Good morning, everyone, and welcome to the Pasithea Therapeutics virtual KOL event. At this time, all attendees are in a listen-only mode, and a question-and-answer session with our key opinion leaders will follow after each formal presentation. As a reminder, this call is being recorded, and a replay will be made available on the Pasithea website following the conclusion of the event. I'd now like to turn the call over to Dr. Tiago Reis Marques, Chief Executive Officer at Pasithea Therapeutics. Please go ahead, Tiago. Good morning, and thank you for joining us. I'm Tiago Reis Marques, Chief Executive Officer of Pasithea Therapeutics. Over the next hour, we're going to talk about neurofibromatosis type 1, a genetic condition that is present in roughly one in 3,000 people and for which treatment options remain remarkably thin. Our lead candidate, PAS-004, is a next-generation macrocyclic MEK inhibitor designed for chronic dosing, once-daily treatment built to be taken chronically. We have three objectives today. First, to give you a clear picture of the two manifestations of NF1 we are developing PAS-004 for, plexiform neurofibromas and cutaneous neurofibromas, and we're going to hear from the clinicians who treat them every day. Second, to walk you through what we know about PAS-004 so far, the molecule, the phase I solid tumor data, and the design of our ongoing NF1 study. Third, to discuss the size and shape of the commercial opportunity. We'll have four speakers in this order. Kartik Krishnan, our Chief Medical Officer, will open with PAS-004 itself. Then Dr. Rebecca Brown from the University of Alabama at Birmingham. She'll cover plexiform neurofibromas. Then Dr. Kavita Sarin from Stanford will cover cutaneous neurofibromas. Finally, I'll close with the commercial opportunity. Just a quick note before we start, this presentation contains forward-looking statements, and the usual disclaimers apply. Kartik, over to you. Thank you, Tiago, and thanks to everyone joining us today. I'm Kartik Krishnan. I'm the Chief Medical Officer at Pasithea Therapeutics. Our program today is focused on the neurocutaneous manifestations of NF1. I would first like to take this opportunity to introduce our molecule, PAS-004, our novel inhibitor of the MEK protein kinase. I'll talk about the molecule, some recent data in advanced cancer patients that we presented at the European Society for Medical Oncology, or ESMO, in Madrid on October 23rd, and then lead into our key opinion leader experts in neurofibromatosis. It's important to understand that PAS-004 was not designed as an anti-cancer MEK. Rather, it is a macrocyclic structure. This macrocycle provides increased bioavailability and a longer half-life. In addition, PAS-004 has no reactive primary alcohols, potentially limiting the conversions into toxic metabolites. The goal of the design of PAS-004 was to find the sweet spot between a robust activity, a low safety burden, and a convenient dosing regimen that allows patients to potentially stay on drug longer and appreciate the efficacy benefit of chronic dosing. First approval of MEK inhibitor was for trametinib as monotherapy for the treatment of BRAF V600E/K mutant metastatic melanoma back in 2013. As such, our first in-patient phase I clinical trial was begun in advanced cancer patients. I did just say that PAS-004 was not intended to be an anti-cancer MEK, but it is an inhibitor of the pathway that is critical in many cancers. Moreover, phase I clinical trials in cancer enroll very quickly at specialized centers that generate reliable data in such areas as PK. In this phase I, we have been able to look at both a capsule formulation of raw API and a tablet formulation. Further, we have begun a pilot food effect study that will give us preliminary evidence on the optimal dosing strategy for PAS-004. PAS-004 is a once-daily dose, so taking it fasting first thing in the morning is fairly easy and routine, but understanding the food effect is good information to have. As with most phase I trials in recurrent metastatic advanced cancer, efficacy is limited. Nonetheless, when we look at the swim lanes that show the time from initiation of therapy to progression or continuation, we see that four of the 34 patients enrolled in this swim plot, three of the patients being too new, were on treatment for more than 300 days or 10 months. If we look at the subset of patients who have BRAF V600E mutant, we see that two of these patients have been on for greater than 500 days, and in fact are continuing on therapy today. While the numbers are too small to provide a categorical conclusion, I can say that for at least these two patients with recurrent metastatic melanoma who had failed prior treatment with combination of BRAF and MEK inhibitors, there is a clinical benefit for that. When we look further at safety in these patients, we see that there were no dose-limiting toxicities, no grade 3 or grade 4 or 5 related adverse events. No discontinuations due to related adverse events, and low rates of rash and diarrhea, which are known toxicities of MEK inhibitors. We have not done a formal exposure safety analysis that I can present here today, but I will say that the patients who were receiving PAS-004 for more than 300 days, including the two who were on for more than 500 days and continue, no rash or diarrhea has been reported. We believe the tolerability of PAS-004 is due, at least in part, to its pharmacokinetic properties. Looking at the day 22 samples, again, these are patients who have been on drug daily for three weeks, we see a very flat PK profile. The Cmin to Cmax ratio is less than 1.5, meaning that at steady state, PAS-004 is essentially maintained at the same level without a spike at Cmax or drop below the potentially therapeutic levels immediately prior to dosing. With a half-life of nearly 60 hours, once-daily dosing should be fairly easy and maintain compliance. As you will hear from our experts, the neurofibromatosis type 1, or NF1, results from a loss of the mechanism that turns off the RAS signaling pathway. RAS in the GDP-bound form is inactive, whereas RAS in the GTP-bound form is active and signals to promote growth. RAS is turned off by a GTPase-activating protein, or a GAP, of which neurofibromin, or the gene mutated in NF1, is one. Loss of this GAP results in hyperactivation of the RAS pathway, and it is here that PAS-004 exerts its activity. Given what I have shown you in the previous slides on tolerability and long-term lack of toxicity, we believe that effective therapies in genetic conditions like RASopathies, like NF1, will be related to chronic suppression that is tamping down of the pathway rather than the total pathway shutdown that is for a brief period that is required for anti-cancer effect. As such, we are evaluating PAS-004 in a phase I trial of neurofibromatosis type 1, looking at the effects of increasing MEK inhibitor doses on the neurocutaneous manifestations of NF1. Tiago will return to detail this evaluation, as well as the regulatory landscape and overall opportunity a little later. Before that, we will hear from Dr. Rebecca Brown and Dr. Kavita Sarin, two