Hello, and thank you for standing by. Welcome to Palvella Therapeutics conference call to discuss new product candidate QTORIN pitavastatin . All lines have been placed on mute to prevent any background noise. I would now like to turn the conference over to Bohan Wei. You may begin.
Thank you, Operator. Good morning, and thank you for joining the Palvella Therapeutics conference call to discuss our new product candidate, QTORIN pitavastatin , for Disseminated Superficial Actinic Porokeratosis. As a reminder, our press release detailing today's announcements can be found in the investor section of our website at www.PalvellaTx.com. Before we begin, please note that today's remarks may include forward-looking statements regarding our development programs, 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. The format of today's conference call will be presentation only. Additionally, as a reminder, we will not be discussing or commenting on our ongoing clinical trials.
On today's call, we are joined by Wes Kaupinen and Palvella's Founder and Chief Executive Officer, Dr. Jeff Martini, our Chief Scientific Officer, Dr. David Osborne, our Chief Innovation Officer, Matt Korenberg, our Chief Financial Officer, and Dr. Keith Choate from the Yale School of Medicine. I would like to turn the call over to Wes.
Thank you, Bohan. Good morning, everyone, and thank you all for joining us on today's call. Today is a landmark day for Palvella. With the introduction of QTORIN pitavastatin for Disseminated Superficial Actinic Porokeratosis, we're expanding the reach of our QTORIN platform to a second product candidate while deepening our mission to bring meaningful innovation to another rare disease community that currently lacks an approved therapy. I'd like to first thank all our physician and scientific collaborators, as well as the Palvella R&D and commercial teams for the years of work that have contributed to today's announcement. Let me begin with a few words on the disease. Disseminated Superficial Actinic Porokeratosis, or DSAP, is a rare, chronically debilitating, and precancerous genetic skin disease that currently has no FDA-approved therapies. DSAP embodies all the hallmarks of a Palvella disease.
It is rare, profoundly impacts patients' quality of life, has well-defined disease biology, lacks FDA-approved therapies, has no other programs in the development pipeline, and represents a commercially attractive market with over 50,000 diagnosed patients awaiting potential treatment upon regulatory approval. We believe this disease represents a compelling opportunity to deploy our QTORIN platform under the leadership of Dr. Jeff Martini, our Chief Scientific Officer, and Dr. David Osborne, our Chief Innovation Officer, to develop a novel targeted topical therapy that addresses the significant unmet medical need for this patient population. Once our team verified that DSAP met Palvella's development and commercial criteria, as you'll hear today, we shifted from a mindset of due diligence to a mode of operational execution, intensifying efforts across product development, clinical development, and regulatory engagement.
Importantly, the entire Palvella team is united by our single objective for this development program: to develop and commercialize QTORIN pitavastatin as the first FDA-approved therapy for patients affected by Disseminated Superficial Actinic Porokeratosis. On today's call, the Palvella team and I are honored to be joined by Dr. Keith Choate. Dr. Choate is a physician scientist and the Chair of Dermatology at Yale School of Medicine, with additional appointments in genetics and pathology. A recognized pioneer in human genetics and genodermatoses, Dr. Choate has identified the genetic causes of numerous inherited skin diseases. His groundbreaking work on the genetics and biology of porokeratosis provided the first mechanistic understanding of this disease and has helped define new therapeutic strategies. Dr. Choate has published extensively in leading journals, and his discoveries have reshaped how rare genetic skin diseases are diagnosed and managed. Clinically, Dr.
Choate is sought after for his expertise in complex and undiagnosed dermatologic conditions. In addition to his research and clinical leadership, Dr. Choate is deeply engaged in collaborative pediatric dermatology research through the Pediatric Dermatology Research Alliance, where as president, he helps advance genetic discovery and translational research for rare pediatric skin diseases. As Yale's Associate Dean for Physician Scientist Development, he is also dedicated to mentoring the next generation of clinician scientists driving innovation in dermatologic therapeutics. I first met Keith in 2019 at his offices in New Haven following an introduction from Dr. John Doux, a dermatologist and member of Palvella's medical and scientific advisory board, who, like Keith, is a leading voice in rare dermatology. Since my initial meeting with Keith, it's been our privilege at Palvella to collaborate with him on how to better serve patients suffering from serious rare skin diseases. Today, Dr.
