Good day, and thank you for standing by. Welcome to the Palvella Therapeutics Conference Call to discuss top-line results Phase IITOIVA study. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you will need to press star one one on your telephone. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Bohan Wei, Vice President of Corporate Development. You may begin. Thank you, Operator. Good morning, and thank you for joining the Phase II TOIVA top-line results in cutaneous venous malformations call. As a reminder, our press release detailing today's announcements can be found in the investor section of our website at www.palvellatx.com. On today's call, we are joined by Wes Kaupinen, Palvella's founder and Chief Executive Officer, Dr. Jeff Martini, our Chief Scientific Officer, and Dr. Michael Kelly from the Cleveland Clinic. Before we begin, please note that today's remarks may include forward-looking statements regarding our development program, regulatory strategy, commercial planning, and financial outlook. These statements are based on current assumptions and are subject to risks and uncertainties that could cause actual results to differ materially. Please refer to our SEC filings for a full discussion of these risk factors. Additionally, as a reminder, we will not be discussing or commenting Phase III SELVA trial evaluating QTORIN rapamycin in microcystic lymphatic malformations. And now, I'll turn the call over to Wes. Thank you, Bohan, and thanks to everyone for joining today's call. Early this morning, we issued a press release announcing positive top-line results Phase II study evaluating QTORIN rapamycin for the treatment of cutaneous venous malformations, a serious rare genetic disease for which there are currently no FDA-approved therapies. Overall, we believe Phase II results, which we'll highlight on today's call, represent a significant step forward towards achieving our objective of QTORIN rapamycin becoming the first FDA-approved therapy for patients living with cutaneous venous malformations. Joining me on today's call from Palvella to Phase II top-line results is Dr. Jeff Martini, Palvella's chief scientific officer. Jeff was closely involved in selecting cutaneous venous malformations as a target clinical indication for QTORIN rapamycin, and he's been instrumental in the design and execution Phase II study as well as our FDA interactions. We're also very pleased to have with us today at Palvella Headquarters Dr. Michael Kelly, a physician scientist and pediatric hematologist-oncologist who practices at Cleveland Clinic. Dr. Kelly is widely recognized as one of the leading physician scientists driving the translation of genetic discoveries into tailored therapies for patients with vascular anomalies. For today's call, I'll begin by providing an executive summary Phase II top-line results and Palvella's planned next steps with FDA. Dr. Kelly will provide a disease overview while highlighting the significant unmet medical need that exists today for patients living with cutaneous venous malformations. Jeff and Dr. Kelly will then together Phase II top-line results and will conclude with a summary before opening up the call to Q&A. I'm very pleased to now report positive top-line results Phase II study that exceeded our internal threshold for advancing the program to the next stage of development. First and foremost, QTORIN rapamycin was highly statistically significant on multiple pre-specified clinician-reported and patient-reported efficacy endpoints, including both dynamic change endpoints and static severity endpoints. On the overall cutaneous venous malformations investigators' global assessment, a clinician-assessed change scale ranging from very much worse, negative three, to very much improved, plus three, the mean effect size at week 12 was 1.5, representing a p-value of less than 0.001. Importantly, on the overall cutaneous venous malformations investigator global assessment, 73% of patients, 11 out of 15, demonstrated a one-point improvement or greater at week 12, and 67% of patients, 10 out of 15, were rated as either much improved, plus two, or very much improved, plus three, at week 12. In addition, statistically significant improvements were seen on key sides of cutaneous venous malformations, including height/engorgement, appearance, and bleeding. In terms of safety, safety is central to the overall benefit-risk assessment for QTORIN rapamycin in this patient population, particularly when benchmarked against the cumulative morbidity, procedural pain, and frequent recurrence associated with the repeated interventional procedures these patients undergo. Phase II study, qtorin rapamycin was generally well tolerated, consistent with previous clinical trials of QTORIN rapamycin. As our principal investigator, Dr. Tollefson from the Mayo Clinic stated in this morning's press release, "Based on the large magnitude of the treatment effect observed in the majority of patients Phase II TOIVA study, QTORIN rapamycin has potential to become first-line therapy and to establish a much-needed standard of care for individuals living with cutaneous venous malformations." We have consistently heard similar enthusiasm from our other clinician investigators about the potential for QTORIN rapamycin for cutaneous venous malformations. At the bottom of the slide represents our next steps in advancing the program. We're engaging the FDA around the potential for breakthrough therapy designation. Importantly, we are applying the same collaborative regulatory approach with the FDA that proved effective in microcystic lymphatic malformations, a program in Phase II data supported the FDA's decision to grant Palvella Breakthrough Therapy designation. I want to now introduce Dr. Michael Kelly. Dr. Kelly is a pediatric hematologist-oncologist at Cleveland Clinic, one of the nation's premier centers for these complex vascular diseases. He is also a passionate patient advocate and serves as the executive director of the Lymphangiomatosis and Gorham Disease Alliance, a patient advocacy organization serving patients with complex lymphatic anomalies. Over more than two decades, he has dedicated his career to caring for pediatric and adult patients with venous, lymphatic, and mixed vascular malformations. He has