experts in the field of neurofibromatosis, who will share their knowledge of the biology, current treatment landscape, and unmet need experienced by patients with NF1. With that, I would like to introduce Dr. Rebecca Brown, who is Director of the Neurofibromatosis and Schwannomatosis Program at the University of Alabama at Birmingham. Dr. Brown? Thank you, Kartik. I am Dr. Rebecca Brown at the University of Alabama at Birmingham, and I am Director of the NF and Schwannomatosis Program. I wanted to introduce plexiform neurofibromas. The incidence of NF1 is approximately one in 2,500 people across the world, across all races and ethnicities, and approximately half of these individuals have a plexiform neurofibroma. The estimated U.S. impact based on the census in 2021 is approximately 137,000 individuals with NF1, of which 68,000 have a plexiform neurofibroma. Most of those plexiform neurofibromas are symptomatic, approximately three-quarters, or an estimate of 51,000 individuals. Of those individuals, only about 5% are on a MEK inhibitor, which is the class of drugs that is currently FDA approved for the treatment of plexiform neurofibromas, which leads to about 48,000 individuals in the United States alone who have an unmet need to be placed on plexiform neurofibroma treatment with MEK inhibitors, and I am going to talk about this a little bit later. Of note, approximately 13% of patients who do have a plexiform neurofibroma are at risk of a malignant sarcoma, which is almost entirely life-threatening, if not life-ending. To give a little bit of background about plexiform neurofibromas, they originate from a type of cell called neural crest cells. Now, during early embryonic development in the human, these neural crest cells migrate out from the neural tube and form a number of different cell types, including melanocytes, which give skin pigment, Schwann cells, which line the nerves, neurons themselves, bone cells, fat cells, and cartilage cells. All of the cells in the human body in somebody who has NF1 have loss of one of the NF1 alleles. However, loss of the second NF1 allele, the remaining healthy allele, very, very early on in embryonic development in these neural crest cells leads to the formation of a plexiform neurofibroma. These tumors are actually present at birth. They may be microscopic, but they have a lifetime potential of growth and, again, of malignant conversion. When the loss of the second NF1 allele happens in the adult, this happens in a mature set of Schwann cells, these are the cells that wrap around the nerves, and it can lead to the growth of cutaneous neurofibromas in the skin. Cutaneous neurofibromas and plexiform neurofibromas are actually both driven by the same molecular process. There are cell surface receptors that lead to the activation of a protein called RAS, and that causes a suite of downstream effects, including activation of RAF, MEK, and ERK. When ERK is activated, that leads to cell proliferation, survival, and differentiation, which can cause the growth of tumors. So in both of these tumors, MEK is hyperactivated. In both of these tumors, they have loss of both NF1 alleles. What is the difference? We think that the main difference is microenvironmental, that plexiform neurofibromas arise alongside very large nerves and nerve plexi, which release signaling factors that cause the indeterminate growth of these tumors and also the risk of malignancy. Now I want to talk about the clinical approach of MEK inhibitors for plexiform neurofibromas. Plexiform neurofibromas form a distinct surgical challenge, aside from any other tumor that I know of. They are fed with very large blood vessels, which causes an increased risk of bleeding, both perioperatively and post-operatively. They are highly infiltrative, so the far majority of these tumors cannot be fully removed, even in the best of circumstances. After they are removed, these tumors tend to heal more poorly than other surgeries. There is a lot of swelling in the surgical bed, and there is a high risk of scarring. Surgeons are very hesitant to take on these challenges. Oftentimes, one single tumor, in order to be removed to the satisfaction of the patient, requires multiple surgeries and a skin graft. When do we use MEK inhibitors? We use them when plexiform neurofibromas are unresectable or not fully resectable, and as I mentioned, this is the far majority of these tumors. Or sometimes patients have already undergone multiple surgeries for other tumors or for the tumor of concern, and they decline further surgery. Plexiform neurofibromas should be symptomatic, but this can mean a number of different things. The tumor can be deformative. It could just be something that the patient finds distinctly undesirable on their body. They can be painful, they can cause weakness or numbness, and sometimes they can cause functional abnormalities, such as a tumor that is so large that a patient can't find clothing to fit around the tumor. If the plexiform neurofibroma is progressive, if it's continuing to grow, that would be a good candidate for MEK inhibitors. If the patient has had a surgery and they don't want the tumor to grow back, sometimes this is a situation where experts will use MEK inhibitors. Sometimes the plexiform neurofibroma can actually be quite stable, but it's just adjacent to crucial anatomy, or it's threatening to compress, or it is compressing. Some examples of this might be the trachea, the aorta, the esophagus, nerve roots along the spine, or the spinal cord itself. When a patient starts on MEK inhibitor, the goal time on drug would be about two years, but patients do remain on these medications for an indefinite period of time, because they only have the benefit from the drug while they are on the drug. Going back to the neural crest cells, these cells actually develop into multiple different organ types within the adult, and that's what I'm showing on the lower right. One of these is the cardiac smooth muscle, which leads to heart contractility, then also multiple different cell types within the skin, the immune system, neutrophils, and the GI tract. The reason I bring this up is that the side effects of MEK inhibitors are on-target side effects that affect all of these different tissue types. Of the MEK inhibitor side effects, dermatologic adverse events are extremely common. Amongst these is rash, which occurs in 90% or more of patients on MEK inhibitors. I'm showing an example of the rash on the upper right. It's widespread, it can be painful, it is, again, deformative, and it is, again, an on-target effect of these MEK inhibitors. Nail infections, like I'm showing on the upper right, are very common, and mouth ulcers. There are also cardiologic side effects. Decreased cardiac output occurs in approximately 12%. Constitutionally, people complain of swelling, which can happen focally in one hand or foot or limb, or it can be widespread. They have weight gain, which is related to fluid retention. They can complain of fatigue, fever, and musculoskeletal pain. All of these adverse side effects happen in a decently large percentage of individuals who are on these