Palvella Therapeutics, Inc.

Good day, and thank you for standing by. Welcome to Palvela's first quarter 2025 financial results and corporate update conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you'll need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised, today's conference is being recorded. I would now like to turn the conference over to your speaker today. Bo Hanwei, please go ahead.

Thank you, operator. Good morning and thank you for joining the Palvela Therapeutics Q1 2025 financial results and corporate update call. As a reminder, our press release summarizing today's updates is available under the investor section of our website at www.palvelatx.com. On today's call, we are joined by Wes Coffinan, our chief executive officer, Jeff Martini, our chief scientific officer, and Matt Korenberg, our chief financial officer. Before we begin, please note that today's remarks may include forward-looking statements regarding our development programs, regulatory plans, commercial outlook, and financial performance. These statements are based on current assumptions and subject to risks and uncertainties that may cause actual results to differ. Please refer to our filings with the SEC for more information. And now I'll turn the call over to Wes.

Thank you, Bohan. Good morning, everyone. Thank you all for joining us today. This past Monday morning, the Paul Vela team, including our scientific and clinical collaborators, investors, senior advisors, board members, and family members converged on New York City for the ringing of NASDAQ's opening bell. Paul Vela becoming a publicly traded company approximately five months ago is an important milestone for the company. And it is a testament to Paul Vela's vision of building the leading rare disease biotech company focused on serious genetic skin diseases with no FDA-approved therapies. It is also a testament to our mission, which is to relentlessly serve those rare disease patient populations who have historically been neglected, and to our strategy, which is to focus our therapeutic development efforts and eventually our commercial efforts exclusively on those diseases with no FDA approved therapies. We want to be first for patients. Becoming public is furthermore a testament to the Pulvella management team who have turned mere concepts into breakthrough designated medicines while turning the challenges of drug development and rare complex diseases into triumphs. The collective sentiment at NASDAQ that day was that our substantial progress to date including both developing a late-stage pipeline with cuturin rapamycin and a compelling platform with cuturin, is truly only the beginning for Pulvella. Our hope is to return to NASDAQ one day in the near future to celebrate the first regulatory approval of cuturin 3.9% rapamycin anhydrous gel, a milestone we believe we're even closer to achieving based on today's exciting update that we have exceeded our enrollment target of 40 patients in the landmark SELVA phase three study of ketoran rapamycin to the treatment of microcystic lymphatic malformations. Four quarters, four anticipated high impact milestones. Moving left to right, microcystic lymphatic malformations are a serious, rare, chronically debilitating and lifelong monogenic disease. The genetics, disease biology, target skin tissue, and natural history of microcystic lymphatic malformations have all been well characterized. Genetically, they're caused by PI3K mutations. Biologically, the PI3K mutation results in the hyperactivation of the mTOR pathway, which ultimately produces malformed vessels that protrude through the skin, as you can see from the picture here on the slide. The target skin tissue is the dermis, which is the site of disease origin cystic lymphatic malformations. From a natural history perspective, the disease is present at birth, has no spontaneous regression, and is proliferative and progressive. The major clinical burden to these patients is referred to as lymphorrhea, which is the leaking or discharge of internal lymphatic fluid onto the skin or into the soft tissues. The result of this is that these patients are at persistent risk of serious infections, including acute cellulitis, which can cause repeated hospitalizations. There are, unfortunately, no FDA-approved therapies for these patients. We'll provide an update today on our Phase III cell, the study of ketorin rapamycin, which has received FDA's breakthrough therapy, fast-track, and orphan drug designations, We anticipate top-line results from the study in Q1, 2026. Moving to cutaneous venous malformations, the disease pathology of cutaneous venous malformations is similarly driven by the mTOR pathway, caused by mutations in either PI3K or Ti2, which leads to over-activated mTOR signaling. Cutaneous venous malformations are a serious disease, and they're characterized by dysregulated growth of malformed veins in the skin, which can cause functional impairment and bleed. Because of the genetic driver of the disease, cutaneous venous malformations continue to grow over time and do not spontaneously regress. There are unfortunately no FDA-approved therapies for patients afflicted with cutaneous venous malformations. We'll update today on our phase two TOIVA study of ketoran rapamycin, which has received FDA's fast-track designation and we anticipate the study will report top-line results in Q4 of 2025. Importantly, if approved, we believe, based on market research, that cuturin rapamycin has the potential to be first-line therapy and standard of care for patients with both microcystic lymphatic malformations and cutaneous venous malformations. Our pipeline beyond our two lead programs and microcystic LMs and cutaneous venous malformations continues to make tangible progress under the strong leadership of our chief scientific officer, Dr. Jeff Martini. In the third panel on this slide, we truly believe ketorin rapamycin can represent a pipeline and a product with clinical and commercial potential that extends well beyond microcystic lymphatic malformations and cutaneous venous malformations. We anticipate unveiling our third target clinical indication for Cuturin Rapamycin in the second half of this year. Moving to the fourth panel, we also anticipate unveiling our next Cuturin program in the second half of this year, which would be our second product candidate from the Cuturin platform after Cuturin Rapamycin. We see both our next Cuturin Rapamycin indication and our next tutoring platform program as key near-term value drivers for Paul Vela. Dr. Martini will provide updates on our progress on both programs on this call. Our strong momentum at Paul Vela is highlighted first by what's presented at the top of the slides. We have now exceeded our enrollment goal of 40 patients in our landmark phase three study evaluating cuturin rapamycin for the treatment of microcystic LMs. On our phase two TOIVA study of cuturin rapamycin for the treatment of cutaneous VMs, we now have six sites open and enrolling, and top-line readout is anticipated in Q4 2025. We recently participated in the Society of Investigative Dermatology and the International Society for the Study of Vascular Anomalies meetings where we gather new insights and deepen our relationships with scientific and clinical leaders in the field. From an organizational standpoint, we've added Jason Burdette to our executive team as SVP of CMC and Technical Operations. Jason brings 30 years of experience in global pharmaceutical development, technical operations, and supply chain to Palvella. and we're thrilled to have him on our senior team as we approach planned NDA submission next year and, if approved, standalone U.S. commercialization in 2027. We also continue to make progress on our search