personally treated thousands of individuals with vascular anomalies, giving him exceptional insight into unmet medical needs and real-world disease burden. Dr. Kelly is also an accomplished clinical investigator, having been involved in more than 100 clinical trials evaluating novel oncology and vascular anomaly therapeutics. His depth of experience in the field reflects both his scientific leadership and a deep commitment to advancing new treatment options for patients. We're fortunate to have Dr. Kelly as a consultant to Palvella and as an investigator Phase II clinical trial evaluating QTORIN rapamycin for cutaneous venous malformations, as well Phase III study evaluating qtorin rapamycin for the treatment of microcystic lymphatic malformations. His clinical perspective and direct experience with the venous malformation patient population have been instrumental in shaping Palvella's program. And now, I would like to turn it over to Dr. Kelly. Thank you, Wes. As Wes mentioned, over the course of my clinical career, I've treated thousands of patients with vascular malformations, including both lymphatic and venous malformations. Venous malformations are the most common form and can involve both internal structures, the skin, or both. Cutaneous manifestations are present in approximately 50%-80% of all venous malformation patients. Before we get into the biology, I want to take a moment to describe the profound unmet need of cutaneous venous malformations in more detail. Cutaneous venous malformations, usually present at birth, are chronic and progressive and can be deeply debilitating for patients throughout their lives, and symptoms include chronic swelling, pain, bleeding, and functional limitations. This is not a cosmetic condition. Unfortunately, the field has remarkably few therapeutic advances, and cutaneous venous malformation remains one of the most underserved areas within the entire vascular malformation landscape. As clinicians, we've had to rely on procedural interventions, which do not address the underlying disease pathology. As a result, patients cycle through compression, sclerotherapy, laser treatments, yet the underlying disease persists and the disease returns. For internal disease, I often prescribe oral rapamycin and have seen impressive clinical responses. Because these lesions require substantial remodeling, most clinicians, including myself, typically see maximum therapeutic benefit after one to two years of continuous treatment. However, the benefit of oral therapy is largely confined to internal disease, with little to no meaningful improvement in the cutaneous aspects of their disease. As a result, there remains a significant unmet need for patients living with cutaneous venous malformations who would prefer a targeted topical therapy without unwanted potential side effects of a systemic therapy. For many families, this lifelong burden is overwhelming, and the lack of targeted disease-modifying therapies for cutaneous disease has been a major gap in our care toolbox. That's why this first prospectively designed clinical trial that we're discussing today in cutaneous venous malformations is so important for the field. For the first time, we are systematically evaluating a biologically targeted therapeutic approach that could potentially change how we care for these patients. This level of rigor and attention is long overdue for patients with this debilitating condition. Cutaneous venous malformations are a genetically well-characterized disease with known causal drivers of pathology. They are caused by somatic activating mutations, most commonly in the TEK or PIK3CA genes, resulting in persistent hyperactivation of mTOR in venous endothelial cells. This signaling interferes with normal endothelial maturation, resulting in abnormal cells and then dilated venous channels. The abnormal architecture drives a relentless disease cycle. Blood pooling leads to the formation of blood clots, resulting in inflammation and further dilatation of veins. This cycle results in progressive pain, bleeding, and limited mobility. Clinical lesions enlarge and become increasingly engorged, rising from the skin surface with dark red to purple discoloration that correlates with disease severity. The therapeutic goal is to specifically target this genetically driven pathway, slow or halt the disease progression, and meaningfully improve key signs and symptoms of the disease. The picture of the cutaneous malformation that you see in the center of this diagram is a baseline photo from a participant Phase II TOIVA trial. You can see the clinical signs of the disease, including lesional height and engorgement and the dark purple color indicating severe disease. I am pleased to say that this patient achieved a meaningful response in the trial after 12 weeks of treatment on QTORIN rapamycin. When we look at how cutaneous malformations are currently managed, it becomes clear why patients and clinicians remain frustrated. The available tools are largely procedural and destructive, and they do not address the underlying biology of the disease. This is particularly challenging in cutaneous disease, where lesions are often diffuse and cross the dermis and epidermis. In these situations, procedural approaches become less effective, and while we have systemic options like oral rapamycin for internal disease, its biodistribution to the skin is limited, so it offers little benefit for cutaneous involvement. Procedural interventions also fail to modify the driver pathway. The mTOR-driven endothelial overgrowth and abnormal venous architecture remain intact, so that even when we surgically debulk or laser ablate a lesion, abnormal cells and vessels persist and regrow, which help explain why any improvements following these procedures are limited in short term. These procedures are also highly invasive and destructive, often damaging normal tissues without providing durable disease control. In addition, they require anesthesia for children, further increasing their risk and adding to the burden of care. Ultimately, the disease will reliably occur more often extensively than before. This is why we urgently need targeted therapies that intervene on the biology rather than relying on repeated destructive procedures. And now, I