Choate will provide us with his expert perspective on Disseminated Superficial Actinic Porokeratosis, including the urgent need for an FDA-approved topical mevalonate pathway inhibitor. With our vision of building the leading rare disease biopharmaceutical company addressing serious rare skin diseases comes a steady and exciting cadence of high-impact milestones. Moving left to right, number one, we are charging towards the clinic with our QTORIN rapamycin for clinically significant angiokeratoma program, our third clinical indication for QTORIN rapamycin. Number two, today we achieve our second of four milestones with the announcement of our next QTORIN platform program, QTORIN pitavastatin for the treatment of Disseminated Superficial Actinic Porokeratosis. As noted on the slide, over the midterm, we anticipate extending QTORIN pitavastatin development to other debilitating forms of porokeratosis, an opportunity to positively impact more patients living with other subtypes of this disease.
Moving to our clinical programs, number three, I'm pleased to share that our phase two TOILA study of QTORIN rapamycin for the treatment of cutaneous venous malformations is on track for top-line readout in mid-December of this year. This program has been granted FDA's fast-track designation and could be eligible for FDA's breakthrough therapy designation pending a potentially positive phase two outcome. Number four, next quarter, we anticipate reporting top-line results from our ongoing SELVA phase three study of QTORIN rapamycin for the treatment of microcystic lymphatic malformations, a program which has previously been granted FDA's breakthrough therapy, fast-track, and orphan designations. Importantly, last month, we press released the receipt of the second year of funding from FDA's orphan drug product grant program.
We are grateful to FDA for their continued financial support of our single-arm baseline controlled phase three study, which we continue to believe could serve as the basis for filing an NDA next year. Overall, we look forward to reporting top-line results from both programs and reaffirm our objective of establishing QTORIN rapamycin as the first approved therapy and standard of care for both microcystic lymphatic malformations and cutaneous venous malformations. Over the next few slides, Dr. Choate and the Palvella leadership team will share why porokeratosis represents an exceptional opportunity for Palvella and how QTORIN pitavastatin is uniquely positioned to potentially be first-line therapy and standard of care for patients living with this chronic, progressive, and precancerous genetic skin disease. I will now hand the call over to Dr. Choate. Dr. Choate?
Thank you, Wes. I'm Dr. Keith Choate, chair of dermatology at Yale School of Medicine. I first became interested in porokeratosis more than a decade ago when I began seeing patients and families affected by this chronic, debilitating, and precancerous skin disease. The lesions are persistent, expanding, and disfiguring, and they never spontaneously regress, causing a major impact on patients' quality of life. There are several different subtypes of porokeratosis, each caused by mutations in the same mevalonate pathway, but differing in where and how they appear on the body. All forms of porokeratosis share a common pathogenic mechanism driven by mevalonate pathway mutations, leading to clonal keratinocyte dysfunction. Though they differ mainly in the extent, distribution, and environmental triggers, we are focusing today on Disseminated Superficial Actinic Porokeratosis, or DSAP, the most common and UV-associated subtype, which shares three fundamental disease features.
DSAP presents as numerous expanding lesions on sun-exposed areas that cause burning, itching, and discomfort. It is a severe and symptomatic disease that affects patients throughout their lives. In addition to symptoms, patients with DSAP carry a risk of malignant transformation, most often to cutaneous squamous cell carcinoma. This reinforces that porokeratosis is a chronic, serious, and precancerous disease with significant unmet need. There are no FDA-approved therapies for any form of porokeratosis, including DSAP. Existing treatment approaches, such as cryotherapy, laser ablation, photodynamic therapy, and topical or systemic agents used off-label, are invasive, temporary, and largely inadequate, failing to address the underlying genetic cause of the disease. This population represents a truly underserved group of patients with no FDA-approved therapy today. Porokeratosis has a fascinating scientific story that's unfolded over more than a century.
