So, good morning. Actually, good afternoon to our guests that 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 along this journey. 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 of 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 our company deck, but we introduced several changes that were meant to respond to frequently asked questions by you guys over the last month or two. And I hope this presentation will add clarity in those aspects that were maybe not fully clarified until now. So to introduce ourselves. Sorry. Introduce 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. And 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 corrects the situation is that our VP of Clinical and Regulatory Affairs, Dr. Ofra Levy-Hacham, has two jobs, both of Regulatory and Clinical. And in reality, I can tell you, she does a job of two executives. Hi, Ofra. And this slightly corrects the imbalance. But we are fully aware that a right company these days should consist of more balanced gender. Okay, now again. So just in 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, maybe 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, 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, employed 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 the designation, it's an orphan drug and a 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.
Only patient that completed 12 months treatment. This was not the data that was submitted to the FDA, but it is the data after we eliminated those people, patients that did not comply, that did not show up, that do not have the final data. I am making note of it because this was the source of some questions that we have been asked about the past. The PellePharm 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? Here is the first graph. It is a post hoc analysis and show that patients who do not have the PTCH1 mutation do not respond any better than a placebo.
This is very surprising observation. Although it makes sense, it is still surprising because other studies made on hedgehog inhibitors did not make this distinction. We know that it is valid for our drug, and we suspect that it is valid for other topical hedgehog inhibitors if in the future someone will think about developing. This is very, very important and makes much of the change in our study. Patients without mutation has a very same response as placebo. Let us go further. I am accustomed that someone else does this job for me, so I apologize. Here, this is one of the changes that 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. Here is the data and please listen to the definition.
In the post hoc analysis, a greater number of BCCs at baseline was associated with larger treatment effect favoring patidegib over vehicle. Large treatment effect means the separation between the drug and placebo. What you can see here is two things. First of all, patients that have less than 10 onwards, eight onward, six and up, had the very same efficacy as those of 10 and onwards, the same efficacy. Had we used a larger patient selection, namely from six BCCs onward, we would have reached the same p-value, more or less. 10 was used for some reasons, maybe for statistical considerations, to increase the likelihood of success in the study. But the drug's efficacy is equal for two BCCs, for three BCC, for five and with 10. The efficacy is equal because the mode of action is equal. We just inhibit the hedgehog system.
We inhibit the transcription factors downside to PTCH, and the proof is the reduction of the levels of GLI in the tumor. The drug does not know if it is two or 10. It is 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, stable disease do not grow new BCCs, and therefore it is impossible for the drug to overcome the placebo and to show its advantage, because the drug is supposed to prevent BCCs to grow. If the BCCs do not grow in the first place, there is no way for us to show the advantage of the drug.
Again, I would like to hammer this because all baseline BCCs respond to the drug, but the difference is dramatic in placebos. The placebo of low BCC number, they simply didn't grow in this particular study, not in real life. In real life, patients with one or two or three can suddenly experience a breakout of BCCs. 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. 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 significant bit of additional amount in order to support the study. 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 dramatic 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 three months or six months, it probably will be level off at about 3 because it's already asymptotic, as the technical word is. But here, the slope is growing. In all likelihood, three months from now, it would have been eight against three. So the protective effect will be five BCCs. It means five more surgeries spared.
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 again about the patient selection. You see that one year is not enough to capture the full protective effect of this drug. That is the biological process. A good company when planning a 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 selections that will be able to reveal the potential of the drug within the limitation of number of patients, the severe disease, and with the limitation of time. In one year, we have to show as much as possible.
If we take patients that maybe will take them two years to respond because they have a stable disease, these patients are not suitable for that studies. This is the reason that convinced us to go on with the product. Let's go. Sorry again. Now, this is something interesting that maybe will give some color to the interaction with the FDA and as a background to our confidence that the FDA will be forthcoming and agrees to our thinking. It's so important I will read it with your permission. "We recommend," says the FDA, "conducting a new adequately powered randomized vehicle control 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 patients population among Gorlin patients or including a broader population such as subjects with non-Gorlin high-frequency BCC. What you see here, what we did is precisely what the FDA recommended. We started a new study with what we believe is the more sensitive patients, the patients that are likely to respond to the drug. 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 all the improvements that we introduced in the studies. Two of them refer to patient selections.
We use facial BCC three and above. It was the previous study, and our study was 10 and above. PTCH mutation was not mandatory in the PellePharm study, and it is mandatory in our study, and that's it. In terms of operational improvement, we introduced several important changes that we think will improve the accuracy of the study, reduce false positive or false negative, and as we already know, has also reduced the number of dropouts patients. As a result, every patient that drops out costs dearly to the statisticians. So the fact that we have only 10% dropout is the result of some of our measures taken.
First of all, because we're talking about Gorlin patients with many small red dots that may be diagnosed either as BCC or as rosacea or something, it was very important to use dermatoscope, here it's called dermoscope, in order to make the right differentiations. We know for a fact that it works because in the previous studies, we experienced a lot of what we nickname as zigzag effects, namely high number of visit seal, then the second visit low, and then high again. This doesn't happen in this study, so we made it mandatory to use a 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 negotiate the primary investigator and the KOL from the review board until they come to the agreement.
If no agreement, it's the decision of the review board member. We simplified the number of visits. There were too many, and this was very tedious to only six visits. The rest is virtual. This is just another summary, and you see everything that I was talking about. In addition, you see there were 41 sites, 184 patients were screened, and then enrolled only 113 that met all the inclusion and exclusion criteria. 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 of the last time. Primary 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. Don't pay attention that it's Q4. It's going to be next month. NDA submission will be in April. Then approval in Q2, and then approval somewhere after six months because we have the orphan drug status, and breakthrough status, and launch in the beginning of 2028. We have strong IP protections that we believe will be an iron wall, at least until 2045. We plan to continue with new applications. Now, about the market opportunity. Our planning is based on 11,000 patients in the United States, out of which, after eliminating 10% of patients that do not have significant BCCs, despite the fact that they are diagnosed with Gorlin.
Pediatric patients that right now are not included because of safety reasons. But we believe that given the fact that our topical absorption is one-hundredth of the absorption of the blood level that we reach is 1% compared to the absorption of oral hedgehogs. We believe that we will be able in one year or more to also get pediatric use and add also pediatric patients. We'll do it gradually. We'll start with patients that are close to the normal heights because oral hedgehog 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. Then we figure something like 80% adherence. That will be part of our job to maintain it.