would like to turn the call over to Dr. Jeff Martini, Palvella's Chief Scientific Officer. Thank you, Dr. Kelly. As we look at the trajectory of the field, it's remarkable to see how rapidly our understanding of these debilitating diseases has advanced. The key genetic drivers of venous malformations, including TEK and PIK3CA mutations, were first identified and characterized in 2009. That discovery fundamentally shifted how we think about these diseases. Since then, there have been more than 26 published studies evaluating rapamycin in venous malformations, primarily using oral rapamycin to treat internal disease. These studies reinforce the central role of mTOR hyperactivation and demonstrated that targeting this pathway can provide meaningful benefit when the drug reaches its intended target at therapeutic concentrations. But despite the progress, outcomes for patients with cutaneous venous malformations have remained poor. Oral rapamycin has limited biodistribution to the skin, and procedural approaches, as Dr. Kelly nicely described, are destructive and short-lived. That's what brought us to the TOIVA trial in patients with cutaneous venous malformations, which is the first prospectively designed clinical trial focused specifically on this population. QTORIN rapamycin is our patented topical formulation designed to deliver high concentrations of rapamycin directly to the skin with low systemic exposure. In addition to our clinical data, we have an extensive CMC package with long-term room temperature stability and a reproducible and scalable manufacturing process. Shown here is the study design of TOIVA, Phase II baseline controlled study in cutaneous venous malformations. TOIVA enrolled patients age six and older, all of whom apply once daily QTORIN rapamycin. It is a 24-week study with each patient serving as their own control, allowing us to assess change over time. This innovative study design was developed in collaboration with significant input from U.S. and European KOLs, including Dr. Kelly. The data we are presenting today reflect the 12-week time point. Because of the time to maximum effect of greater than one year that Dr. Kelly described earlier, patients here remain on treatment through 24 weeks, and we will continue to collect both safety and efficacy data with plans to report additional data at a future date. The study evaluates safety and tolerability as well as multiple measures of efficacy with no predefined primary endpoint. Efficacy assessments include the cVM- IGA, a seven-point clinician-rated change scale, and the cVM-MCSS, supported by additional clinician and patient-reported outcomes. From a statistical perspective, analyses are conducted in the intent-to-treat population using available data at each time point and analyzed according to a predefined statistical analysis plan. The study population enrolled patients with cutaneous disease with eligibility confirmed by an independent third-party expert review team. While the disease is genetically well understood, genetic confirmation is not common in real-world practice and was not required for our trial. We enrolled 16 participants who were dosed, with one participant lost to follow-up. Finally, TOIVA is being conducted at leading U.S. academic centers, including the Mayo Clinic, Cleveland Clinic, CHOP, and Stanford, among others, underscoring strong investigator engagement and execution quality. I am pleased to share the 12-week efficacy data from TOIVA across all treated patients with 15 participants evaluable at this time point. On the clinician-rated outcome, overall cVM-IGA, we observed a mean improvement of 1.5 points, which was highly statistically significant. Importantly, these improvements were consistent across the key visible drivers of disease. Lesion height improved, and appearance of color and of affected veins improved, both with strong statistical significance. We also saw a meaningful reduction in bleeding with a statistically significant improvement at just 12 weeks. These clinician-assessed findings are supported by patient perspective, also with a statistically significant improvement on the PGIC. Taken together, these data demonstrate rapid, consistent, and statistically significant improvements across both clinician and patient-reported measures at the 12-week time point. On this slide, I'm going to go into more detail on the overall cVM-IGA, which is the clinician-assessed dynamic change scale used in the study. The cVM-IGA is a 7-point scale ranging from very much worse, minus 3, to very much improved, plus 3. At week 12, we observed a mean effect size of plus 1.5, with a p-value of less than 0.001. Looking at individual patient responses, 73% of participants, 11 out of 15, achieved at least a 1-point improvement on the overall cVM-IGA at week 12. In addition, 67% of participants, or 10 out of 15, were rated as either much improved, plus 2, or very much improved, plus 3. Importantly, no trial participants were minimally worse, minus 1, much worse, minus 2, or very much worse, minus 3 at week 12. Notably, among the 10 participants rated as much improved or very much improved, these improvements were observed across genetic subgroups, including participants with genetically confirmed TEK mutations, participants with PIK3CA mutations, and participants with non-TEK PIK3CA mutations or unconfirmed genotypes. For internal decision-making, we had established a 30% improvement threshold as the level at which we would consider advancing the program. The results we saw with 73% of patients improving and 67% of patients reaching much improved or very much improved substantially exceeded that internal benchmark. We continue to collect additional genetic data from participants, and we plan to present genotype stratified analyses at a future medical meeting. Importantly, based on analysis of data at week 12, we do not anticipate requiring confirmed genotypes or genetic testing in future studies. We also see a clear time-dependent increase in clinical response, consistent with a strong pharmacologic exposure-response relationship. When we look at cVM-IGA, the proportion of patients achieving a greater than or equal to 2-point improvement increases steadily with continued dosing. 