VYNE Therapeutics Inc. (VYNE)

R&D Day 2019

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Jan 24, 2019

Hello. Good morning or I guess, good afternoon. My name is Mujah Harsh and I'm the company's General Counsel. Thanks to everybody for coming today. I have to read this disclaimer because we are being recorded and this video this webcast is going to be recorded and posted on our website. So hopefully I don't have my glasses, but welcome to Foamix's R and D Day. To the extent that statements contained in this presentation are not descriptions of historical facts regarding Foamix. They are forward looking statements reflecting management's current beliefs and expectations. Forward looking statements are subject to known and unknown risks, uncertainties and other factors that may cause our industry's actual results, levels of activity, performance or achievements to terminologies such as may, will, should, expects, plans, anticipates, believes, estimates, predicts, potential, intends or continue or the negative of these terms or other comparable terminology. Forward looking statements contained in this presentation include, but are not limited to, statements regarding the timing of anticipated clinical trials for our product candidates, the timing of receipt of clinical data for our product candidates, our expectations regarding the potential safety, efficacy or clinical utility of our product candidates, the size of patient populations targeted by our product candidates and market adoption of our product candidates by physicians and patients, the timing or likelihood of regulatory filings and approvals and our revenues under our agreements with our licensees, including LEO Pharma and other companies. Although we believe that the expectations reflected in the forward looking statements are reasonable, various factors may cause differences between our expectations and actual results, including but not limited to unexpected safety or efficacy data, unexpected side effects observed during preclinical studies or in clinical trials, lower than expected enrollment rates in clinical trials, changes in expected or existing competition, changes in the regulatory environment for our product candidates and our need for future capital, the ability to protect our IP and the risk that we become a party to unexpected litigation or other disputes. Please check our registration statements and our filings filed on sec.gov and also on our Foamix website. Doctor. Hilary Baldwin, Associate Professor of Clinical Dermatology at the Robert Wood Johnson Medical Center and Doctor. Jonathan Weiss, adjunct assistant clinical professor of dermatology at Emory University School of Medicine are participating in today's presentation on behalf of Foamix. Doctor. Baldwin and Doctor. Weiss were principal investigators in our clinical studies for both Foamix101103. They are paid our property and are used for reference purposes only. Such use shall not be construed as an endorsement of the Foam Technology or product candidates of Foamix. Okay. So on that, I'd like to introduce our CEO, Dave Domzalski, who many of you are familiar with. Dave is going to get us started. So enjoy your lunch. Well, thanks, Muthia. That was a tough job for today's session. So again, thanks to everyone for coming. We have a full house and we have many people that are participating live on our webcast. So thanks to everyone that's dialing in. Looking forward to an exciting afternoon. We're very fortunate that joining us today are 2 incredibly experienced board certified dermatologists with significant expertise in the fields of acne and rosacea amongst a whole host of other dermatological conditions. We have Doctor. Hilary Baldwin, who is the Medical Director of the Acne and Treatment Research Center in Morristown, New Jersey and Associate Professor of Clinical Dermatology at the Robert Wood Johnson Medical Center in New Jersey, was past President of the American Acne and Rosacea Society. We also have with us Doctor. Jonathan Weiss, who is with the Quininta Dermatology Research Center and is an associate clinical professor of dermatology at Emory University and also is a member of the Board of Directors for the American Acne and Rosacea Society. So I want to thank you both for taking time out of your very busy schedules to join us today. In terms of the agenda, I have a few opening comments regarding our corporate focus and objectives in the near term and midterm. I'll turn it over to Doctor. Baldwin, who will talk about the current acne therapy landscape and review our key pivotal data for FMX101. We'll then turn the podium over to Doctor. Weitz, who will do the same for the rosacea marketplace as well as review our data for FMX103. After that, we have Doctor. Iain Stewart, who is our Chief Scientific Officer and Head of Research and Development. So that will take us through some additional recent data for FMX103 and also talk about our medical communications plans for the next approximately next year. We'll introduce then Matt Wiley, who is our Chief Commercial Officer, who will talk about the commercial plans for FMX101. Doctor. Stewart will come back up and give you a high level overview of some of the pipeline activities that we have. And then at the end, I'll wrap it up. And we'll save Q and A for just one Q and A session with both Doctor. Ball and Doctor. Weiss, Doctor. Stewart, Matt and myself. So if you could just hold your questions until the end, and we'll have a comprehensive Q and A session. And I believe we'll also have the ability to take some questions from those that are participating on the webcast as well. So in terms of our objectives as a company, 2018 was an exceptional year for us. We completed successfully our 3rd confirmatory Phase III trial in acne, which again Doctor. Baldwin will speak to it shortly, an exciting time for us, an exciting milestone. We also successfully completed our 2 double blind pivotal studies for rosacea and also filed our NDA for FMX101 and acne before the end of the year. So in terms of milestones for the companies, these were crucial milestones for Foamix. We're very excited about the past year and very much looking forward to what's in store for us in 2019 and beyond. So obviously, if you take a look at corporate strategies, and I could obviously speak to you about very long term horizon objectives. I don't believe they provide a whole lot of value right now. I want to try to keep our discussions tight on what are we doing over the next, call it, 12 to 36 months. But certainly in the near term perspective, our focus has been, as you know, to leverage the synergies of both FMX101 and 103 and to establish our development and commercial presence in these acne rosacea marketplaces. When I took the CEO post approximately 2 years ago, we had 3 fundamental areas of focus. 1 was to execute on our pivotal trials. 2 was to manage our cash burn, if you will. And then 3 was to start advancing our pipeline. I believe the team has done an exceptional job certainly on all these fronts, especially the first two. And then now we look forward to providing at least some insight on what we're looking at from developing our pipeline. If I go beyond, say, the next 12 to 24 months, it's important for us to create durability of these franchises for accrualization and begin to diversify our portfolio. We'll do that through our own internal developments and we're also open to selective acquisition opportunities as they may deem be appropriate, whether they be technologies or assets. In terms of our imperatives, it's important obviously that we establish a very efficient commercial model to successfully launch FMX101 and FMX103, and Matt will talk about that to some extent a little bit later on this afternoon. We've obviously been working to expand our R and D and our drug development capabilities, quite pleased with how that has begun to come into focus, especially over the course of the last 6 to 12 months. We are clearly looking at identifying complementary markets for product developments, again using acne and rosacea as called a beachhead and to build off of that. And then certainly since we've gotten very positive Phase III results for 101 and 103, The dialogue on out license partnerships with other potential collaborators has increased significantly, and these would be for ex U. S. Rights. We also look as we move towards mid term initiatives. I do believe that we have an opportunity, and we will look to advance our development programs 1st and foremost for the next generation products in acne and rosacea. We are also in the process of advancing what I would call adjacent clinical development programs in medical dermatology as well as aesthetics. So we are clearly looking at and doing quite a bit of work in areas such as atopic dermatitis as well as we believe our platform has a lot of utility for areas such as aesthetics. And then as I've outlined here in the slide, we'll look to leverage our platform and our development capabilities to expand additional collaborations with partners. But for purposes of today's discussion when we move towards our dialogue around our pipeline activities, it's we want to focus on what I have here boxed out is how are we going to create durability for the acne rosacea franchise. So we'll spend our time focusing on that. In a future session, we'll talk about some of the other categories that we're developing products for. So with that, I want to turn the podium over to Doctor. Hilary Baldwin that will talk about the current acne landscape and FMX101. So thank you. Thank you. So it's a pleasure to be here today to talk about the current acne landscape and the way in which I predicted FMX101 will fit into our acne toolbox. We have quite a few drugs in our toolbox. It's always nice to have a new one, and I think this is going to replace several of the things that are currently players in my toolbox. I'd like to start really briefly going off over pathophysiology of acne, not in any kind of detail, but because I think most thoughtful dermatologists, when we sit down and see a patient in front of us, have this in the back of our minds. You may already know that the average successfully treated acne patient is on 2.53 acne medications. And that shows you that the pathophysiology of acne is multimodal. And what we're trying to do is to come at the problem from several different directions so that we can reduce the burden on the patient to the greatest extent. So we're thinking about the increased sebum production. We're thinking about follicular hyperkeratosis, which ends up giving you the clogged pores. We're thinking about P. Acnes living in the follicles. I will continue to call this P. Acnes. ACNES. Many of you probably know that it's now referred to as C. ACNES. I am way too old to change at this stage in my life. So I'm going to continue to say P. ACNES, all of which leads all roads lead to inflammation in the acne world right now. So if we think about what drugs we might use to treat those different aspects of this whole process, when we're talking about androgens, when we're talking about sebum production, we're talking about androgens. Suppressing male hormones with hormonal therapy orally generally. We can also use a topical anti androgen if we had one. We don't yet. Many of them are in development. And isotretinoin is a great drug to reduce sebum production. We might think about topical retinoids, maybe Benzoyl Peroxide and certainly isotretinoin when it comes to decreasing the clog in the pore. We're going to be thinking about antibiotics when it comes to reducing the P. Acnes in the follicle. Isotretinoin also reduces P. Acnes in the follicle, not because it's directly antibacterial but because it starves little suckers to death by depriving them of sebum, which is what they eat, it makes them starve to get death. So the number of p. Acnes go down. We used to think of acne as being an inflammatory an infectious disorder, and now we're thinking of it as an inflammatory acnes still plays an important role, but it plays a role mostly in the fact that it causes this whole inflammatory process to occur to begin with and maintains it. So acne process now is considered inflammatory from birth to the very end resolution of every single acne lesion. So inflammation is the name of the game, not anti infection, right? So all the medications we're looking for, yes, they will kill P. Actus, they will reduce P. Actus concentration because P. Actus leads to inflammation, but they also ideally will be anti inflammatory drugs as well. And lastly, we're looking at inflammation again with our antibiotics, with our topical retinoids, which are also anti inflammatory drugs. And finally, once again, isotretinoin. And you can see here why it is that isotretinoin is such an effective drug for the treatment of acne. When we're talking about our antibiotics, what we're looking at primarily is the tetracycline class of antibiotics. To a lesser extent, trimethoprim is also helpful, although you don't hear much about it. It's a very good anti inflammatory and antibiotic in the treatment of acne. So the tetracycline class of antibiotics are highly effective in treating our acne patients both because it kills P. Acnes but also because of all of these anti inflammatory activities that it has. It's why it's such an effective medication in both acne and in rosacea, as Doctor. Weiss will show you in a few moments. The question remains, is topical minocycline, what we're talking about today with FMX101, also anti inflammatory. And you're going to see some more information on that in a few moments. And I think some of the data that you have seen and will be seeing support the role of topical minocycline also as an anti inflammatory medication. So when a patient walks in the door and I'm I take a seat and I take a look at the patient, how am I deciding which one of those 2.53 medications I'm going to use on this particular patient? If you ask a dermatologist how long it takes them to make up their mind how they're going to treat an acne patient, probably most of us say maybe 5 seconds, 2 seconds, 10 seconds. It's very obvious what we need to treat them with. And the reason for that is that we have an algorithm that we all go over in our heads, and it may be different for each person. But for me, the first thing I'm looking at is lesion type. Is the patient primarily comedonal or inflammatory? Or is there a combination of the 2? If it's primarily inflammatory, I'm going to start thinking about antibiotics, topical and oral, maybe topical DAPSTONE. If it's primarily black heavy kind of stuff, I'm going to be thinking about topical retinoids. If it's both, I'm going to need both medications. I'm looking at the number of lesions, the size of them. We could have 100 tiny little papules, and I'm going to pick a different treatment that if I have 10 big huge inflammatory lesions. And then I'm going to, in my mind, put them into mild, moderate and severe comedonal inflammatory or both. And that's how the decision is made so quickly. Location also matters. Is it face only? Or is this chest and back and arms and face? At which point, using topical medications gets very cumbersome. Am I going to use 2.3 on the face and a different 2.3 on the back and chest? That is never going to happen in real life. You're not going to get those prescriptions filled. The patients are never going to use them. So that's when we start to think about using oral medications, for example, to take care of all of the problems with one particular drug. Presence or absence of scars is very important, both psychological scars as well as physical scars. The psychological overlay of this condition is very, very great, especially for our teenagers and our adult females. But the physical scarring, obviously, very important as well. We're treating acne both to get rid of the pimples that they have now and to make sure that they don't have scars for the rest of their lives. And the last issue, which I'd save for last but is sometimes the biggest issue is all the baggage the patient brings with them. Is their insurance company going to pay for the treatment that I thought of in only 5 seconds? Is do they play a sport where the use of the zit is going to ruin the entire day or maybe even her entire career? And then, of course, patient preference. Some people like pills, some like creams, some tolerate irritation, some don't. So the patient baggage is often the biggest part of the visit that we have. So I've converted this patient into mild, moderate, severe in my head. And so here we have a picture of some mild to moderate acne patients. So I might consider topical retinoids alone, topical Benzoyl Peroxide alone, topical DAPZONE, combinations thereof And I might even think of an oral antibiotic, especially for the patient on the left. Now that's where the baggage might come in. If his baggage was, by the way, my prom is in a month, well, then I better haul out my oral antibiotics because it's going to take a while for this patient to get better with topicals. So that's part of this whole decision making process. A topical retinoid can make this patient better