Based on all this, we reached about 6,100 eligible patients based of the demographics of today and expect at peak sales, a 65% penetration that will lead us to 4,000 patients. In Europe and rest of the world, there are 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, I will not elaborate about this, there is pricing issues, and we have to first make sure that whatever commercial decision we take outside the United States, probably because of price control in 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 million. The price will be comparable to very expensive topical drugs that were introduced and still half of the price of VYJUVEK that paved the way, I would say, for expensive topical drugs. In the past, topicals, irrespective of their efficacy and importance, were always assigned the low price category. This is no more the case. So the question is, how are we going to commercialize ourselves in the United States? There are obviously several models. One is to license a drug and get royalties. This, of course, is not the right model for us because we want to keep the majority of the economics. We decided to go independently to launch in the United States.
America first, the rest will be done probably with partners. 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, patients are maybe something like 200 centers of excellence, something that a team of 20 FTEs sales reps would be sufficient. The other thing that we expect, based off all our interaction with physicians mainly, but also with patients, that the uptick will be very high, very fast. Why that? Because sometimes rare drugs come to the market with a very complex mode of action that the physician may not be familiar, may be skeptical, and therefore, it will take time to educate him.
This is not our case. Doctors know perfectly well about the efficacy of oral hedgehogs, but most of the patients cannot tolerate it, so they are waiting for a drug that will have close efficacy to oral hedgehog, but do not have the side effects. I believe that this is our situation. So when we come to the doctor and say, "Here is the drug that works very well, and showed clinical data, and has no side effects," we are sure that the doctor will be keen to try it. If the success is as we expect, we've done our job. So I know the time pressure, so I'll go quickly. So how are we going to commercialize it? My commercialization plan has four pillars. The first pillar is increase the awareness.
We know that every drug, and particularly orphan drug, that doesn't have a therapy, both the disease. Sorry. 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 made available, we will see an uprise 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 we'll take the right experts to first of all, raise the awareness. The second thing is to identify them. Awareness is not enough. Again, social medias 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 thousand. We would like to know each one by its name and to send a Christmas card each year, Christmas greeting at the right time. Continue this close rapport with the patient. 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 to different places to get treatment. We would like to integrate ourselves into this system, to be part of the system.
We'll, of course, support it also financially in order to make this happen as soon as possible and increase 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. 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 with chronic drug, especially if they see that their condition is improving, they tend to say, "Okay, now I'm okay," and then maybe be less strict about usage of the drug.
We will be there to support them, to encouraging there, and to use all kinds of measures, webinars, and others to hammer 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 if you reach a certain level to ensure adherence to which increase your revenues by ensuring adherence than look for the patient number 4,001. So that will be one thing. 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 code of several genetic disorders. So we already started this proactive work and didn't wait for the approval. No signal.
I think. Please go back. I think I'm close to my. Yeah. So here is just.
There we go.
That is it. That is okay. That is the last slide.
This is what I have been speaking about right now. The broad and intensive commercialization effort that will start already now to create. People ask us about the future of drugs. There is many, if you say growth engines. One of them is simply the human body because unfortunately, all parts of the body are afflicted with BCCs. The most sensitive one both aesthetically and in terms of incidence is the face, and therefore we started with the face. 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. This is just within the same patients, one important growth engine. The second one is high-frequency BCCs, which is as important.
Maybe it's more prevalent, maybe less devastating in terms of the number of BCCs, but very important market because it's a bigger market. Here the big challenge will be to select those patients within the high-frequency BCC that have a high enough incidence. We will have to use, again, very sophisticated social media analytics in order to identify them for the studies. In the real life, again, doctors will not be that stringent in terms of the number of BCC, but it is important for us for the success of this study to identify the right patients. 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 in this study. Although it's not an endpoint, we will monitoring it.
If that will be the case that we can reduce the size, there is an important market out of the 3 million, sorry, 3 million. You see, I'm already thinking only in the billions when thinking about Sol-Gel. But within 3 million procedures of BCCs, there are about 100,000 that could be labeled as difficult to treat, namely simple Mohs surgery would not do the job either because the tumor is very close to sensitive areas like the eyes or something else. Or 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 cause side effects, and actually, we are starting a study this month. Maybe it's already started, for downsizing BCCs in sensitive areas of the face in the framework of neoadjuvant therapy.
Namely, you first reduce and then perform the surgery. But the data that we will gain is both for the concept, let's say, of the neoadjuvant, but also. Yes, I'm finishing. But also for the phase that relates only to reducing the size. So there's much potential. We believe this product could be a pivotal element in the treatment of every BCC. But first of all is the few thousand patients that will provide us the first billion dollars of sales, and then we'll worry, as they say, first take Manhattan, then we take other parts of the business. Thank you very much. I apologize for not controlling myself.
Hi. 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 five years, the President of the Board of Directors. Her early career began as a physician assistant. Julie and her two 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 multi-system disorder, as well as advancing drug development for rare diseases. Julie, please.
Thank you all for being here today. It truly means the world to me. As Ofer said, my kids and I have Gorlin syndrome. They are 34 and 33. This is something that we have and will be monitored for every year throughout our lives. There are lots of manifestations. Basal cell carcinomas are the biggest burden that we face every day. We have no FDA-approved treatments for any of the manifestations whatsoever. As you'll see, we desperately need something, particularly for the basal cells. Honestly, patidegib will be life-changing for us. Life-changing. I know that sounds dramatic, but it's true. This is a collage of my face from 2- 65. Couple of photos here to point out.
On the bottom row, second from the left, I'm bald from using the hedgehog inhibitor Erivedge. In the bottom row on the far right, I'm recovering from having a basal cell removed and 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. I hope this by telling you today, you'll have a feel for what it's like. I was diagnosed when I was 12. At that point, I had three large jaw cysts removed with two surgical procedures. I had had manifestations since a newborn, but we didn't know that at the time. My first BCC was removed then. Since then I've had over 1,000 removed.
I'm seen by a dermatologist several times every year and have never, ever left one of those appointments without having at least one biopsy and one excision, along with a scheduling of a Mohs procedure for 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 BCCs, 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 nevus syndrome or basal cell carcinoma nevus syndrome. Incidence is approximately one 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. The de novo mutation or spontaneous mutation rate is about 31%.
