Sol-Gel Technologies Ltd. (SLGL) Earnings Call Transcript & Summary

So good morning. Actually, good afternoon to our guests who took the trouble to visit us here and to everyone that is listening to us and the Sol-Gel team that are also watching us in Israel and is our biggest support when we are along this journey. And first of all, I would like to thank our great guests the scientists who agreed to speak to you. They will be introduced later, one after the other. And we, the team have Sol-Gel and the management team that is here are very excited to talk to you about the prospects that we see in revolutionizing the treatment of Gorlin and introducing such a profound change in the life of Gorlin patients with our new drug SGT 610. So thank you again. I will now start our presentation. Many of our investors are familiar with the presentation because it was in a company there, but we introduced several changes that were meant to respond to frequently ask the questions by you guys over the last month or 2. And I hope this presentation will add clarity in those aspects that were maybe not fully clarified until now. So to introduce ourselves to introduce that. Sorry, sorry, sorry, introduced ourselves, Sol-Gel is an experienced dermatological company. Specializes in severe or, if you will, rare diseases in dermatology. SGT-610 being the first product that is now approaching approval. This is our team. You see the team all very serious looking people. And one thing that makes me feel a bit apologetic is that we have only one lady here. In fact, when I stepped up as the CEO last year, I was concerned about it, and I was asking myself, how can I make a change, but all these people are so talented so experienced, so diligent. There was no one I could replace. So what slightly correct the situation is that our VP of Clinical and Regulatory Affairs Dr. Ofra Levy-Hacham has 2 jobs, both of regulatory and clinical. And in reality, I can tell you, she does a job of 2 executives. Hi, Ofra. And this slightly corrects the imbalance, but we are fully aware that right company these days should consist of more balanced agenda. Okay. Now again, so just in the highlights, what we are going to talk about our drug is, of course, first and foremost, is targeted at Gorlin patients. I'm saying first and foremost because in the future, I believe there will be additional indications may be even bigger than that. But right now, we concentrate on Gorlin patients. The mechanism is a well-known mechanism. It's the blocking of the hedgehog signaling pathway. And the development history as we know now is that we acquired the drug from PellePharm. PellePharm did not fail in the study or did not meet the statistical significance that they expected. We've made a lot of due diligence, a lot of employees, several independent statistical teams as well as world experts and decided that the data that we will review later is really compelling, and we are biased as we are, we are quite convinced that this drug will be a success. In terms of designation, it's an orphan drug and breakthrough and will be the first drug to treat Gorlin patients after so many years. So we are very excited about this. Now let us start with the data. This is the raw data of PellePharm Phase III with one addition is that we are showing here only the observed data. Then the only patient that completed 12 months treatment. So this was not the data that was submitted to the FDA, but it's the data after we eliminate those people who -- patients that didn't comply they didn't show up. They didn't -- don't have the final data. I'm making note of it because this was the source of some questions that we've been asked about the past, the telephone data shows this one and you show that one. This is the data that our experts has done our statistical team based on the raw data of PellePharm. what did we learn from the PellePharm study? What observations led us to believe that this is going to be a great drug. So here is the first graph the support hoc-analysis and show that patients do not have the PTCH1 mutation, do not respond any better than placebo. This is very surprising observation. Though it makes sense, it is still surprising because other studies made on [indiscernible] inhibitors didn't make this distinction. We know that it is valid for our drug, and we suspect that this value to other topical hedge inhibitors if in the future, someone will think about development. But this is very, very important and makes much of the change in our study. Patients without mutation has the very same response as placebo. Let's go further. I'm customed that someone else does this job for you, so I apologize. And here, this is one of the changes that we introduced in order to overcome this block of 10 BCCs that people feel that -- this was somehow just a drug for people with 10 BCCs and more. So here is the data and please listen to the definition in the post analysis, a greater number of BCCs at baseline was associated with larger treatment effect, favoring [ protegic ] over vehicle. Large treatment effect means the separation between the drug and placebo. So what you can see here is, first of 2 things. First of all, headwind patients that have less than 1010 onwards, 8 onward, 6 and up had the very same efficacy very same efficacy as those of 10 and onwards, the same efficacy. And had we used a larger patient selection, namely from 6 businesses onward, we would have reached the same p value more or less -- so 10 was used for some reasons, maybe for statistical considerations to increase the likelihood of success in the study. But it is certainly but the drug efficacy, the drug's efficacy is equal for 2 BCCs for 3 BCCs for 5 and was 10. The efficacy is equal because the mode of action is equal. We just inhibit the Hedgehog system EBITDA subscription factors downside to PTCH and the proof is the reduction of the levels of Gle in the tumor. So the drug doesn't know if it's 20 or 10. It's the same efficacy. What is different is the response of the placebo patients. What we have realized is that while the drug is always the same, patients with a mild disease, mild stable disease do not grow new BCC and therefore, it is impossible for the drug to overcome the placebo and to show its advantage because the drug is supposed to prevent businesses to grow. If the businesses do not grow in the first place, there is no way for us to show the advantage of the drug. So again, just I would like to hammer because all baseline BCCs respond to the drug. But the difference is dramatic in placebos, though the placebo of low BCC number, they simply didn't grow in this particular study, not in real life. In real-life patients with 1 or 2 or 3 can suddenly experience a breakout of BCC. But in this study, these were mild patients with stable disease, and therefore, we were not able to see in that small group of patients, the advantage of the drug. Let's go further. So now on the right is the graph that convinced our management to do the deal with [ patidegib. ] And for me and my family to invest a little -- a bit -- a significant bit of additional amounts in order to support the study. So everything is in this graph. You see despite the small number of patients that qualify despite the high standard deviation -- despite all this, we show a dramatical difference between the drug and the vehicle, and a statistically significant one. What I would also suggest to take note of is that you see that the graph of the drug is almost leveling off. If we continue this graph for another 3 months or 6 months, it probably will be a level of at about 3% because it's already a symptotic as the technical word is but here, the slope is going is growing. So in all likelihood, 3 months from now, it would have been 8 against 3. So it will be the protective effect will be 5 BCC. That means 5 most surgeries, the spade. So this is a very powerful demonstration of how effective is the drug. And it also you may recall, we may go back to this slide. When we talk about, again, about how many the patient selection. You see that 1 year is not enough to capture the full protective effect of this drug. That is the biological process. So a good company when planning study. And that is something that the FDA has also suggested, we'll come to it in a moment, has to find the ways -- have to find the selection that we'll be able to reveal the potential of the drug within the limitation of number of patients, this rare disease. And with the limitation of time. In one year, we have to show as much as possible. So if we take patients that maybe will take them 2 years to respond because they have a stable disease, these patients are not suitable for that study. So this is the reason. With this that convinced us to go on with the product. Let's go. That's up -- sorry again. Now this is something interesting that there may be will give some color to the interaction with the FDA and to -- as a beckon to our confidence that the FDA will be forthcoming and ages to our thinking. So it's so important I will read it with your permission. We recommend as the FDA, conducting a new adequately powered, randomized vehicle-controlled trial to support the efficacy of your product. However, it may be possible to identify study design elements from the completed trial that could be modified in the future trial to increase the power, such as identify more sensitive patient population among the goal in patients or including a broader population subject with non-Gorlin high-frequency BCC. What you see here, what we did is precisely what the FDA recommended. We continue -- we started a new study with what we believe is the more sensitive patients the patients that are likely to respond to the drug. And again, I wouldn't say that we are aligned with the FDA because FDA can do whatever they choose right. But certainly, it is something that is in the spirit of the recommendation of the FDA. So this is a summary, again, of what -- if all the improvements that we introduced in the studies -- 2 of them referred to patient selections. We use facial BCC 3 and above. It was the previous study and our study was 10 and above, PTC mutation was not mandatory in the perform study, and it is mandatory in our study. And that's it. In terms of operational improvement, the we to do several important changes that we think will improve the accuracy of the study reduced for positive or negative. And as we already know, has also reduced the number of dropouts patients. As a result, every patient that drops out cost dearly to the statisticians. So the fact that we have only 10% dropout is part of is the result of some of our measures taken. First of all, because we're talking about Gorlin patients with many, many, many small red dots that may be diagnosed either as and BCC or as rosacea or something. It was very important to use the [indiscernible] what we call here it's called [indiscernible] in order to make the wide differentiations. We know for a fact that it works because in the previous studies, we experienced a lot of what we names zigzag effects, namely higher number of BCC than the second visit low and then high again, we have -- this doesn't happen in this study. So we made a mandatory use dermatoscope, we introduced a very qualified and central photography review board, namely every diagnosis is then revised by the specialists for the review board. If