all by itself. This is from the tazarotene 0.1 percent cream study originally. And you can see at week 12, this patient is dramatically better just with a topical retinoid, but that took 12 weeks. Acne patients don't wait 12 weeks to get better. They want results much, much sooner than that. The next problem, of course, with topical retinoids is often the patients get very dry and very red. So ideally, we would like a topical that works that fast, that well and does not create this kind of a problem. Benzoyl Peroxide has been a workhorse. It's now 80 years old. It's a very old drug. We're still using it as a stand alone for inflammatory and, to a lesser extent, non inflammatory lesions, has a rapid onset of activity and it's not associated with any antimicrobial resistance. But it has a lot of baggage in and of itself. We have concentration dependent irritation. About 5% to 10% of patients are said to be actually allergic to it, although I think it's mostly people who are irritated by it, and we just never really got a chance to look at whether it's irritation or allergy. And in addition to that, it bleaches the heck out of clothing and stains white fabrics. And that's a really big problem. And often people pooh pooh that, but the patients hate it, especially if you expect them to be putting benzoyl peroxide on the chest and back. You're asking a patient to get up in the morning, take a shower and then to consider what color am I going to wear today. And if they're wearing white, they can put on their Benzoyl Peroxide. And if they're not, they can't really then ask that of a teenage boy. That stuff is never going to end up on them. So what I'm looking for is a topical that does not cause irritation, does not cause contact dermatitis and does not bleach fabric. So when we're talking about moderate and severe inflammatory acne, the current topicals that we've been talking about don't work well enough or fast enough to take care of most of these problems. So we're going to be adding oral antibiotics to our topicals, never oral antibiotics as a stand alone. If it's a woman, we might think of hormonal therapy with topicals. And we might even consider isotretinoin for this woman. It depends on her baggage. If her baggage includes suicidal ideation, you bet you. I'm on to isotretinoin right away. If it includes scarring somewhere, absolutely isotretinoin immediately. So let's talk about the oral antibiotics then. Oral antibiotics, as we said, tetracycline class usually because it's both antibiotic and anti inflammatory. They work very well. They give us our fastest onset of activity when a patient needs to look well as soon as possible. But we have a lot of systemic side effects with our oral antibiotics, including GI distress, photosensitivity with our doxycycline and tetracycline, vestibular side effects primarily with our minocyclines, hyperpigmentation issues, rare severe side effects with the oral medications and concerns about antibiotic resistance, which is a real issue now in this day and age. We didn't think much about this 10 years ago. We put people on antibiotics, and we kept them on it for years. But now the CDC, of course, is calling for us to be better stewards of our antibiotics. And I think dermatologists are finally listening to this, and we're turning away from the use of oral antibiotics whenever possible. What about our severe nodular inflammatory acne? I was on an interview yesterday with a reporter, and she all she really wanted to know is what are our alternatives for isotretinoin in patients who look like this. So I said, I'm sorry, we can just stop this dialogue now because the treatment for this patient is isotretinoin, isotretinoin or isotretinoin. That's what this patient needs, and that's what they're going to get if they come to our offices. And this is the sort of thing that isotretinoin is capable of doing. So I want you to keep that image in mind. When you think about all the potential side effects for isotretinoin, which I would like to suggest are much more perceived than they are real. I think John will agree with me that, the bulk of the things that our patients are concerned about don't really happen. They're hype. They're Internet hype. Isotretinoin is one of those 1800 bad drug drugs because there's a lot of legal issues surrounding it. But in reality, if we take good care of these patients and check their blood tests and follow them carefully, this drug has less side effects than many of the others that we use for treating our acne patients. Teratogenicity, of course, being the only one that's of major concern because you can't go back once you create a problem of that sort. So this whole thing is really a problem, and the reason why we're talking about all these medications is that acne is a chronic disease. This is not a one and done. Patients come in to see me with this chronic relapsing course over many years. They have all of the psychosocial overlay, And I'm going to treat them acutely right now with something. And then moving forward, we're going to be treating them with something else for maintenance purposes. And that maintenance teenager. It could be 20 years in an adult female. So when you're looking at medications and their importance in our toolbox and frankly as investment issues, the medicines that are going to be used for maintenance are the ones that are going to be refilled over and over and over and over again as time goes on in order to maintain the improvement achieved by the acute therapy. So acute therapy is almost less important in terms of the pharmacoeconomics than is the maintenance. Maintenance also, however, adds to frustration. Patients don't want to be using medicines forever. Unfortunately, that's a reality for a lot of our adult female patients with acne. We have to find something with a delicate balance of efficacy, tolerability and acceptability. Can't expect them to be using Benzoyl Peroxide and worrying about their color, their fabrics bleaching and switching over to white sheets and pillowcases for the rest of their natural life. It's bad enough for a couple of weeks, right? And the need for bacterial resistance also adds to this bacterial the need for maintenance therapy also adds to this whole bacterial resistance issue because even if I can get you under control with oral antibiotics, can't do that forever. Going to have to stop it in a couple of months, so I've got to find an alternative. So what might be one of our alternatives? We're going to turn now to the top line pivotal study results for FMX101, and I know that you've all had access to this, so I'm going to go over it relatively 3rd study. As you're well aware, FMX101 had a little problem with its first Phase III trial. 2005 met its endpoints, 2004 met most of its endpoints but missed the IGA. So they had to go ahead and do a second study, which was called 22 instead of 'six, which is what I would have called it, Study 22. And in this study, there were 1500 patients who were 9 years of age or older, and they applied this medication once a day for 12 weeks. The primary co primary endpoints were IgA of success, which was too great improvement and clear or near clear. So if they started off as severe, they had to go to moderate to mild to near clear. So this is a very tall order. The average number of lesions at baseline was very high at 31 inflammatory 51 non inflammatory. So we're talking more than 80 acne lesions on the face of the average person who entered this study. And rather than just glossing over that, I'd like you to think about what you would have done this morning if you had woken up with 80 acne lesions on your face. Would you be here? Or would you have sent somebody else? I wouldn't be here for sure. So what we're looking at here is 1500 patients with moderate to severe acne with a lot of acne with a very high, very tall order for success. So now we're looking at the patient demographics and baseline characteristics of Study 22, which was very similar with the exception of being a much larger study to the successful 5 study on the right. Otherwise, all of these match up quite similarly, including the number of lesions at baseline and the fact that about 85% of patients were moderate and 15% were severe. So now we're looking at the efficacy data. And this first one is the co primary endpoint of the absolute change of inflammatory lesion counts at week 12. On the left, again, in Study 22, we see a nice healthy statistically significant difference between the drug and the vehicle with a reduction of 17 of those original 30 to 31 inflammatory lesions compared to 13.5 in the vehicle treated side. So Study 22 did much better than the original Study 5. Looking now at the other co primary endpoint of the IgA, which is treatment success. Again, a highly statistically significant difference between the drug and the vehicle with a success rate of 30.8%. That is an extraordinarily high number for any acne study. In fact, it's about 10 points higher than the newest oral acne medication to enter into the marketplace just last week. And compared to Study 5, it was even more highly statistically significant than the original study. Here, we're looking at the key secondary endpoints, which is percent change of inflammatory lesions over time. And you can see at the end at 12 weeks, we're talking about a 56% reduction in the 22 study and a 43% reduction in the 5. Those numbers also comparable to that which is reached with the use of oral medications for the treatment of acne. You can also see that it became statistically significant as early as week 3. That is no small issue. You have to get into the patient mindset. At week 3, with most topical acne medications, they're already experiencing a great deal of cutaneous irritation. And they look into the mirror and they see no change whatsoever. So they're hoping to see an improvement in their acne. They see none and what they see is more redness and more dryness than they did before they started using the medication. And it's a moment that I like to call the crisis of confidence. They have lost confidence in that drug and they have lost confidence in me. And it's highly unlikely that they will continue with the medication past that point if they don't see signs of improvement and if they continue to see a lot of cutaneous side effects. So as you'll see in a few moments, these folks did not experience a great deal of cutaneous irritation, redness and dryness, and they did see improvement at week 3. So I think they're liable to continue to use the product moving forward at a much higher rate than they would have had it not kicked in quite as early as it did. So now we're looking at absolute change of non inflammatory lesion count. I think this was kind of an actual little boost for you. We don't usually think of topical antibiotics as having an effect with non inflammatory lesions. That's usually the bailiwick of topical retinoids. Our topical antibiotics are generally we're using them more for our inflammatory lesions. But here, a nice healthy reduction, statistically significant of non inflammatory lesion count as well. Not as big a number. We subtracted here at 19 lesions, but that's a nice big number. And if you ask me to speculate, which granted you didn't, but if you ask me to speculate, I would think that maybe that shows adds credence to the thought that maybe topical minocycline is anti inflammatory because how else would it result in a diminution of non inflammatory lesions. There has to be some way in which it accomplished that. And since inflammation precedes the development of those comedonal lesions, perhaps this is demonstrating to us an anti inflammatory activity to this medication. So what about safety? We talked about this a few moments ago. What we're looking at here is treatment emergent AEs, and these are all AEs, which as you are well aware, could include things like hangnails and being hit over the head with a baseball bat, right? And on this list, I think you'll appreciate that most of them don't have anything to do with a topical acne product, for example, a ligament sprain, unless you sprained your ligament while putting on your cream. I can't see that as being an association. And it was quite low with no treatment related serious AEs reported in either group. So now let's look at the AEs that really might be related to the medication. We're looking at our local tolerability issues. And here, we see that 95% of signs and symptoms were classified as mild to moderate. So it was uncommon. And when it did happen, it was mild to moderate. And you can look at the separation of erythema, dryness, hyperpigmentation, skin peeling and itching. And you can appreciate on the left, which is the drug and on the right, which is the vehicle, no difference between those columns and most of them weighing in as mild to moderate. I'd like to spend one moment talking about the hyperpigmentation. You're all well aware, I'm sure, that oral minocycline has been associated with hyperpigmentation. It's associated with this after a long treatment duration of about 4 grams of total dose and probably 4 to 5 years of use, especially now with our use of lower dose of oral minocycline. So it's a long term problem. And of course, it was important to make sure that this didn't occur with the topical minocycline. So this hyperpigmentation, as you can see, no difference between the vehicle and the drug. It was not the kind of hyperpigmentation that we see with minocycline on the face, which is in the base of pitted acne scars. It was the kind of hyperpigmentation that we see as inflammatory acne lesions resolve. Especially in our patients of color, when their lesions resolve, they for a short period of time have brown dots on their face. And that's what this hyperpigmentation was in my experience and in Doctor. Weiss' experience as he shared with me. It was not the hyperpigmentation that one might see from minocycline. So safety summary. Again, very few AEs. The ones that were probably related to the product were mild and rare. The severity was none to mild. No treatment related serious AEs were reported. And one of the markers of how much an irritation bothers the patient is did they pull out of the study, right? So if patients complain of irritation, but they didn't decide to leave the study, that irritation becomes much less important. So what was the discontinuation rate? It was extremely low and similar between the vehicle and the treatment group. And overall, the safety results for the 3rd trial, 22, were similar to those of 2004, 2005 and the long term safety extension. So no red flags. The overall summary is that we had a statistically significant disease improvement with FMX101 compared to vehicle with all of the co primary endpoints and secondary endpoints with an additional bonus of non inflammatory lesion count reduction at week 12 being statistically significant. Points. Treatment emergent AEs were few and mild, as we said before. No serious ones, no discontinuations other than a couple that was the same in the treatment and the vehicle group and patient satisfaction, as you see in a few moments, high in all of these studies. So where I've been asked to talk a little bit about where I think FMX101 might fit in my acne regimen. So I see this as monotherapy for inflammatory acne, maybe even for non inflammatory acne, frankly. Monotherapy probably for my milder patients, I would probably be using it in combination. I think probably with the topical retinoid, first thing that springs to mind, give me a little extra boost dealing with my non inflammatory lesions. With moderate to severe, I'm going to add it on to my oral therapies and on to my other topical therapies as well, especially hormonal therapies. But most importantly, I think, is for maintenance. I see a big role for this drug in maintenance, which, of course, again, can extend for years years. As monotherapy, maybe, the numbers look as if it's good enough to just be used as monotherapy, which, again, is not going to bleach their clothes, it's not going to be irritating, it's not going to cause contact dermatitis, all of the things that were on my initial wish list for a topical product. I may also end up using it in combination with a retinoid as far as maintenance therapy is concerned, especially for our adult female acne patients, which, of course, off label, kills 2 birds with 1 stone since the topical retinoid can be utilized as an antiaging medication as well. So what's it going to replace in my toolbox? For sure, clindamycin. But I have to admit that my toolbox didn't have much clindamycin in it to begin with. Our fellow dermatologists love standalone clindamycin. Apparently, the last number I saw was 26% of topical acne products are still being written for clindamycin. I don't get that. I never use clindamycin, bless you, unless it's in combination with Benzoyl Peroxide. It's not a terribly good product to begin with in my mind, and the antibiotic resistance problem has increased that issue dramatically. It's always been said to be an anti inflammatory. It may have anti inflammatory properties, but it's never been shown to be anti inflammatory in the