Good afternoon, everyone. We are delighted to have you with us. During today's call, we plan to discuss our strategic and corporate development plans, including our decision to focus on developing differentiated medications for patients living with moderate to severe acne, and to move our lead drug candidate, denifanstat, into a phase III registrational study for the U.S. in the second half of this year, subject to IND clearance. For today's presentation, I will provide a brief overview of Sagimet, highlighting our FASN inhibitor development programs. Robert D'Urso, our Senior Vice President and head of new products, will discuss the significant market opportunity for a novel oral FASN inhibitor in moderate to severe acne.
Julie Harper, an internationally recognized dermatologist and thought leader in acne and rosacea, will then review denifanstat's novel mechanism of action and the strong phase III clinical data with denifanstat in moderate to severe acne trials conducted by our partner, Ascletis, in China. Finally, Dr. Andreas Grauer, our Chief Medical Officer, will then highlight our planned clinical development programs, followed by a Q&A session with our panel. Julie Harper is a board-certified dermatologist practicing in Birmingham, Alabama. Julie Harper is the founding director and past president of the American Acne and Rosacea Society, a fellow of the American Academy of Dermatology, recently served on the AAD acne work group, and also is a former president of the Alabama Dermatology Society. As we get started today, I'll take a moment to give us a quick snapshot of Sagimet.
We recently announced a strategic decision to advance denifanstat with its novel mechanism of action into patients and families living with moderate to severe acne for the U.S., where we see a strong opportunity to make this differentiated product available for this large and underserved patient population. Our decision to move ahead with development of denifanstat for the U.S. builds on the recent successful phase II and phase III clinical trials in China for denifanstat in moderate to severe acne conducted by our license partner. Top-line data from the phase III study showed that denifanstat met all primary and secondary endpoints. These data, which are currently being reviewed by the Chinese regulatory agency for approval of denifanstat in China, give us confidence as we prepare to initiate our own registrational phase III study in the U.S. in the second half of this year, subject to IND clearance.
Acne impacts about 50 million Americans, with approximately 10 million suffering from moderate to severe acne, and we believe that these patients are underserved by their currently approved treatments. If approved for the treatment of acne, denifanstat could be a convenient once daily oral medication and the first innovative oral treatment approved for acne in more than 40 years. We are also advancing a second oral FASN inhibitor that is currently in a phase I study with initial data expected in the second half of this year. Upon completion of the phase I study, we will consult with regulators regarding the design of a phase II proof of concept study, which is expected to begin in the second half of this year. Our pipeline underscores our prioritization of our dermatology programs as our lead strategic focus.
As noted, we are planning to take denifanstat into a phase III trial in patients with moderate to severe acne, which is expected to begin in the second half of this year, to continue the development of our second oral FASN inhibitor with a phase II trial also expected to start in the second half of this year, and to advance our topical formulation FASN inhibitor toward an IND submission. On Monday, we announced a $175 million underwritten offering of Series A common stock, which strengthens our balance sheet significantly and enables us to fund our current operations comfortably through 2028, including through readout of the development programs that we will discuss today. As we move forward with our strategic focus on acne, we have the fundamentals in place to support execution.
Now I'd like to turn the call over to Robert D'Urso, our head of new products, who will take you through the acne market landscape.
Thanks, Dave. The global acne market's a large market, as Dave indicated. It's forecasted to reach roughly $20 billion globally by 2034. Within the U.S., there are roughly 50 million people that suffer from acne on an annual basis, of which roughly 20% or 10 million of them suffer from moderate to severe acne, which is the target indication for oral denifanstat. On an annual basis, roughly 5 million of these of these acne patients are seeking professional treatment, and this highlights the potentially large underserved population currently not seeking treatment. The current available treatments have profiles that potentially limit their effectiveness to treat moderate to severe acne. On the next slide, I'd like to show you just the acne treatment landscape as it currently stands today. In mild disease, treatment consists primarily of topical products alone or in fixed dose combination with each other.
On the far right side, on the opposite side of the spectrum, patients with the most severe form of acne, otherwise called cystic disease, are treated with oral isotretinoin. Isotretinoin is an effective option. The drug has prescribing limitations due to the FDA required iPLEDGE program or REMS program. This is 1 of the most restrictive programs in the industry for physicians, pharmacists, and patients. Oral isotretinoin is also not indicated or considered a treatment option for other mild or moderate disease forms due to its unfavorable risk to benefit ratio. For patients with moderate severe patients that come in, dermatologists will typically add oral treatments to the topicals that they're using for more milder patients.
However, these oral patients, which are currently typically oral tetracycline class agents, carry undesirable side effects, including GI intolerability, photosensitization, CNS side effects, and the complications that develop due to the potential antibiotic resistance caused by overusage. In addition to all of these prescription medicines, dermatologists generally recommend a skincare routine to help manage the symptoms associated with the typical side effects of topicals and orals, such as local dryness and some mild irritation. These recommended skincare routines can effectively address the dry skin and irritation concerns, which enable patients to also remain on these prescription medicines for longer periods of time. Now, thinking about denifanstat, we anticipate that denifanstat 50 milligram oral once a day will, if approved, be prescribed to treat patients with moderate to severe acne.
In addition to our oral program, we are in development and pursuing a topical FASN inhibitor, which we would anticipate could be used to treat more mild to moderate forms of acne. I'd like to invite Julie Harper to share her thoughts on the therapeutic space, including the potential role of an oral FASN inhibitor in the treatment of moderate severe acne. Julie Harper?
