Good day, and thank you for standing by. Welcome to the CellQD Victoria 1 trial call. At this time, all participants are in listening mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. 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 Cellcuity. Please go ahead.

Good morning. Thank you for joining us today. I'm Brian Sullivan, CEO and Co-Founder of Cellcuity. Before we begin, I must point out, and let's turn now to slide two, that some of the comments today contain forward-looking statements that are subject to risks, uncertainties, and assumptions. In particular, our expectations around Geta Solicit 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 three. Joining us today is Dr. Sarah Hervitz, the co-principal investigator of the Victoria I study and the senior vice president of the clinical research division of the Fred Hutch Cancer Center and president and head hematology and oncology at the University of Washington and School of Medicine. Dr. Hurwitz will present the detailed results from the PIC3CA mutant cohort of the trial. Dr. Sarah Tulaney, 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 PIC3CA mutant advanced breast cancer. Dr. Igor Gorbachevsky, 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 get it to listen. Despite the importance of the PIC3CA or PI3K-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. This reflects the PAM pathway's complex structure, which requires multiple components to be inhibitors to comprehensively blockade the PAM pathway's activity. When only a single component is targeted, 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, too toxic, or both. Gatatelisib overcomes these challenges by over-inhibiting all four classrooms, and both mTORC1 and 2, with a potency and PK profile that patients can tolerate well. Let's now turn to slide five. Today is an important day for patients with HR positive HER2 negative advanced breast cancer. Both get a solicit regimen double the likelihood of a patient's survival without disease progression or death compared to alpalyptus plus colvestrin. The clinically meaningful improvement in progression-free survival, showed by both the get a solicit triplet and doublet from the PIC3C and mutant cohort of our Victoria I trial, is now the second positive Phase III read-I'll forget it's elicit, provides further demonstration of the clinical benefit comprehensive inhibition of the PAM pathway. With positive Phase III results now in both the PIC3CA wild-type and mutant cohorts of Victoria I, we're well-positioned to offer potential standard-of-care therapeutic combinations for all patients in this second-line setting. We believe these results also offer 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 Victoria 1 trial, these results established several new milestones in the history of drug development for HR-positive HER2-negative advanced breast cancer. First, Victoria 1 is the first phase 3 trial to demonstrate superiority of one PAM inhibitor versus another. And second, the greater than 11 months' medium progression-free survival for the GEDDAS solicit triplet and doublet are the highest reported by any Phase III trial for a regimen including endocrine therapy in this second-line setting. And third, the 49% objective response rate for the GEDDAS solicit triplet is the highest reported by any Phase III trial for a regimen including endocrine therapy in the second-line Now let's turn to Igor Gorbachevsky, our Chief Medical Officer.

Thank you, Brian. I'm very happy to introduce Dr. Sarah Hervis, with whom we're very happy to work for the last five years as a co-principal investigator for Victoria I study. As Brian mentioned, Dr. Hervis is currently serving as the Senior Vice President of Clinical Research Division of Fred Hutchison Cancer Center and Professor and Head of Hematology and Oncology at University of Washington School of Medicine. So, I will turn to Dr. Hervis to review results of Victoria I, Study II, in patients with 6-3-C mutation positive disease.