It can affect every organ system of the body. There are over 100 possible manifestations. The most common are the basal cell carcinomas. Jaw cysts, the odontogenic keratocysts are the second most common. The psychological burden of anxiety and of living with this disease is next. 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 soles of our feet. Medulloblastoma is a malignant brain tumor in infants and toddlers. Hydrocephalus, large skulls, meningiomas or benign brain tumors, ovarian and cardiac fibromas, cleft lip and palate. 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 odontogenic keratocysts, the OKCs. In my teens, we were told that these 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. You may lose permanent teeth, you may have permanent lip numbness as a result of these surgeries. We need something to help reduce that recurrence rate. Just to explain these slides a little bit, the image on the left there, the sinus where you see a gray bubble, that is an OKC in my son.
The image on the right is an MRI of another individual, and the sinus should be black. It is solid gray. It is totally opacified with an OKC that required very extensive surgery. The scans on the left were taken 18 months apart, and they show on the top you can see the arrows pointing to a cyst. On the bottom, the image shows three cysts 18 months later. One is a recurrence and two others had to be removed. Since then, that and the upper jaw has been surgically resected. Historically, the cysts were packed with something initially called Carnoy’s solution. That is banned now because it had chloroform in it. Not good stuff. 5-fluorouracil has been used by impregnating the gauze, packing it into the cavity, and that has had variable success. My hope is that the use of patidegib gauze impregnated with patidegib will make a difference for us.
Just briefly to give a bit more context, I have had a total of eight OKCs removed so far. My kids have had nine and eight, and we have all had at least two recurrences. I am going to talk about the basal cells now. They are really a menacing presence, and I just want you to be prepared because some of the slides that I am 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, a parent, and an individual representing people with Gorlin syndrome, I look at numbers in terms of the volume of basal cell carcinomas. For the majority of us, these are big. It is not just a basal cell. It is 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 is available to us is barbaric. Let me briefly run through these photos for you. Top left is the red areas and oozing areas are basal cells. The next image, I am on the left there, having completed a six-week course of Efudex on my scalp. That is why my hair is so red and short. The woman next to me holding her infant son both have Gorlin syndrome, and she is aiming to have more children, and so she has stopped all treatment 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 jaw cysts 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 is my son on the left, me in the middle, and my daughter on the right, two years ago. She had a Mohs surgery of a lesion right here, and it ended up being a 3.5 in by 4 in defect that required significant plastic surgery to reconstruct it. For everyone affected and involved, the disease burden is obviously tremendous and never goes away. Just like the sun rises and sets, the BCCs never stop developing.
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 BCCs on the face, neck, and scalp. 45% of the respondents at that time had 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. 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.
The oral hedgehog inhibitors, they are great, but for most people, the BCCs come back and they are hard. Chemo. They are 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. Immunotherapy is available, LIBTAYO, though it has not 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. Those numbers are from a global survey that we did a few years ago. We desperately need more options, ones that do not cause a scar.
Ideally, they are not painful, there are no injections, and while recovering, there is no oozing or scabbing like you saw in some of the images earlier. Sol-Gel's product, patidegib, offers just this. No scars, no oozing, no injections, fewer physician visits, less time lost from life. There is nothing else that does that. Nothing. Over the last five years, the Gorlin Syndrome Alliance has surveyed the community three 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, "Would a preventive treatment that reduces the development of new basal cell carcinomas by 30%, with no challenging side effects, be an improvement on your current options?" 94% said yes. A patient-preferred and clinically meaningful reduction of the volume of BCCs by 30% is hugely desired. We are born soldiers, fighting lifelong battles.
We didn't enlist in them. We desperately need something that slows or interrupts the constant tide of 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 we have now are adequate. It's simply not possible to keep pace with the rate with which we produce BCCs. 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 view life through a lens of 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 her 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 a practicing dermatologist 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 publications have appeared in the New England Journal of Medicine, Nature, and Science. Dr. Epstein.
I don't believe I've followed our previous speaker before. Tough act to follow. Very moving. I've been interested in this disease since 1970, 50 years, but never had the experience of living with it like she did. Very remarkable. In addition to what was said before, I think I am a Co-Founder and a 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 BCCs. Specifically, the BCCs are driven by excessive hedgehog signaling pathway activity, and that patched mutant BCCs are susceptible to smoothened binding, hedgehog inhibitors, including most particularly patidegib gel. The question is, how did we get here from Gorlin syndrome to the hedgehog in his signaling as a driver of all BCCs?
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 he can possibly have. In 1980, 20 years after he described it, Christiane Nüsslein-Volhard and Eric Wieschaus published the results of a massive fruit fly mutagenesis study. They zapped fruit fly larvae and looked to see what kind of mutations would develop, and they found lots and lots of them, remodeled the whole disease, and included the hedgehog phenotype. Why did they call this phenotype hedgehog? Because other names were already taken, including particular the other one.
In 1996, we, as part of the global village, identified the PTCH mutation as being the site of the mutations that underlie most cases of Gorlin syndrome. That raises the question, what is a signaling pathway, right? Who's comfortable with what is a signaling pathway here? Wow, 0%. That's terrific. Anything I say you'll believe. To me, I think the easiest way to think about it is it's the nervous system of the individual cell. You bake a cake, you put your hand on the cake, you say, "Oh my goodness." There are signaling receptors here in the palm that say, "Hot." They send that message up to the back of the spine, and the spine sends out signals saying, "Move your arm, dummy." It changes the behavior of your hand based on the information that they find from the outside. That's what these 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 what they find outside. What specifically is the hedgehog signaling pathway? Specifically, it is one of the major pathways by which this amazing thing happens. I don't think anything is more amazing in biology. A single fertilized cell turns into the multicellular newborn, and it does it in nine months, in the dark with no instructions. This is how it does its thing. Specifically, what is it on the molecular side? These are old pictures, but they're the easiest. The more modern ones are harder to understand.