Thank you very much. Thank you for the opportunity to be on the call today. Let's switch gears a little bit and talk about how this FASN inhibitor might work in our current understanding of the pathogenesis of acne. I think Rob did a great job, but I will say that it really doesn't matter if you have mild, excuse me, mild, moderate, or severe acne. We are trained to think about the 4 key drivers of acne and the pathogenesis of acne when we sit down in front of a patient and we're trying to decide how to best treat it. Those 4 key drivers are here on this slide. They are sebum, and really increased or excess sebum. They are follicular plugging, so follicular hyperkeratinization. They are C. acnes, Cutibacterium acnes or bacteria, and then inflammation.
Those are the four things that we are always trying to target. Right now in the market, there's only one drug that targets all four of those, and that's the drug isotretinoin. This is the Accutane drug that Rob just talked about. It is certainly effective drug, but it does have some limitations based on the potential risk of the drug. It also really is something that we prefer to use in people with more severe disease. If you look at these four triggers or four drivers, how might a dermatologist address these? Well, a very common combination would be to use something like an oral antibiotic. What would that target? That would target the last two there. That would target C acnes and inflammation. That leaves two things untreated. We might add to that, for example, a topical retinoid.
This is just one example. That's a really common combination for us to use, and you can see that there's one that gets left out when we do that. Historically, sebum has been the hardest target for us to hit. We can hit it with isotretinoin, but we've already said there's risk associated with that, and not everybody can take or needs isotretinoin. We can hit it with combination oral contraceptives. Obviously, we're only gonna use those in women. That's the same thing with oral spironolactone. There's just limitations to what we have. We do have the newer Winlevi product. This is a topical sebum inhibitor, and it's working through that androgen pathway, but we can use it in either gender because it is a topical product. Where would FASN potentially work in this, a FASN inhibitor?
It would work on 2 of these as well. It would work on sebum by blocking just sebum lipogenesis, but it's also anti-inflammatory. It would also be hitting 2 of these. If you look over at the top right, what's unique about this? We've already talked about isotretinoin. That's a retinoid. It's working through a retinoid pathway. Everything else I mentioned that would target sebum works through the androgen pathway, through the male hormone pathway, and that's why those oral drugs we can only use in women. This is a whole different pathway. This is looking at de novo lipogenesis. That's where 80% of the sebum lipids come from. This FASN inhibitor is gonna insert itself. It's really gonna act as a roadblock in that pathway, blocking sebum lipids.
If you block this, if you put this roadblock in there, and the one we're talking about today is denifanstat, we're putting this roadblock down kind of far in this metabolic pathway. When you do that, you would expect then to see less of the end product, less of sebum, and in particular, less of the two that you see listed there, palmitate and sapienic acid. We're gonna look on the next slide to see, do we have any evidence that that's actually what happens in the presence of this drug. This is not an acne study. In this case, this is from a phase I clinical trial in oncology looking at denifanstat. The main outcome here was certainly not acne, and it wasn't really even skin.
In this phase I study, they used what's called SebuTape, which is a tape that is put on the skin that wicks sebum up off of the skin. When the sebum comes up on that tape, it changes the opacity of the tape. You can measure the sebum based on that. If you look at the diagram on the bottom right of this slide, if you look at the Y-axis, we are looking at what we just talked about, sapienic acid and levels of that on the tape. If you look across the X-axis, now you're seeing days of treatment, and in parentheses what you see is the number of subjects for each one of these. At day 1 and day 2, we would kind of be establishing a baseline of the sebum lipid that is on the skin.
By day eight, you start to see that this is being reduced, and by day 15, it's substantially reduced by about 90%. If you see those two asterisks above that means this is a statistically significant difference from baseline, and that happens fast. 15 days is fast, and it doesn't stop at day 15. This continues. If you look at the end of your X-axis there, you can see that we're going out to day 93. What we see with this product, the denifanstat is more than 90% reduction in sebum lipids by day 15, and it maintains this reduced level of sebum lipids throughout the entire study. That's kind of the why behind why we would even look at this. Let's take a look now at something I'm super familiar with, and that is acne data.
We do have a phase III clinical trial. This is the one that was performed by the partner Ascletis in China. This is a phase III clinical trial, and in this trial, they enrolled people with moderate to severe acne. I want to deviate for just a minute and explain what we mean by that because it is important when you then look at the primary endpoints. When somebody has moderate to severe acne, we are looking at an IGA score. That is Investigators Global Assessment score. The G could also be for like gestalt because you are looking at a person kind of at arm's length, and then you are rating their acne as a zero, one, two, three, or four point zero would be clear, one would be almost clear, two would be mild, three would be moderate, and four would be severe.
Everyone in this study coming in had to be a three or a four. They were moderate or severe. This has a great design. This is a well-run study. It's multi-center. It's placebo-controlled. It's randomized one-to-one. For every person who's on denifanstat, they are matched with 1 person who is on placebo. Also, obviously, this is double-blinded. That means neither the investigator nor the subject know which arm they're in, and that helps to keep the efficacy very meaningful, the assessments, and also the tolerability and safety evaluations blinded and very meaningful. This is a once daily product, and I'm gonna go ahead and say here that in dermatology, we really prefer once daily versus a drug that has to be taken twice daily. We definitely lose some of our patients' ability to follow our directions when we make things more complex.
They enrolled 480 patients in this study. 240 were in either arm. Again, this is a 12-week study. We're gonna start them day one as moderate to severe acne. Take this every day for 12 weeks, either this or placebo. At the end of 12 weeks, we're gonna be looking at our primary efficacy endpoints. Those two primary efficacy endpoints, they're always the same in acne studies. They are IGA assessments. We wanna take that IGA of three or four, moderate or severe, and we wanna see how many people we can get all the way down to zero or one. It is not how many people improve, it is how many people go from moderate to severe all the way to clear or almost clear.