It all began with Vittorio Mibelli, who first described this debilitating disorder of keratization that, at the time, had no known cause or treatment. Fast forward to 2011, where Amy Paller published a landmark paper in the Journal of Investigative Dermatology, providing the first proof that a statin-cholesterol combination therapy could work in a disorder of cholesterol biosynthesis when she treated patients with Child Syndrome using cholesterol lovastatin to really profound benefit. Building on that foundation, our group, including Wehe Atzmony, uncovered the second-hit mutation that explains why DSAP lesions appear later in life and predominantly in sun-exposed areas. That insight led directly to the first clinical trial in DSAP, demonstrating the first pathogenesis-targeted and effective therapeutic approach to treating DSAP.
Now, through close collaboration with Palvella's team, who have led extensive product development efforts and initiated drafting of the clinical trial protocol, we're all unified behind one goal: to bring forward the first FDA-approved therapy for patients with DSAP, individuals who have suffered too long without an effective treatment. DSAP is driven by a single well-defined cause: loss of function mutations in the mevalonate pathway, leading to loss of skin barrier integrity. On the left, you can see how the primary germline mutation plus a secondary post-zygotic mutation in the skin in one of five enzymes, including MVK, PMVK, MVD, FDPS, and FDFT1, interrupt the pathway, causing the buildup of toxic upstream metabolites resulting in hyperkeratosis and loss of skin integrity. This biochemical imbalance drives the abnormal keratinocyte behavior that defines DSAP and gives rise to the clinical lesions that we see in our patients.
On the right, shown is the characteristic histologic feature of DSAP: a narrow vertical column of parakeratotic corneocytes called cornoid lamella, caused by a mutant keratinocyte clone that extends upward from the basal layer of the epidermis. The reason this is important is that in order to achieve maximum therapeutic benefit, penetration deep into the skin is required to be able to inhibit the root cause of the disease. By directly addressing the underlying mevalonate pathway defect, our approach aims to normalize cellular signaling and restore healthy skin architecture, attacking DSAP at its root cause. Although oral statins inhibit the same mevalonate pathway, they are not a viable therapeutic option for DSAP. Because they are extensively metabolized first pass in the liver, there's limited biodistribution to the skin and subtherapeutic concentrations there at the site of disease.
The first clinical study in DSAP, conducted by our group and published by Wehe Atzmony in 2020, was a pivotal step forward, demonstrating that targeted topical inhibition of the mevalonate pathway could meaningfully impact disease biology. Since then, more than 20 independent studies have built upon this foundation, further validating the scientific rationale and clinical potential for a topical pathogenesis-directed approach. Despite this growing body of evidence, patient outcomes remain poor. Unapproved and highly variable formulations continue to limit both access and reliability of treatment. There remains a clear and urgent need for an FDA-approved standardized topical therapy that can consistently deliver drug to the site of disease and finally address this longstanding unmet need for patients living with DSAP. I would like to turn it over to Dr. David Osborne, Palvella's Chief Innovation Officer.
Thanks, Keith. I'm David Osborne, Chief Innovation Officer at Palvella. I officially joined the company about two months ago, but I actually began working on this program nearly a year ago. From the outset, I was deeply inspired by Palvella's mission to help patients with serious rare dermatological diseases, and I was scientifically inspired by the versatility and promise of the QTORIN platform. Before I get into the specifics of QTORIN pitavastatin , I want to spend a few moments on QTORIN itself. Because while our mission is to serve patients with rare disease that have no FDA-approved therapies, QTORIN is the technological foundation that enables us to do that efficiently and effectively. I like to think of topical drug formulation as a mountain, where even small changes in the product can result in rapid descents in performance.
At the very top of the mountain is a narrow summit, which is where QTORIN sets a precise balance point where a formulation can deliver therapeutic levels of drug deep into diseased skin while maintaining tolerability and low systemic exposure. QTORIN is built on four pillars shown on the slide here that make it both differentiated and durable: high drug loading, demonstrated safety and tolerability, deep dermal engagement, and strong intellectual property protection. With that foundation in mind, when we set out to develop a targeted therapy to treat porokeratosis, we began with a clear target product profile with five key objectives. The first objective is chemical and formulation stability. We must ensure the molecule and vehicle remain stable over time and under real-world conditions. The second objective is targeted dermal penetration. We must achieve sufficient drug levels where the disease manifests with low systemic exposure.