there is disagreement, they negotiated the primary investigator and the KOL from the review board until they come to the agreement. If no agreement, it's a decision of the review board member. And we simplified the number of visits. There were too many and this was very tedious to only 6 visits. The rest is a virtual. This is just another summary and you see everything that was already told I was talking about. In addition, you see there were 40 on site, 184 patients were screened and then enrolled only 113 that met all the inclusion and exclusion criteria. And finally, 102 completed just 10%, which is something that we already know and we are very happy about it. The endpoint is the same as was the last time, primarily is the number of new BCCs and key secondary number of new SEB, which means those BCC that grow to become surgically eligible BCC. We will be monitoring also other -- because this is an important treasure of data, other parameters, but they are not part of the endpoint of this study. Here is the milestone, top line next month. And they don't pay attention that it's of Q4. It's going to be next month. And NDA submission will be in April and then approval in Q2 and then approval somewhere after 6 months because we have the orphan drug status and breakthrough status and launched in the beginning of 2028. We have strong IP protection that we believe will be an iron wall at least until 2045 and we plan to continue with new applications. Now about the market opportunity -- we work -- our planning is based on 11,000 patients in the United 8 out of which, after eliminating patients that do not have significant BCCs despite the fact that they diagnose with gorlin and pediatric patients right now are not included because of safety reasons. But we believe that given the fact that our absorption -- topical absorption is of that absorption of -- the blood level that we reach is 101% compared to the absorption of Hedgehog, Oral hedgehogs, we believe that we will be able in 1 year or more to also add -- get theatric use and also pediatric patients. We'll do it gradually. We'll start to pension that are close to the normal heights because all hedge may affect the growth of children and then gradually go down as more safety data is accumulated. But here, in this conservative calculations, pediatric patients were eliminated. And then we figure something like 80% adherence that will be part of our job to maintain it. And based on all this, we reached about 600,000 million eligible patients based on the demographics of today and expect peak sales a 65% penetration that will lead us to 4,000 patients. In Europe and rest of the world, there, obviously, more patients than in the United States. We know that there is a significant market. We are approached by patients from all parts of the world where can I get your drug. But as you know, and I will not elaborate about this -- there's pricing issues, and we have to first make sure that whatever commercial decision we take outside the United States probably because of price control, the other markets will be lower than the price of the United States. We want to make sure that, that will not have a negative repercussions on our American business, and therefore, we are not calculating them in our forecast, which is 860. The price will be comparable to very expensive topical drugs that were introduced and still half of the price of [ Viju ] paved the way I would say, for expensive topical drugs in the past, topicals, irrespective of the efficacy and importance. We always assign the low price category. This is no more the case. So the question is how do we -- how are we going to commercialize ourselves in the United States. There are obviously several models. One is to give the drug -- license a drug and get to all this. This is, of course, is not the right model for us because we want to keep the majority of the economics. And we decided to go independently to launch in the United States, America first, the rest will be done with probably with partners. And the reason why we think that a small company like us can do it successfully is that all the features of this drug commercial features are suitable for independent commercialization. The drug is expensive. The contribution for us is very high. The costs are low given the fact that the target doctors are maybe something like 200 centers of excellence, something that team FTE sales reps would be sufficient. And the other thing that we expect based on all our interaction with physicians mainly, but also with patients, the uptick will be very high, very fast. And why that? Because sometimes rare drugs come to the market with a very complex mode of action that the physician may not be familiar, maybe skeptical. And therefore, it will take time to educate them. This is not our case. Doctors know perfectly well about the efficacy of all hedge hogs, but most of the patients cannot tolerate it. So they are waiting for a drug that will be as efficient or have to close efficacy to all hedgehog but do not have the side effects. And I believe that this is our situation. So when we come to the doctor, I say here is the drug that works very well and showed clinical data and has no side effects, we assure that the doctor will be keen to try it. And if the success is as we expect, we've done our job. So this is -- I know that time pressure to all go quickly. So how are we going to commercialize it? My commercialization plan has 4 pillars. One, the first pillar is increased the awareness. We know that every drug, every drug especially in a particular orphan drug that doesn't have a therapy, both the disease, every disease that doesn't have a drug the disease itself and the patients go under the radar because there is nothing to give them. That is how it works. The moment a drug is available. We will see an up rise in the number of patients and the interest. So first of all, we have to increase the awareness, use all the modern measures and social media and will take the right experts to, first of all, raise the awareness. The second thing is to identify the awareness on. Again, social media and other measures, including, of course, the relations with the physician will enable us to identify and then establish a direct contact with the patients. Ideally, we would like to know each patient. We're talking about 1,000 and 2,000 and 3,000, not millions and not hundreds of thousands. We would like to know each one by its name and to send Christmas card each year, so creating at the right time. So and continued this close report with the patients. Here, we are planning to collaborate with the Gorlin society. And they plan to establish regional centers of excellence that will provide patients with comprehensive treatment of the disease rather than the situation today where they have to run into different places to get treatment, we would like to integrate ourselves into this system to be part of the system. Well, of course, will support it also financially. And so in order to make this happen as soon as possible. And increased the support to these patients, facilitate genetic testing and everything that has to be done for the purpose of promoting the drug, but also for the purpose of assuring the best treatment to the patient. And then the last thing, which is no less important and we'll have a specialist that will handle this is the retention. This is a chronic drug. And here, Gorlin will not be any different than other diseases patients is coding, especially if they see that condition is improving. They tend to say, okay, now I'm okay. And then may be less strict about usage of the drug. We will be there to support them to encouraging there and use all kinds of measures, webinars and others to handle the fact that like in many chronic treatment, you have to adhere to the prescriptions. So adherence is a very important part of the business. It is sometimes easier at a certain, you reach a certain level to ensure adherence to which increase your revenues by ensuring deals, they then look for the patient number 400. So that will be one thing. And as part of the work of ensuring -- starting with the first pillar of awareness, we already applied for an ICD code for Gorlin disease. So far, it was part of a more broad cut of several genetic disorders. So we already started this proactive work and didn't wait for the approval. We are no signal I think I'm close to my -- so here is just a No. So this is the -- what I've been speaking about right now, the broad and intensive commercialization effort that will start already now to create -- and people ask us about the future of the drug. So there's many, many, if you say, growth engines. One of them is simply the human body because unfortunately, all parts of the body are afflicted with BCC, the most sensitive one, both aesthetically and in terms of incidents, is the phase, and therefore, we started with the phase, but there are other areas that need protection. Each one has its own challenges, but we are definitely going step-by-step to cover the whole body with this drug. So this is just within the same patient, the one important growth engine. The second 1 is high-frequency BCs which is as important. Maybe it's more prevalent, maybe less devastating in terms of the number of businesses but very important market because it's bigger market. Here, the big challenge will be to select those patients within the high-frequency BC that has high enough incidents. We would have to use, again, very sophisticated social media analytics in order to identify them for the studies. In the real life, again, it will be that doctors will not be that stringent in terms of the number of BCC, but it is important for us for the success of the study to identify the right patients. And then the other thing is size reductions. The data that we have so far from the previous studies, suggest that we can reduce the volume of the BCC by about 50%. We have to verify this study, although it's not an endpoint, we will monitor and if that will be the case that we can reduce the size, there is an important market out of the 3,003,000,000 I'm already thinking only in the billions when thinking about Sol-Gel. But that's 3 million procedures of BCC, there are about 100,000 that could be labeled as difficult to treat, namely simple more surgery would not do the job either because the tumor is very close to sensitive areas like the eyes or some lines. Because the patient is fed up and say I cannot endure more surgery. So for this, our product could be a very good solution. It's topical. It doesn't call side effects. And actually, we are starting a study this month, maybe it's already started for downsizing BCCs in sensitive areas of the phase. In the framework of neoadjuvant therapy in [indiscernible] reduce and then perform the surgery. But the data that we will gain is both for the concept, let's say, of no adjuvant, but also -- yes, I'm finishing, but also for the phase that relates only to the size reducing the size. So there's many -- much potential. We believe this product could be a pivotal element in the treatment of every BCC -- and -- but first of all, is a few thousand patients that will provide us the first $1 billion of sales, and then we'll worry as they say, we first take Manhattan, then we take other parts of the business. Thank you very much. I apologize for not controlling myself.