This is with monotherapy with a product here that's hitting two of those four targets in the pathogenesis of acne. The other primary endpoint is lesion counts. Not only do we do the gestalt assessment from arm's length, but we get in there and we count lesions, and we count acne lesions. Those, we're gonna look to see what is the reduction of lesions over time with this as well. There's also, at the end of this 12-week study, about half of the people in the study will go into a 40-week extension study. That's always about safety when you take this out to 52 weeks. That becomes open label.
No longer is there a placebo arm. That's just because we want everyone exposed to the drug. We can really look at safety with this drug over an entire period of a year. When you look at the results from this, the top half of this just tell us where we started. We look at the baseline demographics. I will take two seconds here. If I was giving this lecture or presentation to dermatologists, I would always remind us by asking, "How many zits on your face does it take to mess up your day a little bit?" The answer is never five. It's always one. Well, these people had on average over 100 acne lesions on their face. That is still moderate to severe. That's a lot of acne.
Out of all of that acne, more than 40-43 lesions out of that 100 were inflammatory lesions. That means they're visibly red, many of them pus-filled. What's the rest of the lesions? That would be what we call non-inflammatory lesions or comedones, and that's the smaller blackheads and whiteheads. On the whole, these guys had moderate to severe acne with over 100 lesions. The bottom half of this slide is looking at efficacy. I won't go through all of this, but we're looking here at our treatment success and our change in lesion counts, whether it's inflammatory or non-inflammatory. You see the columns. We have our active arm with 50 milligrams of denifanstat once a day. The next column is placebo, and there is always gonna be a placebo effect with acne.
A lot of that just has to do with the fact that this is a condition that waxes and wanes on its own. What's important is that that next column looks at the adjusted rate. That means the difference between the result we saw with denifanstat minus the effect that we saw with placebo. Probably most important on here is that last column that says we won in all of these. In every single one of these, we had a positive outcome, and it was statistically significant. I will take a minute to look at the very first of the efficacy endpoints, and that's treatment success. What % of people did go all the way to clear or almost clear with this drug? It was 33% of people.
It absolutely lapped the placebo, twice as good as placebo, and this is statistically significantly true. Now, just to level set, and I wanna be careful that I don't want to make this sound like there was a head-to-head study because there hasn't been. If you went to most of our oral antibiotics and you looked at their IGA success rate at the end of their studies, the numbers that would be in their package inserts, you're gonna see numbers in the high teens and the low twenties. This is a good number just to kind of level set that for us. Now, anytime we talk about efficacy, we have to be fair and balanced, and we have to talk about safety, tolerability, and adverse events.
I do think that's particularly important in a condition like acne because our patients are young for the most part, and they're healthy. We're using something, we wanna be able to balance the risk and benefit of the drug against the risk and benefit of acne, which is, yes, life-altering, but not usually something that is life-threatening. In these studies, denifanstat, 50 mg a day, was generally well-tolerated during the entire 12-week study. There are always treatment emergent adverse events, and that, by the way, does not mean treatment-related. It just means treatment emergent. That's why we'll always see things like nasopharyngitis as listed as a TEAE in every single study. There were two categories in this that had an incidence rate of 5% or more.
One of those was dry eye, and that was reported in 10.9% of the denifanstat-treated subjects and 9.2% in the placebo group. Not really very different between the two arms of the study. Dry skin was a little bit different. It was reported in 6.3% of those treated with denifanstat versus 2.9% in the placebo group. That one did trend a little more toward denifanstat. Keep in mind here that this is still just 6.3% of the entire population of this. All of these AEs were mild to moderate. None of them were rated as grade three, which would be severe, or grade four. There were no serious AEs reported with this at all, and there were no deaths associated with this.
Lastly, we also have that 40-week extension study. If you think back to that last slide, we said we saw dry eye, and that was at 10% or roughly that, and we saw dry skin that was at 6%. Those are the kind of questions we're asking ourselves as we go into a long-term extension study. Are we gonna see that number creep up with continued use? We wanna know what happens when you're exposed to this drug for a longer period of time. These long-term extension studies are not about efficacy. They're all about safety. We don't have a placebo arm anymore, so we won't be comparing. Let's see what happens.
There were still two categories of treatment emergent adverse events that had an incident rate of 5% or more, and they are dry eye, that was in 5.5% of denifanstat-treated subjects, and dry skin in 5.2%. When I was looking at this data, I liked seeing that. The numbers certainly didn't go up. They seemed to go down. Those are the two that we did see listed early on. Still, albeit very low numbers. All of these AEs, again, were mild to moderate. There were none that were rated as severe, grade three or four. There were no related permanent discontinuations. There was one grade 1 hair thinning in the study experienced by only one patient, but this resolved by itself in eight weeks without ever changing the dose, without coming out of the study.
As far as serious AEs go, there were no drug-related serious AEs. There were two non-drug related serious AEs that both resolved during the study. One was a breast lump, and one was a contusion. These long-term studies are all about safety, but we do look at efficacy. Because they're about safety, I don't have all the big efficacy data here in front of me, but I can tell you that over the long-term extension, we saw continued improvement in IGA success with more people falling into that category. We saw continued reduction in lesion count over time as well. I think we have a good why to use this. This impacts sebum. We know that we've seen the effect of that on the skin with that SebuTape that we looked at, and we've got good early data here from this phase III trial.
This is something that we in dermatology are gonna be very excited about.