On the left, the pathway is inactive, and on the top, you see at the outside of the cell, at the cell surface, on the left is a protein called smoothened, and on the right is a protein called patched. You see that? Yes. Please nod. Thank you. You're good. You nod. When the signaling pathway is inactive, the patched inhibits signaling by the smoothened. Okay? That's inactive. On the right, when hedgehog comes along the outside of the cell in the environment, it stops inhibiting smoothened. Smoothened acts and sends the message to the brain of the cell, affectionately known as the nucleus, and that sends out new messenger RNA, 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 cartoon. You see there's a little expressance on the outside of the cell, a little, as we in dermatology call them, pimple. This is a signaling hub that does a lot of the signaling work of the cell. What patched does is it keeps the protein of smoothened outside of this, because if it gets in, as shown on the right, then it sends a signal to the brain, to the nucleus, "We got to do something different, guys." These are outdated, but they're easier to understand than the more modern ones. 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. There are four series here of data that argue for that.
The first and functional one, foundational one, was in 1996. Our lab plus a dozen other labs in the global village identified that most cases of Gorlin syndrome, which has lots of BCCs, of course, as you've just seen, that the PTCH gene has the mutations which underlie 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 PTCH 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. That's the main thing is that if you look at patients in their families, the gene that's passed down from one to another that's mutant is PTCH1.
Secondly, if you take that information and you're a mouse person, you make a mouse that has an abnormality that upregulates hedgehog signaling, and these mice get basal cell carcinomas. In fact, despite it being by far the most common of 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 PTCH1, then they get lots of BCCs, especially if you treat it with ultraviolet light or radiation, which will give BCCs to all of us. Third is the hedgehog signaling pathway, as assessed by the amount of messenger RNA that encodes 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.
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 knew 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 Erivedge. This is not results with oral. It's results with oral Hedgehog inhibitors, but not patidegib. But the patidegib results are published in what, if dosed orally, has about the same results as does Erivedge. But this is Erivedge. On the right, you can see what happens if they take placebo, and on the left, you can see what happens if you take vismodegib. Each line of the spider plot represents an individual patient.
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. In the ones on vismodegib on the left, they didn't go up. Probably the ones that went up were ones that we personally missed seeing. Below is the results, not in preventing development of new BCCs, but in shrinking existing BCCs. So you can see the one on the left, they all got smaller. In fact, that study shows that if you take one pill of Erivedge for a year, you have an 80% likelihood that all the BCCs 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 under the microscope, they're also gone.
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 what I think is an absolutely great story, and I would recommend to you, wait till we're through, but afterward, go to your-
YouTube. Thank you. Thank you very much. Go to YouTube and look up the mystery of the one-eyed sheep. Here is a one-eyed sheep on the left. There was an epidemic in the '50s in Idaho of one-eyed sheep being born, as well as a bunch of other bad things happening to them. Government, you remember the federal government went out and did things and was good? They went out and they found out that it wasn't an infection, it was that the pregnant ewes were eating the California corn lily. On the middle is the picture of the flower, and on the right is the weed. Later, in the '60s, somebody came out and actually isolated the alkaloid that produced this mutation in the sheep, in the lambs. How many people go to the movies here? How many people have time to do that?
You see this handsome-looking fellow? He is Polyphemus, right? This is a picture of him as shown in the recent "Odyssey." This handsome-looking dude is eating some of Odysseus' men. Since he was a Cyclops and named Polyphemus, this alkaloid was named, of course, cyclopamine. 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 cartoon that shows that reduction, how you can reduce new basal cell carcinomas. On the top line, there's no reduction. You can see that the normal skin on the left is converted into a beautiful basal cell carcinoma on the right. You all see that, right? Good. In the middle is prevention.
Like if you did gene therapy on a patient with Gorlin syndrome and you eliminated the very first starting of the BCCs, there would be no basal cell carcinomas. That's probably not what we're doing. What we're probably doing is the thing on the bottom, which is interception. We are preventing them from getting big enough to bother. That's the same with Erivedge, because when you stop it, they come back. Here you can see on the left that the hedgehog inhibitor in the middle is inhibiting the development of BCCs. That's interception. This is a concept Elizabeth Blackburn introduced 15 years ago and a concept that other people have been talking about.
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 the development of new pancreatic cancers in people who are going to get these otherwise. 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 pre-cancerous squamous cell carcinomas for 60 years. This is just building on that well-trodden path. These are the four bases on which this lies, and if it works well so orally, surely it'll do the same topically. How could we miss? Thank you very much.
Thank you. I would like to introduce Dr. Kavita Sarin. Kavita is a Professor of Dermatology and the Director of the Stanford Skin Cancer Genetics program at Stanford Cancer Institute. She received her medical degree from Stanford University School of Medicine and holds a PhD in genetics from Stanford University. Her lab applies cutting-edge sequencing and imaging technologies to better understand skin cancer and rare immunologic skin diseases. Dr. Sarin, please.
Thank you very much. Well, Julie 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'll find between all of our talks today is that there's just really a desperate need for treatment. My one disclosure is that I've done some consulting with Sol-Gel on their genetic testing program. As Dr. Epstein mentioned, Gorlin syndrome 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 one in 31,000 to one in 256,000.
I will tell you personally, it is much more likely to be closer to the one in 31,000. I will see a lot of patients who have not been diagnosed until adulthood, till they come into our clinic with Gorlin syndrome. There is a severe under-diagnosis of Gorlin syndrome, and because of that, an over-surgerization of patients. 20%-40% of patients come in newly diagnosed with Gorlin 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 non-sun exposed areas too. They 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 are 20.
Three quarters by the time they are 40, and they can develop hundreds to thousands in a lifetime. What is unique, I see a lot of tumor predisposition syndromes in my clinic, but what is really unique about Gorlin syndrome is how tightly the mutation is tied to the drug target. PTCH1 is mutated in 85% of patients with Gorlin syndrome. I will not go over the pathway. Erv just did a beautiful job doing that. I think the point is that PTCH1 is a direct inhibitor of smoothened, which is the drug target. So it is very rare when an oncologic disease or tumor predisposition syndrome to have both the genetic mutation just so tightly tied to the therapeutic drug target.
There is a second mutation that we see, which is SUFU mutations, but that occurs in only about 5% of patients with Gorlin syndrome and is downstream of the drug target, so downstream of Smoothened. As I mentioned, I am diagnosing a lot of patients as adults who have been missed as children. The diagnosis is primarily clinical. Basal cell cancer is one of the hallmarks of the diagnosis. But especially when we are diagnosing them as kids, a lot of times we are diagnosing them because they are referred from an oral surgeon because of the odontogenic keratocyst of the jaw, which can be really devastating, actually. Then they get referred in for evaluation for Gorlin syndrome.