And I would like to introduce Julie Breneiser. Julie is the Associate Director of the GSA, the Gorlin Syndrome Alliance. Prior to this, Julie was Executive Director for 5 years, the President of the Board of Directors. Her early career began as a physician as a physician assistant Julie and 2 children are affected with Gorlin syndrome. Julie's work with the GSA focuses on collaboration with the industry to bring potential treatment to clinical trials. Julie speaks nationally and internationally, raising awareness of Gorlin syndrome and the burdens of this multisystem disorder as well as advancing drug development for diseases. Julie, please.

Thank you all for being here today. It truly means the world to me. As Ofra said, my kids and I have Gorlin syndrome, they are 34 and 33. And this is something that we have and will be monitored for every year throughout our lives. And there are lots of manifestations. Basal cell carcinomas are the biggest burden that we face every day. We have no FDA to approve treatments for any of the manifestations whatsoever. And as you'll see, we desperately need something, particularly for the basal cells. And honestly, patidegib will be life-changing for us, life changing. And I know that sounds dramatic, but it's true. This is a collage of my face from 2 to 65 a couple of photos here to point out. In the bottom row, second from the left, I'm balled from using the hedgehog inhibitor [indiscernible] And in the bottom row on the far right, I'm recovering from having a basal cell removed in a skin cancer of a BCC with a skin graft on the tip of my nose. My story isn't all that unusual for people with Gorlin Syndrome. And I hope this by telling you today, you'll have a feel for what it's like. I was diagnosed when I was -- at that point, I had 3 large justice removed with 2 surgical procedures. I had manifestation since a newborn, but we didn't know that at the time. And my first BCC was removed then. And since then, I've had over 1,000 removed. I'm seen by dermatologists several times every year. and have never ever left one of those appointments without having at least one biopsy and on excision, along with scheduling of a MOS procedure for a more extensive removal. All of these were painful. All of them left scars. That started 56 years ago when I was 12. Separate from all of these BCC I've had 19 major surgical procedures for the other manifestations of Gorlin syndrome. A brief fact sheet. You'll hear more about some of these later. It's also called basal cell [ Neva ] syndrome or basal cell carcinoma never syndrome. -- incidence is approximately 1 in 31,000 it's an autosomal dominant disorder, which means that you'll have a 50-50 chance of passing it on to your children. And the de [ novo ] mutation or spontaneous mutation rate is about 31%. And it can affect every organ system of the body. And there are over 100 possible manifestations. The most common are the basal cell carcinoma Justice, the odonogenic keratosis are the second most common and the psychological burden of anxiety and of living this disease is next. And again, we have no FDA-approved treatments. Some of the other manifestations I just want to mention, pits on the palms of our hands and souls of our feet. Medulloblastoma is a malignant brain tumor in infants and toddlers. Hydrocephalus, large gulfs, meningiomas. Benign brain tumors, ovarian and cardiac fibromas cliff lip and pallet, the list really goes on and on. Before I dive into the Sol-Gel product patidegib, where it will have the most impact for us and our quality of life, I want to touch briefly on something that Mori had in one of his later slides where it could help and that is with the second most common manifestation, the odonogenic keratosis, the OCs. In my teams, we were told that these were -- are benign, but malignant in their recurrence rate, which is over 40%. Surgery to remove them has to be aggressive and extensive to reduce that recurrence rate. And you may lose permanent teeth. You may have permanent lip numbness as a result of these surgeries. So we need something to help reduce that recurrence rate. And just to explain these slides a little bit, the image on the left there, the sinus where you see a gray bubble, that is in OKC and my son. The image on the right is an MRI of another individual and the sinus should be black. It's solid gray. It's totally pacified with a that required very extensive surgery. The scans on the left were taking 18 months apart, and they show on the top, you can see the arrows pointing to assist. On the bottom, the image shows 3 cyst, 18 months later, 1 is a recurrence and 2 others had to be removed. Since then, that in the upper jaw has been surgically resected. So historically, the assists were packed with something initially called [indiscernible] solution, that's banned now because it had chloroform in it, not good stuff. 5-floor Urosil has been used in by impregnating the [indiscernible] packing it into the cavity. And that's had variable success. So my hope is that the use of patidegib goes impregnated with patidegib will make a difference for us. And just briefly to give a bit more context, I've had a total of 8 OKCs removed so far. My kids have had 9 and 8, and we've all had at least 2 recurrences. So I'm going to talk about the basal cells now they're really a menacing presence. And I just want you to be prepared because some of the slides that I'm about to show may be disturbing and they show why we need this product. As investors and analysts, you look at numbers in terms of dollars as a patient apparent and an individual representing people with Gorlin syndrome. I look at them in terms, I look at numbers in terms of the volume of a basal cell carcinomas. For the majority of us, these are big. -- it's not just a basal cell. It's hundreds and hundreds in private places in sun-exposed places in non sun exposed places and they never stop developing. As you view these images, remember that we have no FDA-approved treatments, and some people feel that what's available to us is barbaric. So let me briefly run through these photos for you. Top left, is the red areas and oosing areas, our basal cells. The next image, I'm on the left there, having completed a 6-week course of Efudex on my scalp. That's why my hair is so red and short. The woman next to me holding her infant on both have Gorlin syndrome, and she is aiming to have more children. And so she has stopped all treatments to prepare for it. The rest of the images show people with many, many basal cells. These are images of children and adults undergoing various types of currently available treatments. The boy on the bottom right is in the recovery room after having Justice and removed and at the same time, while under general anesthesia, he had a number of basal cells treated with laser by his dermatologist. This is a difficult slide to view for me for lots of reasons. The bottom row is a family affair. That's my son on the left, me in the middle. And my daughter on the right, 2 years ago, she had a most surgery of a lesion right here and it ended up being a 3.5-inch by 4-inch defect that required significant plastic surgery to reconstruct it. For everyone affected and involved disease burden is obviously tremendous and never goes away. Just like the Sunrise in sets, the BCCs never stopped developing. So back in 2021, the Gorlin Syndrome Alliance completed a global survey. And one of the questions we asked was about the number of BCCs that you have developed. On the left, you see numbers of DCCs on the face, neck Scout. 45% of the respondents at that time, it had over 50 BCCs on their face, neck and scalp. The slide on the right represents respondents with BCCs on other parts of their body. 42% had over 50 and 5% had over 1,000. So what are our options? There are lots of them. All of them are difficult. All of them are particularly with the number of BCCs that we have. The surgical ones all cause pain, permanent scarring and disfigurement. The topical ones often are painful, messy, they scar and they can take weeks. And the oral hedgehog inhibitors, they're great. But for most people, the BCCs come back and they're hard, chemo, their oral chemo. You lose your hair, you lose your ability to taste many foods. The muscle cramps vault you out of bed in the middle of the night. So sleep is heavily disrupted. And immunotherapy is available, [indiscernible] though it hasn't shown success in people with Gorlin syndrome. All of this put together all of these treatments end up causing us to lose on average 25 days per year to treatments and life and recovery because it takes time. And that was -- those numbers are from a global survey that we did a few years ago. We desperately need more options, ones that don't cause a scar. Ideally, they are not painful. There are no injections. And while recovering, there's no using or scabbing like you saw in some of the images earlier. Sol-Gel's product patidegib offers just this. No scars, no losing, no injections. Fewer physician visits, less time lost from life. There's nothing else that does that, nothing. Over the last 5 years, the Gorlin Syndrome Lance has surveyed the community 3 times asking a question about what would make a difference. One of these was during our externally led patient-focused drug development meeting for the FDA. The affected audience was asked with a preventive treatment that reduces the development of new basal cell carcinomas by 30% and with no challenging side effects, the improvement on your current options. 94% said yes, a patient-preferred and clinically meaningful reduction of the volume of BCCs by 30% would be as hugely desired. We're born soldiers fighting lifelong battles. We didn't enlist in them. We desperately need something that slows or interrupts the constant tie to basal cell carcinoma development and reduces the size of those that are present. We are not nor will we ever be cancer survivors. We live with it every single day, and we're considered never cancer-free and never in remission. We can never ring the bell indicating that our treatments are done. None of the treatments have -- we have now are adequate. It's simply not possible to keep pace with the rate with which we produce BCC. Another way to say this is that the rate of BCC development is greater than that of removal. Those of us living with Gorlin syndrome, fuel life through a lens of not knowing that we will -- or knowing that we will always have cancers developing, always have appointments with dermatologists, skin cancer surgeons and other specialists. As one parent wrote, the ache of knowing a future, I cannot shield her from is deep and penetrating. It comes with a morbid assurance of constancy. There will never be a time when she won't have to worry about cancer when she can pause the march of cuts across our body. Patidegib can change this for us. Thank you in advance for helping us keep scars off these cute little faces.