Well, thank you so much, Dr. Harper. That was a wonderful presentation. Made it all very clear and makes my job really easy. I have the opportunity today to talk about our phase III clinical trial design. As Dave Happel presented at the top of the call, Sagimet is preparing to file an IND to enable the development of denifanstat for moderate to severe acne in the U.S. As you see here on this slide, our phase III acne clinical trial design, pending FDA agreement, would enroll approximately 800 patients. What's interesting and different about this trial compared to the trial executed in China is we would enroll patients 12 years and older based on feedback from the FDA.
It's a double-blind trial, 12 weeks long, 12-week the primary endpoint. We would then roll over the subjects into a 40-week-long extension trial, long-term extension trial. Our goal is to initiate this trial in the second half of this year, which will be, you know, very exciting to move this forward as quickly as possible. Now let me quickly turn to our second FASN inhibitor. It's called TVB-3567. Like denifanstat, TVB-3567 is as potent and selective as a FASN inhibitor, while it has a different chemical scaffold. We have an ongoing phase I trial, which is a double-blind, randomized, placebo-controlled, which assesses the safety tolerability and PK and PD of both single and multiple ascending doses of TVB-3567. It does that in both healthy participants and in participants with acne.
For the pharmacodynamics, we measure sebum reduction via the Sebumeter, and then the quality of the sebum via SebuTape, as Dr. Harper has presented before. As is typical in the phase I trial, you know, we start with a single ascending dose and then follow with multiple ascending dose cohorts in these healthy participants. Then we will also have a multiple ascending dose portion of the trial in participants with acne. Lastly, we will look at the food effect in a small, 12-person subset. Once we've completed this trial, we anticipate we will be able to select suitable doses to take into a phase II clinical development.
We will, we plan to initiate this phase II study by like in the second half of or by the end of 2025. As noted, this is contingent on discussions with regulatory authorities and the outcome of the phase I study, obviously. Currently, we anticipate that the phase II trial would be conducted like the phase III trial for denifanstat in patients with moderate to severe acne, that the primary endpoint would be at 12 weeks, and that the endpoint structure would be similar to what our China partner, Ascletis, has done in their phase II trial, including the IGA treatment success and the reduction in inflammatory lesions. With that, I would like to hand it back to our CEO, David Happel, to conclude the our presentation.
Thank you, Andreas. To wrap up, as Rob presented earlier, there is a significant opportunity for novel therapies addressing the sizable moderate to severe acne population. As Julie Harper highlighted, denifanstat with its novel mechanism of action has demonstrated significant clinical efficacy for moderate to severe acne patients. Our IP estate and market exclusivity for our development portfolio are strong, and our development path is clear. We have the fundamentals in place for success, including the capital from the existing cash balance and the recent financing to reach our next milestones with a cash runway that will comfortably take us through 2028. We look forward to working with the dermatology community and updating all of you as we progress through the next stages of development.
With that, I would like to take a moment to thank Julie Harper and all of you for joining our call. Now, Tara, I think we can open it up to Q&A.
Great. Thanks, Dave. Yes. Please hold for a brief moment while we poll for questions. Our first question comes from Ritu Baral at TD Cowen. Please go ahead, Ritu.
Good afternoon. Thanks for taking the question. I've got one on some more details of the side effect profile seen in the previous phase III Ascletis. Then one for Julie Harper on her comments about sebum composition. Was there any worsening of the severity of the dry skin or dry eye seen in those patients who, I guess it was all the patients, who had it in the double blind portion and then stayed through the extension? I guess, did you look at like the rates of moderate dry skin and moderate dry eye to see if they increased, and if there were sort of downstream complications of that, especially around the eye? My second question was for Julie Harper. Julie Harper, you mentioned that the composition of sebum was palmitic acid and sapienic acid.
I was wondering, like, in the mechanism, right, would you see a shift in the balance of those two in the sebum makeup of patients with this mechanism? Could that have an impact on inflammatory lesions versus inflammatory lesions and sort of those four, well, the sebum and inflammatory and potential bacterial load aspects of acne. Thanks.
Yeah. Julie Harper, why don't you go ahead and address the first question.
Sure
Then we'll come back to the.
Great
the rate of AEs through the extension study for Andreas.
Thank you for that question. That's a very scientific question about sebum. I will say that sebum is certainly more than just those two lipids that we talked about. That would be the end product of the de novo lipogenesis pathway, and many of the sebum lipids, 80% of the sebum lipids are gonna come through that pathway. That's gonna include things like triglycerides and fatty acids and wax esters. There are other lipids that are part of sebum that don't go through that pathway, and that would be things like squalene. Sebum is more than just those two things. What's interesting though is that this pathway, this de novo lipogenesis, is responsible for the bulk of the sebum lipid that's involved in acne. Now, changing the composition of that, we could do a whole another lecture on that.
That's likely very important, shifting concentrations, and I don't know that we really have that whole story figured out right now. Those two are not the only two, they're just the end stage of the de novo lipogenesis pathway. As far as what you said, and I think I was understanding where you were going with this, I don't know that I can link sebum directly with inflammatory versus comedonal lesion count. What I can say is that we think, at least indirectly, if you reduce sebum, you absolutely are gonna impact C acnes because Cutibacterium acnes, the bacteria, part of its food source is sebum. That's not a primary way that this drug or any drug that reduces sebum plans to work, but I think it's probably a secondary effect of many of those.
I don't have any evidence to back that up from these guys. Just what I know about acne, I would say that it would stand to reason that you could kind of indirectly impact that by taking away the food source. I hope that answered your question. If not, just ask again.