Thank you so much. 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 multi-component 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, getitolosib is a highly potent multi-target PAM inhibitor that targets all class 1 PI3 kinase isoforms, as well as mTORC1 and mTORC2 for comprehensive blockade of this important pathway. Victoria 1 is a randomized open-label two-part study designed to evaluate getitolicib-based therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, after progression on a CDK4-6 inhibitor and non-steroidal aromatase inhibitor. Study one, 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 fulvestrin in patients with PIC3CA wild-type advanced breast cancer. For the triplet, the median progression-free survival was 9.3 months versus two months for fulvestrin with a hazard ratio of 0.24, and the doublet had a medium PFS of 7.4 months versus two 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 two, which evaluated geftolicid-based therapy in patients with PIK3CA mutated disease. Next slide. VICTORIA-1 is a Phase III global, open-label, randomized, two-part clinical trial that assign patients to Study I or Study II, as I said, based on tumor PIC3CA 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 to 3 to 1 ratio to the triplet of getotolicib-palbicyclid fulvestrant or alpelicib fulvestrant or getotolicib fulvestrant. The primary endpoint was progression-free survival, comparing the triplet, RMD, to alpelicib 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 getatolosib triplet versus the alpelosib fulfestrant 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 end points comparing the getatolosib doublet to alpelosib fulvestrin, 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 to 1 to 3 ratio, and most patients in each arm received their allocated treatment. There were more patients who discontinued treatment with the standard alpelesib fulvestrin than with the getatolisib 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 alpalosib-fulvestrant arm compared to the getotolisib arm. 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 three-quarters of patients, and about 15% of patients had endocrine resistance disease, as indicated by a short time to progression of six months or less. Consistent with real-world usage patterns, there were significantly more prior ribocyclib and palbocyclib treated patients relative to abemocyclib overall, and usage was similar for the getatolusib triplet and alpelusib fulvestrin arms. Next slide. Here are the progression-free survival data. Victoria 1 study 2 met its primary endpoint. The getatolusib triplet produced a statistically significant and clinically meaningful reduction in the risk of disease progression or death relative to alpelusib fulvestrin. The hazard ratio is 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 3 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 Getatola subtriplet was generally maintained across all subgroups. All hazard ratios were less than 1.0, although some of the confidence intervals of upper limits include 1.0. And as was seen in the wild-type cohort in study one, results were consistent across the different CDK4-6 inhibitor subgroups. Next slide. The gettolacib 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 gettolacib triplet. So 0.51 versus 0.50 respectively, as was the median progression-free survival, 11.1 months 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 getatolosib doublet versus alpelosib 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 getotolicib-based regimens than for opelicib fulvestrant. To our knowledge, the 49% objective response rate for the gettolacib triplet was higher than has been previously reported by any Phase III trial for a regimen including endocrine therapy and second-line hormone receptor-positive HER2-negative advanced breast cancer. Additionally, nearly three times as many patients in the alpelacib fulvestrant group experienced disease progression compared to the gettolacib ARMS. Next slide. Getatolosib-based treatments also produce a clinically meaningful duration of response as seen here for the getatolosib triplet on the left and the getatolosib doublet on the right, both compared to alpelosib fulvestrin. The median duration of response was doubled with the getatolosib triplet, 15.7 months versus 7.5 months, and triple does with blitz. 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 getotolacip arms, 2.6% for the triplet, and 3.8% for percent for the doublet. In contrast, 7.1 percent of patients in the alpelisib fulvestrant arm discontinued treatment due to AEs. There were three grade five events deemed related to treatment by the investigator, one in the getotolisib triplet and two in the alpelisib fulvestrant. The safety profile of getotolisib was generally consistent with that reported for study one with the most common treatment-related AEs, including neutropenia in the triplet arm, which is likely or most likely related to the palbocyclib, and stomatitis in both arms, 61.4% any 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 getatolacib arms than in the alpelacib fulgent group. In summary, getatolacib, next slide, plus fulvestrin, with or without palbocyclib, significantly improved progression-free survival compared with alpelacib fulvestrin in patients with hormone receptor-positive HER2-negative PIK3CA-mutated advanced breast cancer in Victoria 1 study 2. Patients in the getatolacib triplet and doublet groups were two times as likely to survive without disease progression or death compared to alpelacib plus fulvestrin. Adverse events associated with the getatolacib-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 alpelicib and fulvestrin, hyperglycemia was 58% and diarrhea was 40%. Stomatitis was the second and first most commonly reported treatment-related adverse event for the getatolacib triplet and doublet, respectively. But studied treatment discontinuation due to these adverse events, was 2.6% for the triplet, 3.8% for the doublet, and higher in the alpalosib arm at 7.1%. Geditolosib fulvestrin 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 Victoria 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, Sarah, for this presentation and your leadership you provided for this program. I would like to provide a brief overview of this result 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. And the results presented by Dr. Fergus confirmed that you did illicit measurement show the strongest efficacy results. We compared them to reported results from other studies. And as you can see, both medium 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 for almost 50% for the triplet, 36% for the doublet. when it compares to other agents in this class with the median progression-free survival very similar between alpelotip and fulvestrin of 5.6 and 5.5 months and objective response rate for 26% in alpelotip, fulvestrin, and a diversity of 23% in a previously reported study in patients who previously received the decay treatment. Let's move to the next slide. And the data that we presented last year, Dr. Hervitz presented it as in 2025 as the study one met its primary endpoint, which was very statistically significant, and the lowest hazard pressure ever reported in randomized phase 3 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 standards 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 and results when we compare to standards of care are very significant in the treatment regimen. Medium progression-free survival was improved by almost five times with a triplet agent and almost four times with a doublet agent in the disease. And as you can see, some of this product 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 It is a list of, as I already mentioned, triplet regimen in wild type reported the lowest hazard ratio reported to date of 0.24 percent and the double 0.23 percent, which compared favorably to other studies reported in the recent years. Let's move to the next slide. Right now, I'm very happy to introduce Dr. Sara Teleni, who is the chief of division of breast oncology at Harvard Cancer Institute and associate professor of medicine at Harvard Medical School. And Dr. Teleni kindly agreed to talk with us to provide her impression of the data that was shared with Dr. Hergis. So, Dr. Teleni, in the first question, I would like to hear your initial impression of the results from study 2, evaluating the delusive regimen in TICC-3C mutated disease, especially when we compare it to other agents in this class. What would be your initial impression?