medications. I should say that these percentages were taken from the average of all the adverse events that were reported in the trials that led to FDA approval. For GI side effects, a number of people, close to 100%, have GI side effects of diarrhea, nausea, vomiting, constipation, or all three. Patients can have vision loss. It could either be a blurry vision, which is caused by serous retinal detachment or chorioretinopathy, which is low grade, or they can have sudden profound vision loss, which is caused by retinal vein occlusion, which is basically a mini stroke inside the back of the eye. Because of all of these side effects, MEK inhibitors, at least in the registrational trials, but I also see this in the real world, are frequently underdosed or discontinued. This gives you the percentage of patients who discontinued or had a dose interruption or a dose reduction in all of the registrational trials, and you can see that it's quite significant, up to 80% in the SPRINT trial in children. The dose reductions occurred for reasons of rash, skin or nail bed infections, nausea, vomiting, diarrhea, abdominal pain, fever, illness, swelling, and weight gain. Dose reductions occurred in about 17% of patients overall, whereas discontinuations occurred in approximately 12%. I should say here that these are the most motivated patients on these clinical trials. They have frequent follow-ups with their doctors. There is a great interest in keeping them on the drug for the duration of the trial, so the real-world discontinuation events are much, much higher. What are the limitations of existing FDA-approved MEK inhibitors? First of all, there's still some room for improvement. If you look at the graph on the upper right, what we see that while children tended to respond, or a greater percentage of children responded to MEK inhibitors in the registrational trials, in adults, the response rate was a fair bit lower. So there is room for improvement. Both selumetinib and mirdametinib are weight-based dosed, and they're given twice daily. With selu, it's given twice daily every day of the month, and with mirdametinib, it's given twice daily for three weeks, and then patients have a one-week drug holiday. This twice-daily dosing can be inconvenient. NF1 patients at baseline often do have IBS, and many of them are low in the socioeconomic ladder, and they work service jobs or night jobs, and twice-daily dosing can be quite difficult for them. There are extensive adverse events that patients experience while on these medications, and frankly, our medical system is not equipped currently to deal with all of these adverse events. Unless you're very familiar with these medications, it can be very daunting, for example, for a community oncologist or neurologist or primary care doctor to manage all of these multi-organ adverse events. If the doctor does feel comfortable with all of these multi-organ adverse events, then that requires excess clinic time and multiple follow-up appointments in order to manage these AEs. Most NF patients do follow with community doctors. There are multiple states across the U.S., which is probably the best-served country in the world, where there is no NF expert. There is 100% risk of adverse events in patients. I gave you the breakdowns on the previous slides, but 100% of patients do experience at least one of these adverse events. NF patients already have baseline pain, deformity, and GI issues. They're not willing to suffer very much more and also suffer increased deformity from rash, for example, when that is the goal of the treatment in the end. The AEs that occur with MEK inhibitors happen very early on, from days or one month or three months within starting the drug, whereas the first tumor response is expected approximately seven months after starting the drug. The response rate and percent tumor reduction that I showed in the upper right, frankly, could be improved upon. My final message is that plexiform neurofibromas are common. They are symptomatic. Most of those patients who have plexiform neurofibromas are not on the medication that would benefit them the most. The two MEK inhibitors that are FDA approved are not serving the far majority of patients who could be on them, and most of this is due to adverse events, which are a major deterrent to patients for starting and staying on drug, and also a major deterrent to prescribers, given the time, expertise, and liabilities associated with taking on these multi-organ adverse events. The potential is there if there could be a new MEK inhibitor that had fewer adverse events, we really could reach a massive number of the untreated population. As a reminder, those patients can remain on drug indefinitely, and there's room for improved efficacy as well. Thank you very much. Thank you, Dr. Brown. At this time, we will now be taking questions from the audience. Our first question comes from Sara Nik at H.C. Wainwright. Sarah, please go ahead. All right. Thank you, and thank you, Dr. Brown, for the talk. It was very informative, and I have a few questions. To start with what you discussed of the approved MEK inhibitors in plexiform neurofibromas, do you see that responses can continue to deepen beyond six to 12 months? In your view, how much follow-up would you want to see before judging a new agent's PN data? That is a great question. It is true that the nadir, the maximum shrinkage of the tumor, can happen far past six or 12 months. The reason that the minimum goal treatment is two years is that, on average, we see the nadir or the maximum shrinkage between 18 months and two years, but in some individuals, it's more than two years, up to three years or more. It is important to keep the patient on drug. Sorry, could you repeat the second part of your question? How much follow-up you would want to see before judging a new agent's PN data? Oh, I think the key question here is actually how. We have at least a decade's worth of data from the selumetinib registrational trial up until the present real-world data, and we do see that there is a durability of response. I do not think that the real issue is going to be how long we follow up these patients, but really how quickly we can get them to a treatment effect and how well can we keep them on drug. Okay. I guess maybe following up with that, why do you think that some of the PN patients or some of the PNs respond deeply while others can plateau or, in some cases, continue to progress? Is it more of a pathway reactivation, feedback signaling, or more related to the tumor microenvironment? Another great question that we could write books upon. In my assessment, what I feel is that part of it is due to the area under the curve of the drugs that are currently FDA approved. I do not think that the tumors are actually being exposed to therapeutic levels of drug for a long enough period of time for us to see a maximal or an improved response. In addition to that, some of the tumors are not growing at the time of instituting the drug. If you look at the data from the mirdametinib trials compared to the selumetinib trials, the trials that required that a patient have a growing