disease of acne itself. Daphson, never been a favorite of mine anyway. And if minocycline has anti inflammatory properties, that's what DAPZONE does for a living. So why wouldn't I use something that both suppresses P. Acnes and is anti inflammatory? Benzoyl Peroxide, one of my favorite drugs, but that staining issue is a real problem for maintenance therapy. And if the numbers are correct, this is giving oral minocycline a run for its money. And again, if I could use the topical minocycline without systemic exposure, without the risks of the systemic symptoms that can be associated with minocycline, why wouldn't I use a topical? So that's what I have to tell you about acne, and I'm going to turn it over now to my colleague, Doctor. Jonathan Weiss, who's going to talk about rosacea, and I'll be happy to answer any questions that you might have. Well, thank you, Hillary. So that's a tough act to follow. And also, my Apple Watch is telling me I should be taking a lap around the room at this point. I won't do that, but it's great. Wearable technology is wonderful. So I'm going to start talking a little bit about the history of rosacea. Unlike acne, which we've had a pretty good handle on how to treat it and what we need to do since the 1950s or 60s, rosacea is a condition that has evolved a little bit since then. Before 1992, when a company, a small company called CureTek came out with a product called MetroGel, which I believe they may have licensed from 3 ms and then was bought by Geldirma. Rosacea was a sort of condition to dermatologists that reminds me of a quote by Potter Stewart. Does anyone here know who Potter Stewart is? You're all very young. Potter Stewart was a Supreme Court Justice in the 1960s who was quoted in an opinion on an art film that was banned, I believe, in Alabama, They made it all the way to the Supreme Court, and they were trying to decide what is free speech and what's pornography. And Potter Stewart famously said, I can't define it, but I know it when I see it. And that's how dermatologists felt about rosacea through the 1980s '90s, that we didn't have a definition of it, but we had someone present to us and we knew they had rosacea. And we basically treated them with an oral tetracycline. In 1992, the small company came out with this product, Metrogel. And as all the drug This was a good thing because it got dermatologists thinking about a condition that we all took for granted. And it started a cascade of research that has helped us define it much better today. So as a result of that in the National Rosacea Society and the American Acne and Rosacea Society, which followed later in the late 1990s or early 2000s, we have 2 classifications of rosacea, the 2,002 classification and the 2016, 2017, which I will refer to as the 2017 classification because that's when it was published. So the 2,002 classification was largely based on clinical presentations of rosacea. Not a bad way to go. We really did not understand the pathogenesis of rosacea at that point. And they broke it into 4 categories, erythematotelangiectatic rosacea or ETR, papulopustular rosacea, basically the pimples we see are PPR, 5 minutes rosacea, which you is which was best encompassed by W. C. Fields nose, an old actor who had this bulbous nose that was lobulated and ocular rosacea or the eye rosacea. The weakness of this is that it segregated rosacea into groups. And there was not a whole lot of accounting for overlaps, which we do see a lot. In contradistinction, by 2017, a group of experts got together and said, We really now have a large understanding of the pathogenesis of rosacea. And that understanding encompasses that it is a disease of vascular blood vessel reactivity and inflammation. And this new classification accounts for overlap. So with this understanding of the pathogenesis, we now can diagnose rosacea if 1 of 2 factors are present, just absolutely. And that is central facial erythema or redness of the central face that may periodically intensify or the finest changes, those bulbous changes of the nose, the cheeks, the forehead or the chin. Most patients do not present like that, however. Most patients present with 2 or more of what we call the major phenotypes. And that would be the papules and the pustules, the inflammatory bumps, the flushing, telangiectasia or the ocular manifestations. I would say over 90% of the patients who present to my practice for treatment of rosacea or not for treatment that I then wind up treating have papules and pustules and either flushing or telangiectasia. That's how we make the diagnosis most of the time. However, there may be someone sitting in front of me who has that central facial erythema. It's just that becomes a much greater conversation and a much more difficult type of patient to treat. So we don't do that. And then again, the ocular manifestations are really somewhat poorly defined and understood. Now adding to those major phenotypes are what we call the secondary phenotypes or symptoms that help us make the diagnosis if someone's borderline. And 1 or more may be present with the other diagnostic features and that would be burning and stinging, edema, little bit of swelling in the face, the patients complain about and you can see if you know them quite well or that dry appearance, that flaky appearance, which is somewhat different from seborrherosacea overlap. And then again, ocular rosacea, I'm not going to deal with that anymore today because it's very poorly understood by both dermatologists and ophthalmologists, and it can occur with or without dermatologic disease. If they have no other symptoms, which is very rare, if someone comes with papules and pustules and they have rosacea, they almost certainly have some telangiectasia or flushing, it might help a little bit. And my treatment, if I treat them systemically, may actually help the ocular rosacea. And one final note is that ophthalmologists and other doctors who treat the eyes have a very poor understanding of this disease. They actually are putting steroids in the eyes. And if ocular rosacea is anything like cutaneous rosacea, you do not want to be putting steroids on cutaneous rosacea. And I can't imagine that the pathogenesis is that different, that they're not causing rebound in their patients by putting steroids in the eyes. So I think that is an area that is ripe for research. And as a group of investors, you might want to spur some companies in the ophthalmologic realm to kind of look into that. I think it is an area that has vast, vast potential. So how do we treat rosacea in 2019? Currently, most of our colleagues are treating according to the 2,002 criteria. Anytime you get relatively new criteria, they take about 5 to 10 years to take hold. So I'm going to present these in both contexts. So ETR or ethematous plangiectatic rosacea is largely treated with topical alpha adrenergic agonist, the vasoconstrictors for the background erythema. Those would be bromonidine or Mirvaso and oxymetazoline orophate. 2 products that have not done well, quite honestly, because these drugs tend to be used more episodically by patients when they need them. The coverage has not been great to this point. Hopefully, they're going to correct that. But those 2 drugs do need some boost to help their use. There are surgical options for the telangiectasia or procedural options, including laser, IPL or what I like to call the poor man's laser electro desiccation, which is a 1950s or 60s technology that actually works quite well, but is not quite as specific as laser or IPL. So for refinements rosacea, you're looking at procedural or surgical options. Electrosurgery or hot loop is probably the best way to go about this. And interestingly, whenever I've sent patients for that, I think there have been about 5 or 6 in my community that I've sent for it. Whenever they send the shavings off, they do it the hot loop to pathology, there is skin cancer underneath the FAMOUS rosacea. I am 5 for 5, and this is something that's not well known. It is another reason to treat rosacea because the I don't know what your experience is, Hillary. Yes. So it is something that has not been publicized, published that I know of or anything like that. But it is a very strong reason to treat rosacea to keep it from getting so bad that, that occurs. Other ways you can treat it are with laser surgery or cold steel surgery. Cold steel, just standard treatment, not a great idea because of the amount of bleeding, which is why they use hot loop and or laser. Now where we're going to focus today, papillopustular rosacea, you have obviously topical therapy with antibiotics or anti hominthics, metronidazole, azelaic acid or finacea, ivermectin, seulantra and sodium sulfacetamide and sulfur, which is really actually a pretty poor medication, but it's available in a wash, which nothing else is, and patients love washes. Systemic antibiotics are well known largely of the tetracyclines, doxycycline, either in what I call full dose. And I'm not saying you use like 100 milligrams twice a day, but I'm talking about the full size pill or the sub antimicrobial dose, which the name brand would be our ratio, but there's also a doxycycline 20 milligram that's available generically. Minocycline is used in multiple brands and is highly effective. And then for patients who are tetracycline resistant or tetracycline allergic, there are various others, amoxicillin, again, Bactrim or trimethoprim and the macrolides quite commonly, erythromycin, which is hard to get, but clarithromycin or azithromycin. So I want to share with you something that is a personal observation, and I'd be curious what Hillary thinks about this. When I think about rosacea, I've observed rosacea for 30 years. There are basically 3 paths that a patient can take. A very few patients, probably far less than 10% have a single episode of rosacea related to some trigger factor, they get treated, it never comes back. The vast majority have what I have come to call chronic relapsing rosacea. They have the first episode. They get a remission from our treatment. And that remission may last for weeks, months or even years. But they are going to flare again. And that's what I tell most of my patients when they present. You are likely to have this more than once. And maintenance treatment in that group prolongs remission. So I try to get my patients onto a maintenance regimen. Then there's what I call chronic constant treatment, chronic constant rosacea, which is the patient who you put them on medication and you go to take them off or you try to reduce it and they relapse almost immediately. And that's probably a 10% to 20% group of patients. So how is rosacea treated in clinical practice today? Well, for me, I generally start with a full dose oral antibiotic, probably doxycycline or minocycline 100 milligrams once a day, sometimes 50 milligrams if it's a smaller patient. It is rosacea can be exquisitely sensitive to even lower doses. And the majority have vast improvement in 1 month. I like to I combine that with a topical agent and I try to continue them on a topical agent plus or minus a sub antimicrobial doxycycline. The minority have partial improvement in 1 month and those patients require 2 to 3 additional months of a full dose antibiotic with the topical agent. Then I try to wean them to sub antimicrobial therapy with the topical agent. And for long term management, I like them to use a topical agent daily. Some patients use intermittent treatment, and you can read that as patient directed or non adherent. It's not the best way to go. But some patients, especially men, just don't use it constantly. So how does FMX103 fit into what I do? I would like to point out that FMX103 and 101 are very different medications. FMX103 is a 1.5 percent doxycycline and 101 is 4%. Minocycline. Minocycline, Sorry, it's topical minocycline, and it's 1.5% versus 4%. And it is because I believe they are very different pathogenetically that you can use a far lower concentration of minocycline topically to treat rosacea. So this shows the program design. We are going to focus on the double blind studies that were done. There were 2 studies. They were 100 sites total, over 1500 patients enrolled, self applied once daily for 12 weeks. Inclusion criteria were 15 to 75 inflammatory lesions. The lesion count was much higher than one would normally expect in a topical study of rosacea, which speaks to the management of the study by Foamix. And the IgA 5 point scale was on a 5 point scale of 0 being clear up to severe being a 4, so a 5 point scale. The co primary efficacy endpoints were a mean change from baseline and absolute inflammatory lesion count and the proportion of subjects with IgA scores of clear, almost clear with an improvement of at least 2 grades. Now this is also an important point in these studies and that you had to hit both of these endpoints for success. So this is no minor feat for a topical product to attain. And the safety evaluations were fairly typical of the adverse events, anything that came from physical exams, vital signs, tolerability or from labs. The demographics for this study, very similar to what you see in most rosacea studies, around 750 to 7 70 enrolled in the two studies. Number of sites, about the same. Interestingly, I believe we were in the 11 because my site has terrible time attracting rosacea patients for studies. The mean age, right around 50 years old. Gender break about what you see in most rosacea studies about 30%, 70% male to female. And the ethnicity, largely a Caucasian population. I will point out that we are seeing more and more skin of color rosacea patients. And I would expect that to shift, maybe not in studies over the next several years. But for those patients coming into the dermatologist, I'm seeing more and more patients with skin of color, both brown and black skin coming into see me that we recognize with rosacea now. The baseline inflammatory lesion counts, these were quite impressive, sitting right around 30, 28.5 to 30 lesions with a median of 25 to 26 lesions. These are patients with a lot of rosacea. And so when Ian goes through with you the patient satisfaction, I think that's very important to keep in mind because the standard for patients with rosacea is they expect to be clear in about a month to 3 months. They don't anything short of that is active disease to them. It's not like acne where I tell a patient, we're going to have you it's going to be 5 to 6 months. I usually give my acne patients target dates. Like if I'm seeing them in at the end of the school year, May ish, I say, we hope to have you better for homecoming, but think about Thanksgiving. That's when I want you to get better. In rosacea, they're thinking a month to no more than 3 months down the line to be better. So and then the breakout of moderate to severe for IgA was about 90, 10, 85, 15, pretty much what you would expect from a rosacea study. So the efficacy results, on the left, you see 17.5 to 18.5 lesion reduction, and that's a mean lesion reduction, and high statistical significance in both study groups. Very nice to see. One thing I would like to point out is you're looking at the vehicle group. Topicals are not studied against placebo. A drug is a combination a topical drug is a combination of its vehicle and its active. And so I wouldn't worry about separations because what a patient is getting is the combination. The reason you go against vehicle is to get it approved by the FDA. And so it is I think it is outstanding that they got such strong statistical significance. The with regard to IGA, you're looking at a 50% level of clear, almost clear. Very unusual for a topical rosacea drug. Again, clearly getting good penetration, clearly getting strong results, both also with strong statistical significance. Secondary endpoint, again, as you're looking at the percent reduction in lesion count, the mean percent reduction in lesion count, you get statistical significance by week 4. Again, very important like we talked about. People want to be seeing results by week 4, and you're seeing a mean of 64% 61% to 64% reduction in mean lesion count. Adverse events, just like the ACME study, largely noncutaneous in those that are occurring in over 1% of the subjects. A lot of things you would expect to see in the population that was studied over 18 Caucasians and studies that occurred with during influenza season a couple of cases of flu, nothing that you could really attribute to a topical agent. So to summarize the safety, the most common systemic adverse event was upper respiratory tract infections, both studies with incidence rates less than 3% for both FMX103 groups. Treatment area cutaneous treatment emergent adverse events in the 103 treatment groups were few, most mild and included instances of dermatitis, rash that was a sister to pain pruritus, hyperpigmentation, which again was post inflammatory hyperpigmentation, not that bluish gray dyspigmentation that we see with long, long term oral minocycline therapy. And some people, not surprisingly, developed actinic keratosis, little sun damaged precancers, again, unrelated. No treatment related serious adverse events. And