There are other findings as well, as Julie mentioned, but I would say the basal cell cancers and the odontogenic keratocysts are probably the two 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 is almost always straight to genetic testing at this point. This is an example of a child, one of my kids with Gorlin syndrome. He is of Indian descent, and I just wanted to bring this up with both the photos I have chosen to use today is to say this is not just a condition that affects white European patients. I see patients who 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 cell 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 moles or skin tags on the face and on the shoulder here in the sun-protected area. Every single one of those is a basal cell cancer. This young child had over 50 basal cell cancers on their skin. Then the palmar pits, which are the plantar pits, which don't show up as well. For this child, he was referred in for as odontogenic keratocyst, which can be quite devastating. In the course of three years, he underwent surgery four times under general anesthesia for the treatment of odontogenic keratocyst.
And I also similarly went in while he was under anesthesia, and similar to one of the photos Julie said, we actually did a different thing what we called an ED&C, a scrape and burn. We scraped and burned his basal cell cancers while he was under general anesthesia. The basal cell cancers in children can look actually even histologically a little bit different than adults. A little bit more primitive almost while they're young. This is a patient, even though he meets clinical diagnostic criteria for Gorlin syndrome, that we order genetic testing. At this point, we're ordering genetic testing for every patient where we suspect Gorlin syndrome. 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. 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 PTCH1 mutations, you might be more likely to get odontogenic keratocyst 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 smoothened inhibitors also depends on the PTCH versus SUFU mutation.
Because SUFU is downstream of smoothened inhibitors or hedgehog inhibitors, patients with SUFU mutations are more likely to be resistant. 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. 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. So we really have to shift the mindset. We're not going to try to cure every single basal 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 three-six months. We certainly discuss photo protection. The way we do our photography is we have this Canfield 2D image full body photography. Patients stand kind of like this in different poses, and we take a full body photography of all the lesions on their body so we can track all the tumors. Our goal again is triage rather than treat and cure everything. There are some good 2026 guidelines, consensus statements on sort of the severity of Gorlin syndrome. But for every patient with Gorlin syndrome, it is pretty much getting full body photography and at least every six month clinical exams. This is another patient. This is a Hispanic patient on the right. You can see the development of pigmented basal cell cancers. They can look like moles.
I think sometimes people think they have melanoma. But I just want to show kind of the variety of what these tumors can look like. While you see two 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. What are our treatment options? Well, topical, we have sort of three options that we can consider. Imiquimod, which is a topical immunotherapy, 5-fluorouracil, which is a topical chemotherapy, and photodynamic therapy, which is a photosensitizing destructive therapy. All three 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. Imiquimod, six 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 is a little lower with Gorlin syndrome. I am not sure why, but that is the case. 5-FU, topical chemotherapy also causes a lot of crusting, irritation, scabbing, but can also help with the most superficial basal cell cancers. Photodynamic therapy is very similar. It causes redness and crusting in the areas that are treated, but can work. The reason this is not effective, we do not use this more broadly outside of the side effects, is that it really only works for the most superficial type of basal cell cancers, which are the minority of basal cell cancers that form in these patients. Again, we do use this, though, because we want to reduce the number of surgeries. Procedural therapy, so electrodesiccation and curettage.
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. You can do multiple. Each one of those can leave a depressed scar on the skin. Then certainly the definitive therapy for removing a basal cell cancer is excision and Mohs surgery. So we will refer for those as well. We do not use radiation therapy in this group of patients because they are photosensitive. They are highly likely to develop new tumors in the site of radiation. This is an example of one of my patients on oral hedgehog inhibitors. This is the one I showed earlier. So you can see the basal cell cancers in addition to the two big ones, which do not change underneath his left eye.
I want you to look at all those tiny ones, and you can see that many of the tiny small ones actually completely disappear fully and not visible at all under treatment. You can also see some of the hair loss that continues to develop over time in patients. What you can't see are the side effects. Oral hedgehog inhibitors, the genetics kind of prove out the hedgehog inhibition, but oral hedgehog inhibitors, I feel like, prove it out in clinical trials and in clinical experience. They have very high efficacy in decreasing the number of new surgically eligible BCCs in the study that Dr. Epstein ran and in clinical experience. The bigger problem is the tolerability. 54% of patients discontinue the drug because of adverse side effects, and those adverse side effects can affect daily life.
They can be like muscle cramps, which make it difficult to work or do your daily activity. Taste changes. I've had patients stop for taste changes. It's quite amazing how much someone's enjoyment of life depends on their ability to taste food. Stopping the ability to taste food can actually be a huge and unexpected to me at least initially, until talking about these reasons why patients will stop treatment. Then there's the hair loss, weight loss, fatigue, other things. I would say those three, the taste changes, the muscle cramps, I would say those two are probably the biggest reasons for discontinuing treatment. It's also highly teratogenic, as you saw from the earlier photos that Erv showed. We don't use this in kids because of the side effects as well.
While this works for our advanced and metastatic basal cell cancer patients, these toxicities really are very limiting for long-term use for a chronic condition like Gorlin syndrome. In practice because basically 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. There is data to support. This is the MIKIE trial. The MIKIE trial examined two different doses of intermittent use of Hedgehog inhibitors. It found actually very high efficacy between 54% and 62% efficacy. So very high efficacy with intermittent hedgehog inhibitors, a decrease in tumor size.
This worked both in Gorlin syndrome as well as patients with high-frequency basal cell cancer. I'd say the positive of this is that it significantly reduced the side effects. About 23% discontinued 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 hedgehog inhibitor, and 47% paused for some reason. So this helps, but it's not perfect. We need better treatments. That is pretty much. I'm not going into the immunotherapy because I don't think it works very well in Gorlin syndrome, though 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 Gorlin syndrome. So I think surveillance and photography is standard. Everyone's going to get it.
Everyone has it. It's just part of care. The topical is for the most superficial tumors. They have side effects, but for very superficial ones and individually treated, they can be effective. The other treatments like electrodesiccation and curettage and certainly Mohs surgery are much more definitive, but they leave scars and could lead to significant surgical exhaustion. The oral hedgehog inhibitors are a mainstay. Over half my patients on Gorlin syndrome are on oral hedgehog inhibitors. 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. 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 Billingsley. Dr. Billingsley is a Professor of Dermatology at Penn State University College of Medicine and practices dermatologic surgery and Mohs surgery with Penn State Health. She received her medical degree from Penn State College of Medicine. She does clinical research and trials in cutaneous oncology and Gorlin syndrome, and she's the past President of the American College of Mohs 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 on skin cancer, and I have done recently some clinical trials with Regeneron and Sol-Gel as well, and I also have done some consulting in the area as well. We've 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. 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 clinically can be disturbing. I'm going to be showing similar pictures because it's 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 studded 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. Basal 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. 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 two small.