tumor had a slightly better percent response rate. Tumors that are growing respond better, and experts in the community also feel that there may be, although this hasn't yet been proven, but there may be an effect of where the tumor is located. For example, tumors of the face and neck may respond better than tumors located elsewhere in the body, but we just don't have that confirmatory data yet. I'm not. Thank you. Lastly, going to a bit of where you discussed the current limitations of the MEK inhibitors and maybe where they could fall short. In your view, are you thinking that, in terms of ranking, would you rank safety as important as efficacy when considering chronic dosing? With the patient populations that you're treating, have you noticed that parents might be delaying treating their children due to the side effects that you mentioned? Yes. I would rank safety very highly for the reasons that I mentioned, is that these patients are already going through an awful lot, and putting them through more, especially if we're not expecting to see 100% of the tumors reduce in size, is asking too much. There are a class of patients for whom stability of the tumor is the goal, and those patients, we would hope, would stay on the drug for a long period of time, even if they're not seeing tumor shrinkage, and that is fine. Sorry, the second part of your question again? Since this can affect the pediatric population, are you seeing that parents might be delaying treating their patients due to that- Yes tox profile? 100%. Not just the parents, but I've seen experts at even the major centers that are treating children with NF tell the parents of the child that the tumor is not of a quality that they think might respond well, so they're not offering the drug. On both sides, yes. All right. Thank you so much. You're welcome. Great. Thank you both. I'd now like to turn the call over to Dr. Sarin. Well, thank you, Tara. I'm a dermatologist at Stanford, and I direct the Skin Cancer Genetics Clinic at the Stanford Cancer Institute. I also co-lead the REiNS Cutaneous Neurofibroma Working Group. In the next 20 minutes, I'll cover what cutaneous neurofibromas are, why they matter to patients, how they're treated today, and what MEK inhibition has shown so far. We'll also discuss the ways we can measure a treatment effect that both regulators and patients can recognize. My disclosures, I'm an advisor to NFlection Therapeutics, which is developing a topical MEK inhibitor for cutaneous neurofibromas. I consult for Pasithea, Alexion, and SpringWorks. As I mentioned earlier, I co-lead the REiNS Cutaneous Neurofibroma Working Group, and I've received research funding from NTAP for cutaneous neurofibroma research. Cutaneous neurofibromas affect nearly everyone with neurofibromatosis type 1. NF1 affects about one in 3,000 people. To put this into perspective, roughly 100,000 people in the U.S. and 2.5 million people worldwide are affected with NF1. More than 95%, virtually every one of these adults with NF1, develop cutaneous neurofibroma, many up to hundreds or thousands. These tumors begin in childhood and in puberty and keep forming throughout life. They're mostly on the trunk, but about 10% can occur on the head and neck. So what is a cutaneous neurofibroma? Well, it's a benign, meaning a non-malignant tumor of the nerve sheath Schwann cells. These Schwann cells lose both copies of NF1 and over-activate the RAS/MAPK kinase pathway. These overgrown Schwann cells in the skin are embedded in a stroma of fibroblasts, mast cells, macrophages, and dense collagen, and they never turn into cancer. But this composition matters for therapy because only the Schwann cells carry the activated MAPK kinase pathway. A MEK inhibitor could be expected to shrink the tumors, but not necessarily remove the collagen scaffold around it. But what's interesting is that in mouse models, MEK inhibition actually has been shown to reduce the macrophages and the matrix proteins that the fibroblasts secrete, which could explain sort of a non-cell autonomous effect on the overall microenvironment for MEK inhibitors, even if it's primarily affecting the Schwann cells. Visibly and clinically, these cutaneous neurofibromas can really vary widely. They can progress from nascent lesions, these are lesions you can't even really see, but you can just feel just underneath the skin, to flat ones, which are ones you can see, but are not raised above the skin. They can be sessile, globular, which is like a really large extruding component above the skin, and even pedunculated, which is a large tumor that hangs on a tiny stalk. One of these patients can actually have several types of these tumors all at one time. This matters because we don't necessarily expect all of the measurements for these different kinds of tumors, nor the treatments, to necessarily behave the same across these different stages. For example, a flat lesion will not have a height measurement, but will be visible. A pedunculated lesion will be difficult to measure because there's a big extruding component, but a tiny little stalk. If you measure just surrounding skin, you'll see just the measurement around surrounding skin will be very tiny, but the lesion itself is much larger. Our Stanford NF1 genetic study gives a direct picture of tumor burden. What we did is we had patients submit photos of their skin, seven body parts, and we scored photographs from 583 adults ages 40 and over. What we found was that two-thirds of our participants had more than 100 cutaneous neurofibromas in their photographs, and a third had more than 500. Actually, only 6% at this age group had fewer than 10. Many of the tumors were small, but 15% carried much larger tumors, and facial involvement was present in nearly 90% of our cohort. These are photo-rated figures, so they're not necessarily fully investigated rated, but they match the literature. The lesions tend to occur in childhood and puberty and then continue throughout the decades. By 40, most people have surpassed 100 tumors. This is one reason why procedures alone cannot keep up with treatment for these tumors. We also measured quality of life in our study using the CNF-Skindex, which is a quality of life measure. What we found was that quality of life worsened with tumor number, with tumor size, and with facial involvement. Of the quality of life metrics, the emotional domain was actually hit the hardest. What was interesting is we even saw an effect in just patients with just a few, like fewer than 10 tumors, already reported effect of their cutaneous neurofibromas on their quality of life. This is consistent with earlier European and Australian cohorts, which found that the same finding, that visibility predicts skin-related quality of life, and that a treatment that reduces maybe number or size, especially on the face, is likely to translate into a benefit that patients feel. In further support of this, in 2021, the REiNS Cutaneous Neurofibroma Working Group surveyed 548 adults with NF1 through the Children's Tumor Foundation registry. We asked in our survey how much each feature of their cutaneous neurofibromas bothered them, and