I would like to introduce Dr. Ervin Epstein. Dr. Epstein was practicing dermatologists for more than 50 years in the San Francisco Bay Area. He led an academic research lab funded by the NIH for 45 years. Dr. Epstein has also served on the Board of numerous dermatological organizations, including the American Dermatological Association. His publication have appeared in the New England Medical Journal of Medicine, nature and science Dr. Epstein.

I don't believe I've followed our previous speaker before tough act to follow. Very, very moving. I've been interested in this disease, it's 1970, 50 years, but never had the experience of living with it like she did, very remarkable. In addition to what we said before, I think I'm a co-founder and consultant to PellePharm, the preceding company that developed this drug, and I've been a consultant to Sol-Gel since they took over the baton. My topic is overall the study of -- the story about hedgehog signaling and hedgehog inhibitors in BCC and specifically. The BCCs are driven by excessive hedgehog signaling pathway activity and the patch mutant BCCs are susceptible to smooth and binding hedgehog inhibitors, including most particularly [indiscernible] So the question is, how did we get here from Gorlin syndrome to the hedgehog and signaling as a driver of all BCC. In 1960, Robert Gorlin, who was a dentist, was the last person to describe the Gorlin syndrome. In the same way that Columbus was the last person to describe America. He got the credit for it. He published in the New England Journal instead of in the dermatology journals. He deserves all the credit can possibly have. In 1980 to 20 years after he described it. [ Christine Neuschlein Volhardad Eric Visha ] today published the results of a massive fruit-fly-muted Genus study. So they zapped fruit fly larvae and look to see what kind of mutations would develop. And they found lots and lots of them. We remodeled the whole disease and included the hedgehog phenotype. And why did they call this phenotype hedgehog because other names were already taken, including particular -- the other one. And in 1996, we as part of Global Village identified the patch mutation as being the site of the mutations that underline most cases of Gorlin syndrome. So that raises the question, what is a signaling pathway, right? Who knows who's comfortable with what is a signaling pathway here? Wow, 0%. That's terrific. Anything I say you'll believe. So to me, I think the easiest way to think about it is it's the nervous system of the individual sell. You bake a cake, you put your hand on the cake, you say, "Oh, my good news. There are signals -- there are signal receptors here in the palm that say hot. They send that message up to the back of the spine and the spine sends out and go say, move your arm dummy. It changes the behavior of your hand based on the information that they find from the outside. That's what the signaling pathways do. They monitor the environment of the cell and then they tell the cell, how to behave differently and change their behaviors in accordance with the with what they find outside. And what specifically is the hedgehog signaling pathway. Specifically, it is one of the major pathways by which this amazing thing happened. I don't think anything is more amazing in biology. A single fertilized cell turns into the multicellular newborn, and it does it in 9 months in the dark with no instructions. This is how it does it stay. Specifically, what is it? And on the molecular side, these are old pictures but they're the easiest. The modern ones are harder to understand. So on the left, the pathway is inactive. And on the top, you see at the outside of the cell, the cell surface on the left is a protein called smoothen and on the right is a protein called patched. You see that. Yes. Please, nod. Thank you. You're good. You nod. And when the signaling pathway is inactive, the patch inhibits signaling by the smoothing. Okay? That's inactive. And on the right, when hedgehog comes along outside. The outside of the cell in the environment, it stops inhibiting smoothen. So smooth and c, it tells goes -- send the message to the brain of the cell, effectually known as a nucleus and that sends out new messenger A which says make proteins, change the behavior of the cell, go make an eye, go make a head, go make a hair follicle, okay? So that's the basics. For those of you who want to be more in the weeds, there's this funny signaling pathway chart. You see there's a little expresses on the outside of the cell, although as we in dermatology call them pipe. And this is a signaling hub that recognizes that does a lot of the signaling work of the cell. And what patch does is it keeps the protein of smooth and outside of this because if it gets as shown on the right, then it sets a signal to the brain, to the nucleus. We got to do something different guys. So these are outdated, but they're easier to understand than the more modern ones. So I said earlier that BCCs are driven by excess hedgehog signaling, that's the crucial thing. That's what I want to leave you with. So there are 4 series here of data that argue for that. The first and functional 1 foundational 1 was 19 our lab plus a dozen other labs on the Global Village identified that most cases of Gorlin syndrome, which has lots of BCCs, of course, as you've just seen, is the patch gene has the mutations, which underline the Gorlin syndrome in most cases. In the United States, in the EU, at least in our study, the Phase II trial that you've seen discussed before, 85% of clinically diagnosed patients with Gorlin syndrome have a mutation in patch that you can readily identify by current standards. Less than 5% have a SUFU mutation, a downstream inhibitor, a downstream block and at least 10%, we don't know where they are. Okay? So that's the main thing is that if you look at patients and their families, the gene that's passed down from 1 to another that's muted is patched on. Secondly, if you take that information and you're a mouse person, you make a mouse that has an abnormality that upregulates hydro signaling. And these mice get basal cell carcinomas. And in fact, despite it being by far the most common human cancers, there was no mouse model before this of basal cell carcinomas. But when you make a Gorlin mouse that has a mutation in patch on then they get lots of PCCs, especially if you treat it with Ultraviolet or radiation, which will give VCCs to all of us. Third, is the hedgehog signaling pathway as assessed by the amount of messenger RNA that codes proteins that are downstream effectors of the hedgehog signaling pathway. If you look at that, they are upregulated in all human BCCs whether it's sporadic or in people with heritable disorder. Okay, okay. Not all have been tested but enough have been tested, that you can say it's pretty much all of them and be pretty confident. Finally, oral hedgehog inhibitors, as we've heard before, and I bet most of you know about that. are very strongly effective in inhibiting BCC formation, remarkably so. As shown, I think, yes, in the next section, which is a paper that we did looking at Arrivage. This is not results with oral -- it's a result with oral hedgehog inhibitors, but are not potent. But the patent results are published in what juiced orally has about the same results as does arrivage. But this is arriving. And on the right, you can see what happens if you take placebo. And on the left, you can see what happens if you take this mothership at each line of the spider plot represents an individual patient, okay? So on the upper right, you can see that in the placebo, lots of new BCCs were developing during the course of the year of the trial. They all went up. And in the one on is motors on the left, they didn't go up, probably the ones that went up ones that we personally missed seen. And below is the results not in development -- prevailing development of new BCCs but in shrinking existing BCC. So you can see the one on the left, they all got smaller. And in fact, that study shows that if you take one pill of arrivage, from here, you have an 80% likelihood that all the BCC that are there at the beginning, maybe 100 of them are gone. If you look at the skin and if you biopsy the skin and look at it the microscope, they're also go. But when you stop it, they come back. So the other question is, why do we think that small molecules could inhibit hedgehog signaling -- it is a, what I think is an absolutely great story. And I would recommend you go -- wait until we're through. But afterwards, go to year go to YouTube. Thank you. Thank you very much. Go to YouTube to look at the mystery of the [indiscernible]. Here is the one eyed ship on the left. And there was an epidemic in the 50s in Idaho of 1 sheet being born as well as a bunch of other bad things happening to them. And government -- remember, the federal government well did things and was good. They went out and they found out that it wasn't an induction. It was that the pregnant use were eating the corn Lilly, the California [indiscernible] Lilly. And on the right, as I know is the picture of the power and on the right is the weed. Later, in the '60s, somebody came out and found that they actually isolated the alkaloid that produced this mutation in the sheet in the labs. Here is -- how many people go to the movies here? How many people have time to do that. You see this handsome looking fellow. He is [indiscernible] right? And this is a picture of him as shown in the recent odyssey. And he is doing this had some looking to is eating some of [indiscernible] has been. And since he was a cyclops, and name polyfemus. This alkaloid was named, of course, [indiscernible] patidegib is a derivative of that material. So the object here is to reduce the burden of basal cell carcinomas right? Okay. So here is a car to that shows that reduction, how you can reduce new baseless cell carcinomas. On the top line, there's no reduction. And you can see that the normal skin on the left is converted into a beautiful base is how cards to do on the right. You all see that, right? Good. In the middle is prevention. Like if you did gene therapy in a patient with Gorlin syndrome and you eliminated the very first starting of the BCCs that would be -- there would be no basal cell carcinomas. That's probably not what we're doing. We're probably doing is a thing on the bottom, which is interception. We are preventing them from getting big enough to bother. And that's the same with arrivage because when you stop it, they come back. So here, you can see on the left that the tug inhibitor in the middle is inhibiting the development of BCCs. That's interception. This is a concept Blackburn introduced 15 years ago and a concept that other people have been talking about. And indeed, it's a very hot thing in oncology these days because there have been papers in the past year that have been very exciting, showing a reduction in the development of new lung cancers and a reduction in development in new pancreatic cancers and people who are going to get these otherwise. So this is a big deal, and we're right in the middle of that kind of thing. But we bring a history of being dermatologists where we've been using 5-fluorouracil to treat precancers squamous cell carcinomas for 60 years. So this is just building on that well trodden path. So these are the 4 bases on which this lies and if it works well, so oily, surely do the same topic, how can we mix. Thank you very much.

Thank you. I would like to introduce Dr. Kavita Sarin. Karvita is a Professor of Dermatology and the Director of the Stanford Skin Cancer Genetics program at standard Cancer Institute. She received a medical degree from Stanford University School of Medicine and holds a PhD in genetics from Stanford University. Her lava [indiscernible] cutting-edge sequencing and imaging technologies to better understand skin cancer and rare immunologic skin diseases. Dr. Sarin, please.