31% of patients responded by week 4, rising to 50% at week 8 and to 67% at week 12. This progressive increase indicates that longer duration of treatment translates into greater clinical effect. From a development standpoint, these results are particularly compelling. We had set an internal benchmark of approximately 30% responders to justify progression into Phase III. That benchmark was reached by week four and substantially exceeded by weeks eight and 12. Taken together, the data support a robust pharmacological response and provide strong confidence to advance QTORIN rapamycin in cutaneous venous malformations. In addition to the dynamic change scales, we also observed statistically significant improvements on key static severity measures at week 12. Overall disease severity, as well as lesion height and appearance, all had statistically significant improvements. These clinician-rated findings are supported by patient assessments with a significant improvement on the PGIS. Taken together, the data demonstrate concordant improvements across both dynamic change scales and static severity scales, strengthening confidence in the clinical data. Dr. Kelly will now provide a review of photographs from the trial. Thank you, Jeff. The first patient I want to highlight is from the clinic of Dr. Denise Adams at the Children's Hospital of Philadelphia. Dr. Adams is the director of the Vascular Anomaly Clinic and lead author on the fundamental 2016 publication evaluating the use of rapamycin in vascular malformations. I spoke to Denise about this case. Her case is a 17-year-old young lady with a confirmed TEK or TEK mutation whose disease was widespread and severely impacted her quality of life. In fact, it was also documented that she had six previous interventional sclerotherapies to try to treat her disease, which unfortunately resulted in disease recurrence each time. At baseline, she presented with significant swelling and pain to the point that basic daily activities, such as putting on a shirt, wearing a bra, or leaning back in a chair, were extremely difficult. After 12 weeks of treatment, this patient showed marked improvement with substantial reductions in disease burden, swelling, and pain, translating into meaningful improvement in the day-to-day functioning. The second patient I want to highlight is one who I treated. This is a 13-year-old who had cutaneous venous malformation associated with a mutation in the PIK3CA gene. He experienced progressive pain and bleeding with even minor trauma, so much so that he had to quit his sports team. On the left, you can see the baseline disease with markedly elevated vesicles, venous engorgement, and a dark purple coloration, all features consistent with severe disease. After 12 weeks of treatment, we observed a remarkable improvement, including flattening of the lesion and significantly lightening of color, which translated into meaningful clinical benefit. Importantly, this visible improvement aligns with the patient's own experience. As reflected in the quote on the slide, the patient reported that bleeding largely stopped, the color faded, and the height resolved, indicating a high level of satisfaction with the response. Notably, these improvements occurred rapidly, and a plateau has not yet been reached at the time of the assessment, suggesting the potential for even greater benefit with continued treatment. When we see these patients in clinic, we often hear of the impact on quality of life. I describe what I heard with the patients I treated in this trial, which was very positive. But I credit Palvella for incorporating qualitative interviews in this study to understand the impact on quality of life and to help interpret the clinical meaningfulness of the changes that we saw on various endpoints. I will pass it back to Jeff to describe the rigorous method used in some of these early findings. Thanks, Dr. Kelly. What Dr. Kelly is referring to is FDA's guidance on patient-focused drug development. In this study, we incorporated a priority semi-structured qualitative interview process at baseline and week 12. At Palvella, elevating the patient voice is fundamental to our mission of serving patients. We were struck by how profoundly cutaneous venous malformations affect daily life, including pain, swelling, bleeding, mobility limitations, and emotional distress. Importantly, the improvements patients describe in their own words align closely with the objective clinical data we reviewed earlier. This concordance between patient-reported experience and clinician-assessed outcome provides a compelling and comprehensive picture of treatment benefit. We plan to share this qualitative evidence with FDA as it meaningfully contextualizes baseline disease burden and what constitutes meaningful improvement from the patient perspective. I'll conclude with a brief summary of the safety profile before handing it back to Wes for his final comments. Overall, QTORIN rapamycin was well tolerated, in line with what we've seen in our previous clinical trials. The most common treatment-emergent adverse event was erythema, occurring in 25% of patients. All treatment-related adverse events were moderate or mild, with no unexpected adverse events reported. Importantly, as expected, systemic absorption was very low. Rapamycin levels were below the lower limit of quantification two nanograms per mL in systemic circulation on a standard lab assay for all participants at all time points in the study. Taken together, these safety results support QTORIN's potential as a well-tolerated, targeted therapy for cutaneous venous malformations, and now I'd like to turn the call back to Wes for some concluding remarks. Thank you, Jeff. In summary, we believe Phase II study was successful, demonstrating highly statistically significant results across multiple pre-specified clinician-reported and patient-reported efficacy endpoints. 