the respondents reported that appearance, location, number, and size were the most bothersome. Nearly 60% were very much or extremely bothered by these features. Interestingly, itch, pain, and firmness mattered less to the participants than these other features. Actually, as a clinician, I've found that many of my patients don't even experience itch or pain with their cutaneous neurofibromas. There's really quite a range of patients, but many will not experience those symptoms at all at baseline. Across every survey of adults with NF1, cutaneous neurofibromas consistently rank as one of the most distressing features of their condition. Our same survey asked, "What's the minimum decrease in tumor size or number that would make participating in a trial worthwhile?" The way we did this was we used actually photographs that were digitally altered to show either a 0%, a 33%, 66%, or 100% reduction in either the number of tumors in that photo or the size of the tumors. Respondents could only choose among those four photographs as what they would accept for participation. Three-quarters chose a partial reduction between 33% and 66%. Very few of our participants expected complete clearance. Anecdotally, patient reps told us that if we could just stop growth, just stop them from continuing to grow, that itself would be a win, particularly if the treatment was started when the tumors were small. Because cutaneous neurofibromas are benign, we did ask about side effects, what side effects our patients were willing to experience for their treatment. Roughly half of respondents were somewhat to extremely willing to accept the side effect, and about half were not. Scarring and skin color change were mostly accepted, but about half would and half would not risk nausea, vomiting, or a rash. Our survey did not stratify by tumor count, so it's possible and very reasonable to expect that maybe someone with hundreds of tumors might weigh their risk-benefit ratio different from someone with a handful. I think the takeaway is that there really is a balance between treatment and tolerability, and the balance of those two will decide whether or not a patient decides to use the medication. Based on the results of the study, the REiNS Cutaneous Neurofibroma Working Group came up with a general recommendation, and this is just to quote their recommendation. "Based on their responses, balancing desired outcomes with side effects, we propose a topical or oral formulation of medication to target CNFs. Identification of or development of a PRO measure that captures the burden of disease and psychosocial concerns, which will be sensitive to changes in CNFs, is critical. Endpoints for a clinical trial should include a PRO measure to assess clinical benefit, as well as a measurement of CNF size to test the efficacy of treatment in decreasing the size of CNF, even if a trial does not achieve a 100% decrease of target CNFs." That was sort of what we recommended based off this 2021 survey study and what many of the currently published trials have kept to, both having a PRO measure as well as a measurement of CNF size or number. What is the landscape of current treatments? Well, it's primarily procedural. Surgical excision is the default for most patients with a few tumors or painful tumors, and lasers can be used for patients with more tumors that have maybe many small lesions in an area, which can be treated in one session. Electrodesiccation and radiofrequency, which is kind of like burning the tumors, can treat hundreds at a time, but they also leave a scar. None of these treatments prevent tumors, and each can trade a tumor for a scar. They are helpful. We do them a lot for our patients, but really, all of our patients really are desiring a sort of a non-scarring approach for the treatment of their tumors. This is just an example of what surgery looks like in practice. It is an office excision done under local anesthesia. It can be done in less than 30 minutes. We inject the tumor, if it is a small tumor, with some lidocaine, and then cut out the tumor, but then the patient is left with a scar. These scars are more noticeable in patients with darker skin. We can also excise a bunch of tumors at once. We do an elliptical excision around the tumor. You can see here, this is effective for removing that particular area that we cut out, but it again leaves scars on the skin. Laser ablation scales better, so you can do many tumors at once in one session, typically under general anesthesia. The trade-off again is sort of pale or dark scars at every site, and these cutaneous neurofibromas can regrow. Like surgery, these also only address tumors that we can actually see that already exist. Rebecca really nicely covered the plexiform story, so I will just only say that selumetinib and mirdametinib proved the principle for plexiform neurofibromas, that blocking MEK with a MEK inhibitor can shrink NF1-driven tumors. We believe the same will hold for cutaneous neurofibromas because they share the exact same pathway, that they both have loss of NF1 in the Schwann cells with overactivation of the RAS and MAP kinase pathway. Really, because of this, cutaneous neurofibromas are a logical scientific target for the same class. What we do not know is whether or not cutaneous disease needs the same dosage or the same degree of pathway inhibition. They are smaller, they are less fibrotic, so it is possible, but we do not know this, that a drug might be able to penetrate more easily and may have an effect on cutaneous neurofibromas at a lower dose. The only published oral MEK inhibitor trial in cutaneous neurofibromas is the NCI and UAB selumetinib pilot. This enrolled 11 adults and measured 209 tumors by caliper and took photographs. The best response was a 28.5% reduction in tumor volume. The median best response, I should say, this was the median best response, was a 28.5% reduction in tumor volume. Six out of eight evaluable participants had at least a 20% shrinkage. In the patients who completed 12 cycles, the number of tumors counted inside their 10-by-10-centimeter paper frame also fell by a median of seven, or about a third, though the mechanism is unclear. It is possible that some tumors may just have shrunk below their counting size, or were small enough that they just visibly disappeared. It does highlight that a count endpoint is not impossible. Safety is what you would expect from this class and from the MEK inhibitor studies in plexiform neurofibromas. Everyone had a drug-related side effect, mainly rash, dry skin, GI symptoms. Actually, only four out of the 11 who were originally enrolled in the trial completed the study. In a couple participants, the tumors were shown to regrow after treatment was discontinued. mirdametinib is also being tested in cutaneous neurofibroma studies, but there are no published results yet. NFlection's topical nedometinib gel is the other MEK inhibitor that is being tested in cutaneous neurofibromas. In this study, 199 adults applied the gel to 10 target tumors for six months, and these tumors were distributed in areas they could reach, so basically face, trunk, and extremities. In this case, a patient was considered a volume responder if five or more of their 10 treated tumors shrunk by at least half in volume. A participant was considered a height responder if five or more of their 10 treated tumors, so more than half of their tumors, shrunk by at least half, so 50%. Based off of this, 44% on the high dose, which is the 1.5% nedometinib gel, were volume responders versus 24% of vehicle. 