in total, 9 subjects discontinued the studies due to treatment emergent adverse events, including 7 in the FMX103 treatment groups and 2 in the vehicle groups. So the overall summary, again, statistically seen significant improvement in FMX103 versus vehicle was achieved for both co primary endpoints of absolute reduction of inflammatory lesions and IgA treatment success. At week 12, treatment emergent adverse events were few in type and frequency and most were mild in severity. No treatment related serious adverse events, subject discontinuations due to treatment emergent adverse events were low in both studies and FMX103 was shown to have a favorable safety profile. Now again, I've been asked to give you my impressions of where might FMX103 fit in the rosacea regimen. And I would suggest that for the patients that present to my practice as opposed to those that were studied, it would be in just about every patient type. Certainly, monotherapy in milder patients, which it was not studied in, but the a lot of my rosacea patients who come in to my practice are coming in for other issues and I happen to notice it. And FDA. And I think that's the reason why we're doing this is because we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're doing this. And we're experience in the trials is a topical agent that will work well in monotherapy for the patients who are to the milder side of moderate and maybe less than that, even though that will not be an indication for the drug. Once it's out there, I expect in my experience, it will be used in patients in whom it could not be studied. Combination therapy, obviously, I think it will be a great first line therapy with the systemic agent. It will be a natural to bring a patient down to that. And I think it can also be used in those patients who have systemic antibiotic phobia in addition to another topical agent. I think it will be great, especially a non antibiotic topical agent. And then for maintenance therapy, this is a no brainer. This is exactly what I want in a maintenance topical therapy. Where does it fit my treatment toolbox? It definitely falls ahead of metronidazole. When I first spoke on metronidazole back in the 1990s, I was talking part of my talk in order to legitimize the fact that I was speaking on it was to explain how these studies were done for FDA approval and not for clinical use and that there were ways to use metronidazole in the clinical setting other than monotherapy like they were using the study. With ivermectin and azelaic acid, I feel it will supplant a lot of those patients in my armamentarium and will also be used in combination, as I stated before. And with oral doxycycline in systemic therapy or oral minocycline in systemic therapy, I see it again being used in combination with those agents. So to me, based on what I've seen of rosacea therapy and topical rosacea therapy, this is a great boon to my practice. And I believe that is my last slide. Now let's see. Thank you, Doctor. Rice and Doctor. Baldwin, for your review of the respective landscapes and review of our data. So my name is Iain Stewart. I'm the Chief Scientific Officer for Foamix. And it's my pleasure to present some new data that has come from our pivotal studies, FX201611 and FX201612. Starting with local tolerability, Doctor. Weiss touched on that. We didn't present it earlier on. So these are the local tolerability assessments that we are regulatory mandated to follow, but also touches on the disease set itself. For example, telangesia or what's colloquially known as spider veins, I'm sure people who know people with rosacea have seen this. The burning and stinging, what we talked about, clearly is causes a major impact on quality of life. Flushing and blushing is certainly an element of disease. The dryness that can happen both during therapy and fundamentally with disease. Itching really does speak to tolerability of the product itself applying to the skin. Remember, these patients expect and they should expect good resolution of disease with very little irritation at all, if any. The peeling and disquamation that you can see both the natural disease state itself and therapy and hyperpigmentation we talked about. So patients deserve to have none and what we are seeing here is a baseline, the patients who actually came into the clinics, the centers, the 100 centers that we had, who had none of these symptoms. So you can see there, if you think almost inversely, if you only have 12% had no telangisia, the vast majority did. They're mild, moderate, severe. Same with burning and stinging, flushing and blushing, majority of patients had some degree of that, etcetera, etcetera. So after therapy, you can see in all cases, 6 of this all of these factors improve. Starting on the left hand side, we did see some resolution on telangisia. The burning and staying, these percent of patients that actually had no burning and staying, we're not talking about almost or slightly, we're talking about no evidence of self reported burning and staying. The flushing and bushing, which is very clearly an important clinical manifestation of disease and is obviously very embarrassing to have people having these flushes, these episodes that can be triggered for a variety of environmental considerations. Dryness is very important because that does speak also to peeling and disquamation and hyperpigmentation again. So in all of those categories there's improvement. But I think what it's actually telling, if you look at it at the category level, we managed to of 6 of those 7 assessments, over 50% of those patients had none, nothing, no evidence of those clinical manifestations of signs and symptoms. This is pull data from both studies on the active treatment. So 1,000 patients were assessed at baseline with 895 at the end of the study. Obviously, you have dropouts in studies like any other study. But these are real patients. This is not imputed data. And this is quite impressive to have a topical therapy where really you manage to get the number of local signs and symptoms in proportion of patients with these signs and symptoms effectively to none. Moving on to clinical erythema. Again, this is something we also assess. This is a 5 point scale. This is one that's used primarily when we're assessing the background erythema or ETR subtype of rosacea that Doctor. Weisz talked about a little bit earlier. So just cast your eyes to the plot on the left hand side. So at baseline, we had roughly 2 thirds of the patients had moderate background erythema. Remember, this is not the basis of the study. This is a papulopustular study. This is the lumps and the bumps. This is the lesions that Doctor. Weiss was talking about when he was reviewing our data. But what this actually does speak to is the multifactorial clinical presentation of rosacea. Some patients may not have any material erythema, some may have very, very intense erythema as well as the papules and postures. So we had 2 thirds of patients had moderate disease and at the end of therapy at week 12 we managed to reduce that down to under 20%. So that's a material stepwise improvement on background erythema as well as Doctor. Weiss had presented earlier on the papules and pustules. Looking at the other side of the coin which is looking at clear or almost clear based on clinical erythema assessment. As I said earlier, you don't always have to present with erythema baseline. There is going to be a proportion of patients who really don't have much of a background erythema, but clearly qualified for the study based on lesion counts and ultimately IgA. So we had roughly around 6% of those patients at baseline, which you would recognize as clear, almost clear of background erythema. At week 12, we managed to get nearly 45% of patients clear or almost clear of clinical erythema. And this really does speak to the multimodal action of minocycline. We talked about this effect in acne earlier on. And here we're really as it's driving primarily as an anti inflammatory agent and the effect it has on clinical erythema. Moving to subject global assessment, we talk a lot about investigator global assessments as the primary endpoint. You see that if you're working in dermatology. It's a very important regulatory hurdle that drugs need to cross to ensure that there really is a minimum clinically meaningful resolution of disease. Normally it's clear or almost clear. This is the other side of the coin as it relates primarily to the patient experience. So they're not looking obviously at specifically clinical assessment, but we ask very basic questions comparing them to before they started treatment and where they are now, was there were they slightly better, much better? Was there disease states that's basically the same, slightly worse or even significantly worse. And what you will see here that we had approximately 50% of patients not only said they were slightly better, that they were a lot better. So this actually jives very neatly with the corresponding IgA treatment success. If you remember back to Doctor. Weiss' presentation, we had approximately 50% of patients in the active arm that were clear almost clear of disease. So this is very encouraging data clearly and is highly consistent between the IGA and the SGA. Moving to satisfaction, 3 questions we obviously ask again of the subjects. So overall speaking, what is their satisfaction level with the product? And yet nearly 72% of patients were very satisfied or satisfied with FMX103. With respect to ease of use, we had 90% of patients thought it was easy to use. Supporting patient compliance through a topical therapy is key. If they find it complex to use, they will not use it. If they do not use it, guess what happens? They don't get the clinical response that we all hope that they will. So this, again, very encouraging perception of how easy it is to use FMX103. On the right hand side, how does the product feel on your skin? Now this is really an acid test. Doctor. Weiss talked very elegantly about burning and stinging. These patients have extremely irritated skin. And anything they put on their skin that could potentially impact on their satisfaction, they will obviously speak to through this product. But again, we have nearly 2 thirds of patients and if you include the ones that are somewhat neutral, nearly 80% of patients were satisfied with the feel on the skin. And this is critical because again speaking to the ease of use, speaking to the application experience, If they don't like how it feels on their skin, they're not going to use it. I'm also pleased to give you an update on the pipeline. I'm sure you've seen slide many, many times before, but it's pleasing to actually give you a little bit of an update and a change of guidance here. In relation to FMX101, Dave talked at the start relation to our NDA filing. We're pleased to do that just before Christmas time this year. I'm very pleased that R and D group put up a huge amount of effort to convert our FMX 20 seventeen-twenty two Phase 3 study, get it ready for registration in record time and we're very pleased that we did that. And of course, the projected PDUFA action day will take us into Q4 2019. So the corresponding time lines for FMX103. We presented the top line data in November, early November, as you're aware. I am also pleased to update this as new information. We have actually had our last subject out of the open label extension, what's called FX 20 sixteen-thirteen. That has already happened in early January. So our team are working very quickly and judiciously with the corresponding clinical sites to make sure that our clinical data is cleaned and ready for data lock and to we will present top line data in due course after that. But what was key here is that we've been talking for the last year or so that there would be approximately a year of gap between our FMX101 and FMX103. We're pleased to announce that we will actually bring that NDA forward. So we plan to submit that in mid year 2019 rather than towards the latter part of the year, which was earlier guidance. And of course, you have a consequential move on the equivalent PDUFA action date. So we're very excited that the team has put a lot of effort in here to continually move our pipeline forward judiciously with high quality, but also in ensuring that we have all this good clinical data and this great product actually makes the market as soon as we possibly can do. So we're pleased to announce that. Changing gears a little bit differently. So what are we doing just now in relation to medical affairs? Clearly, our commercial footprint is a little bit further out just now. We're doing the regulatory process for FMX101. But I want to give you an idea of what the basic themes that we will be communicating to the dermatology community over the next year as we move through this kind of pre launch, peri launch phase and ultimately into commercialization. It really speaks to 3 matters beyond our clinical data. We will clearly be communicating that widely and we continue to do that through one to one discussions with thought leaders such as Doctor. Weiss and Doctor. Baldwin, a lot of work done at conferences, and I'll touch on that as well, and of course, our publication footprint. So these three areas of the triangle really are pretty critical points of scientific communication related to both of these products, but primarily starting with FMX101. Vehicle matters, you've already seen that from our presentation. We have a very sophisticated, well tolerated and elegant vehicle system that in of itself has direct effect on the disease status. So understanding why this happens is going to be very important for physicians to understand as they make their prescribing decision making. Minocycline disposition, what does that mean? So how does minocycline actually get to where it needs to get? It's very important to understand when you apply a product to the skin, is it getting to your site of action and sufficient concentration that but no more. We certainly don't want to have significant systemic exposure because then that plays back into some of the limitations you have with oral tetracyclines. And microbiology. Microbiology is the key. We are dealing with an antibiotic and so we have to address some of these concerns upfront. So speaking on these areas in a little bit more detail, I'm going to have a few slides on each one of them about the key messages that we'll be communicating over the next year. Is a unique hydrophobic foam. No one has done this. This is first time that a micronized top of minocycline formulation has been produced. The keywords in and around this is stable. Many people have tried it over the years, not many have succeeded. And we are certainly the most advanced of those who are currently looking at these types of products. And then liquid seaborne liquefaction, we want to talk a little bit more about that and how that actually impacts the disease status that our vehicle itself actually has the capability to interact with sebum which is a key progenitor to acne and actually help as a partner with the antibiotic and disease resolution. Microbiology, we have a highly potent antibiotic. We will talk about C. Acnes. Sorry, Hilary. The young folks are talking about C. Acnes these days. We have a tremendous direct impact on C. Actis, which is our target microbe. It is pro inflammatory, not in and of itself, but it's as it replicates, it does generate pro inflammatory molecules within the pilospatial unit that really does trigger additional inflammatory cascades. Low resistance potential, we will talk a little bit about this in a few slides' time, but we actually have some very interesting data from our own in house work. We actually did a phenomenal amount of microbiology profiling of minocycline as part of both of our NDA and of course part of our scientific communications moving forward. Minimum collateral effect in systemic and commensal organisms. So where you have very, very low systemic exposure, then the fitness cost of a microbe to adapt really isn't there. And one of the biggest concerns you have with systemic antibiotics is you're providing an environment where you are allowing them to potentially develop resistance mechanisms or trigger resistance mechanisms against that particular antibiotic. Disposition targeted delivered to the pilosobasis glands. This is where we want to go. So this is the idea of outside in rather than inside out. We really want to make sure that we target where the C acnes resides, that we have that direct inflammatory effect directly into the pilosobasis unit. And ultimately, what we're trying to get to is resolution of disease. We do have high concentrations in the stratum corneum, and that's really important to make sure that we suppress C. Axis as much as we possibly can do. And as I talked about, very low systemic exposure. But I want to pick on one just now on the vehicle matter side. Sibon liquefaction, why is that important? So the sebum plug really does provide the optimum physiological environment for C. Acnes to replicate. C. Acnes is the anaerobic bug, so it doesn't like oxygen. It likes to grow in an oxygen