73% of patients, 11 out of 15, demonstrated a one-point or greater improvement on the overall cVM-IGA at week 12, and 67% of patients, 10 out of 15, were rated as either much improved, plus two, or very much improved, plus three at week 12. Based on these results, near-term discussions with the FDA are planned to, number one, explore the potential for breakthrough therapy designation, a regulatory program that could serve to expedite QTORIN rapamycin's development, number two, to align on the Phase III pivotal study, and number three, to engage on the newly announced plausible mechanism pathway based on the strong mechanistic rationale and growing clinical evidence supporting mTOR inhibition in cutaneous venous malformations. Phase II results support the potential for QTORIN rapamycin to become the first FDA-approved therapy and a potential first-line standard of care therapy for the estimated more than 75,000 individuals in the United States living with cutaneous venous malformations. Phase II results reinforce Palvella's pipeline and a product strategy for QTORIN rapamycin, supporting advancement across microcystic lymphatic malformations, cutaneous venous malformations, and angiokeratomas, each representing a potential first-in-disease FDA approval and establishing a foundation for expansion into a broader set of mTOR-driven skin and vascular indications. In closing, we are deeply grateful to the patients and to the families who participated in this trial, to Dr. Kelly and to all our TOIVA investigators, to the research teams at our sites whose partnerships made this study possible, and to the Palvella Clinical Operations, Clinical Development, Regulatory, and CMC teams whose unrelenting commitment every day is the foundation of our company's success. We all remain relentlessly focused on our mission to serve patients with no FDA-approved therapies, our strategy to be first in developing a targeted therapy for each of these rare disease patient populations, and our vision to be the leading rare disease company developing and commercializing therapies for serious rare skin diseases. Thank you all for your time, and we'll now open up the line for questions. Certainly. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile our Q&A roster. Our first question will be coming from Josh Schimmer of Cantor Fitzgerald. Your line is open, Josh. Great. Thanks so much for taking the question and congrats on the results. Maybe just to clarify, of the estimated 75,000 patients with cVM in the U.S., what% have superficial lesions that would be amenable to QTORIN rapamycin? And perhaps as part of that, maybe you can comment on the screen failure rate in the study for depth of lesion or other considerations. Thank you. Great. Hey, Josh. Thanks for being on, and appreciate the congrats. To address your question first about the estimated 75,000 patients that have cutaneous venous malformations in the United States, there's a recent publication that Jeff and many others were a part of that was a real-world occurrence study. We surveyed a large sample size of physicians and had those physicians report the number of patients who they currently manage with cutaneous venous malformations. The outputs of that real-world occurrence epidemiologic study were that there's approximately 135,000 patients that are estimated that have cutaneous venous malformations in the United States. There's approximately another 60,000 that have both cutaneous and internal disease. So that's very recent evidence that's published. We've also looked at some of the literature as well in conjunction with some of our outside epidemiologists, and that's where we really derive our more conservative estimate of greater than 75,000. I'll pass it over to Jeff just to comment on the screen fail rate. Thanks for the question, Josh. We haven't disclosed screen fail rate. We plan to present that detail at a future medical conference. It is in line with previous clinical trials with QTORIN rapamycin. Importantly, the process for selecting patients was really a twofold process. The patients would come into the clinical site, evaluated according to the inclusion/exclusion criteria, and then we had a third-party independent consult team that looked at patients to make sure that we're getting the right patients into the trial. Can I just clarify then that when you say cutaneous, you're referring to very superficial lesions and not ones that might be slightly deeper in the skin and, as such, less amenable to a topical approach? Yeah. The way we define superficial is in the dermis or epidermis. When you say cutaneous, that's superficial cutaneous, yeah. Correct. That's correct. Okay. Thank you very much. Our next question will be coming from Ritu Baral of TD Cowen. Your line is open. Good morning, guys. Congrats on this data set. A couple of quick questions here. Well, maybe not so quick, but I'll limit myself here. Sorry. Natural history, I would say. How would you have expected, based on natural history, any sort of placebo arm would have performed on the primary endpoint? And amongst the numerous secondaries, are there any of these that are particularly, I would say, impervious to placebo effect? Great. Thanks for the questions, Ritu. I'll take the first one regarding natural history and then pass it over to Jeff for your second question. Since we initiated our development in venous malformations, there's been a natural history study that has published. First author is Fujino and published in 2024. What that natural history showed, and I'll summarize it, is that there is no spontaneous regression in venous malformations. That's entirely consistent with our understanding of the genetics and the biology of the disease as well. And so to maybe now address your question regarding how a placebo arm would perform, we would expect there to be no placebo response based on this being a progressive disease, given that underlying biological activity with the hyperactivated mTOR signaling constantly firing and in constant chronic overdrive. Jeff? Yeah. So for the secondary endpoints, really all endpoints, this is a genetically driven disease. We know that these mutations are programming these endothelial cells to rapidly proliferate, to grow, and it results in this abnormal architecture. We also know, in talking with our key opinion leaders and investigators like Dr. Kelly, that nothing works for these patients. So that's why we believe inhibiting this overactivated pathway gave us the trial results that we presented today. Got it. And then just going to slide 16, this was the time course of benefit on two-point improvement. Wes, what does this tell you about what you're thinking about