These are not actually big surgical defects after clearing the tumor, and this is with getting clear surgical margins. But in looking at her, looking up on her temple, there's five more spots that at some point we are going to have to treat. We want to treat them when they're small. Thinking, what is the goal in how we can help our individuals who have Gorlin syndrome? The goal truly is, can we prevent the basal cell development? We're 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? 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 is support. Emotional support, keeping our patients involved. Don't give up. Don't neglect your care. Because I am a surgeon, I'm going to be talking really about the surgical approach.
We did hear about curettage or electrodesiccation and curettage. That's a burning that you can do with the scraping, excision, and Mohs surgery. Those are the three main surgical approaches we have. This is curettage. The curette is that instrument on the right there. It's just sort of like a sharp little scraping 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 tend not to do this on the face nearly so much. But you can see even with Gorlin, these are two 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 sew it up, and the patient goes home. This would be a Gorlin patient. You can see small other scars on her neck. At this point, she wouldn't need Mohs surgery with this, but we can cut out this lesion and sew it together. Mohs 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.
What Mohs surgery is, for anyone who doesn't really know, it's an excisional technique where while the patient is waiting, we actually take that tissue into our lab, and we examine 100% of the surgical margin, which is different than a standard excision. 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 spare more tissue. We have appropriate use criteria for performing Mohs surgery, and the one we do feel it is indicated is for tumors that are recurrent. They've been treated and have come back because with other methods, when there's scar tissue, the cure rates drop. Tumors where the tissue conservation is critical.
If you have a tumor on the eyelid margin, on the lip, on the tip of the nose, or on the ear, you really don't have a whole lot of extra tissue to take, so you really want to take it with a small clinical margin. Aggressive histology, some basal cells, though they don't behave necessarily more aggressively, under the microscope they're more aggressive in that they infiltrate more widely. Mohs surgery is in the appropriate use criteria. Gorlin syndrome patients are in the appropriate use criteria for Mohs surgery because of the need for tissue sparing. The problem is it takes a long time, so we cannot treat every skin cancer with Mohs 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 is a very small basal cell on the eyelid margin. This is not a Gorlin patient. This is just to show you how Mohs surgery can remove it. A very small defect. That's nice. That would be very effective. Here's an example of a basal cell on an upper lip, and although that looks like a large wound, it's much smaller than will be needed with a standard excision. If we go back to our Gorlin patients, if you can see, many of these lesions would qualify. They could be treated with Mohs surgery, but each one of these would be another visit of a three or four-hour appointment. It's actually overwhelming to think of treating each one of these small basal cells individually with Mohs surgery. So it's an overwhelming task, although it would work.
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 wound, smaller scar. Patients have different goals. Some patients want all of their skin cancers treated. Other patients want just the ones that are becoming more crusted, more aesthetically bothersome. I'm very focused on when tumors are close to the eye, because we don't want anything to infiltrate into the eye. 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.
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 per patients, fewer scars, smaller scars. Also, having another treatment option creates an optimism and a motivation for our patients, because we cannot lose them. We cannot have them disappear. In thinking about 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 off work, 30% fewer scars. This is actually the sister of the woman I showed you in the very beginning with the wound on her nose.
You can see she's got lots of small, tiny basal cells. 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, small basal cells, even as you cut each one out, the defects start running into each other, and 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'd 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 manage their disease with treatments that are much more acceptable to their life and improve the quality of their life, I think we've made a difference. 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 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 used topically and built into a regimen, it also increases a 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 affected with Gorlin syndrome, to come in and have a few small lesions removed. I am going to show this gentleman here, who is a wonderful young man. This was probably about three months ago. He is in his 40s, and we cannot keep him coming back to clinic. He disappears. He comes in, we will treat him, and then he goes away. He is a caterer. He has his own catering business.
He cannot take time off of work. He hates surgery. He came in because a spot on his right cheek was bothering him, and it was bleeding and all over his pillowcases and was becoming 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. 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 him through it. When I brought him back to talk about, now he has got this large one on his nose. He said, "I am going to disappear for a while." He was very straightforward.
He has 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 is not going to have to undergo another extensive surgery and lose his 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, disfigurement, 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 are going to be dealing with this forever. Thank you.
Okay, thank you all for the presentations.
They are very important.
Thanks.
Thank you all for your presentations. A few questions. Dr. Epstein, what is your vision for SGT-610 in the future of cutaneous dermatology?
That's a big question. My hope is that people who need it, who have had BCCs, I've had five, I'd use it, will be able to not have any more. 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 idea. If we could treat one cell tumors, we may have much better cures than anything else for this and put all the Mohs surgeons out of business.
That's okay.
I've heard that from other Mohs surgeons, that these people are very difficult to treat, and getting them off the plate would be a wonderful thing for them as well as the patients.
Thank you. Dr. Sarin, if SGT-610 lives up to its promise, would you expect to use it in patients for whom you currently use oral hedgehog inhibitors?
Yeah, I think what we need is a treatment that doesn't have the same side effect profile. If it's highly tolerable with a 30% decrease in new tumors, I couldn't see a reason why every single patient, almost every patient I have with a moderate to high burden of basal cell cancers would not want to be on this. I would probably prescribe this to the majority of patients, including many who are on oral hedgehog inhibitors. There may be some who stay on oral hedgehog inhibitors because they may have such a high surface area, including truncal 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 highly popular among almost all of my patients.
Dr. Billingsley, do you think patients with low burden of the disease should also be treated with SGT-610?
Yeah, I think with a low burden, because we know that life goes on and eventually even a low burden should become a high burden. There 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 BCCs would you consider as clinically meaningful?
As I mentioned, I think 30% is a reasonable, acceptable rate because that is 30% 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 would 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 every few months.
Thank you. 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 post hoc analysis showed around 50%, so I think that will be even better. 50% is better than 30%, and 60% is better than 50%. We keep hoping, and if we do not reach that high number this study, we will do it in our next study. We will try to improve it until we reach the vision of having no more tumors, no more surgeries.