The third objective is selecting a potent molecule, one with a strong scientific rationale and pharmacologic activity against the core drivers of porokeratosis. The fourth objective is optimizing release from the vehicle. We must engineer the formulation so the drug diffuses predictably and maintains therapeutic levels over time. Finally, we must keep the patient in mind. Designing a formulation that's easy to apply, non-irritating, and supports adherence for a chronic skin condition is essential. Our overall developmental strategy was to identify the best molecule for treating porokeratosis that could synergize with the QTORIN platform. When I first looked at porokeratosis, it was clear that oral statins are not effective for this disease due to the extensive first-pass metabolism and limited biodistribution to the skin. That Dr. Choate just described. Based on the excellent work by Dr. Choate and Dr.
Paller, as well as others in the field, our goal was to use the QTORIN platform to develop a topical mechanistically directed therapy capable of locally inhibiting the mevalonate pathway. As part of our development strategy, we conducted a comprehensive screen across a wide range of mevalonate pathway inhibitors, including multiple statins and related compounds, to identify the optimal candidate for porokeratosis. Each molecule was rigorously evaluated across three dimensions: potency, skin pharmacokinetics, and formulation stability within the QTORIN platform. Atorvastatin emerged as a clear leader. It consistently demonstrated the strongest balance across all three: high potency, robust dermal penetration, and retention in the skin when formulated in QTORIN, and excellent chemical and formulation stability. The pitavastatin is a next-generation oral statin originally developed for high cholesterol. It's recognized for its high potency, favorable safety profile, and low systemic drug-drug interaction potential.
Characteristics that made it an ideal candidate for localized delivery through QTORIN. With QTORIN pitavastatin , we've achieved our formulation target product profile goals: a greater than 2% concentration, dermal drug levels well above the IC50, low systemic absorption, encouraging preliminary stability, and intellectual property protection, both through our formulation patent filings and a license from Yale University. We're now in the final stages of formulation optimization for QTORIN pitavastatin and plan to begin IND enabling studies early next year. I would like to hand the call over to Jeff to discuss the clinical development plan.
Thank you, David. I'm Jeff Martini, our Chief Scientific Officer here at Palvella. As Dr. Choate described, Disseminated Superficial Actinic Porokeratosis, or DSAP, is a well-characterized disease driven by mutations in the mevalonate pathway. It is primarily caused by an autosomal dominant mutation but can also result from a de novo germline mutation. At Palvella, DSAP fits squarely within our discipline disease selection framework. It is serious, rare, has clear and validated biology, is commercially attractive, and most importantly, has no FDA-approved therapies. Clinically, DSAP presents as multiple persistent ring-shaped lesions that appear primarily on sun-exposed areas, such as the arms and legs. The disease carries a risk of malignant transformation to squamous cell carcinoma, has a significant impact on quality of life, and is progressive. Lesions increase in both number and size over time with no spontaneous progression.
Based on our initial work, we estimate there are more than 50,000 patients in the United States living with DSAP, individuals with a lifelong, visible, and burdensome disease for which there are currently no FDA-approved treatments. As you've heard, we are developing QTORIN pitavastatin due to Bhutab with statin stability and pharmacodynamic performance. With that foundation, we're executing an efficient and capital-disciplined development plan to potentially bring this therapy to patients as quickly as possible. Our goal is to advance from concept to the clinic for under $10 million and reach phase two proof of concept data within about two and a half years. We believe this can be enabled by our established QTORIN platform and our experienced clinical development team. We're working with the same FDA dermatology division that guides QTORIN rapamycin for consistency and efficiency.
In parallel, our endpoint development work is ongoing in collaboration with leading clinicians like Dr. Choate and other academic experts, as well as porokeratosis patients, to capture meaningful and clinically relevant outcomes for the trials. We've also filed intellectual property covering both the QTORIN pitavastatin composition and its use in porokeratosis and licensed the foundational method of use IP from Yale University, further strengthening our position. Our plan is to meet with the FDA in the first half of 2026, complete IND enabling studies, and initiate a phase two clinical trial in DSAP patients in the second half of 2026. We believe this represents a rapid, capital-efficient, and highly executable path towards delivering the first FDA-approved disease-modifying therapy for porokeratosis while continuing to expand the potential of the QTORIN platform across rare dermatologic diseases.