Andreas, you wanna address the Ritu's question about the extension data versus the initial 12-week randomized?
Yeah. Overall, the number of adverse events of dry skin and dry eye were relatively low and not very different from placebo in the first 12 weeks. Over the extension period, we saw overall relatively similar numbers of those adverse events, so no marked increase or marked change in severity.
Thank you.
Great. Thanks for the question, Ritu. Our next question comes from Seamus Fernandez at Guggenheim. Please go ahead, Seamus.
Great. Thanks for the question. Just wanted to get a sense of two things. You know, from Julie Harper, could you help us understand the importance of kind of multimodal approaches here? Being able to not only have an oral in this space but also to be able to bring potentially a topical as well, which do you find is kind of more important, or are they equally important or is the oral substantially more important for the treatment of acne? Second question is, can you help us understand the importance of recent sort of updates to AAD guidelines and recommendations to suggest reduced utilization of oral antibiotics, how you're using oral antibiotics today, and how an oral
An impact on inflammatory lesions and the sebum and inflammatory and potential bacterial load aspects of acne. Thanks.
Yeah. Julie Harper, why don't you go ahead and address the first question.
Sure
Then we'll come back to the.
Great
the rate of AEs through the extension study for Andreas.
Mm-hmm. Well, thank you for that question. That's a very scientific question about sebum. I will say that sebum is certainly more than just those two lipids that we talked about. That would be the end product of the De novo lipogenesis pathway, and many of the sebum lipids, 80% of the sebum lipids are gonna come through that pathway. That's gonna include things like triglycerides and fatty acids and wax esters, but there are other lipids that are part of sebum that don't go through that pathway, and that would be things like squalene. It's sebum is more than just those two things. What's interesting though is that this pathway, this De novo lipogenesis, is responsible for the bulk of the sebum lipid that's involved in acne. Now, changing the composition of that, we could do a whole another lecture on that.
That's likely very important, shifting concentrations, and I don't know that we really have that whole story figured out right now. Those two are not the only two, they're just the end stage of the de novo lipogenesis pathway. As far as what you said, and I think I was understanding where you were going with this, I don't know that I can link sebum directly with inflammatory versus comedonal lesion count. What I can say is that we think, at least indirectly, if you reduce sebum, you absolutely are gonna impact C acnes because Cutibacterium acnes, the bacteria, part of its food source is sebum. That's not a primary way that this drug or any drug that reduces sebum plans to work, but I think it's probably a secondary effect of many of those.
I don't have any evidence to back that up from these guys. Just what I know about acne, I would say that it would stand to reason that you could kind of indirectly impact that by taking away the food source. I hope that answered your question. If not, just ask again.
Andreas, you wanna address the Ritu's question about the extension data versus the initial 12-week randomized?
The number of adverse events of dry skin and dry eye were relatively low and not very different from placebo in the first 12 weeks. Over the extension period, we saw overall relatively similar numbers of those adverse events. No marked increase or marked change in severity.
Thank you.
Great. Thanks for the question. Just wanted to get a sense of two things. You know, from Julie Harper, could you help us understand the importance of kind of multimodal approaches here? Being able to not only have an oral in this space but also to be able to bring potentially a topical as well, which do you find is kind of more important, or are they equally important or is the oral substantially more important for the treatment of acne? Second question is, can you help us understand the importance of recent sort of updates to AAD guidelines and recommendations to suggest reduced utilization of oral antibiotics, how you're using oral antibiotics today, and how an oral
An impact on inflammatory lesions versus inflammatory lesions and sort of those four. Well, the sebum and inflammatory and potential bacterial load aspects of acne. Thanks.
Sure
Certainly they have an impact on C acnes as well. I would love to not use them, and in fact, over the last year or two I've used them much less often than I used to, and that's because we do have, we have a product topically that's become. It's more effective than some of the oral antibiotics, so I'll get to use that product. If you can just avoid them altogether. My first example was you have an oral antibiotic that is hitting C acnes and inflammation, and you combine it with a topical retinoid. You're hitting three out of the four pillars of acne right there. I could see this drug coming in. I don't use that oral antibiotic at all. Now I use denifanstat orally, and I mix it with a topical retinoid. Now I've hit.
With denifanstat, I've hit sebum, I've hit inflammation. I wasn't gonna say it, but since the question already came up, I might indirectly be impacting C acnes. That's a maybe. Then I add my topical retinoid for retinization and I've covered my bases there. So I absolutely see this coming in and being not something that you, "Oh, let's try antibiotics first, and if they don't work, let's do this." I think the time is ripe because we're so concerned about antibiotic resistance just on the whole. The time is ripe for people to come in and use something like this really as a first line oral medication.
Thank you.
Thanks for the question, Seamus. Our next question comes from Jay Olson at Oppenheimer. Please go ahead, Jay.
Hey everybody. Thank you so much for providing this update and taking the questions. Maybe first to start with a question for Julie Harper. Could you please just talk about what % of your patients that you are currently seeing would be candidates for an oral systemic version of denifanstat, and also, what % would be candidates for a topical version of denifanstat?
Okay, I've gotta think about that. I really honestly think the difference would be. Now, this is all I've. You know, we don't have the topical yet. I haven't seen efficacy data for that. If they work equally, I think it's gonna be a matter of just patient preference. Who is a candidate for a sebum inhibitor? Every single person with acne, because it's an important player in the acne market. Again, it just depends on patient preference if you're talking about an oral versus topical. I'm really trying to think about who I would not give this to, and I'm having trouble coming up with something for that.