for an exceptional chief commercial officer with that higher plan for the second half of this year. For this position, we're seeking a proven leader with experience launching novel therapies that were first to market in serious rare diseases. In addition to the proven experience commercializing in rare diseases consistent with Palvela's historical and current model of operating with capital efficiency, we are seeking to recruit a leader who can lead a launch in a thoughtful and capital efficient manner. We look forward to keeping everyone updated on our progress. And we've also expanded our intellectual property portfolio with the issuance of our fifth US patent with anticipated claims from that patent into 2038. Moving to our lead program, Cuturin Rapamycin for the treatment of microcystic lymphatic malformations. I'm pleased to share, thanks to the dedicated efforts of our phase three investigators and the research coordinators at clinical trial sites, our patient advocacy collaborators, the highly committed Pauldella Clinical Operations Team, and most of all, the patients living with microcystic lymphatic malformations that we have exceeded enrollment of 40 patients in our pivotal phase three trial, evaluating cuturin rapamycin in patients with microcystic LMs. The study has generated strong interest with all 13 sites, including institutions such as Stanford University, the Cleveland Clinic, Children's Hospital of Philadelphia, the Mayo Clinic, to name a few, all enrolling patients into the study. In terms of concluding enrollment, We're anticipating closing study enrollment in June after all pending enrolled patients have completed screening. As a result of the diligent efforts and commitment from investigators and sites beyond these pending enrolled patients, there is additional potential for more patients to enter the study. We believe that it is in Palvela's best interest to honor the site's work and their relationships with patients and accommodate additional patients into the study in a timely manner. At the same time, now that we've exceeded our enrollment target of 40 patients, our goal is to bring the Phase III trial to an orderly close while communicating closely and clearly with our study investigators and sites on defined study closure timelines. As you can see from the graphic at the bottom of the slide, if patients meet study eligibility criteria, they are then enrolled into the study. Patients first move through an eight-week baseline period before moving to the efficacy evaluation period of 24 weeks, followed by the treatment extension period of 24 weeks. We look forward to providing more detail on final patient enrollment numbers at the time of achieving full enrollment in the near future. Overall, we are pleased. that we've been able to accomplish our phase three study enrollment goals while remaining on track to report top line data in the first quarter of 2026. In addition, as you'll hear from our CFO, Matt Kornberg, later in this call, we are also staying on track for our 2025 cash expense and long-term cash runway forecast. Moving to our regulatory overview, we've all been carefully monitoring the recent and ongoing changes at FDA, and the Paul Vela management team will continue to remain vigilant in doing so along with our regulatory advisors. For Paul Vela's cuturin rapamycin, we wanted to provide additional clarity that our program is regulated by the Division of Dermatology and Dentistry which is within the Center for Drug Evaluation Research, or CDER, which you can see listed at the top of this slide. Importantly, the Division of Dermatology and Dentistry continues to be led by Dr. Jill Lindstrom, a dermatologist and the division director who began as director of the division in late 2023 and continues in that role today. Due to our Plan 505 pathway for our NDA submission, we anticipate division-level leadership, in this case, Dr. Lindstrom, would be responsible for the NDA review and approval decision. So while there have been many changes across the FDA that we've all read about and that we continue to track, there has, by contrast, been consistency for Paul Vela in terms of, number one, the division regulating Paul Vela's program, dermatology and dentistry, and number two, the leadership of that division, in this case, Dr. Lindstrom. As a reminder, assuming positive phase three data, we anticipate that our program could potentially be expedited as a result of some of the designations we've achieved over the years. In Q4 of 2023, we were awarded FDA's breakthrough therapy designation based on the results from our phase two baseline controlled single arm study of 12 patients. Breakthrough therapy designation was added to our previously granted fast-track and orphan drug designations. Additionally, out of 51 applications received by FDA's Orphan Products Grants Program in fiscal year 2024, Paul Vela's Phase III Selva trial was one of just seven clinical programs and the only Phase III study to be named an awardee of a non-dilutive FDA grant. In our case, we anticipate up to 2.6 million from the FDA over multiple years in non-dilutive funding to support the phase three study. Moving to the bottom of the slide, in terms of the regulatory environment for our other planned pipeline programs, the Paul Vela team is closely monitoring emerging regulatory frameworks, including a newly proposed plausible mechanism accelerated approval pathway for certain rare diseases that has been publicly highlighted at a conceptual level by Commissioner Dr. Marty Makary. We were encouraged by the comments about the need to expedite therapies to patients living with rare, ultra-rare, and oftentimes serious diseases, and we will continue to follow updates from FDA on these new pathways and their potential relevance to our earlier stage programs. I'd like to now turn to the commercial opportunity we see ahead for ketoran rapamycin. As a reminder, at a high level, Palvella firmly believes that the opportunity to develop and commercialize in serious rare diseases where Palvella can introduce the first FDA approved therapy can represent very attractive commercial opportunities, especially considering the lower competitive intensity dynamics in these markets compared to more conventional and competitive rare disease markets, which are already well served as a function of having existing approved therapies in most cases. As this slide shows, for microcystic lymphatic malformations, a recent epidemiology study conducted by a multidisciplinary team that leveraged an extensive medical claims database resulted in the following estimates. In terms of estimated diagnosed U.S. prevalence of microcystic LMs, the study indicated that there could be greater than 44,000 diagnosed U.S. patients, figures that are largely in line with Paul Della's previous estimates. In terms of estimated annual incidence of microcystic LMs, the study indicated that there could be 1,500 or more new microcystic LM cases per year. When taking these prevalence and incidence estimates and overlaying them with anticipated orphan pricing levels, the data supports that microcystic lymphatic malformations could be a multi-billion dollar total addressable market in the United States. Importantly, the poster also indicated that about one-third of diagnosed patients are currently managed at vascular anomaly centers, which are already established centers of excellence for diagnosing and treating microcystic lymphatic malformations and other vascular malformations. We look forward to providing more information related to the commercial opportunity and Palvela's commercial planning as we onboard a chief commercial officer in the coming months. With that, I'll turn it over to our chief scientific officer, Dr. Jeff Martini.