40% of the high-dose nedometinib arm were height responders compared to 10% for vehicle. This vehicle response was higher than expected, and maybe because the vehicle is like a hydrating gel, rather than just a pill you would take. Hydration can blur tumor borders, pump up the surrounding skin, and maybe make the measurements look like they were smaller because of the surrounding skin. It is also possible that measurement variability contributed to this or regression to the mean. This vehicle response decreased in the height endpoint, maybe because of the surrounding skin effect. It is consistent that when a drug is applied to the surface, maybe it would affect height more than a change in the surface area. What is interesting is that even though systemic side effects were largely avoided by using a topical treatment, local reactions still occurred and actually led to a quarter of the high-dose group to stop treatment. This is because the side effect is really an on-target side effect of the drug, and so the rash is still occurring even with local treatment. It only occurred in the area the drug was applied. Because this is a topical treatment, it only works on the CNFs that are treated, so it really positions it for treatment of selective lesions rather than widespread disease. The next question is, how should we measure these tumors? Scott Plotkin's group published this great study back about five years ago, and in their study, they basically had three examiners measure 57 tumors in 10 adults, and they were measured with three methods: digital calipers, 3D photography, and high-frequency ultrasound. All the three of these measures validated. Ultrasound and 3D photography had an intraclass correlation of 0.97, and calipers of 0.81-0.96. Calipers and rulers are the most easy method to implement because they are cheap and they are available in all the clinics. What they found was that for all 3 of these measurements, that reliability improved in target tumors that were 5 millimeters or larger, and surrounded by normal skin. The NITA-METNIB trial used a standardized ruler for measurement and calculated volume by basically using a model of an ellipsoid above the surface. Length, width, and height were measured with a standardized ruler, and then the tumor volume was calculated as a pi over six times length, times width, times height. You can see, this is just half of an ellipsoid, and so this really measures the area that protrudes above the skin. You can see in the ultrasound that an ultrasound will capture the volume below the skin, but this is really measuring only the height above the skin. This is really where the change happens first, especially with a topical treatment, and also the part that actually bothers patients the most, which is the part extruding above the skin. In this nedometinib study, height was the dominant contributor to the change in volume. This is a high-level summary of clinician and patient endpoints. On the clinician side, we discussed validation of calipers, rulers, ultrasound, or 3D photography. There is also global scales, 5-point and 7-point investigator IGA scales that investigators can use. The selumetinib study used lesion counts and paper frames, and we are also exploring photography with AI counting, though that is very exploratory at this point, as another measure. Laura Fertitta published the Nef-ASI, which is a photographic severity index, similar to what is used as a visibility index used across dermatologic conditions, but this has not been validated in trials yet or in response to change. On the patient side, there is really no specifically validated CNF PROs, though there are some academic scales that exist. The PGIC, which I will talk about in a moment. The CNF-Skindex, which is a quality of life scale. It is an adapted version of the Skindex, which is used commonly across cutaneous disease. Again, the CNF-Skindex has not been used in trials or to measure sensitivity to change. The FACE-Q, which is an appearance scale of the face. Then there are standard one to 10 scales for itch and pain. The strongest evidence we have for these PROs is the Patient Global Impression of Change scale, because this was used in the nedometinib study. This is the PGIC scale. In the nedometinib trial, participants rated each of their tumors. Each tumor was individually rated on a 7-point scale of improvement, and they also reported for each tumor whether or not the change was meaningful to them. Patients rated the change as meaningful for 42% of tumors on the high-dose arm compared to 23% in vehicle. They also divide the participant level scale, which is that at least half of the tumors showed an improvement and were rated meaningful. So they had to be rated both meaningful and improved, and at least five out of the 10 tumors that were treated. What they found using this participant level scale was that 37% of participants had a meaningful improvement in the nedometinib 1.5% arm compared to 9% in the vehicle. Exit interviews with 40 participants showed that a one-category change was considered meaningful. I think most importantly for this PGIC scale was the correlation between the objective tumor volume and the patient-reported outcome. Of the tumors that met the objective 50% decrease in volume, those were three times more likely to be rated meaningfully improved. The objective shrinkage and patient-perceived benefit correlated together, and this highlights the value of the PGIC as a patient-reported outcome. To summarize, there is a need for a treatment for cutaneous neurofibromas. They affect more than 95% of adults with NF1, and they are the features that patients most want treated. Unfortunately, our current landscape is primarily procedural, which leaves permanent scarring, cannot keep up with the hundreds of tumors that develop, and do not have any effect on prevention of new tumors. These cutaneous and plexiform neurofibromas share the same MEK pathway biology, have the same rationale for MEK inhibition, and empirically, this pathway has been proven out with oral MEK inhibitors, which has been shown to shrink both plexiform neurofibromas and, in smaller studies, cutaneous neurofibromas. They have been primarily limited by the tolerability of the skin rash and the GI side effects that occur with this treatment. There are some validated measurements for measuring change, such as digital calipers, rulers, that can be made more reliable by repeated measures, and there is a three-dimensional volume calculation that has been shown to be able to capture flattening and shrinkage of volume, and has been able to discern a significant difference in the nedometinib study. We have shown that there is a PRO, the PGIC scale, which actually