Well, I was very impressed with the data. You know, 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 fulvestrin to albulisib. And in the U.S., we're often using fulvestrin to capivacertib. And what we're seeing with fulvestrin to capivacertib 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. Trollani. In other questions, we want to follow up on, as we presented previously last year in Study 1, and as Dr. Hervis mentioned, and we presented results from Study 2, treatment discontinuation due to adverse events was low in this study, below 4% for both triplets and doublet regimen across both studies when we look at your dimension currently used agent in this disease what's your initial impression about safety profile low discontinuation rate and especially those side effects as dr. Hervis mentioned related to time inhibitors diarrhea and hyperglycemia what's your the initial impression of those results?

Well, I'll say we never get a discontinuation rate this low with a PI3K inhibitor, so it is very impressive. I mean, I think we are challenged right now in the clinic with using the current treatments, you know, while Kepa-Visertif was certainly a step forward, I think, compared to Alpolysev in terms of tolerability, it still requires monitoring. I have to do pochometer teaching with my patients, have them do finger sticks, which is challenging. the rate of diarrhea is over 70%. Patients are often using lopiramide. These drugs are not easy for us in the clinic, and patients can often need to discontinue therapy due to rash. And so, you know, it has been a challenge. So, again, to see a discontinuation rate under 5% is not something I've ever seen with a pediatric kinase inhibitor, so very impressive.

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

Well, here I think, you know, combining the totality of the data across both studies within Victoria 1, it does suggest that there's benefit for genetolicib, you know, in honesty, feed, interrespective 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 regimen. I think the PI3K wild-type population, as you pointed out, you're reviewing the current landscape is a bit more complex in terms of thinking about, you know, various treatment options. But I think, again, this gives a very broad utilization in a post-CDK population, which which is really nice for me.

Thank you so much for your time. We really appreciate it. Thank you. So let's turn to the next slide. I will finish my part of discussions with a general summary of overall observations for the results. Evaluating patients in a mutation-positive disease, it exceeds statistical assumptions that we would set it up before. As you see, in both hazard ratio and based on the assumed expected median progression through survival, statistically significant improvement with hazard ratio of 0.5 and 0.5. The next important point is that control arm in this study, Alpalosib-Fuldestrump, actually represents to date 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 Alpalosib-Fuldestrump when we look at the previously reported saguosal telesis. The higher number of sites participating and enrolled in patients and 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 lower adverse event rates resulting in treatment discontinuation for L-telisib actually indicates that this efficacy outcomes are not associated with drug exposure and provide very realistic efficacy for L-telisib-pulvestrin combination in real world for patients with advanced breast cancer who were previously treated with cell cycle inhibitors. And the last point to summarize that efficacy and safety profile of genditalisib is explained by the illicit mechanisms of action, PK profiles, and route of administration. All of those are responsible for significantly improved efficacy and safety compared to oral agents targeting a single component of this PAM pathway. With 300 times more potent activity, illicit can be dosed infrequently, which results in significant improving AUC. Also, by passing initial GI tract metabolism, it is illicit intravenous administration results in significantly lower number of immune mediates and metabolic side effects, such as diarrhea. I will be concluded with my part of presentation and turning back to.