If I've got a clean adverse event profile, I've got, I'm hitting kind of an important trigger or driver in the pathogenesis of acne that's otherwise hard for me to hit, I don't know why I wouldn't use this.
Thank you. That's good to know. Maybe just 1 follow-up.
Mm-hmm
... question for the Sagimet team. You've got a portfolio including Denny and 3567. You've got the potential for both oral and topical formulations. really nice portfolio of potential acne therapeutics. How do you plan to optimize the development, clinical development and commercialization of this portfolio?
No. I think it's a great question, Jay. You know, look, we think each program potentially has its own place. I think Julie Harper elucidated on that quite well. Ideally, if we have an oral FASN inhibitor like DENNY that is such a strong efficacious product with a safety tolerability profile that it seems to possess, it offers a great option for so many patients, particularly those that have torso acne and may have difficulty in applying or having a topical applied to be able to control the condition. Therefore, having a topical in addition to that makes a great deal of sense.
We're still in the early stages of formulation development with the topical, so we won't really have an opportunity until as the next year or so progresses to be able to understand exactly what we have, and then to prepare it for an IND, and first in human in beginning of 2028, when obviously we'll get a much clearer readout. With regard to the next gen FASN inhibitor that we are developing, we do see potential places for that that could be really intriguing.
It does appear that it is a more potent version of denny, and whether that potency translates into increased efficacy without compromising the safety tolerability of, that we currently enjoy with denny, or if it has the same treatment response and maybe a slightly enhanced safety tolerability profile, I think there are a number of things that we need to look at once we get the data.
We're going to take that into a definitive proof of concept study in the second half of this year, and we should have data, as I think we've communicated publicly, towards the end of next year when we will get a, I think, You know, Jay, to answer your question about where the 2 oral FASN inhibitors fit, then I think we can answer that then. The topical's gonna take a little bit more time to understand as we, as we move it through formulation and then into humans.
Great. Thank you for taking the questions.
Thanks for the questions, Jay. Our next question comes from Debanjana Chatterjee at Jones Trading. Please go ahead.
Hi. Thanks for taking my question, and of course, congrats on all the recent exciting developments. My question is actually for Julie Harper. I would love to understand the insurance dynamics in the acne landscape and what has been your experience. You know, do you frequently get insurance pushbacks, or you think if there's a safe and effective therapy like denifanstat out there, it would be easy to get access? If there are step edits or like, you know, prior authorizations, what kind of hurdles do you think prescribers have to go through to prescribe a therapy like that?
Yes, I would say in the current market, pretty much every branded acne drug that we have is something that we're likely to have to do a prior authorization for, but we're very familiar with that. We either know how to do that. Most people who come to us for acne in a dermatology clinic have already been on treatments. They've already been on over-the-counter benzoyl peroxide, salicylic acid. We even have a topical retinoid now that's available over the counter in the form of adapalene. When somebody comes in and we have to state a case to get something covered, people come in and they've already used things. I have good success getting things covered, but I would expect for any branded acne drug that you are gonna be, you know, working against some type of prior authorization.
sorry.
No, you're good.
Sorry.
Uh-huh.
I had a quick follow-up.
Okay.
You know, given that, you know, it targets sebum, what other diseases do you think that, you know, you are most excited to probably expand the use of denifanstat in? Do you anticipate any off-label use?
If I can answer this question, this is just me talking again here. How would I as a dermatologist think about using this? You know, there are other conditions certainly that are associated with sebum. Seborrheic dermatitis comes to mind, so that might be a place where I would use this certainly off label. It's not being studied for that right now. Perhaps even in sebaceous hyperplasia. And I'm thinking about where we have used some of our other products that work through this pathway of sebum inhibition. There are other places certainly that this could be used.
Appreciate it. Thank you.
Thanks for the question, Debanjana. Our next question comes from Katherine O'Hokrani at Citizens JMP. Please go ahead, Katherine.
Hi. This is Katherine calling in for John. I just have a quick question about the topical, and just how do you expect efficacy to compare to the orals? Is it possible to create a topical formulation that'll be as potent as the orals, or is there some element of having FASN inhibition systemically that might result in better coverage?
I don't know if I'm the best person to answer that one. I might pass that one off.
I think we'll find out, right? I think that's the question.
Yeah
we want to answer is, you know, could a topical, could our topical be as effective? Maybe, again, I think it's important, I think Julie Harper talked about it at some length in terms of where a topical could fit, which, you know, genders may prefer a topical over an oral, and also the ability and the capacity for that topical to be used on the torso, particularly on the back, which most of the time requires a caregiver, somebody to help apply the topical to ensure some level of efficacy, which makes the systemic one that has a nice safety tolerability profile so attractive. Katherine, I think, if I understand your question correctly, the ability to determine whether a topical, if it has the same efficacy, will be used instead of an oral.
I think we're going to try to answer that question, if that makes sense.
Have you guided to when you're expecting to start trials of a potential topical?
Yeah. I think right now we're targeting the first part of 2028 to submit an IND and to start first in human, that'll be our first real opportunity to evaluate it.
Thank you.
Thanks for the question, Katherine. Our next question comes from Yun Zhong at Wedbush. Please go ahead, Yun.
Hi. Good afternoon. Thank you very much for taking the question. The first question is for Julie Harper, please. I understand that Accutane is restricted to very severe patient population, but I just wanted to ask about your experience using Accutane. Have you ever used Accutane in maybe moderate to severe patient at all? Regarding the REMS program, how big a burden is that, and does that affect male patient as well? The second question to Sagimet management team, please. Regarding the number of patient that you estimate will be enrolled into the open label extension study, and what was the rationale for your estimate in terms of patient number?