depleted environment. So the lid, if you like, that sits on top of the follicular mechanism really does provide that environment so that C actins can actually develop. So there's 2 components to this sebum plug. 1 is dead corneocytes. So this is cellular debris that happens to the natural shedding of cells from the follicular shaft out into the dermis out into the epidermis and then there's sebum itself. Okay, many sponsors have looked at should we remove sebum, deplete sebum. But sebum is a very important part of maintaining good skin conditioning. If you don't maintain good conditioning, drying, irritation is really a factor of that. Bringing these two things together provides this plug that sits in the Pilosysbases unit. So what we've done is actually compared our vehicle system to what's called an oil and water emulsion. Really what that means is your classical dermatological cream. You've seen them in CVSs. Any dermatological assets have been based on primarily these basic creams. And these are oil and water emulsions. So what's actually happening is that the skin temperature is a little bit under body temperature, it's around 36 degrees. But and sebum itself doesn't melt until 37 degrees. So sebum in its natural physiological state within the follicle is in a kind of jelly like semisolid state, okay? It's a perfect environment for things to stick to it and provide this plug. When you actually mix oil and water emulsions or creams with sebum, that actually increases the temperature of the combination. So if anything is making the sebum harder, it comes a little bit more solid like. But when we mix it with FMX101, it actually reduces the effect of temperature. So the thermodynamics of this process allows that you have much improved miscibility of our vehicle system with CBOM. So let's show pictures. What we have here on the left hand edge is really that kind of yellow interface here, that is CBOM. And the kind of pink interface is our vehicle FMX101. And below that is the equivalent interface in combining the vehicle with sorry, the oil and water vehicle with sebum. And this is at 25 degrees. So basically sebum at 25 degrees is solid, okay? As you start to increase the temperature to 35 degrees, so just below skin temperature. Again, focusing on oil and water, that margin between the 2, both the vehicle system and CBAM is still pretty defined. But you can start to see with the vehicle system for FMX101, that barrier start to break down. So what's happening is that they're beginning to become miscible with each other. When you hold at 35 degrees temperature, you can see it in the top right hand, they are becoming very much miscible. So the system is becoming liquefied at 35 degrees, whereas at 35 degrees with oil and water system, you still have this very clear margin. So what we're already seeing here that the vehicle itself has a direct impact on the physical state of sebum potentially in the pilosabaceous unit. Microbiology. This is some very key and I'm quite excited about this because it's not rare I've been doing this for a while. It's very rare for actually to reshape thinking in relation to something as important as the use of antibiotics, in particular with the dermatology community. And here we'll be actually introducing some new concepts to the dermatologists. One is called mutant prevention concentration and the other one is a mutant selection window. I talked about earlier that again C actase, our drug is particularly important, but one of the key concerns with the prescribing dermatologists isn't so much resistance developing against the target organism. I see acne is superinfectious, not life threatening. Their concern is primarily cross resistance with other commensal bacteria such as staphylococcus aureus and other microbes that could be potentially life threatening should resistance develop against a particular therapy. So we have evaluated the MICs against 102 C. Acnes isolates, clinical isolates. And we have very, very potent on target effect against that. And it's not just about potency, it's about consistency. Sometimes you can have some isolates who have very, very low MICs and some are very high. So you may have a patient basically walking in, have a great treatment response or be a clinical failure. And it's extremely difficult to determine which is which. We have that consistency across the 100 that we looked at. Frequency of stepping set mutations is very, very low. Always remember that bacteria are always in balance with each other. You have susceptible possibility of growth of resistant bacteria does accelerate. Possibility of growth of resistant bacteria does accelerate. But what I want to talk about here is this concept about immune prevention concentration. So in the body with FMX101, we have extremely low systemic exposure. So it's actually 100 fold below the MIC against our target organisms. So what does that actually mean? That means there is no fitness cost. So this is Evolutionary Biology 101. Microbes will only develop a resistance against a particular microbe if they feel the result the cost benefit is there for them. If they feel that it's not that the levels within the system are so low, they do not have the energy. They don't want to expend the energy to develop that resistance mechanism because it does take energy. That's classical dharmonism. So in the body, which is really the primary concern about effect on commensal and bacteria, we have a very, very low systemic exposure. On the other side in the skin, we have a very, very high exposure in the skin, many 100 fold higher than the MIC. And what actually happens and this is something that we will be discussing at great length with dermatology community is that the opposite actually happens. So there really isn't much potential there for resistance to have a meaningful impact on clinical failure as it relates to resistance. You're delivering so much of the antibiotic there that the ratio of wild type to the resistant species actually goes back the other way. The current thinking is that the more antibiotics you use, this ratio gets worse and worse and worse. So the resistant species become the most dominant one. It's not as actually bell shaped curve like this. It reaches a maxima and then goes back down the other way as the ratio recorrects itself because you're actually using delivering an antibiotic at such high levels where it matters the most. What does that mean looking at comparing to oral minocycline? The mutant prevention concentration really is that minimal concentration will actually or the MIC for the least susceptible microbe. When you compare that with oral minocycline, you have dose limiting toxicities that come into play here. Ideally in the body, we want to make sure that we continually remain above the mutant prevention concentration. But quite frankly, pharmacology and toxicology dictates that, that will just not be feasible. Our colleagues who work in oncology are well aware of you kill the issue, but you could kill the host as well. So basically the therapeutic index basically disappears to nothing. Here we're talking about Cmaxes of 3 nanograms per ml, well, well below the MIC. But if you compare that with odominocycline, which is about 1 microgram per ml, really what's happening in there is you're providing an environment for the microbe itself or microbes itself to kind of get used to the presence of that antibiotic. And really this is what's commonly known as the mutant selection window. So you're allowing an environment to develop within the body that actually supports the development of resistance. You can see the ratios between concentrations in the skin and concentrations in the plasma are greatly favoring obviously skin versus plasma for FMX101 in relation to when compared to omenocycline. Okay. Minocycline disposition. Again, this is all well and good if we can't actually get minocycline into where it needs to be, which is deep within the pilosobasis unit where C actins resides, that is all for naught. So this is ex vivo work that we've done with human skin, looking at the penetration profiles, not just through the strata of the skin itself, but again looking directly down the follicular shaft to ensure that we are actually delivering sufficient concentrations of FMX101 or minocycline deep to where it needs to matter, where it matters. On the bottom axis here, you can actually see the concentrations in the epidermis and the dermis. Again, it should go down if you're dealing with a topical with higher concentrations in the epidermis, lower concentration in the dermis, as minimal as possible going through the basal cell layer because that ultimately relates to exposure. The plot in the middle is called FMX101 SA. We actually managed to pluck out the sebaceous appendage of the skin itself. So it allows us to actually to look at concentrations deep within the pilosubaceous unit, not just meaned out across the skin. And as you can see there, we nearly have 3.5 micrograms per sebaceous unit of minocycline being deep into the follicular apparatus, which is particularly important. But the corresponding side of respect to exposure, this is this receptor solution, so this is a surrogate for systemic exposure. It's extremely low. And you'll see alongside that for we have the equivalent data for FMX103 and you can see there's a dose dependency ratio. And obviously, we have different concentrations. So medical communications, we have a lot of very powerful scientific messages and a lot of work that we have done over the last year and we'll continue to do. That's all for naught if we don't communicate it to the prescribing community. I want to take you through very briefly through the plan. I'm not going to go 1 by 1, you'll be pleased to know. But this year, we are actually greatly accelerating our medical affairs activities, both a combination of presentations at conferences. My VP of Medical Affairs is back from winter clinical, which has happened last week. And we will continue to be very present at conferences throughout the whole year as we lead up to our perceived action date and of course beyond that. So the boxes in the top there really are poster presentations that we plan to communicate. I'll pick out a few key ones here. The FX201722 poster is obviously a marquee study for us for FMX101. We'll continue to communicate that information broadly and widely through the community, the dermatology community. Dermal safety is critical and it isn't just about local signs and symptoms. Hilary actually talked about photosensitivity as it relates to the oral tetracycline. So part of our regulatory work is to determine to assess in Phase 1 studies things like phototoxicity, photo allergy, cumulative and repeat insult patch testing. It's a very classic battery of tests that needs to be done. As you take a dermatological product topical dermatological product through to market, we will communicate that broadly as well. Field safety is important, particularly in safety. The bigger the end, the more likely you're going to see any potential issues, but we clearly haven't seen any of that. We will communicate that broadly. Looking on to manuscripts, everything will be published. We will put them into a variety of journals over the course of the next year, again starting with 27 day 22 study, the phototoxicity, the work that we've done on microbiology we think is extremely exciting and quite revolutionary and especially as it relates to the current understanding of the dermatology community about the judicious use or stewardship of antibiotics as Doctor. Balmain talked about earlier on today. So we're extremely excited for the work that we're doing here and we'll continue to report on our activities as time moves on. And with that, I'm going to pass over to my colleague, Weil, who is our Chief Commercial Officer, for an overview on our commercial activities. Thanks, Ian, and good afternoon. As this is the first time that I'm presenting in front of a group like this, I'll give a little bit on my background. I've spent over 20 years in the industry, all of that in commercial, most of that in marketing. I've worked in small start up companies like Salix, during the launch of Colazal. And also Azure Pharma, I was the 3rd U. S. Employee, at Azure. I've also worked in midsized companies like Ceflon and Jazz, most recently heading up the sleep business unit there. This is my first time working in dermatology, but I can assure you that I've worked in virtually every disease state beneath the skin. So this is a discipline of breaking down markets that I'm familiar with and I've had the opportunity over the last 10 weeks to gather some pretty good insights on this market. Why did I join Foamix? I think about it in 3 different ways. First of all, I worked with Dave at Azure. So I knew the management team here. The management team that I met, I have a high degree of confidence in their ability to bring drugs to market, both near term and long term. The products themselves, so I spent some time doing my diligence on FMX101103. And I think as you saw earlier this afternoon, the data is very favorable. And I also looked at the market sizes of these drugs and previous launches to better understand the opportunity that I'd be walking into. And then the third is the opportunity to build out a commercial infrastructure from the ground up. This is something that I've been a part of in previous lives and one that I'm very excited to build out here. Okay. So let's talk about some early market entry considerations in the acne market. First of all, there's a large market. I'll spend a little bit of time going through the size of the market and kind of how we see it. Consumer activation and engagement, so this seems to be a forgotten cohort. And so I'll walk you through some data that we have about the consumer play that may be available to us here. Market access is something that every new launch is dealing with. As I left Jazz, we were working on an NCE launch plan and understanding not just where market access challenges are today, but where they're going. So you want to skate to where the puck is going to be, not where it is. And then finally, competitive spend. This is a competitive space. There are a lot of players in the market. There's a lot of noise in the market. So how are we going to cut through that? So first, let me talk about I want to juxtapose acne and rosacea here because I think it's important as we're talking about the launch strategy for FMX101. So first of all, the acne market, the prevalence is about 50,000,000 U. S. Acne, suffers. 80% of those are between the ages of 12 24, and I'll get to why that's important momentarily. And as we look through claims data over the last 5 years, there are about 7.5 1,000,000 unique patients under physicians' care. And looking at longitudinal trends, we see that this is a fairly durable market, one that's evergreen. So this is a market that doesn't need to be built. There is a ready made market here. The same can be said for rosacea. The prevalence in rosacea is 16,000,000 in the U. S. The patients here are generally over the age of 30 years old. And we see a durable population here as well, 2,000,000 unique rosacea sufferers over the last 5 years via claims data. Again, this is an evergreen population. Now as you look at the age groups for these two categories, you see that they are discrete. And so that's important as we think about any direct outreach to patients and consumers. We're not tripping over ourselves with different messages. So a couple of reasons to have a look at recent and maybe a little bit further back for launch surrogates. The first reason is you look at the most recent launches to understand whether or not there are there is any impact due to market access in the 1st 12 months. And so as we look at the most recent launches in acne, we see that there is a decent uptake. So when we look at dollarized prescriptions here, it's anywhere between about 100,000,000 dollars $230,000,000 in the 1st year, dollarized. And then as we look at 5 year surrogates, we can see that the dollarized volume here is anywhere between 200 and about a quarter 3 quarters of a 1,000,000,000 dollars in dollarized revenue. So it's important as we look at surrogates not just to look at the 5 year history because it's going to tell a different story and uptake in the 1st 12 months again because the market access landscape has changed so dramatically over the last 3 years. So both of these are instructive, but both point to the fact that these are markets that have been successfully penetrated with new brands and have good, successful uptake over time. Okay. So as we think about targeting, this is from a slide that we've presented at investor conferences in the past. I would say that this is the more traditional approach. You define your prescription volume market basket. You relegate that then to the specialty that you want to call on and then you do a top to bottom volume deciling exercise. And that's basically what we did 5, 10 years ago. But it doesn't account for where the patients are. So when you're only looking at prescription volume, not all of those