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 Gettotilisib.

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 PIC3CA wild type and mutant patient populations can position get it to LICIP 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 two years, they have each built highly experienced and deeply skilled teams designed to meet the specific market needs for launching Get It's List. 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 healthcare practitioners, for patients. Let's turn now to slide 31. Moving on to market opportunity. Within the U.S., approximately 37,000 patients with HR-positive, HER2-negative advanced breast cancer receives second-line treatment each year following progression on CDK 46 inhibitors of these roughly 60% of PIC3CA wild-type 40% are PIC3CA mutant and importantly approval for both indications would allow get a solicit to address 100% of this market with the simplicity of a single PIC3CA agnostic treatment approach this would be a major differentiator versus currently available drugs that are restricted to either a wild type or mutant patients there remains a significant unmet need in this market for therapies that deliver better efficacy without compromising safety get a solicit's unique mechanism of action as a potent pan pi3k mTOR inhibitor combined with its pharmacokinetic profile and iv route of administration provided distinct efficacy safety profile relative to existing oral agents taken together we believe get a solicit 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 six billion dollar total serve market opportunity across both pick 3ca wild type and mutant patient populations let's turn now to slide 32 moving on to the launch readiness and preparations for the pic 3ca 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 NCC and 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 salesforce field marketing and medical affairs teams are fully built and prepared we 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 pampathway.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. 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 Get It To List as a new standard of care in the PIC3CA wild-type market, and it's approved for both indications across the entire HR-positive HER2-negative second-line treatment patient population. We're confident that Get It To List'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. Back to you, Brian.

Thank you, Eldon, and let's now turn to slide 37. I'm 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 Geta Thalissib 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 Geta Thalysib 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 Geta Thalysib. I'll let you now turn. We have a number of several important milestones coming up at the back half of this year. First, we're expecting an approval decision from the FDA by our Purdue from a date of July 17, 2026 for the Victoria 1 Vic3CA wild type cohort. Second, we have several data updates later this year. We expect to update data from our phase 1b metastatic castration resistant prostate cancer study in the fourth quarter and to provide updates 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 US FDA in the third quarter this year. And secondly, we expect to submit a marketing authorization application, or MAA, to the European Medicines Agency. And 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 submitted questions, and we'll go from there.

Thank you. As a reminder, to ask a question, please press star 11 on your telephone keypad and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compel the Q&A roster. Our first question comes from the line of Maury Raycross with Jeffries. Your line is now open.

Hi, good morning. Congrats on the data and the strong PFS HRs in both the triplet and doublet. But 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 PI3, PIK3CA mutations and whether they would use the triplet or the doublet?

Okay. Well, thank you, Maury. Both Sarah, 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 you know probably five to one the triplet versus the doublet and and part of that is related to the idea that with these patients and second-line setting you know providing complete coverage of the disease pathways it's very appealing and also knowing that if for whatever reason polycyclic 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're, to be frank, I mean, surprised to 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 that you can think of a 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 The potential most coverage of the tumor drivers may be a higher preference for the doublet than in the wild-type setting. Overall, what we think this demonstrates is that both regimens, and by having both regimens, we're providing flexibility to doctors. This is a very heterogeneous population, and so we think having options and having strong data for both, essentially provides a lot of flexibility and optimization for the doctors to tailor the treatment that best reflects the patient's characteristics.

Got it. That's all really helpful. Thank you, and congrats again. Thanks.

Thank you. Our next question comes from the line of Tara Bancroft with T.D. Cowan. Your line is now open.

Hi. Good morning, and thanks for such a great detailed presentation.