Thank you, Wes. In April, I had the opportunity to represent Pulbella at the International Society for the Study of Vascular Anomalies, or ISVA, conference in Paris. The leading global scientific and medical forum focused on vascular malformations, including microcystic lymphatic malformations and cutaneous venous malformations. While there, I met with many of the field's foremost clinicians to discuss our two lead indications, MLMs and CVMs, as well as other serious rare skin diseases that may be strong candidates for ketorin rapamycin and future ketorin-based therapies. Several themes emerged that reinforced the direction we're headed. First, the field is clearly moving towards targeted therapeutic approaches based on the underlying genetic drivers of each vascular anomaly. Second, there's a real need for therapies that can improve efficacy while reducing the systemic side effects associated with current treatments. many of which were originally developed for internal infiltrative diseases rather than localized cutaneous lesions. And third, there's a significant opportunity to expand treatment options across a broader spectrum of cutaneous vascular malformations, both within and outside the mTOR pathway, which we are actively pursuing as part of our pipeline expansion activities. These insights continue to support the potential of the cuturin platform and help guide how we prioritize future indications within our development strategy. Moving on to our clinical trial of cutaneous venous malformations. Our TOIVA study in CVMs is actively enrolling. This single-arm baseline control trial includes patients aged six and over and evaluates both clinician and patient reported outcomes. The purpose of the study is to, one, evaluate safety and tolerability, and two, determine which endpoints are most sensitive to change with Ketoran Rapamycin. We currently have six sites open, five of which came online in the past two months. Top line data from TOIBA are expected in the fourth quarter of this year. As we continue to build momentum behind our lead programs, we're very focused on expanding our Ketoran platform through two distinct development tracks. First, we are advancing additional indications for ketorin rapamycin itself. Based on what we've seen in the clinic and through ongoing dialogue with experts in the field, we view ketorin rapamycin as a pipeline in a product. We've identified several diseases that fit the stringent Povella criteria of serious, rare skin diseases that lack FDA-approved therapies and where mTOR dysregulation is a key driver of the disease pathology. These opportunities fit directly within Pavel's development strategy and offer the potential to further extend the impact of our lead asset. Second, we're progressing a novel Ketoran-based program that delivers a different therapeutic agent, or API. This effort is being guided by our close collaboration with many of the world's leading rare skin disease experts, clinicians who frequently see the limitations of current therapies, and who help us identify promising targets both on based on both biology and real-world treatment experience, including off-label use of systemic drugs. Internally, each candidate is rigorously evaluated through our disease selection process, which links biological rationale with commercial viability and alignment with Paul Vela's mission. Both programs, our next cuturin rapamycin indication and our novel cuturin asset, have identified lead diseases, and the latter has progressed to defined target molecules. Importantly, both are tracking towards potential fast-track and breakthrough therapy designation eligibility and remain on schedule to be announced in the second half of this year. With that, I'll turn it over to Matt to provide a financial update.