I hope this is not premature, but are you able to comment on the plan for filing, assume that the study will meet the primary endpoint at 12 weeks? Thank you.
Okay. I'll go first. Yes, I will use Accutane, we'll call it that, isotretinoin, in moderate to severe disease, but it's not ever going to be a first-line agent there. Where I use isotretinoin is in severe cystic scarring acne, but also in individuals who have failed other treatments. Unless somebody comes in and we already see evidence of scarring, it's not going to be a first-line treatment. As far as the REMS program goes, yes, that is for both males and females. That's for everybody who takes that drug. It is a little bit easier as far as the guys go because we don't have to document a monthly pregnancy test, which we do with every single female who takes it. Even if they're not sexually active, we have to take and document a pregnancy test every single month.
The REMS is for both men and women
Andreas, do you wanna tackle the open label and long-term extension study, the size of the population?
Yeah.
Consequently, when would we anticipate filing for an NDA?
As we put on the slide, you know, we would roll at least 300 patients over, possibly if some more, just in order to have enough patients at the end of the open label period, to have a proper safety assessment. As we are expecting a rolling submission, we do not expect that that would that would affect the filing of the NDA. You know, we're expecting to have the results of the trial by the end of 2025, and file in 2028 as quickly as possible.
Yeah. Yun, maybe I could just characterize a little bit more. In the extension, in the, in the primary randomized 12-week study, we need to enroll, we have to have at least 300 12 to 17-year-olds on denifanstat during that period of time in order to secure a label for that patient population. In order to, like, to keep that patient population label, we need at least 100 12 to 17-year-olds to finish the long-term extension study through the next 40 weeks. We'll have 300 12 to 17-year-olds in the main randomized 12-week study, 150 of, in, on placebo of 12 to 17-years-old, and then of that 450 total, we will need to have at least 100 finish out.
That is somewhat of a consideration and a driver for us to ensure that we have that population, well-characterized, by the end of the study.
Great. Thank you very much.
Thanks for the questions, Euan. Our next question comes from Brandon Folkes at H.C. Wainwright. Please go ahead, Brandon.
Hi. Thanks for taking my questions. Maybe just following on from that, for Julie Harper.
Yep
... are there any subtle differences in the 12 to 17-year-old population versus the 18 plus population in terms of acne, treatment of acne and responses to agents? Similarly, if you can just extend that to how we should think about placebo responses in the 12 to 17-year-old, as well as sort of potential AEs as well, versus what we saw in the Ascletis data.
All right. I'm not certain I understand all of that question, so you may have to re-ask part of it. First of all, are there subtle differences in acne in 12 to 17-year-olds versus 18 and years of age and older? My answer to that is always the pathogenesis remains the same. Those 4 drivers are still the four drivers. It's not a different disease. Sometimes we have a slightly different presentation, where an older patient maybe doesn't have a forehead full of blackheads. They're more inflammatory. If anything, an older population is gonna be skewed toward having more inflammatory lesions versus non-inflammatory lesions. I would say that's one difference.
When it comes to, do we see a difference with medications based on age, it's very common for the, for industry, for people who make these drugs to go back after they've done these phase III clinical trials and to cut the data. They cut the data by age and by gender to see if we can see, do any of these drugs work better in one group than another? The take home message 99% of the time is, "Look, we worked well in everyone. We worked in both genders. We worked in all of the age groups." So I don't expect to really see a big difference there because the pathogenesis in all of this is the same. I think there was a third part to that, and I forgot it.
Just if you'd expect any differentiation in the overall data set?
Mm-hmm
you know, what we saw in China versus what we.
Oh, gotcha.
... may see coming out of Sagimet.
I don't think so. You also mentioned the placebo part. That was the part I forgot. I really don't think so. I've also thought a lot about that, and I've tried to think of any reason why we would expect to see different results here than we did in the study that was performed in China, and I've never seen that in any other drug in acne. I also work a lot in rosacea, and I would say the same thing about that. I would expect that we would mirror that we would see very similar results with our population here.
Thanks. One more, if I may. Again, maybe Julie Harper. You know, if the topical data does end up being positioned, you know, towards the milder acne patient, in practice, you know, if the patient didn't respond to a topical.
Mm-hmm
Would you ever consider moving that patient to an oral of the same mechanism, or would you try something different?
That would depend on a lot of different things. Okay. We're really having to just kinda guess here. That would assume that the oral is more powerful than the topical version. We don't know that yet. Depending on the way this is formulated, which I think is kind of the way a question was asked earlier, I can think of one example where the topical actually in the skin achieves higher levels than the oral does. It all depends. We don't wanna assume that just because it's a pill, it's always more effective. It may not be. You know? It may be that the topical comes in and has quite a punch. It would just depend on that.
The other thing it depends on in dermatology is, let's say. Maybe somebody has super-duper sensitive skin and they find the topical a little irritating, and I've never seen this topical. I don't know that that would even be true about this product. It's certainly true about some of our retinoids and even about benzoyl peroxide. There's a subset of people who have super sensitive skin, they don't do as great with the topicals, so we switch them over to oral medications, and we just have them do good skincare. I don't, you know, again, I'm guessing because I haven't seen any data on the topical, but we'll wait and see on that.
Great. Thank you very much.
Mm-hmm.
Thanks for the questions, Brandon. Our next question comes from Seema Shiroor at Roth Capital Partners. Please go ahead, Seema.
Hi. Thank you for taking my question. I just want to ask if there are any specific measures or protocol learnings that you are planning to implement to your U.S. study, based on, in terms of mitigating AEs that you have seen, from the study in China.