So I guess with the doctors not here, Brian, my question is for you. So maybe, you know, 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 3? Thanks so much.

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'd 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 product were pan-PI3K mTOR inhibitors, and they took that approach for reasons that that was understood, and non-clinical work certainly reflected that, that comprehensive inhibition is required to optimize pathway and maximize potential anti-tumor control. You know, 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's biology. So our view is that single-target inhibition is just fundamentally limited in the level of anti-tumor control that will be available just because of the structure and function of this pathway. I think the results for the alpalipsib arm probably represent real-world experience. You know, our non-clinical work, and I think others' non-clinical work, have shown that Alpalipsib and Cappivacitrib, and 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, and so the results that we saw today actually don't surprise us. In fact, they're very consistent with Cappivacitrib, very consistent with, you know, the other data that we've seen. And Igor explained some of the, what we think the reason why in this robust phase three setting, we probably got the best look at what alpha-lipsib does in the real world setting. And so, you know, again, I think single target inhibitors, particularly those that are focused on this alpha isoform, again, are just going to be limited. And probably alpha-lipsib provides a very good demonstration of that. You know, the fact that alpalipsib's discontinuation rate was very low and that these patients were largely exposed to alpalipsib continuously suggests that, you know, there was not a dose exposure. I think there's been some question about the limitations of alpalipsib because of a safety profile to provide a consistent treatment. 7% discontinuation rate is a quarter of the level that had been reported previously. And so, again, in this setting, you know, seeing Alpalipsib 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 awful target.

Okay, great. Thank you so much, Brian.

Thank you. Our next question comes from the line of Oliver McCammon with LifeSci Capital. Your line is now open.

Congratulations on the data, and thanks for taking my questions. Two questions here. Just given where the alpha-lisid plus fulvastrint 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.

Thanks again. Well, ultimately, you conduct randomized phase three 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 their 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, to be frank that's a fantastic result. I think it's the most relevant finding from the study. In fact it got a solicit as a doublet, you know, 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 your physical 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 as far as how that leads to the endocrine sensitive population again I think what we've shown is independent of the status of TIC3CA it's this pathway, the PAM pathway is relevant. We've reported very encouraging results, preliminary results from our phase 1b study. Small sample size for 41 patients at least. You know, 48 months median PFS which, you know, compares very favorably to what's been reported previously of 24 months for other CDK4-6 electrosol 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 resistance study that we're fielding very helpful thank you thank you our next question comes from the line of Andrew Behrens with Lee Rink your line is now open hi thanks I'm just wondering I think in the doublet arm you saw a much-incroved rate of mucositis, wondering if there was anything in that harm that would

explain it, or is it just simply the low sample cells?

So the polycyclob induces some level of stomatitis. There's a little, oh, yeah, and so the fact that was a doublet didn't have palbo explains the difference in the, so there's a bit of an additive there.

Okay. And the patients were given the same mouthwash?

Yes. No, the regimens, the prophylaxis were the same and very consistent between the wild type and mutant populations. I would say just Igor alluded to this, but, you know, the populations, the baseline characteristics, demographics across the wild type and mutant populations were very similar. Obviously, the major differentiation between the two was the status of TIC3CA. 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 was really nothing different between the two studies in terms of how patients were treated and monitored.

Okay. Congrats on the progress, Brian. Thank you.

Thank you. Our next question comes from the line of Stephen Willey with Stiefel. Your line is now open.

Yeah, good morning. Thanks for taking the questions, and congratulations. I'm just curious as to why you think, I know you talked about the alpalisib exposure, but why do you think there were much lower rates of hyperglycemia in this trial relative to EPIC B5, just given that I believe it was the same HbA1c cutoff?