correlates with objective volume change, so that both patient-reported meaningful improvement as well as objective change in tumor size can be measured together. What we need now are well-tolerated treatments that can prevent, arrest, or shrink these tumors over the years. Thank you. Great. Thank you, Dr. Sarin. We will now be taking questions from the audience. Our first question comes from Sara Nik at H.C. Wainwright. Sarah, please go ahead. Thanks, Tara, and thanks, Dr. Sarin, for the talk highlighting the CNF burden and unmet need. I guess to start, you touched on this, but given the range and how they present, how should CNF response best be measured? Is it surface area, height, volume, or a combination? Yeah. I think we've had valid measures for multiple of these. Volume is the validated measure that's used in the nedometinib trial, so that's effective. But that trial also measures length, width, surface area, and heights, and all of those have been proven by Scott Plotkin's work as reliable measures for use in trials. I think all of those can be used in clinical trials and are validated. Great. Thanks. Beyond shrinking existing lesions, in your view, could a systemic MEK inhibitor work to slow or prevent new CNFs from forming, and is this something a clinical study could capture? Yeah. I think that's a great idea and something we're really excited about with the use of oral and systemic MEK inhibitors. The reason is because this is targeting the exact pathway that's causing them to grow. So, it's theoretically, and I think even likely, that a MEK inhibitor will actually prevent new tumors from forming as long as the patient is on treatment. However, it may be more difficult to measure in a clinical trial, and this is because cutaneous neurofibromas can be slow-growing, and a clinical trial is typically six months to one year in length, and it's very difficult maybe to capture a significant change in the number of new lesions in a clinical trial compared to vehicle because these are slow-growing tumors. But I do think theoretically and scientifically and clinically, it would make sense, and we would expect that an oral MEK inhibitor may prevent new tumors from forming as well. Okay. This is also something that you touched upon in your talk. When it comes to the CNF burden, what is really driving that burden for your patients? Is it the number, location, size? Is there a factor that really matters the most to them? Well, in the REiNS survey, we said appearance, but appearance is not anything other than really a conglomerate measurement of multiple factors. Those multiple factors, I think, were also addressed in the survey and were all found to be really important to patients, which is size, number, and location. I think the combination of those three of them really affect the appearance, which is why it weighs so heavily on the quality of life scores that we see, especially in the emotional domain. Yeah. Building on that, when do these CNFs really arrive and then start to impact patient quality of life? Yeah. We can see them actually even in children. They are very subtle underneath the skin, but they really start to arise with greater frequency in puberty, and so adolescence and then throughout adulthood. In fact, 20s, 30s is really when we see large numbers arising and continuing to arise throughout life. In terms of quality of life, I did not share this today, but we actually did conduct an adolescent survey, and we found that even adolescents with very few tumors, their cutaneous neurofibromas were already affecting their quality of life. One of the major ways it was affecting their quality of life was they were worried about developing new ones in the future. I think the impact is happening as early as adolescence, where they're starting to become concerned about their skin tumors, even though the actual burden and the size and the visibility really increases post-puberty and continues through life. Okay. That's helpful. To round it out for me, if you see that CNFs are shrinking on a systemic MEK inhibitor, does that inform or tell you anything about whether that same patient's plexiform neurofibromas may respond? Yeah. Well, I think on some level, the CNFs and the plexiform data bodes really well for the CNF data, and that is because these are driven almost through the same mechanism, which is the biallelic loss of NF1, so loss of the NF1 gene in the Schwann cells, which is driving these tumors. We believe that if it works for plexiform neurofibromas, it should work for cutaneous neurofibromas, even though dosage may be different. For example, cutaneous neurofibromas may be able to respond with a lower dose than a plexiform neurofibroma, which tends to be larger and maybe more fibrotic. I think, on some level, yes, I would expect them to correlate. Would I expect them to correlate with 100% degree correlation? Not necessarily. That's because, A, drug delivery, B, there could be other mutations or microenvironmental effects that affect how well a specific tumor will respond. I do think that in general, we would expect the same types of effects we're seeing with shrinkage of tumor and plexiform neurofibromas to occur with cutaneous neurofibromas, though potentially on a different scale and with a different dosage. No, that's really helpful context. Thanks. Thanks for taking the questions. Of course. My pleasure. Great. Thank you both. I will now turn it back over to Tiago. Thank you, Kavita. As you can imagine, we are excited to present our plexiform and cutaneous NF1 data next week at the European NF Conference. As you saw yesterday, we are clear to begin our cutaneous neurofibroma trial as our second IND in NF1 is now active with the dermatology division of the FDA. To better understand our progress, let me start by revisiting our NF1 trial design. As Kartik already mentioned, study 103 is a phase I/I-B open-label, 3+3 dose escalation in adults with NF1 and symptomatic plexiform neurofibromas, but we are also assessing the efficacy of PAS-004 on their cutaneous neurofibromas. We have in total six cohorts open, from four to 24 milligram once daily. This is a six-month study, followed by a treatment extension of up to 12 months. We measure the cutaneous neurofibromas at screening and at the end of cycle one, four, six, and then every three months into the treatment extension. We measure up to seven cutaneous neurofibromas per patient. We are also resecting one target cutaneous neurofibroma for pharmacodynamic analysis at cycle one and cycle six. For the plexiform neurofibroma, MRIs are obtained at screening and at the end of cycle four and six, and then every three months into treatment extension. One important thing, as cohorts are enrolled one after another, we will have different time on treatment for each cohort. The lower dose cohorts have now crossed cycle 12, but the higher dose cohorts have only minimal treatment exposure. This is particularly important for the interpretation of the plexiform neurofibroma data. We know that response deepen over many months, and this is something to take in consideration when we report our initial data. Let us go onto the