Thank you very much. Well, we gave such a moving presentation on the life of someone affected with Gorlin syndrome. And I think that probably shares more than even what I can share, but I will share the perspective of a physician who treats patients with Gorlin syndrome. And I think the commonality you will find between all of all of our talk today is that there's just really a desperate need for treatment. My one disclosure is that I've done some consulting with Sala on their genetic testing program. So as Dr. Epstein mentioned, online is an autosomal dominant tumor predisposition syndrome. What that means is that if you have Gorlin syndrome, your children have a 50% chance of inheriting the syndrome. The estimated prevalence has a wide range from 1 in 31,000 to 1 in 256,000. I will tell you personally, it is much more likely to be closer to the 1 in 1,000 and I will see a lot of patients who have not been diagnosed until adult head until they come into our clinic with Gorlin syndrome. There's a severe underdiagnosis of Gorlin syndrome. And because of that, an [indiscernible] of patients and 20% to 40% of patients come in newly diagnosed with Goran syndrome without having any family member affected with Gorlin syndrome. As Julie mentioned, the tumors can appear everywhere frequently on sun-exposed areas, certainly on nonsunexposed areas too. There can be any histologic subtype and they can be pigmented and they can start very young and not look like basal cell cancers. Over half of patients with Gorlin syndrome have their first tumor by the time they're 20, 3/4 by the time they're 40, and they can develop hundreds to thousands in a lifetime. And what's unique, I see a lot of tumor predisposition syndromes in my clinic. But what's really unique about Gorlin syndrome is how tightly the mutation is tied to the drug target. So Patch 1 is mutated in 85% of patients with Gorlin syndrome. And I won't go over the pathway. Herb just did a beautiful job doing that. But I think the point is that Patch 1 is a direct inhibitor of smoothing, which is the drug target. So it's very rare with an oncologic disease, or tumor predisposition syndrome to have both a genetic mutation just so tightly tied to the therapeutic drug target. There is a second mutation that we see, which is souffle mutations. But that occurs in only about 5% of patients with Gorlin syndrome and is downstream of the drug targets. The downstream has smoothen. As I mentioned, I'm diagnosing a lot of patients as adults who have been missed his children. And the diagnosis is primarily clinical. So basal cell cancer is one of the hallmarks of the diagnosis. But especially when we're getting. We're diagnosing them as kids, a lot of times we're digesting them because they're referred from an oral surgeon because of the [indiscernible] caradisis of the job, which can be really devastating actually. And so then they get referred in for evaluation for Gorlin syndrome. There are other findings as well as Julie mentioned. But I would say that basal cell cancers and the adynagetic keratosis are probably the 2 primary ways that patients are getting referred into our clinic. There are radiographic abnormalities. But in this age of genetic testing, I rarely use radiographs to do diagnostic clinical criteria testing. It's almost always straight to genetic testing at this point. This is an example of a child, 1 of my kids with Gorlin syndrome. He's of Indian decent, and I just wanted to bring this up with the photos I've chosen to use today to say this is not just a condition that affects white European patients. ICPs are Hispanic. I see patients who are Indian. I see patients of all skin types and they develop basal cell cancers. And what I want to show you in this patient is that the basal cell cancers don't necessarily look like basal cancers, and this is why they're getting misdiagnosed. If you look at this child and I hope you can appreciate both on the face, these tiny little brown spots, they almost look like molds or skin tags. On the face and on the shoulder here in the unprotected area. Every single one of those is a basal cell cancer. This young child had over 50 basal cell cancers on their skin and then the palmer pits, which the planter pits, which don't show up as well. For this child, he was referred in for as a [indiscernible] which can be quite devastating. In the course of 3 years, you underwent surgery 4x under generates for the treatment of dynegenic caratacist. And I also similarly went in while he was under anesthesia, and similar to 1 of the photos Julie said, we actually did a different thing we called an EDC scrape and burn. We scraped and burned his basal cell cancer as while he was under general anesthesia. And the basal cell cancers in children can look actually even histologically a little bit different than adults. A little bit more like primitive almost while they're young. And this is a patient, even though he meets clinical diagnostic criteria for Gorlin syndrome that we ordered genetic testing. And at this point, we're ordering genetic testing for every patient where we suspect Gorlin syndrome. And why is that? One is for clinical diagnosis. The second is for family testing because if we know the mutation, then we can test first degree family members to see if they also may have undiagnosed Gorlin syndrome, also for prenatal testing or family planning. And the third reason is because it could affect both their prognosis as well as their clinical care. There are some data to suggest that the type of mutation you have in Gorlin syndrome dictates your care, for example, or the types of conditions you might develop. For example, if you have patched 1 mutations, you might be more likely to get a [indiscernible] keratosis than if you have a SUFU mutation. Patients with a SUFU mutation may be more likely to get medulloblastoma. We've also found that treatment responsiveness, and this has mostly been published in case reports. There's not been really great studies done on this, but that treatment responsiveness to oral smooth inhibitors also depends on the patch versus SUFU mutation. And because SUFU is downstream of the mod inhibitors or [indiscernible] inhibitors, patients with soup mutations are more likely to be resistant. So this is the reason why we're ordering genetic testing on every patient at this point who comes into clinic. So once we have diagnosed a patient with Gorlin syndrome, what we really do is shift their view from just surgery to remove every single cancer to monitoring. And this is because surgery, if you have every single cancer removed, just like Julie presented so beautifully, it really can lead to significant surgical exhaustion, functional impairment, disfigurement and so we really just have to ship the mindset. We're not going to try to cure every single base cell cancer from your skin. We're going to try to stop them from becoming life-threatening to watch you carefully and to manage them. So what does that look like? Well, we do a full skin exam every 3 to 6 months. We certainly start to discuss