Thank you. Mori, why does Sol-Gel believe that its proposed commercialization model is optimal?
Well, I listed the reasons why I think that it is optimal. 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 for 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 who wants to retain most of the economics for itself. The price is high and the contribution is high. It means that with a reasonable number of patients, we can be profitable. That is not always the case. If you look at companies like Arcutis, they had to bleed hundreds of millions before they became cash flow positive.
The other thing that has to do with this, we believe that the uptake will be high because all the reasons that you heard today. Physicians, unlike in other cases, are fully aware of the mechanism of actions. They know how effective hedgehog 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 Europe is so complex and segregated. We are sure that with our product knowledge, our great consultants will do a great job, and high motivation will do a great job in the marketplace.
Thank you. One last question to Julie. Are there other areas in the body than the face that could benefit from the treatment of SGT-610?
I think the entire body could benefit from the use of this product, particularly the sun-exposed areas. Ideally, we want to reduce scar burden and disfigurement. So, those would Obviously, face, neck, scalp, maybe for some, hands and legs. Again, those that are most visible.
Thank you very much. Thank you. Thanks for your talks. It was really impressive. Thank you.
All right. So thank you all. Please stay seated. We will now do an open Q and A. Please, in the interest of the folks on webcast, wait until you get a mic from one of us, and please state your name and affiliation.
Hi. Thanks so much for all your time today. We really appreciate all your insightful commentary. This is Stacy Ku from TD Cowen. I have a couple questions, first for the KOLs and then for the management team. First, for Dr. Billingsley, maybe can you help contextualize that 30% reduction that we've heard across the board from patients and KOLs? How does that translate into number of surgeries, fewer surgeries that an average patient that may be on oral hedgehog inhibitors might undergo over the course of one year? So just help us understand what that 30% really means from the patient perspective. That's the first question. And then the second question is for Dr. Sarin.
We wanted to clarify something that you had said very quickly in your slide deck, which was oral hedgehog inhibitor efficacy as it relates to PTCH1 positive patients versus maybe the SUFU positive patients or PTCH1 negative patients. Just help us understand, in the real world, in your clinical experience, what that sounds like. It sounds like you're getting differential efficacy in those two patient populations. As we're looking to the subgroup analysis of the phase III clinical trial design, just help us understand what you're seeing in the real world, and what that means. That's the first two, and I have some questions for management as well.
Okay, sure. In thinking about what does a 30% reduction mean, some of these patients will get 5- 10 new basal cells on their face in a year. If just using, say, 10, if they need seven surgeries instead of 10, that's three fewer visits to the doctor. That's three fewer procedures. Or even if they're ones on the shoulders, it's just less time being spent in my office undergoing a procedure. Is that what you're saying? Just even going from 10 to seven is significant. Even thinking of it as taking days off work. That's a burden as well. Each visit takes time and recovery.
Great. To your question about the genetic testing. We do genetic testing on our patients, and about 80% or so are PTCH1 positive. About 5%, ballpark, have a SUFU mutation. Then there's about 10%, 15%, we don't really know. We can't find it. We can't figure it out. They clearly have Gorlin syndrome. There's some case report of a PTCH2 mutation. We don't really know why. The PTCH1 mutation patients are highly responsive to oral hedgehog inhibitors. Actually, if you look at just sporadic basal cell cancers, 90% of sporadic basal cell cancers, around the same percentage, are driven by hedgehog activation through loss of PTCH1. Now, there are other ways that a basal cell cancer can develop outside of loss of PTCH1, and that can be through activation of smoothened. Now, these activating mutations in smoothened are resistant.
We've shown that, others have shown that, are resistant to hedgehog inhibitors. And they do it through two ways. One is through blocking binding of the drug. There are mutations that block binding of the drug. And they also do it through causing constitutive activation. So when the drug binds, it still doesn't block the hedgehog inhibitor. This is a lot of genetics, but the point is that patients with SUFU mutations are more likely to develop basal cell cancers that are resistant because they don't only develop basal cell cancers through loss of PTCH1. They can develop basal cell cancers through other genetic mechanisms that are non-responsive to the drug.
Patients with PTCH1 mutations, where they have already lost one copy of PTCH1, almost all of their basal cell cancers are going to develop through loss of that second copy, meaning that almost all of their basal cell cancers are driven at the PTCH1 level, so therefore are responsive to the downstream drug. Even though it is mostly case reports that support the resistance, it is also just science. The science supports that the patients with SUFU mutations are more likely to be resistant than those with PTCH1.
Okay. Thank you so much. Then a question for Mori. Maybe discuss the powering of the study. What are the assumptions based on the last phase III, and then maybe the implications of the lower dropout rate? That is the first question. Then a second, if I could venture, are you willing to disclose the baseline BCC count for these patients in the current phase III? Just given the commentary we heard today about really the high risk and high burden BCC count, why wouldn't some of these patients have a very, very high count that are currently enrolled to the study, as we are kind of thinking about what the placebo response or vehicle response could look like? That is the second question for Mori. Then last, we have a little clarification on one of the slide decks. We will do that.
First question was about the powering.
On the powering.
The original powering, the one that we submitted to the FDA, was based on the delta that was obtained in the post hoc analysis of the phase III, the one that I showed earlier, namely 50% or so reduction of new BCCs. In order for that with such healthy data, we needed 58 patients, and that was for 90% powering and to reach statistical significance. During the study, we realized that we probably have a lower dropout, but we decided to continue with the same rate of enrollment, and we ended up with 113 patients minus the dropouts, it's 102. This is way higher than the minimum number we needed for the 90% power. According to our statisticians, that would mean that this power will suffice also for 40% delta, namely 40% reduction.
If the standard deviations will be lower than the one in the original study, which was very high, we tend to believe that it will also provide the statistical backup also for lower than 40%.
Okay. The baseline BCC count in the current study?
I was strictly forbidden by our R&D VP to talk about anything about the present study, except for what I already shared with you, number of patients, number of sites, and dropouts. Please bear with me.
It was worth a try.
I would very much like to share with you everything that I know.
Okay. If we go back to some of the commentary, I think it's slide 12. It sounds like in the middle of the study, PellePharm amended the study for the number of BCC counts. It was in the subtext. I'm not sure if this is something that you can comment.