cutaneous neurofibroma. As I mentioned, I want to highlight that we measure up to seven cutaneous neurofibromas, so the total number of cutaneous neurofibromas measured runs to many dozens. Picking on Kavita's talk, let us discuss the challenge of measuring cutaneous neurofibroma. How did we address this, and how are we measuring the cutaneous neurofibromas in our study? We are using digital calipers, and as Kavita mentioned, this is a validated instrument for measuring cutaneous neurofibroma in NF1, and there is also regulatory precedent with the FDA having accepted this tool in cutaneous neurofibroma clinical trials. We measure, as you can see on the image on the left, we measure the two main dimensions of the lesion, the length and the width, and the lesions are measured in triplicate, and at the end, we average the measurements. Here on the small diagram, you see the geometry of the cutaneous neurofibroma. They are typically dome-shaped lesions, and geometrically, they can be approximated as an half ellipsoid. Why do you use surface area and not volume? Because using digital calipers on a dome-shaped lesion, height is hard to measure reliably with calipers. However, we will also report volumes, and to calculate volumes, we will assume that the lesion shrinks by the same proportion in every direction, what we call an isotropic reduction. Based on this assumption, we can convert surface area into volume, and the conversion table that you see on the right is how a surface area translates into volume. So a 37% reduction in surface area is roughly equivalent to a 50% volume reduction. Something to take in consideration as well when you look to our data next week. Let me speak about the commercial opportunity, and let us start with the cutaneous neurofibroma indication. As I will show, this is a very large TAM and a multi-billion dollar opportunity. The epidemiology is striking, as 95%-100% of people with NF1 develop cutaneous neurofibroma, so there are approximately 150,000 U.S. patients living with these lesions. The lesion burden runs from a handful to hundreds or thousands, so this is a broad severity stratified population. We also heard mention by Kavita that in her cohort, the Stanford cohort, 40% of patients have more than 500 lesions. For these numbers, we use the third-party market research, and we estimated that up to a quarter, so 25% of the patients have fewer than 50 lesions. In these cases, lesions are mostly a cosmetic concern that can be managed with either observation or local and occasional procedures. However, the remaining will have more than 50 lesions, and we define as moderate burden patients having 50 to 500 lesions, and severe burden patients having more than 500 lesions. Here, you concentrate the majority of the patients, over 80,000 patients having more than 50 lesions. Here is where the unmet need is the highest, and the interest in a systemic treatment is also strongest. Ultimately, this is the primary target population for a systemic therapy such as PAS-004. The PN opportunity is slightly different. PN affects, plexiform neurofibroma affects 30%-50% of people with NF1, so there's roughly 50,000 patients with NF1 and plexiform neurofibroma in the U.S. We estimated that about 35,000 are diagnosed. The segmentation here is driven by symptoms and by surgical options. Approximately 45% of the patients, so roughly 16,000, are asymptomatic and just watch. Ultimately, they are future candidates as the disease progress. About 8%, so roughly 3,000, are symptomatic but resectable, and surgery remains their standard of care. They're not a target for systemic therapy. The remaining 16,000 have symptomatic plexiform neurofibroma, and they are not able to be surgically resected. This is where the pain, the neurologic deficits, and disfigurement concentrate and where MEK inhibitors are the only approved systemic option. The regulatory path here established and well-known, there's two MEK inhibitors approved on single registrational trials each, either against historical controls or against placebo, with a confirmed objective response by volumetric MRI as the endpoint, and a trial size somewhere between 50 to 100 patients. Worth mentioning that for the NF1 PN opportunity, we hold fast track and also a rare pediatric disease designation by the FDA. In July of this year, we have run the market research through an independent third party to understand the commercial opportunity of PAS-004 in NF1. We have conducted 35 interviews, 20 U.S. physicians, a mix of KOLs and high-volume treaters that actively manage NF1 patients with both the cutaneous and the plexiform manifestations and are familiar with the approved MEK inhibitors. We also interview five payers, including pharmacy and medical directors, and 10 adult patients with NF1, a mix of patients who have been on Gomekli or Koselugo and patients who have never been treated. Let's start with the physician's view on cutaneous neurofibromas. When we ask them what the systemic therapy will need to deliver, they suggest that 20%-30% reduction in volume could be meaningful. We ask them to allocate their treatment-eligible patients, and this is the chart you see on the left. The use of PAS-004 increases with disease burden, with over 50% allocated to PAS-004 in patients with hundreds of lesions. Doctors also suggest that the share of cutaneous neurofibroma patients who pursue any treatment at all would rise to 40%-50% once an approved agent exists. When we interview patients, we ask them to rate their satisfaction with current treatment options on a Likert scale from 0 to 7. They rate their satisfaction as 2.3 out of seven, and they also rate their interest in a novel treatment as 5.5 out of seven. Clearly, they are unsatisfied with the treatment options, and they are interested in a novel treatment. At least with the patients we've interviewed, they suggest that they strongly prefer a tablet to a topical formulation. They were also equally clear that they will not accept serious risk for a condition that ultimately can be seen as benign. Tolerability is important in this indication. Finally, I want to pass three messages to take away. First, we have a drug that has been designed to be taken chronically. Once-daily drug, able to provide a flat exposure profile and a continuous target inhibition. In NF1, tolerability over years is the treatment goal. Second, a regulatory path with precedence on both sides. In PN, an accepted endpoint and two approvals. In cutaneous neurofibroma, no drugs approved, but the regulatory path is identified through double-blind placebo-controlled trials with clinician and patient-reported outcomes. Third, I want to highlight that we have two large indications in the same disease. 14,000 MEK inhibitor-eligible patients and over 80,000 adults with cutaneous neurofibroma and no systemic options at all. I want to finish by thanking Dr. Rebecca Brown, Dr. Kavita Sarin, and Dr. Kartik Krishnan for their important insights. I invite you all to what comes next, the disclosure of our initial NF1 study data at the European Neurofibromatosis Conference from the 12th to 14th of November. Thank you so much.