Thanks, Jeff. Before I turn to my financial comments, I first wanted to touch on one last point on Jeff's slide. In addition to all the key criteria that Jeff mentioned for choosing new products to develop, We also focus on diseases and programs that align with our capital-efficient approach. For our next QTORN molecule, we're targeting generating Phase II proof-of-concept data within two and a half years and for less than $10 million of clinical spend. We believe this approach allows Pelvela to deliver maximum benefit for both patients and value for investors. Turning now to the financials. Palvella remains in a strong financial position, allowing us to continue confidently on our path towards successfully developing and commercializing drugs to treat rare diseases. Cash and cash equivalents as of March 31st, 2025 were $75.6 million. We're fortunate to have two years of cash runway remaining following the oversubscribed pipe financing we completed in connection with our reverse merger at the end of 2024. led by BVF partners and Fraser Life Sciences, and with participation from our major existing investors, plus a roster of new investors, the financing, combined with existing cash, provided Palvella with a clear cash runway into the second half of 2027. Our current funding covers our major upcoming milestones, including the completion of our Phase III microcystic LM trial, completion of our Phase II cutaneous venous malformations trial, submission of the microcystic LM NDA filing, pre-commercialization efforts as well as the addition of two new programs to the pipeline. Our cash spend and financial results for Q1 2025 were in line with our expectations and I'll briefly review the results reported in this morning's press release. Research and development expenses were $4.1 million for Q1 2025 as compared to just under $1 million for the comparable period in 2024 with the increase driven primarily by the expenses associated with our microcystic LM and cutaneous VM clinical trials. General and administrative expenses were $3.8 million for Q1 2025 as compared to $800,000 for the comparable period in 2024. The increase here was driven by public company costs and the costs associated with our increased headcount. Our net loss was $8.2 million or $0.74 per diluted share for Q1 2025 compared to a net loss of $2.7 million or $1.54 per diluted share for the comparable period in 2024. We remain on track to end the year with at least $55 million in cash and cash equivalents based on our current strategic operating plan. Our cash spend for 2025 remains on track for approximately $30 million in total cash spend. With that, I'll turn the call back over to Wes for some closing remarks before we open up the call for questions.

