Palvella Therapeutics, Inc.

secondary and secondary endpoints with a safety and tolerability profile that we believe supports first line standard of care positioning in this serious chronically debilitating rare disease. The SELVA results, along with our Phase II results in microcystic lymphatic malformations, which supported FDA granting ketorin rapamycin breakthrough therapy designation, provide us with a robust evidence package as we move toward NDA submission later this year. On the NDA, I am pleased to share that our NDA submission remains on track for the second half of 2026. Since our last earnings call and corporate update just a few weeks ago, the FDA has granted Paul Vela an in-person pre-NDA meeting to be held later this quarter. In parallel to advancing towards our NDA submission, we continue to make strong progress preparing for and investing in a potential U.S. launch. I'm pleased to share that we have added commercial and medical leadership with deep experience launching highly relevant therapies in rare diseases and skin diseases, including successful products such as Vigevec, Zareve, Apsilura, Tepeza, and Oxirvate. At the same time, our pipeline progress extends well beyond microcystic lymphatic malformations. In cutaneous venous malformations, we are on track to initiate a pivotal phase three study in the second half of this year. In clinically significant angiocaritomas, a superficial lymphatic malformation, earlier this week, we announced that the first patients dosed in our phase two low two trial. Thanks to our clinical development and clinical operations teams, this study initiated ahead of our original schedule. And in disseminated superficial actinic poric keratosis, or DSAP, we continue to see strong patient and physician interest in our planned Phase II study, including having now received over 40 patient inbound inquiries expressing interest in the study. I wanted to take a moment to share a message I received on LinkedIn over the weekend from an individual living with DSAP. Hi, Wes. I'm so excited to hear about your trials. As a DSAP sufferer, I have tried everything, and nothing has worked. Really need this, as I have been suffering for over 25 years. Testimonials like these reinforce the magnitude of the unmet need and strengthen my motivation and our team's motivation to advance our programs with urgency. Importantly, we are pursuing this next phase of execution from a position of financial strength supported by the upsized $230 million financing we completed in the first quarter with participation from high-quality existing and new investors. We continue to see significant opportunity across a large subset of serious rare skin diseases where patients and families have historically been overlooked, therapeutic innovation has been limited, And Paul Vela has the opportunity to step up for patients and families with targeted therapies designed to address meaningful unmet need. We were pleased to recently announce Dr. John Dew's appointment to our board of directors. John is a dermatologist and one of the leading voices advocating for drug development in rare, chronically debilitating skin diseases. In John's 2015 manuscript in the Journal of Investigative Dermatology, he described how the orphan drug development model had expanded across many therapeutic areas but had not yet meaningfully reached dermatology, a field with many serious debilitating diseases and few, if any, approved treatment options. As John anticipated and as represented by the quote on this slide, the first wave of innovation in rare skin diseases has largely been concentrated in epidermolysis bullosa, where multiple FDA-approved therapies now exist to address this serious rare disease. At Paul Vela, we believe we are driving the next wave of innovation beyond epidermolysis bullosa across several serious rare skin diseases and vascular malformations, indications where historically patients and families have been overlooked, treatment options are limited or nonexistent, and advances in understanding of the genetics and causal biology now create the opportunity to advance first-in-disease targeted therapies that can move patients from zero FDA-approved options to that first FDA-approved therapy. Pulvella's strategy is unique and intentionally designed to stand apart. We are not seeking crowded indications. We are not building around incremental differentiation. And today, we are advancing four programs that fit the Pulvella strategy. Notably, each has an estimated diagnosed U.S. prevalence that is meaningfully larger than the ultra-orphan threshold. We believe these clinical indications, therefore, not only high unmet need, but also underappreciated in terms of the size of the market opportunities they represent. Across the market research we've conducted, physicians have consistently noted first-line potential for a therapy with a profile similar to cuturin rapamycin. Our research shows that upon potential approval, more than 80% of physicians would consider cuturin rapamycin as first-line therapy for microcystic lymphatic malformations, cutaneous venous malformations, angiokeratomas, and disseminated superficial actinic porokeratosis. specifically in microcystic lymphatic malformations, which we believe will be the first