for the next study? I mean, it sounds like based on powering and sort of normal thresholds, you could do a week four, week eight study. On efficacy, would you want to do something longer to show an even better benefit? Do you need it for exposure? How should we be thinking about the next study and what you're going to propose to FDA? Thanks. Yeah. Thanks, Ritu. We believe we saw large effect sizes in a majority of patients at week 12. We'll continue to analyze that data, Ritu. As you saw from the trial design slide that Jeff presented, we are following these patients for an additional 12 weeks. So as we collect that data, that's going to help inform any future study design. Got it. Sorry. And one quick question from a client. Just on the subscales of the cVM-IGA, I think you mentioned that height was a factor and color of affected veins. Are those the two main subcomponents of the cVM-IGA? And how does that overlap with the mLM- IGA, which is your FDA greenlighted primary for TOIVA? Sure, so first, to just describe the overall cutaneous cVM investigator global assessments. Importantly, that is a single-item efficacy endpoint, so a single question that measures change in severity from baseline, and it's a numeric rating scale that goes from negative three to plus three. In terms of the clinical signs that we measured for this study, we measured height/engorgement. We measured appearance. We measured bleeding. Ulceration was also assessed, although there was no disease present at baseline. Got it. And I'm sorry, I misspoke. How does that assessment compare to the mLM-IGA for SELVA? Sorry, I meant SELVA. Sure. The mLM-IGA, similar to the overall cutaneous VM- IGA, is also a seven-point clinician-assessed single-item efficacy instrument that measures change in severity from baseline with a similar numeric rating scale that goes from negative three, very much worse, to very much improved. Great. Thank you. Thanks for the questions, Ritu. One moment for our next question. Our next question will be coming from Sam Slutsky of LifeSci Capital. Your line is open, Sam. Hey, good morning. Thanks for taking the questions and great work on today's update. It's kind of two for me. Any details you can give on cVM average lesion size and the amount of drug needed versus MLMs? Anything related to compliance as well of patients? And then anything to note on discontinuations? And then have one follow-up. Great. So the average lesion size, Sam, in cutaneous venous malformations is typically larger than your average microcystic lymphatic malformation. That's based on feedback that we've gathered from Dr. Kelly and many of our other clinical collaborators. We haven't provided or quantified compliance in this study, but overall, we're very pleased to have 15 of the 16 patients reach that 12-week assessment and be able to report out 15 patients at week 12. Just to, Sam, maybe talk a little bit about compliance, that's why we designed QTORIN rapamycin to be a once-daily at-home administration for these patients. We think, given the genetic basis of the disease and what's very likely to be chronic therapy if the drug is approved in this indication, we want to set the patients up for a favorable dosing experience where they will remain compliant and hopefully maintain the benefit of the treatment effect that we hope to Phase III and ultimately beyond. I'll pass it over to Jeff on the discontinuations. Yeah. So, Sam, thanks for the question. What we're reporting today, we'll provide more detail in a future meeting, including the 24-week data. But one patient in the study was lost to follow-up, and at the week 12 point, we had 15 patients who were evaluable for efficacy assessments. One moment for our next question. Our next question will be coming from Whitney Ijem of Canaccord Genuity. Your line is open, Whitney. Hey, guys. Congrats on the data. Thanks for taking our questions. This is Angela on for Whitney. Just curious, so the results on the bleeding endpoint wasn't as robust. Do you have any thoughts on that, or do you believe that's something that could improve over time with longer treatment? And then we have a follow-up for Dr. Kelly, if possible. Great. Hey, Angela. Thanks for the question. Just to comment on the bleeding results, I'll point everyone to the data table and the press release, which showed that the bleeding results were statistically significant. There was, as noted in our press release and in the table, a limited number of patients who presented with bleeding at baseline, although our analysis of the patients who did present with bleeding at baseline indicated a significant treatment effect. So we were pleased. I think Dr. Kelly did a great job of highlighting one of the patients who had a lot of bleeding and obviously responded well to the drug, and that was noted in a qualitative interview by that particular patient. I'll ask Dr. Kelly to comment as well. Yes. I think that the study medication was actually quite effective in reducing bleeding in the patient that I actually cared for. Our next question will be coming from Annabel Samimi of Stifel. Your line is open, Annabel. Hi. Thanks for taking my question. Congratulations on this high response, especially this early on, given what we know about the time to response for cVM. I guess in that context, yeah, it makes the high response rate that much more impressive. So when you Phase III trial, i know you're going out to 24 weeks, and that MLM is 24 weeks. But given how rapid this response was, and that this will be the second indication for QTORIN rapamycin, is there any opportunity that you might only need a 12-week trial given that you hit on all these endpoints? And I guess the second question is, what exactly is the significance of establishing QTORIN rapamycin as a plausible mechanism pathway? Does that confer any additional benefits from a regulatory point of view? Hey, Annabel. Thanks for both of those questions. I do think there is a scenario potentially Phase III study would be 24 weeks. That decision is ultimately going to be informed by the data we continue to collect Phase II study, with these patients being evaluated for another 12 weeks beyond the 12-week data that we presented today. So like all things at Palvella, we're going to carefully analyze