Great. Thank you, Matt. Looking ahead, Palvela has a clear set of four high-impact milestones. We expect top-line data from our Phase III Selva study in Q1, 2026. We expect top-line data from our Phase II Toiva study in Q4, 2025. And we have planned to announce two new QTORN programs in the second half of this year. an additional cuturin rapamycin indication, and a novel product from our cuturin platform. NDA preparation is underway, and we're actively building towards commercialization, if approved, including the planned addition of a chief commercial officer later this year. In closing, Palvella is positioned for a transformative year ahead, and we want to thank everyone for attending today's call. We'll now open the line for questions.

Thank you. Ladies and gentlemen, if you have a question or a comment at this time, please press star 1-1 on your telephone. If your question has been answered and you wish to move yourself from the queue, please press star 1-1 again. We'll pause for a moment while we compile our Q&A roster. Our first question comes from Ritu Barra with TD Cowan. Your line is open.

Good morning, guys. Thanks for taking the question. Wes, I wanted to ask you about target enrollment for Phase III MLM. Is there a soft target enrollment you have in mind beyond the 40? I know you mentioned keeping the relationships with the KOLs and patients, which is very important, but I'm wondering if there may be some additional powering targets or important subpopulations worth exploring with a bigger N? And then I have a manufacturing-related follow-up.

Great. Hey, Ritu. Thanks for being on today's call. To answer your first question, the target enrollment has always been 40 patients enrolled into the study. So we were really pleased with the demand that we saw from all of our clinical study sites. All 13 have enrolled patients. I'll ask Jeff to briefly comment as it relates to your question around powering and subpopulations.

Yeah. So, Ritu, thanks for the question. This is Jeff. So, we designed the study based on the efficacy results that we observed in Phase II. In that study, all 12 patients were in the top two categories of that seven-point change scale, much improved or very much improved. And based on the results, with 40 patients or more, we're greater than 99 percent powered into the phase three study, and those assumptions remain on track.

Got it. And you know what? I changed my mind. My follow-up question is going to be on something different. How does your poster impact the way that the company is looking at the TAM for MLM? Like if the incidence of MLM is higher than expected, you know, is this – I mean, I know you don't have a chief commercial officer yet, but Wes, given your background, how is this changing your plan in your head on how to target these patients and those, I believe, 142 or 150-ish vascular anomaly centers? Thanks.

Great. Well, thanks, Ritu. As you well know, Ritu and others on this call, in these rare diseases where there's no approved therapies, there's really an obligation by the innovator in the space, in this case, Paul Vela, to do prospective methodical work to try to really understand what the prevalence and incidence are of these patient populations. From our perspective, Ritu, just a little bit of history, we had done a real-world occurrence study that's published in Orphanet Journal of Rare Diseases that estimated that there could be upwards of 80,000 microcystic or mixed patients. We followed that with a claims analysis last year which suggested that there's around 40,000 diagnosed patients in the U.S. So to answer your question on the prevalence side, we think the numbers from the poster are largely in line with what we've been guiding on U.S. diagnosed prevalence. We've been guiding greater than 30,000 diagnosed U.S. patients. What is new, and I'm glad you asked the question, is there hadn't been any rigorous work done around estimated annual incidence of microcystic lymphatic malformations. So Matt and the team are working with our commercial consultants to really closely evaluate our market model to reflect that there could be 1,500 or more new patients coming into that eventual total addressable pool of patients that can be addressed with ketorin rapamycin. On the targeting question, we've certainly wanted to understand, given that there are established centers of excellence, these vascular anomaly centers, we think that that's favorable as we think about commercial dynamics is that these centers of excellence in place. So we wanted to understand from this analysis approximately how many patients with diagnosed microcystic LMs are currently within those about 150 centers. We estimate, as you see from the poster, that about a third of those, so greater than 10,000, somewhere perhaps between 10,000 and 15,000, are in these vascular anomaly centers. We do think, and we've got a lot more work to do from a commercial planning perspective, but we do think that that concentration of patients should provide efficiencies for how we think about building out commercial and medical infrastructure in the United States.