photo protection. And the way we do our photography is we have this Scan field 2D image, full body photography, so patients stand kind of like this and different poses, and we take a full body photography of all the lesions on their body, so we can track all the tumors. And our goal again is triage rather than treat and cure everything. And there are some good 2026 guidelines. Consensus statements on sort of the severity of Gorlin syndrome. But for every patient with Gorlin is pretty much getting full body photography and at least every 6-month clinical exams. And this is another patient. This is a Hispanic patient on the right. You can see the development of pigmented basal cell cancers, they look like on those people think they have melanoma. But I just want to show kind of the variety of what these tumors can look like. And while you see 2 big ones, he actually has numerous probably on the order of 40 or 50 on the face, and they present as tiny little spots as well. So what are our treatment options? Well, topical, we have sort of 3 options that we can consider in [ Micumad, ] which is a topical immunotherapy [indiscernible] a topical chemotherapy and food dynamic therapy, which is a photosensitizing destructive therapy. All 3 of these cause a lot of redness and scaling. And we primarily are using them to treat the most superficial type of basal cell cancer. So [indiscernible] weeks of therapy to a superficial basal cell cancer can cause inflammation, but can lead to a response in about 75% of tumors. I think it's a little lower with Gorlin Syndrome, I'm not sure why, but that's the case. [indiscernible] topical chemotherapy also causes a lot of crusting, irritation, scabbing but can also help with the most superficial basal cell cancers. And photodynamic therapy is very similar causes redness and cresting in the areas that are treated, but can't work. The reason this is not effective. We don't use this more broadly outside of the side effects is it really only works for the most superficial type of basal cancers, which are the minority of basal cancers that form these patients. And again, we do use this, though, because we want to reduce the number of surgeries. Procedural for therapy. [indiscernible] and curitage. This is what I did for the young boy when he was under general anesthesia, sort of a scrape and burn approach to treating them, but it can work that you can do multiple, each one of those can leave a depressed scar in the skin. And then certainly, the definitive therapy for removing a basal cell cancer is excision and most surgery. So we'll refer for that, those as well. We do not use radiation therapy in this group of patients because it's -- they're photosensitive, they're highly likely to develop new tumors in the site of radiation. This is an example of one of my patients on oral hedge to inhibitors. This is the one I showed earlier. So you can see the basic cancers in addition to the 2 big ones, which do not change underneath his left, I want you to look at all those tiny ones. And you can see that many of its tiny small ones actually completely disappear fully, not visible at all under treatment. You can also see some of the hair loss that continues to develop over time in patients. And what you can't see are the side effects. Oral hedgehog inhibitors. The genetics kind of prove out the hedgehog inhibition, the oral hedgehog inhibitors actually like prove it out in clinical trials and in clinical experience. It's very -- they have very high efficacy in decreasing the number of new surgical eligible BCCs in the study that Dr. Epstein ran and in clinical experience. The bigger problem is the tolerability. So 54% of patients discontinued the drug because of adverse side effects. And those adviser side effects can affable life. They can be like muscle cramps, which make it difficult to work or do your daily activity, taste changes. I've had patients stoppage changes. It's quite amazing how much someone's enjoyment of life depends on their ability to taste food. And so stopping the ability of taste food can actually be a huge and unexpected to me, at least initially until like talking to base reasons why patients will stop treatment. And then there's the hair loss, weight loss fatigue and other things. But I would say those the taste changes, the muscle cramps, I would say those 2 are probably the biggest reasons for discontinuing treatment. It's also highly teratogenic as you saw from the earlier photos that Ib showed and we don't use this in kids because of the side effects as well. And while this works for our advanced in metastatic basal cell cancer patients, these toxicities really are very limiting for long-term use for a chronic condition like Gorlin syndrome. So in practice, because basically, every 100% of patients I put on oral hedgehog inhibitors with continuous dosing will stop 100%. There's no one who continues it without stopping we've moved to intermittent dosing, and that's where we put them on for a period of time and then take them off and put them on and take them off. And there is data to support. This is the MIKE trial. The MIKE trials examine 2 different doses of intermittent use of hedgehog inhibitors and found actually very high efficacy between 54% and 62% efficacy. So very high efficacy with intermittent hedgehog inhibitors, a decrease in tumor size. And this worked both in Gorlin syndrome as well as patients with high-frequency base cell cancer. The problem and I'd say the positive of this is that it significantly reduces the side effect. So about 23% discontinue the medication with intermittent therapy compared to the 54% that was with the continuous dosing. But the toxicity is still there, 95% of patients had a drug-related side effect with the hog inhibitor and 47% paused for some reason. So this is helps, but it's not perfect. We need better treatments. So that is pretty much -- I'm not going into the immunotherapy because I don't think it works very well in Gorlin Syndrome, but it works for other cancers very well. But this is pretty much the state of the art of our treatment arsenal for basal cell cancers in gone syndrome. So I think surveillance and photography is standard. Everyone is going to get it, everyone has it. It's just part of care. And then the topic is for the most superficial tumors, they have side effects, but for very superficial lens and individually treated, they can be effective. The other treatments like electric densification and caratage and certainly most surgery are much more definitive. But leave scars and could lead to significant surgical exhaustion. And the oral hedgehog inhibitors are a mainstay over half my patients on Gorlin syndrome are on for oral hedgehog inhibitors, but we're limited by their side effects and even for our patients who do choose to stay on them, they have to live a life experiencing those side effects of the medication. So the gap in our treatment is a tolerable treatment that can lower the rate of new tumors for our patients. without the significant side effects, and that's what we're lacking