the data and let the data really guide our decisions. And those decisions always have to be in the best interests of patients while not losing the objective of getting the drug approved for these patients who are deserving of that first targeted therapy. In terms of your second question on plausible mechanism, published November 12th in the New England Journal of Medicine, was the FDA's new plausible mechanism pathway as outlined by Dr. McCarrey and colleagues. This is still conceptual, we believe, at the FDA, so we're still learning about this pathway. But as we reviewed the five criteria that are outlined in that New England Journal manuscript, there were several of those criteria, if not all of those criteria, that may line up to our QTORIN rapamycin for cutaneous VMs and some of our, candidly, other programs that we have moving forward in the pipeline. So as we noted in our press release, and we highlighted earlier today on the call, we're looking forward to engaging with the FDA to understand how they're implementing this new plausible mechanism pathway and whether this program and our other programs could be a potential fit. Our reading of the benefits of that is that, similar to some of these other more formalized expedited programs, is that this program is designed to expedite therapies to patients. So we'll learn a lot more as FDA implements this program, and we're able to dialogue with the team there in the derm division. Okay, and just one more follow-up for Dr. Kelly. When you think about clinically how you're going to be treating these patients, given that some of them have internal disease as well as cutaneous, do you expect some kind of combination treatment where they get topical QTORIN rapamycin for their cutaneous disease and maybe oral rapamycin at some point to control the internal disease? How do you think, from a practical perspective, these patients are going to be treated? Great question. I think that many of our patients actually have both significant internal disease as well as cutaneous disease. And yes, I do think that many of those patients will require both topical formulations of sirolimus as well as systemic application of sirolimus as well. Great. Thank you. Our next question will be coming from Ryan Deschner of Raymond James. Ryan, your line is open. Thanks for the question, and congratulations on the broadly successful readout. Two quick questions. Can you give us any additional detail on what the static severity scale metrics, such as CGI-S and PGI-S, looked like at baseline? And I'm curious if there was a particular patient characteristic at baseline that was associated with stronger improvement or conversely associated with more modest improvement. Thanks. Yeah. Hey, Ryan. Thanks for the questions. On the Clinician Global Smpression of Severity and the Patient Global Impression of Severity, both of the results there, the mean change from baseline, were statistically significant. We are planning to obviously put out a lot more data here in the near term. I think there's a great opportunity from a publication perspective in presenting this data at medical conferences, and so look forward to sharing more of that data here in the near term. In terms of the patient characteristics, and I'll ask Jeff to respond, according to our analysis of the data to date, we saw a consistent treatment effect across subtypes such as age. You saw the breakout in the press release in terms of patients reaching a plus 2 or plus 3 who had TEK mutations, PI3K mutations, other mutation types, and unconfirmed genotypes. So I think the robustness of the data is partially based on the consistency of effect across the subpopulations that we've analyzed today. Yeah. So overall, severity of disease at baseline, we have certain key inclusion/exclusion criteria for the patients to be moderate or worse of disease severity at baseline. This allows us to enrich the study for these patients and to see movement on these scales. Ultimately, our plan is to release the detailed baseline characteristics at future medical conferences. Got it. Thank you very much. And then maybe just very quickly, was there anything notable or can you give us any additional color on the patient that was lost to follow-up? Thank you. Yeah. We're not disclosing that at this time. Our next question will be coming from Jeet Mukherjee of BTIG. Your line is open. Great. Thanks for taking the question and congrats on the data today. So maybe one for Dr. Kelly to start. Obviously, this is a robust data set, but are there any efficacy or safety measures you would have liked to see greater improvement or better performance on overall? And maybe one for the management team. Just in terms of your interactions with the FDA to date, can you talk about your confidence in the guidance you're getting so far, just given some of the mixed or inconsistent feedback we've seen for other companies developing therapies in the rare disease space? Thank you. Thank you for the question. I think that the endpoints that were measured in this particular study were actually appropriate and clinically relevant, and I believe that the data set shows a remarkable benefit and one that has not yet plateaued, so I think that overall, the response was quite encouraging. Thanks, Dr. Kelly. Jeet, I'll take the second question regarding our FDA interactions. So we're regulated in FDA's derm division. In 2024, FDA granted this program Fast Track designation. I think, as you're aware, our microcystic LM program has breakthrough therapy designation. So there's been strong and consistent leadership in the derm division. I think the derm division also recognizes the very significant unmet need in these serious rare genetic skin diseases where there's no approved therapies. So our goal as a company is to continue that collaborative relationship, as Jeff highlighted earlier, making sure the voice of the patient is always heard at the FDA, highlighting the inadequacy of currently available or lack thereof treatment options, and so we've been fortunate to have a great collaborative relationship with what has been a stable division of the FDA these last couple of years. Our next question will come from Kaveri Pohlman of Clear Street. Your line is open, Kaveri. Hey, good morning. Congratulations