approved indication for ketorin rapamycin, 98% of physicians would consider a therapy with a profile similar to ketorin rapamycin to be first line. Furthermore, 96% of physicians surveyed noted advantages to targeted localized topical therapy for pediatric patients compared to oral mTOR inhibitors or oral PI3K inhibitors. Moving to our U.S. launch planning, the positive Phase III Selva results in microcystic lymphatic malformation and positive Phase II Toiva results in cutaneous venous malformations were important contributors to our ability to complete an upsized $230 million financing in February. I am personally grateful to all the existing and new investors who participated in the financing and have entrusted our management team with their capital. Our management team and I remain committed to working tirelessly to realize the full potential of cuturin rapamycin, the broader cuturin platform, and the rare disease opportunities we believe Palvella is uniquely positioned to advance. The upsized financing does not change our commitment to disciplined capital allocation. It does ensure, however, that if approved, the cuturin rapamycin launch will not be under-resourced. We intend to direct a substantial portion of the incremental proceeds raised beyond our original $150 million target toward launch success, including accelerating investments in our commercial and medical affairs build-out. Proactively identifying and recruiting exceptional leadership to Palvella has been a key strategy for us since our founding. And I'm thrilled that Paul Vela has added two proven, high-integrity commercial leaders to our team in Jennifer McDonough and Kent Taylor. Prior to joining Paul Vela, Jen was instrumental to the pre-launch planning and successful launch of Vigevec, a repeat-dose topical therapy for epidermolysis bullosa, a serious rare genetic skin disease. Ken, most recently, was the Senior Vice President of Sales at Arcutis, where he led the sales organization and was a key driver behind the launch success of Zareef. I'm excited to work alongside Jen, Kent, and our Chief Commercial Officer, Ashley Klein, while leveraging their learnings from past launch successes with our shared goal of making Kutor and Rapamycin the most successful launch yet for all of us. With a strong capital base now in place, we are targeting a field sales force between 30 to 40 reps, revised from our original plan of 20 to 40 reps, with plans to have that field team in place prior to the PDUFA date, this consistent with industry best practices for rare disease launches. We've hired medical science liaisons or MSLs with a clear objective of enhancing disease state awareness around the underlying genetic basis of microcystic lymphatic malformations, the chronically debilitating nature of the disease, and the lifelong disease course. We are continuing to expand this MSL team on a national basis with plans to have several more MSLs start in the coming weeks and months. We are also systematically engaging physicians at high-volume treatment centers, including vascular anomaly centers, to support disease education, better understand patient flow, and prepared for a focused launch model anchored in the centers that are already caring for these patients. This, in contrast to many rare disease launches whose success is predicated on new patient identification and diagnosis. Turning to the peak sales potential for ketorin rapamycin in microcystic lymphatic malformations, we estimate peak U.S. sales potential of greater than $1 billion in microcystic lymphatic malformations for ketorin rapamycin. That estimate is grounded in several factors. First, recent field checks with high-volume centers, as well as further analysis of the annual incidence data from our claims work, continue to support an estimated diagnosed prevalence of greater than 30,000 patients, many of whom are concentrated in vascular anomaly centers. Regarding pricing, in addition to the payer testing and analog work previously performed, we believe based on the efficacy results from the Phase III Selva Study, Futurin Rapamycin has the potential to support orphan pricing within our previously guided range of $100,000 to $200,000 per patient per year. We also believe our current estimates do not fully capture the ways in which first and disease therapies can potentially expand the market over time. When a first approved therapy becomes available in a rare disease, it often can do more than enter a market. Diagnosis can improve. Referral patterns can change. Specialists can become more engaged. Advocacy can increase. Patients who were previously misclassified or untreated may be identified. And treatment can move upstream over time, particularly when a therapy has a favorable safety and tolerability profile, is convenient to use, and addresses a chronic disease that significantly impacts quality of life. That is why we believe cuturin rapamycin has the potential to represent more than the first approved therapy for microcystic LMs. If approved, cuturin rapamycin could establish the foundation for a new standard of care for individuals living with this serious rare disease. And now, I will turn it over to David Osborne, our Chief Innovation Officer, to speak on our Cuturin platform. David? Thank you, Wes.