Thank you.

One moment for our next question. Our next question comes from Annabel Sammy with Stiefle. Your line is open.

Hi, all. Thanks for taking my question. Actually, just following on Ritu's questions about the commercial side and the infrastructure you might need, so clearly you've identified that one-third of the patients are sitting in these centers. But that follows that two-thirds are not sitting at those centers. And so does that require a larger infrastructure than you may have anticipated? Are you going to stick with just targeting the 142 centers and doing separate outreach to bring people into those? And then if I can follow on the payer side, I guess you've said in the past that pricing is really going to depend on the results of the trial. And it's rare that you see 100% efficacy, no less carrying that into phase three. But when you think about pricing, have you established thresholds of efficacy for various price ranges? Like say, for example, 70% reduction will get you X and 90% reduction will get you Y. Or is it still kind of nebulous in that range. What do we need to see to see really clear rare orphan pricing?

Thanks. Thanks for the question, Annabelle. To answer your first question, we think that it's a very attractive commercial dynamic to have greater than an estimated 10,000 patients. concentrated in about 150 centers. So right now, as we stand today, and this is all pending, bringing in a chief commercial officer who's going to refine our plan, we think that that's favorable. The second area, and we're doing more digging on this with some of our consultants, is that beyond those 150 vascular anomaly centers, there's a second wave of academic medical centers that do have a fairly significant patient load. So we think that we can also efficiently go after not just the 150 established vascular anomaly centers, but that second wave of academic medical centers that has a higher concentration of patients. So that's going to be the second wave. And then obviously, from a targeting perspective, those physicians and sites that maybe only have, call it one patient that's diagnosed those We will pursue those in a capital efficient and thoughtful manner, and there are some strategies that have been articulated by our commercial advisors in terms of how to go after that smaller percentage of the market. On the payer front, we can share that we've engaged very experienced pricing and reimbursement advisors with deep experience in the rare disease space, having worked closely with companies like Crystal Biotech. There's a lot of things we believe that go into pricing, but most importantly, let's just talk about the fundamentals of microcystic LMS. Number one, this is a serious, rare genetic disease where when these patients have incidents of lymphorrhea, they can be hospitalized. They can have acute cellulitis, sepsis. So we're talking about a very serious disease and one that we think payers should be motivated to see these patients do better. Number two, there are no FDA-approved therapies. I think precedents will show that companies that launch in diseases where there are no FDA-approved therapies are able to command orphan pricing when you have those two dynamics. At this point in time, we have not established thresholds of efficacy and what the resulting pricing range would be. Um, in my experience, typically, uh, what we would do is we would take the totality of the phase three data. Uh, and then we would work closely with our pricing advisors and, uh, do some third party sort of blinded pair work, uh, to help then establish what we think, uh, the price point would be for Qtor and RapidMice in the U S. So, uh, as we sit here today in may of 2025, we're, we're about two years away from commercialization. I think the most important factor on making sure that we have an exceptional commercial launch, if we're approved, is securing the right leader that's done this before, done it successfully, and can guide these really important decisions, Annabelle, that you're asking about on this call.

Great. Thank you so much.

One moment for our next question. Our next question comes from Louise Chen with Scotiabank. Your line is open.

Hi, thanks for taking my questions here and congratulations on all the progress this quarter. So I wanted to ask you how you think about the market size of the two assets that you will disclose later this year versus the MLM and CBM opportunity. And then do you plan to commercialize your pipeline on your own? I know there's only a few centers to target and the second wave of centers that you mentioned, but would you consider a global partner to help you in the U.S. and outside the U.S.? Thank you.