prescriptions are necessarily going to be in your target population. That's important, especially from a market access perspective. So the way I think about it is slightly different. As I go to where the patients are, not where the drugs are. The drugs do follow these patients. So when we decile based on patient volume, and I've boxed out over here the top 6 deciles, when you think about deciling, deciling is important in so much as it gives you a 10% block of the patient volume from top to bottom. So we can see here that about 5,000 physicians manage 60% of all of the acne patients in the U. S. So as we think about field force size, I know that we've stated publicly somewhere between 50 to 100. This number of targets would give you a good idea of where on that spectrum, we're likely to be. And I put the rosacea data up here as well because I think it's important as we think about the sequential launches of FMX101103, you see that there are 2,500 physicians that account for 60% of the rosacea volume in the U. S. There's only about a 50% overlap between these two groups, which means it's actually a very good thing because we're going to have discrete targets for rosacea. We're going to have discrete targets for acne and we're going to reconcile through incentive compensation how we deal with the 1300 or so that overlap. This is a preliminary view of how we intend to target, but there's a lot more that we do from a predictive perspective as we move forward. So we'll look at things like brand versus generic preference. We'll look at access, etcetera, and we will sharpen our pencil on these models between now and launch. So let me talk about market positioning. And this is the one thing in Pharmaceuticals that cost us no money. A market position is the cheapest thing we do. But if you get it wrong, it's the most expensive thing that you can do. I've been fortunate to work on relaunches of several products over the course of my career. And I can tell you, it's a better experience to understand where previous commercial companies got it wrong because you really learn what can trip you up and what can make for either a successful launch or not. Positioning is one of those. Typically, what happens in market research is, you share the attributes of the drug. The physician will certainly, give you a hierarchy of what's important to them. Most marketers will then position around those attributes. I have yet to see a market research study that doesn't list in this order of importance for physicians' efficacy, safety and convenience. So if you position around those things, there's only one way to cut through the rest of the market and that's to shout louder. And so if you have a unique positioning that doesn't focus on those things but ties back to them in a certain way, that's a much better mousetrap to launch with. And so we believe that there's a built in position here and there are pros of topical products obviously that we're going to tout. Those are oral tetracycline. So we're taking the best of both worlds in this formulation. And then a lot of what Ian just talked about, in the uniqueness of FMX101. And so there are great differentiators that we have. We think we have a unique story. We'll be able to tie that back to the clinical results in a very, hopefully, unique way. As we think about, competitive spend, we looked at some audit data from 2018 to understand where the current players in the space are spending their money. 88% of the spend is in physician related activity, 12% in consumer. So why is this important? Well, as we look at the consumer spend, we can see that only about 16% of that is in Internet search and Internet display. So this appears on the surface to be a relatively unique opportunity, especially as we consider what we talked about earlier is that this population is between 80% of the acne population is between ages of 12 24. So this is Gen Z. Gen Z spends, about 7 hours a day consuming media. Mobile accounts for well over half of that anywhere between 50% to 65%. They spend some time on their social platforms like Instagram, Twitter and Snapchat. 85% grab their smartphone multiple times a day. I'm sure we all do. And then this group spends more time on Netflix and YouTube than they do on traditional television. So the way to access this market wouldn't be from a DTC play, would never be through television. But there are some very unique and innovative ways to get to this audience, where they spend their time. And so we're exploring that now, doing social media audits, etcetera. But we believe that this is a market opportunity that still exists. Now as we talk to payers, one of the things that we have to consider is where they stand with dermatology. So before you read this slide from left to right here, what I'd like for you to do is think about where the payers' heads are as it relates to dermatology generally. So we did this study, 10 payers in this market research And, they cover over 230,000,000 lives. Their impression of dermatology and dermatology drugs is not favorable. They look at this class primarily through an economic lens in mass. However, when we shared with them the product profile for FMX101, a a me to play. They looked at this as something innovative, a novel route of administration. They did believe that would go to a full P and T. So that's an important learning early on. And then as it related to that product profile, what was the expectation for net to plan pricing? And that was anywhere between $200 to $400 net to plan, which means that at least for this group, the value proposition spoke to this type of expectation of cost to them with some minor restrictions. And by the way, so this shouldn't necessarily connote how we're going to price it. We have a lot more work to do with payer strategy and pricing, but this is some good early signs, at least from a payer perspective, that there's a path forward here. And then finally, as we think about how the competitors are spending, so I talked earlier about the importance of positioning. And as you look at the competitors of this space, there seems to be an arms race who can shout the loudest, who can own the messages. And, we believe and I've seen this done in other markets where you can cut through that noise very effectively with a sharp and unique positioning. And so we intend to do that. From a targeting methodology, certainly, you can call on the 15,000 dermatologists that are out there and you can deploy a large footprint to get to them. And you're going to get to all of the acne patients in some regard by doing so. But the smarter approach is to go where the acne patients are, understand the predilection of the physician group for brands versus generics, new market entrants, etcetera, and really focus in on a tight target model. And then finally, fiscal discipline. So we want to deploy some resources where maybe, others aren't in the market. And think through things that are a little bit more innovative, a little bit more outside the norm in dermatology and invest in some of those high ROI tactics that we know through experience do work. So just to wrap up here, these are large markets. Acne is a large market, 7,500,000 unique patients over the last 5 years. There may be an opportunity to engage and activate the consumer. Market access is always going to be, I think on the go forward, an area that we have to understand and work on, but we do have some green shoots from the research we've done. And then from a competitive spend, I think we can be smart about where we spend our money and have a focused and financial discipline that I think is important for a company our size. And with that, I will turn things back over to Ian to talk about our pipeline. Thank you. So we've talked a lot about FMX101103 and of course, Matt's presentation and about our commercial preparedness and our overall strategy is important. But what's next for Foamix? Dave framed up at the start of our presentation today, We will talk about what is our other research interest and primarily in the acne form areas. We do have additional research in other dermatological conditions such as atopic dermatitis and others and of course in the non medical dermatology arena such as aesthetics. But what I want to do today is talk about the 4 projects that we have in development just now. You'll see these codes. I'll refer to them frequently throughout the presentation. The first one is a combination product minocytine with adapalene. We've already heard from Doctor. Baldwin earlier on today about the appropriateness of combination therapy as it relates to targeting multiple areas of pathogenesis of disease. We feel this is a natural next step for the FMX101 chassis or formulation concept in acne vulgaris. FMX109 is nicotinamide commonly known as vitamin B3 and the retinoid form for acne vulgaris. I'll go into this in more detail clearly in the next slides. FMX-one hundred and ten or 110 is a topical doxycycline hyclate gel. So this is our first move outside of the foams arena formulation, looking at papuloposter rosacea, ETR and hidradenitis suppurativa. I'll explain what those particular disease states are in a minute. And the last one, again, speaking to combination therapy, minocycline and Benzoyl Peroxide is a combination problem. Starting with FCD105, combination with adapalimum. So we've already really said Doctor. Bohn has already set this up primarily. We really do need to target multiple areas of the pathogenesis of the disease. We see this in combination therapy throughout the treatment and management of acne. Retinoids themselves, normalized keratinization, I talked about the combination of sebum and corneocytes. If they are not differentiated adequately, we do form this plug and it really cleaning out the follicular apparatus is one of the key mechanisms for retinoids. Minocycline mechanism of acne and acne, again, we talked about it as being a bacteriostatic against the target organism C acnes, which is a primary driver for inflammation. But we know that minocycline itself is also anti inflammatory. The status of this project just now is formulation is actually complete and the product is on formal stability. I'm pleased to say we put in a meeting request, a pre IND meeting request with the FDA just before we actually submitted the NDA for FMX101. Have completed a 3 week dermal mini pig toxicity study with no remarkable findings. So we see the product at this stage at least to be well tolerated albeit a non clinical model. We're about to initiate a 3 month, which is the classical clinical dosing for acne 3 month dermal, mini pig toxicity studying basically this quarter. We actually anticipate having first subject into a Phase II study in Q2 2019. So that's right around the corner from a clinical development perspective. And I want to talk a little bit about that study, proof of concept study. It's a classical monadirate comparison study where we compare the formulation components to each other versus vehicle. So this is actually quite a substantial Phase II study. It's 400 subjects moderate to severe disease. It's not quite a 1 to 1 to 1 randomization, but we have a little bit more because we want to get as much of safety information FCD105 as possible. So we have a minocycline foam comparator arm. We have an adaply foam comparator arm. And of course, we have vehicle itself. The inclusion criteria is similar for the moderate severe acne vulgaris group. But in this case, we will actually attempt to have the full indication for acne vulgaris. I think this makes a lot of sense because we're dealing with multimodal impact on the disease state. So the moderate to severe active vulgaris and the primary efficacy endpoints that you've seen before is the absolute change in inflammatory and non inflammatory lesion count of week 12 and the proportion of patients who have treatment success, I. G. And I. G. Of 0 or 1. So this is certainly an exciting project for us. This is our first foray into combination therapies, and we're excited to get on with this clinical program. FMX109, nicotinamide and retinoid foam, again Doctor. Hilary Baldwin said that's quite nicely. We know that their retinoids are effective therapies, but they also have their challenges as it relates primarily to irritation onset of action. And we already talked about this moment of crisis where patients really are having quite a significant additive profile or reaction to the product, but not really seen the clinical benefits yet. And that really is quite a challenge to do this. And Nexutamide is a vitamin B3 product. And really what it does is it actually enhances barrier integrity and actually has the potential to offset the thinning that occurs through retinoic acid therapy. So really to rebalance this irritative profile, nicotinamide has been used for years in other OTC products. But it's always been known to have an effect in and of itself in acne. But this nice interplay of offsetting some of the deleterious effects of retinoid therapy is interesting. It's also an antioxidant and is used in a lot of OTC products. What it does there is really prevent lipid peroxidation. Peroxidizing lipids deep in the palocebaceous unit is one of the triggers for poor inflammatory cascades. So it's not quite anti sebum, but prevents sebum becoming a problem. And what is very interesting is it actually improves its barrier repair and cosmetic outcome. We feel this is actually going to be quite beneficial, particularly in patients or women who have late incidence acne. It's very difficult to say to a patient, I'm sure Doctor. Hilary Baldwin would agree, that you say, yes, your lesions are clear, but you have a lot of this dyspigmentation afterwards. I mean, that's a nuance. They still look as if they have acne. They still look as if they have scarring. And we want to see if there's a possibility we can at least reduce some of that. So where are we with this one? So this is the clinical benefits that I talked about. I think one of the key things here right at the end is do we have a potential to offset some of this post inflammatory hyperpigmentation as well as having the power of 2 different modes of action directly onto the disease. So we could just take this forward and go straight into Phase II. But what we actually have doing, and we're looking to start this study in February. This is a proof of principle study. This is a small study. It's a bilateral acne model. What does that mean? It means that the patient are actually in their own control. So we can treat one side of their face with one therapy and the other side of the face with the other. So there's no need for a vehicle comparison there because as I say, the patient has their own control. So we're actually evaluating 2 retinoids. We can do this with only 20 subjects. So a very cost effective way to understand the clinical rationale. It's clear that we actually do have this multimodal impact and potential cosmetic outcome that we all hope to achieve. So what we're really looking at is a relatively short 4 week therapy. This is really the crisis point, as Doctor. Balman talked about. The 1st few weeks on retinoid therapy, that's where the irritation comes, hard and fast. And this is we really want to ensure that this concept is proved. So the patients are treated with adapalene and then one side of their face has 10% nectinamide, the other side is a vehicle control and we're evaluating tazarotene and adapalene at their prescription strengths. So really as a dermal safety, so we're actually looking at the irritation profiles very, very carefully. We're also looking at stratum corneum integrity, looking at transepithelial water loss, which is the model to actually determine the extent of dryness. We will look at efficacy clearly. We'll look at lesion counts, but we'll also be looking at sebum production whether or not there is an actual impact directly on sebum as well. And as again, Doctor. Baldwin talked about, that's one of the progenitors of acne itself. But most importantly, also at the end of here, we'll be looking at complexion analysis. What is the cosmetic outcome? Is the thesis proved that we have the potential to repair the mechanism and actually reduce some of the potential residues subsequent to inflammatory acne. So the status just now, we've done penetration studies already for this for the combinations. So what we're doing is prescription strength retinoids with an OTC product here. Proof of principle study is actually ready to go in February. We've submitted the IND to the FDA. We expect to have top line results from this small study in quarter 3 2019. And pending those results, we expect to have first subject into a Phase II in the earlier part of 2020. Formulation developments are working obviously work in parallel with all of this. Moving to FMX-one hundred and ten, doxycycline, hyclate for papilloposter rosacea, ETR and hidradenitis suppurativa. I think doxycycline itself is a very well used product in rosacea space, very similar mode of action to minocycline itself. But as an anti inflammatory impact on matrix metalloproteinases really does protect the capillary membrane that really is ruptured when you go through