I'll now turn to the Cuturin platform and the role it can play in Pulvella's broader strategy. My background, I'm a chemist. And most recently, I was co-founder and chief technical officer at Arcutus. I have now been with Pulvella for more than six months. And I want to share a few observations on what I believe makes QTorrent distinct. QTorrent is a technological foundation that allows us to pursue Pulvella's mission efficiently. Topical formulation is technically difficult. Even small changes in formulation can have large effects on drug loading, stability, release, skin delivery, tolerability, and systemic exposure. Tutorin is designed to sit at a precise balance point, delivering therapeutic levels of drug into diseased skin, including the dermis, while maintaining tolerability and minimizing systemic absorption. We think about the cuturin platform across four core attributes, high drug loading, demonstrated safety and tolerability, dermal engagement, and durable intellectual property potential. Cuturin rapamycin is an important example that 914 Daltons, rapamycin is a large molecule that historically would not have been expected to deliver efficiently through skin based on conventional assumptions, such as the 500 Dalton rule. Yet Q-Torin has demonstrated the ability to deliver rapamycin into the dermis, shattering my perception of the 500 Dalton rule, while also maintaining low systemic exposure and favorable tolerability. With six issued patents, additional applications pending, proprietary formulation and manufacturing know-how, and the potential for orphan drug exclusivity, we believe Cutorin Rapamycin is supported by a multi-layered exclusivity position that could enable a long and durable commercial life. Importantly, this exclusivity strategy may also create meaningful barriers to competition and potential generic entry by protecting not only the composition and use of cuturin rapamycin, but also the specialized formulation and manufacturing capabilities required to reliably deliver rapamycin into affected skin. Since joining Paul Vela, I have also had the opportunity to evaluate multiple molecules within the platform. My view is that cuturin has broad capability across a diverse range of molecules, Importantly, each new molecule can create a new opportunity for intellectual property, including formulation, composition, method of use claims, and disease specific applications. With two positive clinical readouts now behind us, we believe this is the right time to scale additional product candidates from the platform. While remaining true to Paul Vela's operating principles, capital efficiency for investors, and time efficiency for patients who are waiting. I will now turn it over to Jeff to discuss our rare disease pipeline programs.