on the results, and thanks for taking my questions. Maybe one for Dr. Kelly. Can you provide any additional insight on how well do the current trials reflect real-world patients considering the inclusion/exclusion criteria, lesion count, and prior or subsequent therapies? And to what extent could additional clinical data, greater awareness, and the convenience of topical option expand the addressable market, including patients who are perhaps initially managed with monitoring? And I have a follow-up. Thank you for the question, Kaveri. I really appreciate the opportunity to respond. I think that the focus of this clinical trial was on patients that had moderate to severe cutaneous disease features, and again, I think that many of the patients that we take care of in our clinic have moderate to severe disease, so I think that in that respect, I believe that it reflected our clinical experience. I do agree that patients with mild disease or less than moderate disease actually could benefit from treatment as well, and again, I think that we think about this as a progressive process, so intervening early in the process can actually change the natural history or potentially change the natural history of this disease, so again, I think that patients in general with cutaneous venous malformations are potential therapeutic could benefit from potential therapeutic intervention. Got it. That's very helpful. And maybe another question again on Dr. Kelly. And how do you see this therapy fitting alongside current options like sclerotherapy, bleomycin use? Also, given comments previously made by the company that early intervention may alter disease course if QTORIN rapamycin is used first-line, do you anticipate any impact on the effectiveness of subsequent treatments like bleomycin that could influence how you sequence the care? Thank you. Another great question. So thank you. I think that what a topical treatment really allows is earlier intervention. I think that when we talk about procedural interventions, there's a significant risk-benefit assessment, and there are significant risks associated with these interventions, both in children and adults. So my view as a clinician is that the availability of a topical option for treatment would make it much more likely that we would intervene early and be successful in that intervention. Our next question will be coming from Dev Prasad of Lucid Capital Markets. Your line is open. Hi. Thank you for taking the question, and congratulations on the data. I have one. We see strong efficacy, but can you provide any color on 27% patients who did not improve? Were there baseline characteristics or lesion features that may explain variability? Thank you. Thanks for the question, Dev. We're certainly analyzing all of the data. I think what we noted in the press release is that there were four patients who didn't show, out of the 15, improvement at week 12. We're, of course, following those patients for an additional 12 weeks. And then beyond the cVM-IGA, Dev, we're going to look at other endpoints as well as qualitative interviews to understand the experience not only of the handful of patients that you referenced, but also understand the experience of the 11 patients out of the 15 who reported improvement as well. So we'll continue to analyze the data. Thanks for the question. Great. Thank you. Okay. And our next question will be coming from Geulah Livshits of Chardan. Your line is open. Good morning, and congrats on the data from me as well. And thanks for taking the questions. So maybe staying on the topic of early treatment of this trial, I believe is in patients ages six years and older. In the SELVA trial, you guys incorporated a cohort-enabled expansion to younger patients. Is that something you envision doing in the cVM setting as well? And I guess for Dr. Kelly, would you feel comfortable treating very young patients based on the efficacy and safety that we're seeing here so far? Thanks for the question, Geulah. This is Jeff. Yeah, the idea is we'll take that. We'll look at the totality of the safety data as well as the efficacy data when we have our conversations with the FDA. And certainly, overall patient population, including age, is something that we'll discuss with them. And I would agree that actually, the younger we treat, the more likely we are going to change the natural progression of this disease. So given the safety that we see and the robust efficacy signal, I would advocate that younger patients be included in any future clinical trial. Our next question will be coming from Albert Lowe of Craig-Hallum. Albert, your line is open. Hi. Thanks for taking my question. I was wondering for the two patients that didn't improve by overall assessment of week 12, did any of them have any changes, improvements, or worsens at any earlier time points, or was it consistently zero? and also, going back to the natural history that you referenced and the progression of disease, would you expect patients to worsen without therapy over this short period of time? Thanks. Yeah. Jeff will take the first part of the question, and then Dr. Kelly can comment on the natural history. Yeah. Thanks for the question. We'll be looking into all the details of these patients, as Wes mentioned, both the 11 patients who improved on the overall IGA as well as the four who didn't show a response. And we'll be looking at all the subgroup analyses that we described earlier. With regard to the natural history question, I think that we know that this is a progressive disease, and we know that there are certain triggers that accelerate disease progression. Over this period of time, you would see a range of responses from stable to more severe disease depending upon the types of issues that the patient experiences. Great. Thanks. Maybe a quick follow-up. I was wondering if you saw any differences in time-to-response or any other differences by genetic mutation subtype. Yeah. That's a good question. It's definitely something we'll be looking at, and we haven't disclosed the earlier time point data, but we'll be evaluating that and presenting that at a future medical meeting. Okay. Thank you. Ladies and gentlemen, this does conclude our program. Thank you for participating. You may now disconnect.