant in PFS of close to 8 months with patients with nonevaluable disease other studies that have evaluated fulvestrant and broken out the results for nonevaluable disease show that fulvestrant by itself, again, is in the 8- to 9-month range with nonevaluable disease. And so you create a much higher contribution from the endocrine component of a therapy, and that needs to be taken into account. So in that case, if your control is providing 8, 9 months, showing, let's say, 11 months in the study arm would obviously not be a very favorable result. And so again, our perspective is these single-arm numbers aren't very translatable and to be frank, don't carry much weight. Ultimately, the drugs need to be compared to each other in a randomized setting. And we think the data for alpelisib probably is the most representative of what its true efficacy is able to induce. And so we think ultimately, when you go head-to-head against another drug like in this case, if these alpha inhibitors, we'll be comparing head-to-head against another alpha inhibitor, then you're really measuring not necessarily mechanistic for the most part, difference, you're measuring differences that might be related to duration of level of exposure. And that's those are fine hypotheses, but I think it's much more powerful and the potential to improve efficacy is much, much more significant when your mechanism of action is aligned more closely with the underlying biological characteristics of the pathway.

We have time for one more question. Our last question comes from the line of Silvan Tuerkcan with Citizens.

Congrats on these great results. I just have a quick question on the discontinuation rates. So your control on the alpelisib plus fulvestrant, it performed -- the discontinuation was significantly better than, for example, in the EPIC trial. Is that just because you have a more moderate population here, larger population? Or is there -- were there learnings with respect to how to use that doublet? And what does that mean for your discontinuation rates being obviously much lower than that? But would they be roughly half of what alpelisib today, or how would you expect that?

Sure. Well, I think from alpelisib perspective, it's hard to really tease out exactly why that occurred other than the doctors were able to manage these patients effectively, able to the extent the patients require some medications if they require them to help manage any glucose increase that was done effectively. And I think, again, significant study, global study. So we had, we think, a very representative population. I can't really speak to how the other studies were conducted or what their protocols mandated. But we were mindful of essentially making sure patients were given the best chance to stay on their study drugs. And we think these results reflect that. I think what's most interesting about our discontinuation rate results is that they're basically very consistent across the wild-type and populations. And so we saw two different -- essentially two different populations, obviously, similar baseline characteristics. But we saw very similar discontinuation rates for safety profile was also very consistent. And again, we view that as further evidence of how well patients can tolerate this drug and stay on it. And that's a reflection of factors that Igor referenced, PK profile, potency that requires infrequent dosing. So patients are only getting exposed three times a month versus, let's say, 28 times a month, correspondingly lower number of [ Cmax ] exposures, which, again, we think supports the overall well-being or rather enables patients' overall sense of well-being to be enhanced. And so again, with these trials, you run these trials, you really see the results. And we think this was probably the most robust Phase III study done in the post-CDK setting for alpelisib. And you have to take these results face value. And certainly, the fact that they are consistent with [ capoavacererbs, ] which, again, single component inhibitor suggests the results are probably what you see in the real world.

Great. And maybe one last quick one. Do you think there's any way payers can bias use of doublet over triplet, obviously, because it will be cheaper.

I'm sorry, I couldn't quite make out what you're saying there.

I'm just asking if prescribers can jump or push towards the use of a doublet versus the triplet since the net would be cheaper for them, or would it be up completely to the prescribers?

No. Okay. Sorry, I understand. Well, palbo will be going generic next year. So the economic consideration will, I think, no longer be relevant. I think the primary factor they'll take into account is after assessing the patient's profile, determining whether including a CDK makes sense for them. Certainly, it's a different determination when at least the face value of the PFS is essentially the same. And so that gives them much more flexibility. At the same time, I guess we've heard from a number of doctors that we've shown the data that they like the idea of, again, hitting all three pathways to minimize the risk of potential progression for these patients. But knowing that to the extent that the patients either aren't appropriate to receive shouldn't receive CDK4 or aren't tolerating it well, that they can back off, discontinue palbo and have great confidence that the doublet will induce a very important clinical outcome for their patients.

I'd now like to turn the call back over to Brian Sullivan for closing remarks.

Well, thank you for attending our call. We appreciate your participation. We look forward to catching up with you over the coming days.

This concludes today's conference. Thank you for your participation. You may now disconnect.