Yeah, great. So on your second question, Louise, and thanks for being on the call, on your second question, we are going to prioritize standalone U.S. launch for all of our products in the rare genetic skin disease space. I think we've all seen there's been a number of successful rare disease launches. We're going to do everything we can to learn from those launches what are the best practices and incorporate them into our launch. In terms of outside the United States, those are valuable markets, we believe, for guitar and rapamycin as well. We'll look, as any thorough company would do at both standalone launches in Europe and Japan, we'll also look at partnering. I think where we stand today, we want to stick with our core competencies, which is really focusing on resources on the U.S. So it's most likely that we'll prioritize partnering those markets. But again, I think if we're doing this in a thorough way, we'll look at both launching a loan and partnering, albeit with the bias, to leverage others' footprint in places like Europe and Japan to launch. In terms of how we think about our next indications for Keturin Rapamycin, as well as our next Keturin platform, maybe we'll just start with the criteria of serious, rare, and nothing approved. We really want to be first. That is part of the fiber of this company and the entire management team is being first for these patients. We also think that has the benefit of, by definition, being commercially attractive. Just to give a little bit of guidance, so we're answering your question, typically we prioritize those diseases that are rare, not ultra rare. So it's unlikely that you'll see us in these ultra-rare indications with less than 2,000 patients. We tend to gravitate towards those diseases that have 10,000 or more patients. We think that those are commercially attractive in nature and look forward to providing you and everyone else with more detail when Jeff makes his big reveal later this year.

Thank you.

One moment for our next question. Our next question comes from Angela Cling with Canaccord Juduity. Your line is open.

Congrats on the quarter. This is actually Juwon Kim on for Whitney. Thanks for taking our question. Maybe just a quick one from us on phase three. It was very encouraging to see that enrollment had completed so quickly. And so any additional color on how many of those patients are between the three to five-year-old range? And as a follow-up, Can you remind us how you intend to use that data, whether you'll be submitting a cut of that data concurrently with the initial filing, or do you expect that they will be submitted at a later date for potential label expansion? Thanks so much.

Juan, thanks for your comments about the efforts of our clinical operations team and sites and investigators. We're similarly encouraged to have exceeded our enrollment target. We look forward to providing much more information at the point of full enrollment and beyond in terms of the breakout of the patients who are greater than six, as well as this additional cohort of three to five-year-olds. To answer your question from a regulatory perspective, we are going to concurrently include data from three to five-year-olds in our NDA submission. We think that that's the best strategy, assuming that we're seeing a consistent safety and efficacy profile between those two cohorts, the three to five-year-olds, and then the six and above. And so the strategy there would be to concurrently submit that data, keep our NDA timelines on track, and obviously the goal here is to, one, be able to serve patients with this disease down to the age of three, but two, getting that broader label should enrich the commercial opportunity because we're able to dose patients from 3 to 5, and as we've seen from the poster at SID, there's about 1,500 new patients coming into the pool per year.

Great. Thanks so much.

One moment for our next question. Our next question comes from Ananda Ghosh with AC Wainwright. Your line is open.

Hey, hi, good morning. Maybe, you know, switching gears, I just wanted to get, you know, both MLMs and CVMs have been notoriously defined as, you know, as like the patient with, you know, a lot of heterogeneity in terms of, you know, the disease pathogenesis as well as in terms of, you know, the way they respond to the drugs. So how, you know, if you can shed light on the heterogeneity the recruitment the patient recruitment aspect in terms of you know, what what were the screening techniques you have used to maximize the You know the the utility of the phase three that will be very helpful as well as for the driver Yeah, thanks for the question in terms of patient screening for the phase three study we've enriched that study for patients that are that are determined to be moderate to severe and

At baseline, that's important. Having patients in the trial that are less severe, it can be hard to show a delta or separation, show a treatment effect. So that's one point of enrichment. We also have a number of techniques or controls in our protocol to make sure that we're getting the right patients into the study in these rare disease studies where you have sample size, like our Selva study of 40 or more patients. Every patient counts, so we go to great lengths in all of our rare disease studies to have strict criteria, as Jeff mentioned, as it relates to patient inclusion and exclusion. On the Phase II TOIVA study, I'll pass it over to Jeff to talk about how we're optimizing for the right patient population for that trial.