I would like to introduce Dr. Elizabeth M. Billingsley. Dr. Billingsley, is a Professor of Dermatology at Penn State University College of Medicine and practices dermatologic surgery and most surgery. With Penn State Health. She [indiscernible] on medical degree from Penn State College of Medicine. She does clinical research and trials in cutaneous oncology and Gorlin syndrome and she is the past President of the American College of Moss Surgery, Dr. Billingsley.

Thank you very much, and thanks to our previous speakers for really outlining the challenges of Gorlin syndrome and the need for an effective treatment for all these affected individuals. As mentioned, I do clinical research and skin cancer, and I had done recently some clinical trials with Regeneron and Sol-Gel as well. They also have done some consulting in the area as well. So we certainly heard that Gorlin Syndrome, the manifestations. These patients do get tens to hundreds or even as Julie mentioned, can get 1,000 skin cancers over their lifetime. I think the key thing is it's a lifelong condition. We cannot cure these patients. They are going to be developing skin cancers throughout their life. We need a treatment that they can use throughout their life. As a surgeon, I know the numerous surgeries we cause scarring. We scar these patients as we treat the skin cancers. And because of that and because it's a lifelong condition, patients often burn out. They develop surgical fatigue. They get tired of the surgeries they get tired of the pain. They get tired of taking off work. It's a big deal to keep coming in over and over again for a surgery. When they get surgical fatigue, the tumors keep growing, and we eventually see them later on and the tumors are bigger and the surgeries are bigger at that point. Julie showed some pictures that were clinically can be disturbing. I'm going to be showing similar pictures because sort of what I do. I do surgery. This is a patient I saw within the past couple of months. It's a young woman in her 20s. And you can see her skin is sort of studied with basal cells. This is not uncommon. This was her surgical defect after clearing just the spot on her nose. And you can see she's got other lesions as well that are going to need treatment. This is what happens when these patients neglect treatment. If they say, I can't do it anymore. I'm tired of surgeries, they grow. Basel cells, in general, will not spread through the body. It's very, very rare for them to kill a patient as far as metastases, it can happen. In general, what happens is these tumors get bigger and very locally destructive and incredibly disfiguring. And at this point, it's very hard to surgically treat a lesion like this. This is not an uncommon clinical situation for a patient with Gorlin syndrome. The photo on the left shows too small. These are not actually big defects, surgical defects after clearing the tumor and this is with getting clear surgical margins. But in looking at her looking up on our [indiscernible] there's 5 more spots that at some point, we are going to have to treat. We want to treat them when they're small. So thinking what is the goal and how we can help our individuals who have Gorlin syndrome. And the goal truly is can we prevent the basal cell development, were not going to cure the disease. But can we prevent development of basal cells, can we slow the growth? Can we limit the need of surgeries? Overall, can we decrease the number of surgeries these patients have to go through? So we've just heard a bunch of the options that we have, the topical treatments, we can use them. It really takes a whole sort of smorgasbord of treatment options. The topical treatments can work. They're not great. They usually work on the lesions that are very superficial and not all of them. The oral medications as we know, the hedgehog inhibitors can be very effective but are very challenging to tolerate. Photodynamic therapy, again, very superficial lesions, not a pleasant thing to go through, can help for some but surgery really is the gold standard. Sun protection and education is a constant discussion with our individuals. They need to continually be reminded you need to protect yourself from the sun but a big part of it as well as support, emotional support and keeping our patients involved, don't give up don't neglect your care. So because I am a surgeon, I'm going to be talking really about the surgical approach. And we did hear about [indiscernible] and curate that's a burning that you can do with the scraping excision and most surgery. Those are the 3 main surgical approaches we have. This is [indiscernible] that instrument on the right there. It's just sort of like a sharp little scrapping instrument. We essentially just scrape off the skin cancer. We create a brush burn type wound, very effective for simple lesions that are superficial. A patient like this, we often usually use it from the neck down because the scars, they're not pretty, but they are fairly acceptable on the trunk. We don't tend not to do this on the face nearly so much. But you can see from Gorlin, these are 2 different patients, you really would be significant scraping and a lot of destruction of all the skin on their trunk and back, but it is an effective way to take care of these. Surgical excision is essentially when we just cut out the skin cancer with a margin of what appears to be normal skin. We cut it out, send it to the lab, they check the margins, but we saw it up while the patient and the patient goes home. And this would be a Gorlin patient. You can see small other scars on her neck. This point she wouldn't need most surgeries this, but we can cut out this lesion and sell it together. But most surgery is really used very, very frequently for patients with Gorlin syndrome because it offers the advantage of tissue sparing and a little bit higher cure rate. And what most surgery is for anyone who doesn't really know it's an excisional technique or while the patient is waiting, we actually take that tissue into our lab when we examine 100% of the surgical margin, which is different than a standard excision. So when we're looking at 100% of the margin is really how we process the tissue, it allows us to take less normal skin around each skin cancer. That gives us a little bit higher cure rate, but essentially allows us to are more tissue. We have appropriate use criteria for performing most surgery. And the one we do feel it is indicated for tumors that are recurrent. They've been treated and have come back because with other methods when their scar tissue, the cure rates drop tumors where the tissue conservation is critical. So if you have a tumor on the lid margin on the lip on the tip of the nose or on the year, you really don't have a whole lot of extra tissue to take. So you really want to take the small clinical margin. aggressive histology, some basal cells so they don't behave necessarily more aggressively under the microscope, they're more aggressive in that they infiltrate more wide most surgery is in the appropriate use criteria. In Gorlin syndrome patients are in the appropriate use criteria for most surgery because of the need for tissue sparing. The problem is it takes a long time, so we cannot treat every skin can with Gorlin with most surgery shows a clinical example of how you can treat a small skin cancer and preserve a lot of normal tissue. It's hard to see, but on the picture on the left, a very small basal cell in the island margin. This is not a Gorlin patient. This is just to show you how most surgery can remove it, a very small defect. So that's nice. That would be very effective. Here's an example of a basal cell in an upper lip. And although that looks like a large wound, it's not that -- it's much smaller than will be needed with the standard excision. But if we go back to our Gorlin patients, if you can see many of these lesions would qualify, they could be treated with mole surgery, but each one of these would be another visit of a 3- or 4-hour appointment. And it's actually overwhelming to think of treating each one of these small basal cells individually with most surgery. So it's an overwhelming task, although it would work. So from a surgeon's perspective, even though I enjoy doing surgery, I want to decrease the number of surgeries that a Gorlin patient needs to have, decrease the number and also decrease the extent, make the lesions smaller. If we can have a smaller basal cell, it's a smaller surgery, smaller wounds, smaller scar. Patients have different goals. Some patients with all of their skin cancers treated. Other patients want just the ones that are becoming more trusted more aesthetically by, there some I'm very focused on when tumors are close to the eye because we don't want anything to infiltrate into the eye. And it really does take a team approach working with our individuals -- what's their goal for what they want treated. But in general, everybody wants smaller lesions, fewer surgeries. So what would I think is a meaningful efficacy outcome for a new treatment option for treating our Gorlin individuals? Can we prevent new lesions? Can we cure some of the smaller lesions can we make some of the bigger lesions smaller? -- again, fewer surgeries for patients, fewer scars, smaller scars, and also having another treatment option creates an optimism and a motivation for our patients because we cannot lose them. We cannot have them disappear. And then thinking about what -- what kind of reduction would make a difference for a patient? I think 30% reduction in the number of surgeries that a patient has to have is significant. That's 30% fewer days of work 30% fewer cars. This is actually the sister of the woman I showed you in the very beginning with the wound on her nose. And so you can see, she's got lots of small, tiny basal cell. She's not quite as affected as her sister. Something like this where it's small lesions. If we can treat them with something that can make them go away other than surgery or shrink them, the scars will be better, the scars will be fewer. Sometimes when these patients have a lot of tiny, tiny, small basal cells, even as you cut each one out, the defects start running into each other. Many, many small lesions can still create a larger defect, which means a larger scar if we can shrink them or make them go away, that would be ideal. Fewer surgery also keeps that relationship going. We keep talking about the team approach, the importance of motivation and optimism for this patient population. If we can keep them -- if we can manage their disease with treatments that are much more acceptable to their life and improve the quality of our life. I think we've made a difference. And it is just one more option. It's not an option that's going to solve it. we need a basket of opportunities that we can use to treat the patients. But if we can have something that's well tolerated. The other ones, other topical treatments that are -- that we discussed earlier, create a lot of redness, burning discomfort unsightliness, we need something that can be well tolerated. We will really increase their motivation. The other thing about something that is topically and built into a regimen. It also increases the patient's awareness and continual reminder that they need to prevent sun exposure and that every day of their life for the rest of their life, they need to think about protecting themselves from the sun. So prevention, reduction and slowing progression are all meaningful outcomes. This would not be a bad outcome for a patient who is effective with Gorlin syndrome to come in and have a few small lesions removed. But I'm going to show this gentleman here who is a wonderful young man. This was probably about 3 months ago. He's in his 40s and we can't keep him coming back to clinic he disappears. He comes in, we'll treat him, and then he goes away. He is a caterer, -- he has his own catering business. He can't take time off of work and he hates surgery. So he came in because the spot in his right cheek was bothering him. And it was bleeding and all over his pillar cases and will be coming a little unsightly. So we treated it, and that was his most defect from that day, and we were able to put a skin graft on it, but it was a long day. It was not a pleasant day. He was very concerned about the work that he had to do the next day. We got them through it. But when I brought them back to talk about now we have to go -- he's got this large one on his nose. He said, I'm going to disappear for a while. He was very straightforward. He's given up again. And he would be an ideal candidate for something that could be fit into his work routine. That he would not have to take off work, can we shrink it? Can we treat lesions? Can we treat them at an early stage and prevent progression so that he's not going to have to undergo another extensive surgery and loses motivation. So management and care, we want to optimize the quality of life for these individuals. We want to prevent the need for so many surgeries. We want to decrease scarring disfigurant and we need multiple treatment options to really have a long-lasting impact that these patients can have for the rest of their life because they're going to be dealing with this forever.