Thank you, David. I want to spend a minute on the qualitative data generated from our patient interviews in Selva because this is something that's really important to Palvella and to regulators, particularly in rare diseases where there are no approved therapies and no regulatory precedent. We previously shared the quantitative results from Selva, where 95% of patients improved on the clinician-rated MLM IGA. But what this qualitative work does is help us understand just how meaningful these changes are for the patient. I have spent a lot of time going through the interviews and the full analytical report, and what stood out to me was just how significant the disease burden is at baseline and how meaningful the changes are as patients progress through the trials. At baseline, patients described dealing with constant bleeding and leaking and the impact that has on normal day-to-day functioning. They talked about needing bandages and changing clothes throughout the day. When asked what animal best represents their disease, one child described their disease in their own words as fire ants biting on the skin. A second child described their micro-OM as a hippopotamus and stated, because they're so big all the time, the spots keep getting inflamed and big like that. I was pleased that in reviewing these patient profiles, Both of those patients were among the 95% who experienced improvement while on therapy. And at week 24, what patients described lines up very closely with what we measured in the trial. Across the interviews, you hear consistent themes around bleeding stopping, reduced leakage, and lesions looking more like normal skin. You can see a couple of the quotes here, including the patient here who said her lesion doesn't bleed anymore, and now it just looks like normal skin. Ultimately, we see clear alignment between patients and the trial endpoints, and that gives us confidence that these effects are both statistically significant and clinically meaningful. And that's been our goal with this program, to deliver what we consider transformational efficacy and a well-tolerated therapy for these patients. These findings also strengthen the overall risk-benefit narrative, and this qualitative work will be included as part of our planned NDA. As we advance towards NDA submission, we believe ketoram rapamycin is supported by a regulatory profile that is meaningfully different from a traditional new chemical entity NDA or a BLA for cell or gene therapies. First, we are pursuing the 505 regulatory pathway given oral rapamycin is an already FDA-approved drug with substantial scientific and clinical knowledge. This pathway allows Palvella to leverage existing data on rapamycin including the established systemic safety profile. Second, the program is supported by a growing body of real-world evidence and clinical experience with rapamycin in lymphatic malformations, which helps validate the therapeutic rationale for mTOR inhibition in the underlying disease biology. Third, our development program is designed to support a traditional approval, not an accelerated approval based on surrogate biomarkers. The SELVA Phase III study evaluated clinical endpoints, including physician-assessed disease improvement and patient-reported outcomes, rather than relying on biomarker-based evidence of activities. Finally, cutorium rapamycin is supported by two prospective clinical studies demonstrating consistent, large-magnitude, clinically meaningful results with a favorable tolerability profile. As I highlighted on the previous slide, the qualitative patient interview data further reinforce how meaningful these treatment benefits are from both the patient and caregiver perspective. And importantly, when I shared the SELVA data with the FDA's Office of Organ Products Development, which is providing non-dilutive funding for the program, they were pleased to hear that we reached a pivotal milestone. They indicated they are interested in participating in our pre-NDA FDA meeting, which will occur this quarter. We believe tororapamycin has a compelling regulatory profile, the ability to leverage a well-understood molecule through the 505 pathway, combined with the innovation of Pulvelo's dermal targeted formulation and a disease-specific clinical program designed to support traditional approval. Turning to medical affairs, we've strengthened our leadership and are building a strong presence as we move through 2026. As shown, a key focus will be ISFA, who are the platinum sponsor. That includes a late-breaker presentation by Dr. Jim Treat from the Children's Hospital of Philadelphia of our CELVA and TOIVA data, as well as a scientific symposium with study investigators. We're also sponsoring other important meetings, including the Epidermal Differentiation Disorder Symposium in Chicago. As we look ahead, these engagements are an important opportunity for our medical affairs team to educate clinicians on our diseases and the CELVA and TOIVA data, as we prepare for NDA submission in the second half of this year and move towards commercialization. Overall, this reflects our focus on engaging the clinical community, increasing disease state awareness, and laying the groundwork for a potential launch. Cutaneous venous malformations is our second program for ketone malformations, and one where we have a strong conviction as we advance towards phase three, especially given how closely aligned with what we've already demonstrated in microcystic lymphatic malformations. Like the rest of our portfolio, this is a serious, rare disease with no FDA-approved therapies. Biology here is well understood, with mutations that ultimately lead to upregulated mTOR signaling, which is directly aligned with ketoramapumnisin's mechanism of