these blushing. And this is where really telangazia is the ultimate outcome of this. But also has downregulatory cytokines. This is again, we talked about this a little bit earlier on today and its impact on erythema and inflammation. We already saw that with our local signs and symptoms data where we actually see the erythema with FMX101 dose topically is materially improved. Oresha, we've referred to before, is first and second line therapies for moderate severe papillopustular side. But again, we have systemic adverse events compatible to solidine. There is no topical product for doxycycline. This is where we see a very clear value. And of course, we're going to be progressing based on our clinical evidence from FMX103, the effects on clinical erythema. So the status just now, development candidate selections mid this year. IND enabling toxicology, we expect Q3 2019, pre IND meeting in Q4 twenty nineteen. And we're starting the Phase II dose finding study of the gel in the first half of twenty twenty. But it's important to say here that not only will we be progressing our origination indication here, that we'll be progressing an indication in parallel called hidradenitis suppurativa. And I want to introduce you that to what HS actually is. So really this is a newly mediated dermatological condition. It's a serious condition of the fear, follicles, sebaceous and sweat glands. And that's primarily affecting the axillary and the flexors of the body. So if you can imagine the worst possible acne, cystic acne in your armpits, groin and flexural areas, This is extremely life quality limiting disease. The clinical presentations manifestly large comedones, very, very large painful weeping inflammatory nodules as folliculitis like. These are boils, colloquially used terms. What can actually happen is that these cyst and boils, they burst, they leak, they heal. And because you're dealing with flexures, we have skin on skin contact, the possibilities for deep, deep scarring is there. And what you actually get is a concept called tunneling or sinus tracks. What happens is that the skin itself folds back on itself and you get really deep andurated scarring up to the point where it can actually impact on mobility of limbs. So if you can imagine a scenario where you can't move your arm up because the scarring is so dense in your armpits or buttock areas. Treatment options really has nothing indicated. What I would say is that antibodies, corticosteroids, anti TNF alphas, adalimumab or commonly known as Humira, had orphan designation for moderate to severe HS a few years ago methotrexate hormone therapy, all of these have challenges. We've already talked about many of them. But what I'd also say, particularly for Hurley Stage III, so this is, if you like, severe HS, skin grafting is actually an option for these patients. It's that serious. It's that life quality limiting. So there is possibilities here in offering into these indications, and we're certainly we're certainly progressing that. But I just today wanted to introduce to you, it is an acneform like disease state, certainly plenty of utility for tetracyclines in this space, and we're looking forward to progress this project in parallel with our rosacea activities. So what does 2019 look like in 2020? This is our 18 month view of deliveries almost by quarter of what we anticipate. At the top end of the slide here, we have our late stage assets. We've talked about a great deal today. So we expect our Day 74 action letter will be in Q1 if all things go well. We expect kind of in the midyear FMX103 will have our NDA submission, as I talked about earlier in today's presentation. Our action date will happen in Q4 for FMX101 and the launch in the earlier part of Q1 next year. And of course, consequentially, the PDUFA for MX-one hundred and three will be a little bit later after that. On the earlier projects, I talked about FCD105. We'll start a Phase II study in Q2 this year. We spoke to have the clinical proof of principle data for FMX109. This is an x-ray combination with the retinoids in Q3. Moving into next year, clearly a lot of these projects are moving into maturity in the clinical environment. We expect to have top line results in Q2 for the Phase II study for FCD105. That's a combination of minocycline and adapalene. FMX101 will start the study for Phase II in Q1. And we expect to have our 1st Phase II open for FMX10110 doxycycline hyclate gel, again, somewhere between the middle of between Q1 and Q2. And I think with that, I'll pass the floor to Dave. Thanks, Ian, and thanks, everyone, for a robust discussion. Just to wrap it up before we turn it over to Q and A. As I'm proud of saying, as a company, we continue to execute on our milestones on or ahead of schedule for all of our initiatives. And as Ian outlined earlier today, we're pleased to be able to accelerate the NDA submission time line for FMX103, bringing it up almost 2 quarters' worth. Do believe from our discussions today from our esteemed key opinion leaders in dermatology that we do have the ability to address significant unmet needs for patients and health care providers with these two launches, which could be within side of a year of each other. The new data for FMX103, I think, again, reflects positively on the impact of our key secondary endpoints, especially around tolerability of our product and patient satisfaction. We have very unique scientific message platform to talk about for our products. Obviously, this notion of the vehicle matters, I think, plays a very big role. Certainly seems to be in today's day and age, if you can get a favorable view from payers, that certainly bodes well as you prepare for commercialization and at least all the indications continue to reflect positively on that for FMX101. So we were very pleased to see those initial results. As I've often talked about when we look at launching FMX101103, there's a lot of efficiencies, a lot of synergies. It's almost as if you're getting 2 launches for the price of 1 as we like to talk about here. And I think that continues to make sense. It continues to be reiterated from some of the comments that Matt was alluding to earlier. Our near term pipeline activities, we could be very efficient utilization of our cash to get these done. These are not massive Phase III programs. So we can create meaningful catalysts inside of the next 12 months for our shareholders. But then also as we have outlined today, and I wanted to focus our pipeline on the potential durability of the amortization franchises. If you look at just at face value of the programs that Ian outlined, we believe that that gives us traction to 10 to 12 years just on these particular products in acne and rosacea. These are meaningful franchises that we can develop, address significant unmet needs for patients and for caregivers. And then I would say stay tuned as we continue to work on our pipeline activities for adjacent markets in medical dermatology, such as atopic dermatitis, leveraging our platform for medical aesthetics and the like, and we'll provide more insight on that in the future as we come back together. So with that, I'll ask Matt to join me up here, and we'll take some questions from the audience. I appreciate it. Thanks. And for those of you listening on the webcast, if you'd like to ask a question, you can send an e mail to questionslifesciadvisors.com. Once again, that's questionslifesci advisers.com, and we'll direct your question to the panel here. Hi. Thanks for taking my questions. Louise Chen from Cantor. So I had a few here for the doctors. First, what do you expect for the pace of uptake for 101 and 103 assuming they get approved? Second question I had was on the reimbursement for dermatology drugs. How has this changed? Is it still good for patients? Has there been any obstacle to uptake as a result of reimbursement? And last question I get a lot is with respect to RHOFADE and if your product the 103 product can be used in combination with RHOFADE? Thank you. So I never do well with more than one question at a time. I think I remember the first question, which was the expected uptake. I'm sorry? Pace of uptake. Pace of uptake. Okay. I'm sure you're aware that dermatologists are very fond of new products. And lots of people are practicing dermatologists these days, pediatricians, the internists. And what we want is a new product. And we want it because when a patient comes to see us, we're specifically the experts. And if everybody else has already used a product, we're recommending the very same thing that people have used before. So our uptake is always very brisk for that reason, if nothing else. And here we have a product that is actually efficacious as well as new. We've had new products that weren't terribly efficacious, but we prescribed the heck out of them anyway because we just needed something new and a new brand name. So I expect it to be very brisk, especially for acne. And the second was what? Reimbursement. Reimbursements. I have no idea. No clue whatsoever. It's usually pretty good for the 1st 6 months, and then we have to see about it afterwards. Certainly, reimbursement matters a great deal in terms of uptake for some derms more than others. I think John and I are unusual in that we work very hard to do the best thing for our patients to make sure that coupons are used, that we use specialty pharmacies, and we make sure that we really work to get the branded products out to our patients. Not everybody is like that. A lot of our colleagues say, you know, if I get callbacks from the pharmacy, I'm done here. So it all depends on how well that whole thing is set up before the drug comes out. Okay. And the third one was RHOFADE, which I'll take, and I'll go back and mention a couple other things. For RHOFADE, I think they there's no reason to think that they aren't compatible. The question will be if we see the degree of erythema improvement with the topical minocycline, the FMX 103, will patients need to use the RHOFADE? So that I think is a good question there. Compatibility, I see nothing about them that would make them incompatible with each other. Going back to the pace of uptake, Hillary mentioned a lot of different prescribers. Don't discount the number of, mid level providers or advanced care practitioners in dermatology right now. There are some factors that I think are very important there. I think there were dermatologists were 20 30 years ago before the Sunshine Act was in place. They appreciate what the pharmaceutical industry can do for them in terms of advancing their agenda in dermatology. And I think they are very quick on the uptake. And they are seeing a lot of the medical dermatology patients. And this group of executives is very aware of that and has a group of advisers that make them very aware of that. And so I think that the uptake will be probably a little more brisk than you have seen with some of the other products, both based on that mix of dermatology providers and the sensitivity of this group to that. Okay. Thanks. Anthony Vendetti from Maxim Group. Just a quick question for both Doctor. Weiss and Doctor. Baldwin. Ian mentioned that there's a low resistance potential for topical minocycline. And both Doctor. Weiss and Doctor. Baldwin mentioned using the topical minocycline for maintenance, right, for many, many years. So I was wondering if you I mean, it's early yet, but what's your view of long term risk? Obviously, oral antibiotics over extended period of time have a much higher risk. But what's your view of the long term risk in the maintenance mode? And then and maybe Doctor. Baldwin, you can answer this question because on a certain type of acne that you had up there, and I can't remember which one, but you said the first three lines of defense were and I'm pronouncing this correctly isorentinone, isorentinone, isorentinone. So in what act these or what situations would, the topical minocycline be used instead of that product or in conjunction with? I'll take I'll take resistance potential first and then I'll because I think, quite honestly rosacea is an area where you'll get people to use it more because it's a longer longer lifespan of the disease, if you will. Based on my understanding of the science behind it, I don't I think low is an overstatement of how much resistance potential there is. I think this is mainly a systemic issue and the absorption is so low. So if we look at the left side of Ian's curve, I think that's our biggest concern. And that is, and so I think low resistance potential is overstating how much resistance potential there is. And then you look at the other side I mean it's all sitting on the skin. And so you're way above. So I am not particularly concerned about developing resistance. Further, with systemic minocycline, we're not seeing much anyway and it is falling in that range. We've it's been of the all the tetracyclines out there, the number of resistant strains to minocycline is incredibly low. So there's something about this particular molecule now giving it topically with low absorption and low concentration systemically where I'm thinking it's going to be almost negligible. Time will bear that out. I don't know how Hillary feels about that. But that's how I feel about that. Hillary? I totally agree. So first, I'm way more concerned about systemic resistance than I am topical. Affecting the gut is a much bigger story than affecting the skin because the gut is the seat of much of our immune response. And we now see association between gut health and Alzheimer's and atopic dermatitis and even learning disabilities. I mean, it's very widespread. So the fact that it is not systemically absorbed greatly reduces my concerns about resistance in general. The second is that, what was that, 3 or 4 months ago that we learned about your mutant prevention concentration. We were gabberflasted. We got to this meeting. We had never heard of any of this stuff before. This is a completely different way of looking at antimicrobial resistance. And we were just sitting there stunned. And we actually ended up thanking them for allowing us to come to their advisory board when we were finished because it was such new information. And we thank them greatly for bothering to do this and to instruct us on all of this. So it's a completely new way of looking at things and has changed the way that many of us felt about the possible use of topical minocycline as a monotherapy. I think we all went into that meeting saying, well, this is going to be nice. It's going to be helpful. It's going to be a new drug. It's going to be better than clindamycin. But I'm still going to use it with Benzoyl Peroxide because I would never feel comfortable using this without Benzoyl Peroxide because of the risk of resistance. And I think we all left the meeting saying, you know what, not sure I have to do that. I think this might be useful as a monotherapy. So really, it was a complete mind change, in a 2 hour period of time. And the people at that meeting were some of the biggest names in acne treatment both young individuals and people over the last 30 to 40 years. Yes. If I could just quickly follow-up and thank both Doctor. Weitz and Doctor. Baldwin for their comments, echoing both questions. Really comes back to the core of why we're doing what we're doing. I've said all along for the last several years, we certainly do not believe these products that we're developing for patients and caregivers are me too products by any stretch. This is novel technology. This is novel work that we're doing from a clinical perspective. I think that makes a meaningful difference in the minds of caregivers, and also we're seeing it makes a meaningful difference in the minds of payers, which when as we are getting ready to introduce these products are certainly critical in today's day and age. And so I think the information that we share today is actually quite compelling and seems to be that as we've introduced this to, again, payers and to fellow dermatologists. So I know we have more questions. There was part 2 to that question? Yes. The as a retina, the picture was quite stunning, the improvement with that particularly. So those patients would not get better with topical minocycline in my opinion. I mean if they did, oh my gosh, right, it would be a life changer. That's the kind of acne that requires isotretinoin. So minocycline, topical minocycline in my mind would be thoroughly replacing clindamycin, kicking a lot of patients out of topical dapsone, kicking a lot of patients out of benzoyl peroxide only because it's a pain in the neck to use and maybe giving oral minocycline a run for its money. So there are lots of places in which I see this drug surpassing and supplanting currently existing products but not isotretinoin. Hi. I'm Bog Sabar Patna, HCR Partners. On topic of antimicrobial resistance, again, has there have there been any long term studies or papers that have demonstrated actual development of resistance in ActivePort overuse of oral antibiotics? I guess what's driving the AD or other bodies to kind of recommend decreased use of oral antibiotics? And the second question is with the launch