Thank you all for the presentations. Thank you all for your presentations. A few questions. Dr. Epstein, what is your vision for SGT 61 in the future of cutaneous dermatology?

That's a big question. My hope is that people who need it, who have had BCC, I've had 5, I'd use it. we'll be able to not have any more. And maybe it'll be 50% fewer, maybe it'll be more, but I think that the earlier people use it, the more likely it is to be successful. That's the interception I did. If we can treat one cell tumors, we may have much better cures than anything else for this and put all the most surgeons out of business. I've heard that from other most surgeons that these people are very difficult to treat and getting them off the pilot plate would be a wonderful thing for them as well as the patients.

Dr. Sarin, if SGT 610 leaves up to its promise, would you expect to use it in patients for whom you currently use oral inhibitors

Yes. I mean I think what we need is a treatment that doesn't have the same side effect profile. So if it has -- if it's highly tolerable with a 30% decrease in efficacy -- decrease in new tumors, I can see a reason why every single patient almost every patient I have with a moderate to high burden of betas cancers would not want to be on this. And so I'd probably prescribe this to the majority of patients, including many who are on oral heat inhibitors there may be some who stay on oral in hedgehog inhibitors because they may have such a high surface area, including trunk areas, areas on their legs where they might need the benefit of an oral treatment despite the significant side effects that treats their entire body. But I would say this would be a highly popular among almost all of my patients.

Dr. Billingsley you think patients with low burden of the disease should also be treated with SGT 610.

Yes. I think with a low burden because we know that life goes on and eventually even a low burden will become should become a high burden, it will be development of basal cells throughout their lifetime. If you can start the use of a topical that has a preventive effect and you can start that early, you could prevent significant number of surgeries down the road.

What magnitude of reduction in new facial businesses would you consider as clinically meaningful?

As I mentioned, I think 30% is a reasonable acceptable rate because that is 3% fewer visits, 30% fewer scars.

Julie, do you believe that patients will be willing to apply preventive drug every day for many, many years?

Absolutely. No doubt in my mind. I'd much rather and I think all of us would much rather apply this, knowing that our burden will be reduced than knowing that we have to go for surgery over a few months.

Mori, how should investors think about the difference between 30% and 50% reduction in new BCCs?

Well, the 30% figure has already been addressed by Dr. Billingsley, 30% is an excellent number. And that is something that the doctors will be very happy with. Our postal analysis showed the around 50%. So I think that will be even better. So 50% is better than 30, 60 is better than 50 so we keep hoping and if we don't reach that high number of this study, we will do it in our next study. We'll try to improve it until we reach the vision of normal tumors, no more surgeries.

Thank you. Mori, why does Sol-Gel believe that its proposed commercial commercialization model is optimal.

Well, I listed the reasons why I think that it is optimal. I just very fast. I will reiterate the product the target audience, the market, the physicians that we have to address are not very large like with, I don't know, simple dermatological products or psoriasis or atopic dermatitis. You don't talk about thousands of doctors, but about very few hundreds. So this is suitable for a small company was to retain most of the economics for itself. The price is high and contribution inside means that the reasonable number of patients we can be profitable, that is not always the case. If you look at companies like Acutis, they had to bleed in hundreds of million before they became cash flow positive. And the other thing that has to do with this, we believe that the uptake will be high because of all the reasons that you heard today people are physicians, unlike in other cases, are fully aware of the mechanism of actions, the know-how effective hedge of inhibitors are and they're looking for a drug that will do more or less the same job with less side effects. So all these factors favor commercially speaking, economically speaking, an independent launch in the United States. In Europe, it will be different because is so complex and segregated and we are sure that with our product knowledge, our great consultants will do a great job and high motivation. We'll do a great job in the marketplace.

One last question to Julie. Are there other areas in the body than the phase that could benefit from the treatment SGT 610.