action and consistent with what we see in an MLM. Clinically, these patients experience malformed veins in the skin, which can lead to bleeding, ulceration, and functional impairment. Today, treatment is largely procedural, things like laser therapy, or sometimes off-label use of systemic therapies, including oral rapamycin. So there's a clear need for a targeted, well-tolerated topical approach. What's particularly compelling to me is the strength of the Phase II data. As we announced last December, 73% of patients showed improvement, well exceeding our target of 30%. We are planning to present additional findings at ISFA later this month. We're also seeing strong signals of physician adoption, with market research showing that 86% of physicians would consider ketorrapamycin as a first-line therapy. Our clinical and regulatory team is advancing phase 3 planning, with trial initiation expected in the second half of 2026. Our third indication, clinically significant angiocaratomas, is one we announced last year and is progressing ahead of plan. One of the key reasons we selected clinically significant angiocaratomas is how closely they align with microcystic lymphatic malformations. As shown, angiocaratomas are a superficial lymphatic malformation. So from a disease biology standpoint, there's a strong connection between the two. They share a number of key features, including superficial dermal involvement, a lymphatic basis, and clinical manifestations such as bleeding and functional impairment. In addition to the mechanistic rationale, there is also real-world evidence supporting targeted therapy with rapamycin in these lesions. We believe this represents a very logical indication for our ketorin rapamycin pipeline in a product strategy, leveraging what we've demonstrated in microcystic lymphatic malformations into a closely related disease with a similar underlying biology and no approved therapies. The ketoramapamycin program for the treatment of clinically significant angiocaratomas has strong momentum, and as I just mentioned, a clear scientific rationale given its close mechanistic and clinical adjacency to microcystic lymphatic malformations. Since we announced last year, we have achieved a significant and regulatory and clinical milestones. On the regulatory side, we were awarded fast-track designation, which is an important milestone for this program. On the clinical side, thanks to our best-in-class clinical team, we've initiated the Phase 2, Low 2 study and are already dosing multiple patients. This is a single-arm, baseline-controlled study evaluating once-daily ketoramipamycin in patients with moderate to severe clinically significant angiokeratomas. We expect data from Low 2 in the second half of 2022. I also want to highlight some market research we conducted to better understand how ketoram rapamycin may fit into clinical practice. In a survey of 50 physicians who treat clinically significant angiocaratomas, 96% indicated they would incorporate ketoram rapamycin into their practice for this patient population. Our fourth program in development is ketoram pitavastatin for DSAP, or disseminated superficial actinic porocaratosis. a program that I am particularly energized about. DSAP is well-characterized genetic disease driven by mutations in the mevalonate pathway with a clear and validated pathophysiology. DSAP fits squarely within our disciplined disease selection framework. It's a serious, rare, proliferative, and progressive disease, commercially attractive with more than 50,000 diagnosed patients, and has no FDA-approved therapies. Clinically, patients develop multiple persistent lesions on sun-exposed areas like the arms and legs. These lesions are visible, burdensome, and increase over time, with a risk of progression to squamous cell carcinoma. What has been particularly striking is the level of interest we're seeing from both patients and investigators. We've received over 40 inbound, unsolicited patient messages for the planned Phase II study, which really underscores both the disease burden and the urgency for new treatment options. And as one potential patient shared with our clinical team, she describes the lifelong nature of the disease and the frustration of repeatedly having these precancerous lesions treated with procedures like freezing. And as reflected in the quotes on this slide, patients are actively seeking new effective treatment options and are highly motivated to participate in clinical trials. The patients described as being desperate for any treatment. We're also seeing strong engagement from clinicians who recognize the lack of effective therapies and the need for a targeted approach. And we're building on this momentum with a study initiation on track for the second half of 2026. To bring it all together, ketorin and potavastatin fits very cleanly within our overall pipeline strategy and shares key characteristics with ketorin and rapamycin, addressing serious rare disease with no FDA-approved therapies and doing so on the basis of a strong scientific rationale supported by real-world evidence. Upon potential FDA approval, Ketoran-Petavistan stands to potentially be the first FDA-approved therapy while entering a commercially attractive, multibillion-dollar market with more than 50,000 patients in the United States. So overall, we see DSAP as a highly aligned and compelling next program and a strong example of how we're continuing to expand the Ketoran platform and unlock new opportunities across rare diseases. And with David's leadership, we're well-positioned to continue advancing this platform and realizing its full potential. We believe there's significant runway ahead, and we're just getting started. And with that, I'll turn it over to Matt.