Andreas?
Yeah. I mean, the AE profile of the study in China was overall very favorable, right? If we look at the frequency and the severity, we think it was very favorable. I think we will repeat the study in a very similar fashion to what our Chinese colleagues have done. I don't think there is a specific need to mitigate any of these of the AEs that were observed further than any further.
Yeah. Seema, maybe just to add on to that, I think that most acne patients are conditioned and certainly encouraged by their physician or to engage in skincare routines that help mitigate some of the dry skin. This would not be the first medication certainly to have any incidence of dry skin. Antibiotics, certainly retinoids also can cause dry skin and some irritation, and using moisturizers and OTC cleansers have been really effective in managing that.
In terms of eye, using eye drops, we've seen that throughout all of our studies, not just in acne, but also in MASH patients and also in oncology, that the utilization of eye drops for patients who experience any dry eye has been a really effective means to mitigate any further exposure.
Makes sense. Thank you.
Tara, I wanted to ask one question on behalf of Tom Smith from Leerink Partners. I don't think that Tom, maybe he's not with us, but he brought up a couple of good questions, Dr. Harper, primarily for you. Would you expect antibiotics or other orals to be used as a step edit in your patient population to get to deni? The next question, the follow-on question is, how would you think of using denifanstat as an episodic treatment of 12 weeks on, 12 weeks off, similar to antibiotics? Would you use it for maybe continuous therapy for up to 6 to 12 months in order to resolve?
Mm-hmm
... the condition and for chronic maintenance?
Okay. On the first one, 1,000% no. I would not think you need to use antibiotics first. In fact, that's exactly the way I would not do it. This would come in first because we are really, really aware that in dermatology, we write some of the most prescriptions across any specialty, and a lot of it is for acne and rosacea. We are trying to do better on that. Just give us something good that works well, that's an oral, that has a unique mechanism of action, and I think it's gonna slide into place before an antibiotic. I will say, just, you know, scientifically, I can't see why you couldn't use both.
If somebody really, really wanted to use the antibiotic, there's no reason why you couldn't use both, except I don't think you would need them. You could do that. I do not think people will have in their head, "Ooh, I'm gonna wait and I'm gonna suppress sebum only if this oral antibiotic that's also impacting the microbiome of the gut, only if that doesn't work." I don't think we're gonna be thinking like that. I think sebum is important early on, and if we can do it without, you know, the problem of microbiome, even better. The second part was, how long would I use it? Long term. I don't see me coming in and off of this. Again, why would I? I've got a good safety profile. This looks to be well-tolerated.
It's always easier to keep acne clear than to get it clear. Why would I let somebody start pumping out oil again, only to have to come in and, you know, get it back under control? I think it would be useful to use this as a continuous daily product.
Thank you. Tara, I believe that's all we have time for. Is that correct?
We have one question from Jasmine Fels at Barclays, if we can just sneak it in real quick.
Oh, hey, Jasmine.
Hi. This is Jasmine Fels from Ellie Merle from Barclays. Thank you for hosting this webcast. Just if we have time, I have one I'm curious for both your perspective as management and Dr. Harper's perspectives on, about how you would think about the switch or add-on market for Denny. First for Dr. Harper, if denifanstat is able to demonstrate supportive efficacy and safety as an oral, what proportion of patients who are currently treated across all the modalities do you think would be good candidates for switch or add-on? For management, how are you thinking about positioning Denny for switches and add-on treatment from other modalities versus more first-line or new starts?
I'll go first on that. First of all, the only people who wouldn't be good candidates for this are people who are on oral isotretinoin. It wouldn't make a lot of sense to overlap that. Who would I switch to this? Oral antibiotics is the easiest target, it's the most obvious target. Also potentially spironolactone, which is, there's a lot of people on spironolactone, but it has its own set of side effects. We use a lot of it, but it can cause a woman's period to be irregular. It can cause breast swelling and tenderness. It can cause people to feel lightheaded and faint because it's a diuretic and lowers blood pressure. There's, there's reasons we might switch from some of these other products that impact sebum.
answers that part of my question.
Jasmine, I'll let Rob take the second part of your question. If you could just repeat that would be great.
Yeah. Just how you're thinking about positioning, as a more treatment for switches or add-ons versus how you're trying to get to that first line new start market?
Yeah, thanks for the question, Jasmine. I think Julie Harper actually summarized it very nicely. The mechanism of action of an oral FASN is to address sebum, and I think to quote Julie Harper, every single patient has this increased elevated level of sebum in your moderate severe acne population, the modality does have applicability. You know, what we're gonna do is partner with our dermatologists to obviously educate them on the mechanism of action and put them in a position where the product is accessible for their patients so that they can prescribe it as either a first line when patients are coming in, having failed from pediatricians or other modalities.
If they are managing a patient currently today and it's not successful on either an oral antibiotic or other modalities, we'll be positioning it there as well for them. You know, I think from a corporate standpoint, we wanna make the product easy to prescribe, easy for patients to access it. From a positioning standpoint, we're gonna focus on the mechanism of action.
Thanks so much. Thanks for hosting this.
No problem.
Thanks, Jasmine. I'll turn it back to you, Dave, for quick closing remarks.
First of all, I just wanna thank everybody for taking time out of your schedules today to join us, especially Julie Harper. Thoroughly enjoyed having her walk through her thoughts and where denifanstat fits in in the grand scheme of things. I wanna thank all of you for your continued support and confidence in what we're building, and we look forward to keeping you updated on our progress as we move forward. Have a great afternoon, everybody.