You know, that's hard to explain. I mean, there's always some variety from one trial to another, and so, you know, it's really not possible to provide a definitive explanation. And, you know, to the extent that the population we enrolled was able to stay on alpalipsid suggest that they may not have been as sensitive to hyperglycemia 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, you know, indicates that, you know, that patients, you know, appropriately treated. We didn't get the distortion that can occur when you have high dropout rates. You know, when 25 plus percent of the population drops out due to adverse events, like that creates, you know, 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, you know, from our view, you get a real picture. Now, what's interesting is that the Epic B5 study reported, I think, around a 0.5 hazard ratio relative to fulvestrin. And CAPI, in its study, a similar population, reported a hazard ratio. So those two drugs, you know, when you look at them, even when you take into account, you know, potentially the different patient populations, reported very, very similar results. And so the fact that the study for CAPI reported 5.5 results and the study for GETA with Victoria 1 for alpalypsid reported essentially identical results is consistent with prior studies when you look at the hazard ratios that they both reported.

Okay, this is maybe just a quick follow-up. As you think about the single-node PIC3CA inhibitors following you into the front-line 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, you know, typically that's found to be more favorable for the patients, you know, prolong the progression and consequent morbidities that that induces. So, you know, 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 front-line setting. Certainly then the data supports use of GETA in the second-line setting. And so we think long-term that our studies read out the way we hope that, you know, GETA will be part of nearly all patients' treatment regimen, whether it's in the front-line setting or the second-line setting.

Thanks for taking the question.

Thank you. Our next question comes from the line of Bradley Canino with Guggenheim. Your line is now open.

Hi, Brian and team. Congratulations. Now that we have the data, maybe some commercial questions. I guess with this profile, what do you think GEDIC can achieve in the PIC3C and Mutant subgroup? Annualized cappy 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 ALP and CAPI achieved $40 to $50 million. Is there anything to think about for an IV launch relative to these precedents? Thank you.

So really two questions. As far as the potential, I think, you know, CAPI, as you can see with the numbers, has relatively low duration of treatment. It has a reasonably high level of discontinuation. And so, you know, 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, you know, higher peak revenues than what Kappavaceturve has shown. And we think, you know, the overall safety profile, certainly the efficacy profile, suggests that, you know, GEDA will become a new standard of care for these patients. As far as, and then the implications for that, we think drive, you know, 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 you know 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 and 36 to 42 months you know you know essentially it's just the round numbers I'm just going to use round numbers not a production here but if you know for round numbers you said okay you've got a 42-month time to peak, and you're assuming 40% penetration, essentially you're assuming a percent 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, you know, an AZ launching a drug into a space where they already had a significant presence, you know maybe not representative of what we can do but you know again we think there'll be very very significant demand for this drug given its efficacy and safety profile and we've received very very encouraging feedback as we've essentially begun you know meeting with docs with our medical affairs teams you know getting their their perspectives and so you know again I think you know there's always a triangulation to figure out what what's possible but we start off with you know base assumptions and then and work backwards from there thank you our next

question comes from the line of eva fortia with wells fargo your line is now open okay good morning thanks for taking our question a quick one from us can you comment on the differences seen on the original response between the ghetto doublet and triplet thanks hi uh eva i had a little trouble understanding you could could you repeat that question please can you hear me yes but if it's you're muffled sorry oh is it better now yes okay can you comment on the differences seen on duration of response between they get a doublet and triplet thanks well I think it reflects the fact that CDK is still playing a role in this

disease and that controlling it induces an improvement and overall tumor response and you know the extended duration of response you know nearly 16 months versus alphalypsis 7.5 is very encouraging and so again I think it's a question of I think the data for the doublet demonstrates that this PAM pathways is the primary driver CDK is playing a role and that you've got potential improved tumor control when you include that in the regimen and And survival data suggests there may be some differentiation of latency to benefit. And, you know, it's too early to say, but clearly, you know, 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.

Got it. Thank you. Our next question comes from the line of Gil Bloom, West Needham & Company. Your line is now open.

Good morning, everyone, and congrats on the advancement here. So specifically on the Median OS arms crossing and 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 – it kind of creates a bit of a distortion bias. The hazard ratio, you know, that's below one is the most important stat there, showing essentially no decrement. But, you know, 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, can you walk us through the process or whether there is a way to get the doublet data onto the label?

We expect, you know, 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 SMDA we'll be seeking an expansion of the label essentially saying that these regimens can be used irrespective of status of PIC3CA 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 so the study design reflects an alignment with the agency and what would be required to an approval now early days we have submitted the package we haven't presented the data yet to the FDA those those conversations will be coming soon but we certainly think the data supports a little doublet or rather an expansion of the doublet to be used in patients irrespective of their PIC3CA status thank you for taking our questions and congrats again.