of sarecycline, obviously it has a narrow spectrum design that's targeted against P acnes. How may that fit into your treatment paradigm with FMX101 given that profile? Yes. So there are many papers to my knowledge about long term resistance to oral antibiotic resistance to long term use of oral antibiotics in the general medical literature, maybe not with individual individual molecules or individual antibiotics, but especially in the macrolide group. Erythromycin, for example, is basically worthless in acne both systemically and topically. Tetracycline, just plain tetracycline which we can't even get in this country anymore, Pretty much the same story though the oxytetracycline, doxycycline and minocycline have fared better. Seracycline again, it's I'm not sure we have the proof. It is supposedly narrow spectrum, but it's hard to know with systemic agents and plasmids and everything can go on with cross resistance what's going to happen with this drug. It's just a little bit too early. We're thrilled to have it. Don't get me wrong. We did those studies as well. I'm sure Hillary did as well. The results we saw were actually if you look at the data, we're not quite as impressive actually if you look at the data, were not quite as impressive not nearly as impressive as it was with the topical agents. So with this topical agent, now different populations difficult to know exactly who went in, monotherapy. It's hard to know what the vehicle effects were of this. But if you compare it was probably similar investigators. It's hard to know patient populations. But you know it's, they could certainly be used together. And whether or not you would replace it, I think that's just a going to be a long term deal. Yes. And we're increasingly concerned about this worldwide problem with antibiotic resistance. And the very medications that we use are on the list of drugs which have lost their potency over the years. And to John's point before, minocycline has been a particularly hardy antibiotic. But things are changing, especially in Asia. And I think it was Dirk Elson who said that means that resistance here in the U. S. Is only a plane right away. So we are seeing minocycline catching up to the others, and we would obviously like to avoid that if at all possible. Now the tetracycline class of antibiotics have long been considered by dermatologists to be a non issue because they're sort of a garbage pail antibiotic, right? It's not something that's important and it's like 6th line now. It was important when we were residents for syphilis and gonorrhea and it's lost all that importance. But it's still first line for Lyme disease and for non gynecoccal urethritis. So it's still a very important antibiotic and also for MRSA infection. So we really don't want to lose tetracyclines to antibiotic resistance. So I think it's crucially important that we do our best to curtail that. And part of it is not using the orals, trying to avoid it if at all possible. And that was part of my plan about sarecycline. Given that it is in the tetracycline family, could it breed cross resistance with the other tetracycline? So and we just don't know. I mean, as Ian's graph showed with the low concentrations that kind of fall in that mid range of the bell curve, if it falls in those, and I do not know that PK data, that could potentially one at some point be an issue. So especially with MRSA's would be my concern. Hi. Anantra Gaynor here from Credit Suisse filling in for Vamil Divan. I just had a question for Foamix Management. I just wanted to know if FMX101 has been accepted by the FDA or if you've seen any impact from the government shutdown that drop your review timelines? And sort of related to that, have you given any thought to commercializing the vehicle alone as an OTC product if there were to be some sort of impact? Sure, sure. So first of all, regarding the dialogue and time line with the FDA regarding NDA filing of FMX101. Everything continues to remain on track. We've actually had continued dialogue and exchanges communications with the FDA since the government shutdown. We anticipate, again, that we should receive final notification of acceptance of the filing before the end of the quarter. Again, everything all signals indications suggest that there is no change to that, which would continue to keep us on target assuming the product was accepted for filing. We'll put us out of PDUFA somewhere in the Q4 and if approved, again, a launch somewhere around this time next year right after the turn of the year. Regarding commercial opportunities for the vehicle itself, obviously, we're quite proud of the unique technology as well as the intellectual property capacity of our vehicle, which has served us well for products we've developed. I would just say we look at all possibilities. A product such as that is a different commercial entity, if you will. It's an OTC type of product. We'll certainly explore those options amongst others. I think as you can see, we have a pretty full plate right now in preparing for the launch of these products and then advancing some of our near term pipeline candidates. But it's not the first that this topic has come up and one that we clearly take a look at on a routine basis. So thanks. Patrick Dolezal, LifeSci Capital. Just a couple for the KOLs. Starting with Doctor. Baldwin, can you just elaborate on some of the rare but serious AEs associated with oral tetracycline use, kind of perhaps touching on how they're managed and any potential costs associated? Sure. So, doxy since tetracycline really is we use it anymore, we'll talk about doxy and minnow. They have different side effect profiles. Doxycycline, in my opinion, has more upfront nuisance side effects. Nausea being the primary, the Achilles heel of doxycycline is the gastrointestinal tract. So we have a lot of patients with pill esophagitis and nausea and such. Minocycline has and phototoxicity. Minocycline has virtually no phototoxicity, and it has very few initial side effects unless you're using the immediate release minocycline. Which is really a very difficult issue for patients to deal with when taking it for long periods of time. But it has more end loaded issues. They're very rare, but there are some oral minocycline problems that are of considerable import, like lupus like drug eruptions and drug hypersensitivity issues. So most minocycline is a more highly prescribed medication, but and in my opinion, is more efficacious, although there is no head to head between them that actually shows that to be the case. But I think most of us believe that minnow is a slightly more effective medication than is doxycycline. And how we manage those with the GI is with the doxycycline is going to the enteric coated delayed release formulations that end up getting absorbed later in the stomach and into the small intestine to reduce the GI distress, making sure they're consumed with large quantities of water, the patients don't lie down right after they take the medication, perhaps take it on top of food, although we know that decreases the absorption of the medication. So you're trading a decrease side effects for perhaps less efficacy when you do that. For minocycline, the answer in my opinion is to go to the extended formulations, which does away with most of the side effects. Since it also decreases the dose, the extended release formulation is at 1 milligram per kilogram. You also reduce your chances of long term side effects like hyperpigmentation. Great. And then one for Doctor. Weiss as When you're thinking about optimal product characteristics in rosacea, what level of emphasis should be placed on purely lesion reduction versus some of the more holistic aspects such as quality of life, and tolerability factors like improving stinging and burning? You know, I think they're both important. I think it's a conglomeration of everything, so I wouldn't I think you just have to I think you have to present the whole package to people, quite honest. So I don't place one over another. I'm thinking about all of that when the patient is sitting in front of me. So I know that's probably not answering your question the way you want it, but it's the honest answer. Hi. This is a question for both the doctors. What is the average cost sharing by a patient in your practice? And where do you think the dollars will come from for an FMX either 101 or 103, but probably more like 101 product. Do you think it will be a net add for the patient in terms of incremental dollar outspend or a neutral because it will come from the dollars would come from something else? You're much smarter at this than I am. I wouldn't say that. So I don't think I mean, your term cost sharing and I was an econ major, so I kind of know the if you will, the econ speak or the finance speak a little bit. I don't think of an internal cost sharing. I think of it as maximum tolerability of the patient for their dollar spent. And I think that is increasing over time. Started at like $0 to $10 And I see it inching up where they don't bat at $25 and it's getting closer to $50 for a lot of patients, especially in the Northeast market. In beautiful Snellville, Georgia, where I practice, it's probably not quite that high. So my patients can tolerate about $25 For the economic modeling of percentages of cost sharing, I think that is still complex and that's under evolution. I think by the time these products are approved, we're going to have a very different model than what we have right now. The current model is not sustainable where you have the company that owns Solodyne losing $15 on every prescription. That's not going to happen anymore. It's just it just can't. They can't be a start up and do that. So what we're starting to see is acne products released, some of them at a certain dollar where they're going cash only. And the latest formulation of tretinoin did that. And it's a wonderful formulation and previously the uptake would have been much greater. But companies are going to have to model that as to how it works. Seracycline is currently Seysara, is currently coming out under the old model. That will only work for so long. So while I can't give you an absolute number, I think if they can make this product, dollars 25 to $50 to the patient quite strong, especially for the rosacea variant when you're talking about adults and the amount of product that they will use over a specified period of time. It's going to be probably about $15 a month if you go to the high end of that, for the patient, dollars 15 to $20 a month because all of our canisters were returned with a fair amount of product in them. So, and especially if it's coming out of the patient's pocket, they're going to use it judiciously appropriately. So I hope that answers your question to your satisfaction. We'll take the next question. Please state your name and affiliation before Hi. Bill Maughan, Cowen. So for the doctors, to expand a little bit on an earlier answer, can you talk in any specifics that you're willing to give about how the availability of generics and the pricing environment does in any way limit your accessibility to branded drugs? And along similar lines for management, what have you seen in the pricing environment for specific products that are continuing to get reimbursed that gives you confidence in the environment for I'm sorry, I didn't hear that last question. That was for me. That's for me. That's for me. Okay, then I don't need to hear it. So you were asking about the availability of generics. I'm one of those old fashioned dermatologists who believe wholeheartedly in branded topical products for acne. I'm not always prescribing brands for eczema and for psoriasis. But I think in acne, it makes a huge difference in terms of efficacy, but especially in terms of tolerability and also in terms of acceptability for the patients. And I don't think that those things should be undervalued. My patients who many patients come to me as a tertiary acne person already having been on many of the generics that they came off of because of tolerability or they came off of it because it's not effective. I merely switch them over to the branded products with the designer vehicles, and they get better. It's all it takes. So I'm a firm believer in whenever possible utilizing the brands. Now as John pointed out, things may change greatly over the next year. I may not be able to do that anymore. But right now, it's a priority for me. And I spend an inordinate amount of time, as does my staff, working to get people branded products. Not sure that's the case in your average derm office, where time is money, and that might not work quite as well. But for me brands are the answer and generics are subpar second line products for me. Yes. And just to again, I'm going to turn your question or advance around a little bit. To me, it's not availability of generics. It's all about reimbursement. Okay? Generics don't matter. Is it covered or is it not covered? And so to me, this is please don't take any offense to this. This is a question for the management team to ask them what are they going to do to do that. Because it has nothing to do with what else is available. The reason we're here is exactly what Hillary said. We believe in name branded products. Like I said, when I showed you, don't look at the vehicle line so much, look at the combination line because the vehicle is doing so well because it's been formulated exactly for the conditions we're treating. I mean, it has utility in that. Their vehicle to treat the conditions that they're looking at because it really would do well in an over the counter room. So I think I would put it to them at a later commercial stage, maybe Matt, what are you going to do to make it so people like Hillary and I and the PAs and MPs who really want this product for their patients can get it for the patients. Right. And that's an important point because there's going to be a balance between price contracting, patient access tools, synthetic access tools, things of that nature to make sure that the patients can get our drug. And so that's all work that's being done. Regarding your question on competition and where they price and what the access looks like, there's a full battery of analyses that we're embarking on to take a look at just that. Understand where products are coming into the market, where they're priced, what the access looks like over time. We'll also do the same on our drug. So we understand, where, our access cascade will fall over, over the period of time. We do know that in the current environment, new to market brands typically don't have until they go through a full P and T review. That can take anywhere from 3 to 9 months. But there are synthetic options that we can use to make sure that the patients get drug in in that, period of time. That's why targeting is so important to make sure that, we are focusing on the right patient population. So when there is coverage through their insurance, that they're not, boxed out due to an alternative diagnosis, etcetera. Does that make sense? Yes. I think just to add some additional color, I think as Matt outlined earlier today, in his presentation, you can see clearly where the net cost plan needs to be. Certainly, seems and these again were 10 of our largest payers in the category, view this as being a full P and T review product, which is not often the case, especially for products in various derm categories. So all the initial signs, which is actually a continuation of what we've seen in previous research, remains quite positive and we're quite enthusiastic about it. About it. Don't want to at all underestimate the work that will need to take place, and we continue to do this and have continued to do this for the better part of the year. And we'll be doing for the next several months leading up to launch. I think also one important point that goes to some of the pipeline projects that we were outlining. The bar continues to be raised for us to bring new innovative products to the space that are going to address unmet needs. I think our dermatologists here outlined some of the challenges with today's existing topical therapies and also needs to not just clear lesions, which is obviously a major goal when dealing with conditions such as acne and rosacea, but can you actually improve the skin itself? And can you actually improve skin health? And so when we're looking at a combination of products that may have cosmetic benefits, again, that opens up a whole another realm of patient benefits and can bring a whole another group of patients to products like ours if approved. That's it. Okay. So I think that exhausts all the questions. Once again, I want to thank everyone for taking time out of their busy days and schedules, especially for those that are here in the audience working away through the rainy streets of New York City. Thanks again for joining us and for those that are listening and participating on the webcast. Thank you all again very much. Look forward to providing you additional updates in the coming months and quarters. So thanks. Have a great rest of the day. Bye bye.

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