Yeah. In the original study there were three, I think that was referring. The original study was three, but beforehand there were two patients that still sneaked in with two. So for the sake of good order, we mentioned it. It is meaningless. It doesn't have any real effect, but since I noted that analysts are keen on finding such small discrepancies, so for good order's sake, we already mentioned it in the small. Just one or two patients had two instead of three. Didn't change anything in the general big picture.
Okay, wonderful. Thank you so much.
Cool. Sam Slutsky, LifeSci Capital. Two for me, one for the physicians, and then one for management. I guess for the KOLs, if the Sol-Gel asset were to get approved, how quickly might you expect adoption as you consider the Gorlin community, their connectivity, frequency of office visits, and just general awareness of treatments and development?
I can go first. I think it will be adopted very quickly. I think there's two reasons. The first is that it's one of those, everyone is waiting for a treatment. When you have a condition where there is no good treatment and everyone's waiting for one, I think it's kind of like an if you build it, they will come type of scenario, where if it's available, people will come. We've seen this time and time again with dermatologic diseases, some that were considered orphan and were turned out not to be orphan, completely not to be orphan once the treatment became available. The second is that there are societies like the GSA that can also help spread the word. The third is because interestingly, with Gorlin syndrome, it's not like basal cell cancer, which is spread over many different physicians.
It's rare enough that there are certain places that patients tend to seek care when they do get referred. I think that that also helps.
I have nothing to add. That's perfect.
Okay. For management, obviously the phase III has two relevant inclusion criteria of at least 10 facial BCCs and a PTCH1 mutation. If phase III is positive, what's your expectations for what the label could look like regarding eligible patients for treatment? Might you expect a broader use case than what the current trial allows for enrollment?
Whom do you address? Do you address me?
Yeah.
It was also very interesting to hear maybe the spontaneous response of doctors, because they can use also their experience and common sense. Let me start because you asked me. We are fairly confident, although we cannot be sure 100%, but we are fairly confident that based on the precedents, many companies use this type of enrichment in order to increase the likelihood that the drug that they are testing will reveal its efficacy within the framework of a study. Therefore, we're not doing anything that other companies, even in acne, the most simple one, we don't use patients with four lesions on the face. We use 10, 20, 30, because when the patient has too mild a disease, it will either elapse by itself. We will not be able to show the efficacy of the drug.
Precedents of the FDA, enrichment was never translation into a restriction in the including the hedgehog, all hedgehog. All hedgehogs were always done with restrictions. From the first place, not in the second study, in the first place. Usually, people do not read all the small words on procedure of the clinical trial. But the pivotal MIKIE had six BCC as a minimum, at least one or more surgically eligible. Other studies that we located were also using three in the last three years or something like that. This is standard procedure. Only in our case, because it was the second study, it attracted more attention. Such standard type of enrichment do not get such attention.
The second thing is that as my physician colleagues has emphasized, a patient at the beginning of the study has two or three, may have in one and a half years, in two years, he will have many BCCs. You cannot deprive him from therapy or wait until he will get disfigured with 10 BCC and 10 surgeries. It doesn't make sense. The last thing, every patient that ended the study with 10, he wasn't born with 10 BCC. Before that, he was nine, he was eight, he was seven. It doesn't make sense that you wait until he reaches a devastating state in order to try it. We understand it. I think the physician understand it, and I'm sure that FDA understands it.
All right. We actually have time for one more, so I'll hand you the mic.
Thank you. Imogen Mansfield from Cantor. I guess just to follow up on Sam's question with the physicians on the panel. How do you think about the baseline requirement there of the minimum of 10 BCCs as if you were giving the FDA advice on labeling? I guess just thinking about the practicalities, if a patient has had Mohs surgery and they had more than 10 in the past, and you wouldn't not do a surgery just so that they would be eligible for the drug. How do you think about who you think would be eligible based on the study?
Ideally, I would start anybody once they have the diagnosis of Gorlin syndrome.
Yeah, I think you're asking for a question of FDA labeling versus physician use. A 30% decrease. If someone gets two tumors a year or three tumors a year, and that reduces their chance by 30%. Think of it as we all jumped on nicotinamide, and that was a 20% decrease for this vitamin with minimal side effects. That's just for the general public. You can imagine in a Gorlin syndrome patient, we were going to be 20 times as likely to jump on a medication with a 20% or 30% decrease in treatment because we know their chronic course. We already know it. That's what we would do. What we would be allowed to do based on FDA labeling is a very different or what would be, I guess, on label.
We can still use things off label, but what would be on label based off FDA marketing might be different. But, if it's tolerable and it reduces something by 30% in a patient with a chronic condition that's predisposing them to develop tumors, I just feel like it's a no-brainer. We would start very early.
Sorry. Great. One more question for all of you and also for Julie, I guess, as well. There's quite limited data on for across patients, what the baseline number of BCCs would mean in terms of this placebo arm. If you have a higher burden, does that mean that you would be developing BCCs at a higher rate? The evidence from the PellePharm study goes in that direction. But based on your clinical experience and, Julie, based on I guess your own experience and with the foundation, how do you see the number of baseline BCCs trending towards a placebo response? Is a higher baseline going to lead to more lesions over a year?
Yeah, I can take that one too. I definitely think there's going to be a correlation. What that correlation is, I can't tell you exactly, and that's just because we know that patients with higher burden of basal cell cancers, assuming they've been getting treatment, like they're not completely lost and then suddenly come in for this one trial, which is not the people who are being referred to the trial. They are developing many. That's why they have a high burden. If they were only developing one or two a year and not getting treated, they probably wouldn't even know about this trial. This is in particular for the trial. I think this is going to enrich for a vehicle arm that gets more tumors than the original trial.
If I may add just one sentence. I would like to quote from an Israeli expert that we consulted with, and his point is that arithmetic is not the whole thing. It is more important is the slope, the acceleration, the dynamics of it. If a young person never had, has one and then another one, you don't wait to start because you see there is some dynamics. Finally, it should be the decision of the doctor and based not just on pure arithmetics, but on the dynamic of the disease and the acceleration. When you see signs of something new, of acceleration, you should start immediately and not speculate about the next stages.
Thank you.
That's all the time we have. Mori, I've turned it back over to you for any thank yous and final remarks.
Thank you very much, ladies and gentlemen. I hope this session was informative and will be available whenever you need for additional questions. But until the moment that we will get the results, we are always at your service. Thank you