Thanks.

Our next question comes from the line of Calpits Patel with Wolf Research. Your line is now open.

Yeah, hey, good morning, and thanks for taking the questions. 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, And some individuals are going to make some cross-trial comparisons to some of the oral TIC3 inhibitors that are in development. So just curious on how you see the baseline patient population enrolled here versus competition. Sure.

First 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 regression-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, you know, the kind of other studies that have been done, what's important, two things. When you have a randomized study, you're netting out any biases that could occur when you have different patient populations. So you have the same population, and you're showing head-to-head how one, in this case, class of drug, how one drug was different MOA compared to another drug targeting the same pathway. As far as how these single-arm studies that are done, it's always challenging to place much weight on those. They provide important signals. But in particular, you know, with our study, you'd see that most of these patients had visceral mets, you know, liver lung mets. You know, very few patients had non-evaluable 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 non-evaluable 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 three, where typically regulators require to only enroll patients with a valuable 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 disease, non-measurable disease, you create an upward bias in the numbers. I mean, we've seen in our study, and the mutant rather than the wild type, that Fulvestrin can have PFS of close to eight months with patients with non-evaluable disease. Other studies that have evaluated Fulvestrin and broken out the results for non-evaluable disease show that Fulvestrin by itself, again, is in the eight to nine-month range with non-evaluable disease. And so you create a much higher contribution from the endocrine component of that needs to be taken into account. So in that case, if your control is providing eight, nine 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, and to be frank, don't carry much weight. Ultimately, drugs need to be compared to each other in a randomized setting. And we think the data for Alpalipsid probably is the most representative of what is true is able to induce. and so you know we think ultimately when you go head-to-head against another drug that in this case if they use alpha inhibitors you know we'll be comparing head-to-head against another alpha inhibitor you know then then you're you're really measuring not necessarily mechanistic for the most part difference you're measuring differences it might be a related to duration of our level of exposure and you know that's those are fine hypotheses 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 Thank you for taking the question.

Thank you. We have time for one more question. Our last question comes from the line of Sylvan Turkin with Citizens. Your line is now open.

Yeah, good morning, and congrats on these great results. I just have a quick question on the discontinuation rates. So your control on the appellate plus sylvestrant, it performs the discontinuation with significantly better than, for example, in the EPIC trial. Is that just because you have a more modern population here, larger population, or 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 a pellicid plus a bloodline is today, or how would you expect that?

Well, I think, you know, from an alpalypsid perspective, it's hard to really tease out exactly why that occurred, other than, you know, the doctors were able to manage these patients effectively, able to, to the extent the patients required some medications. If they required 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, you know, we were mindful of essentially making sure patients were given the best chance to stay on their study drugs. And we think, you know, these results reflect that. You know, I think what's most interesting about our discontinuation rate results is that they were basically very consistent across the wild type and youth populations. And so we saw, you know, two different, you know, essentially two different populations, obviously similar baseline characteristics, but we saw very similar discontinuation rates for Getta. Safety profile was also very consistent. And again, we do 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, you know, again, you know, these trials, you run these trials, you really see the results. And we think this was probably the most robust phase three study done in the post-CDK setting for alphalipsib. And you have to take these results at face value, and certainly the fact that they are consistent with capovaciturbs, which, again, single-component inhibitor, suggests the results are probably what you see in the real world.

Thank you. And maybe one last quick one. Do you think there's any way payers can buy a few of doublet over triplet, obviously, because it will be cheaper? I'm sorry, Sullivan.

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

I'm just asking if prescribers can shunt 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?

Oh, no. Well, Palvo 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 you know determining whether you know including a CDK makes sense for them certainly it's a different determination when at least at face value the PFS is you know essentially the same 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 to 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 CDK or shouldn't receive CDK or are tolerating it well, that they can back off, discontinue Calvo, and have great confidence that the double will induce a very important clinical outcome for their patients.

Thank you so much, and congrats.

Thank you. 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.