Our initial clinical focus is on the more than 50,000 individuals in the U.S. with DSAP who currently have no approved therapy and are living with this chronic and progressive disease. Once we establish proof of concept in DSAP with QTORIN pitavastatin , we plan to expand into other forms of porokeratosis, including porokeratosis Mibelli and linear porokeratosis. These conditions share the same underlying mevalonate pathway dysfunction, potentially giving us a clear and efficient path to broaden the clinical impact of QTORIN pitavastatin . Beyond porokeratosis, we're also evaluating additional genodermatoses driven by mutations in the mevalonate pathway. These disorders share a common biological foundation, one that we believe QTORIN is uniquely positioned to address. After completing additional preclinical and translational research, we plan to add these indications to our development plan.
In short, we're starting with DSAP, but we see the potential of QTORIN pitavastatin to help transform treatment across a spectrum of serious rare dermatologic diseases. I'll now hand the call over to Matt to discuss the commercial opportunity.
Thanks, Jeff. We believe that DSAP represents not just a significant clinical need, but also a very compelling market opportunity, as confirmed by Ashley Kline, our Chief Commercial Officer. Ashley's intensely focused on launch preparation for microcystic lymphatic malformations but contributed significantly to the insights I will review here. QTORIN pitavastatin would be the first targeted therapy for the disease, addressing a population of more than 50,000 diagnosed patients in the U.S. alone. Similar to the initial epidemiology studies we conducted for our three QTORIN rapamycin indications, we conducted a real-world evidence study with Clarity Pharma Research. This initial epidemiology study included 277 physicians surveyed earlier this year. The results of the survey estimate that there are more than 50,000 patients with DSAP in the U.S. and confirmed our findings from reviewing existing literature.
From a pricing perspective, we anticipate orphan pricing due to the patient population size, severity of disease, and lack of any FDA-approved therapies. Similar to our three QTORIN rapamycin indications, to further understand the unmet need and potential market adoption, we conducted separate market research with physicians to give us detailed insights into the real-world practice patterns and treatment attitudes. In a survey of 55 physicians across the United States, an overwhelming 100% would incorporate a topical mevalonate pathway inhibitor into their practice, and 96% of physicians surveyed would also consider our drug as first-line therapy for DSAP patients, especially given the lack of FDA-approved options. In summary, DSAP represents a large, underserved market with strong clinician demand, a clear path for rapid adoption.
This positions a product with a target profile of QTORIN pitavastatin to transform the treatment landscape for this serious, rare, and debilitating disease. I'll now turn the call back to Wes to summarize the key takeaways from today's call. Wes?
Thanks, Matt. Overall, we have achieved key scientific, medical, commercial, product development, and regulatory milestones represented on the slide here. We are truly thrilled to be advancing QTORIN pitavastatin's development with support from key opinion leaders such as Dr. Keith Choate, Dr. Amy Paller, Dr. Dirk Elston, Dr. Jim Treat, Dr. John Du, and others who are the pioneers and thought leaders in this disease. The stage is now set for a phase two study commencing in the second half of next year. In summary, QTORIN pitavastatin for Disseminated Superficial Actinic Porokeratosis represents a compelling rare disease program for Palvella, sharing key characteristics with our first QTORIN program, QTORIN rapamycin, addressing a 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 FDA approval, Palvella stands to potentially be the first approved therapy while entering a commercially attractive multi-billion dollar total addressable market with more than 50,000 diagnosed patients in the U.S. with this disease. In closing, today marks a meaningful milestone for Palvella and, more importantly, for patients and families living with Disseminated Superficial Actinic Porokeratosis who, until today, have been underserved by the biotech industry. What changes today is the tangible potential for a pathogenesis-directed therapy that could significantly transform their lives. Palvella remains fully committed to dedicating our talent, our passion, and our resources to potentially deliver the first approved therapy for these patients and for physicians like Dr. Choate who care for them every day. Thank you for joining us on today's call. Operator, you may conclude this call.
Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.