Thank you, Wes. So, as a reminder, the Phase II TOIVA study is our first study in this disease. We'll be looking at safety and efficacy and then looking at a number of different endpoints to see how the patients potentially respond to treatment. We're repeating a lot of what we did in MLM, which was successful, which was number one, training all the clinicians as they start the study. I'm involved in training all those clinicians. The patients that are of moderate or worse severity, so we've been rich for disease severity there, And then they go through as well an external third party check just to confirm eligibility and make sure these are the right patients for the trial.

Great. Thanks. One moment for our next question. Our next question comes from Dev Prasad with Lucid Capital Markets. Your line is open.

Hi. Thank you for taking my question. Could you talk about steps and timeline to NDA submission once top line data is released in the first quarter of next year? Additionally, do you need to do some additional work around 505 submission package? Thank you.

Hey, thanks, Deb, for those questions. So our goal after top line data in Q1 of 2026, that data will be presented on a top line basis to the FDA. and then we expect to submit the NDA in the second half of 2026. That puts us on an approval trajectory, assuming those timelines are met or exceeded, which is our goal of having the drug approved in Q2 of 2027. So top line dev, Q1 of next year, and then second half of next year to have that NDA submitted. We will, as we're modeling this out, looking at timelines, we will be eligible for priority review. That's as a function of both breakthrough designation and fast track designation, so we expect potentially a six-month priority review based on having those designations in hand. In terms of the 505 pathway, that's really a pathway that's designed to streamline the review process, we're able to reference existing data. In our case, the reference listed drug is oral rapamycin or oral sirolimus. So we have the right advisors assembled who are familiar with 505 submissions. I've done those before many times and done them successfully. And we expect to work closely with those advisors so that we have a detailed list of every item that needs to be submitted in the 505 pathway but overall we think that that having 505 augment breakthrough fast track and orphan is favorable for the program good thank you one moment for our next question next question comes from catherine novak with jones trading your line is open

Hi, morning. Thanks for taking my question. I just want to ask a little bit about the difference between the scales, phase two, phase three. Did physicians not have to reference photos in phase two? And as well, do you have confirmation from the FDA that this new scale satisfies the need for static measures of LMs as well as the improvement relative to baseline? Thanks.

Great, so to answer your first question, in phase two, physicians were able to access the photos that were baseline photos, but they were not required to in the protocol. Given that we extended, Catherine, treatment duration from 12 weeks to 24 weeks, we felt that the addition to the protocol of requiring the physicians at that primary endpoint visit, which is a live clinician assessment, at 24 weeks to reference back to that baseline photo, we think that that added an important layer of objectivity to that assessment. So that was a change that we supported and we think strengthened the data. It also helps to mitigate recall bias when a physician is trying to recall what a patient's status was or lesion severity was 24 weeks ago. Jeff, I'm going to pass it over to you to answer the second part of Catherine's question.

Thank you, Catherine. This is Jeff. We've had extensive conversations with the FDA on the primary endpoints. Starting with the breakthrough therapy designation, we presented the clinician interviews from the trial as well as clinician testimonies. This was the most sensitive endpoints. Subsequent to that meeting, we did apply for the FDA breakthrough therapy designation. And that was, or sorry, not spray, the FDA Orphan Drug Grant, which we were awarded. And overall, we are aligned on the endpoints with the FDA.

Got it. And then, you know, I think you had disclosed your power and assumptions that it could detect a .5 point change on the scale. Is that correct? Is that? Yeah, that is correct. Or to what extent would an improvement be considered meaningful to these patients?

Yeah, so Catherine, on that question, in rare diseases, typically you're not defining minimal clinically important differences on a pre-specified basis. I think what you're referencing on the 0.5 improvement is what we would need to see to achieve the lower threshold of statistical significance. So zero on our scale, which goes from negative three, very much worse, to plus three, very much improved. Zero is no change. With 40 patients in the study, if the mean change is 0.5, which would be significantly below what we saw in phase two, which was about a 2.42 average change, with a standard deviation that's higher than what we assumed in phase two, we'd still be at a threshold of achieving statistical significance according to our biostatistical assumptions.

Okay. Got it. Thanks. That's helpful.

And I'm not showing any further questions this time. And as such, this does conclude today's presentation. You may now disconnect and have a wonderful day.