Thanks for joining us here at Guggenheim's Emerging Outlook Conference. This is our biotech summit for 2026. We've hosted this event annually for several years now, but really excited to have Sagimet join us here today. I'm Seamus Fernandez, one of the biopharma analysts here at Guggenheim, and I'm really pleased to have Sagimet with us. We have Dave Happel immediately to my left, Eduardo Martins, the Chief Medical Officer, is to Dave, the CEO's left, and then Rob D'Urso, who's SVP of new products and is also kind of uniquely focused on the acne market. So, you know, thanks again for joining us. You know, maybe just to you know, kick us off, Dave, for those less familiar with Sagimet, maybe just kinda give a high-level view of the company, you know, both from a MASH and acne perspective.
Yeah, happy to, and thank you for the invite to come out and speak. So Sagimet Biosciences is a clinical-stage biopharmaceutical company, and our approach really begins with understanding how overactivity or overexpression of fatty acid synthase or FASN plays such a critical role in the development of a number of underserved conditions and diseases, specifically our focus in MASH, acne, and in certain solid tumors. To solve for this overactivity of FASN, we have developed a portfolio of novel FASN inhibitors led by our lead program, Denifanstat, that really target an underlying cause that is common to all of these diseases, and that is fat accumulation or de novo lipogenesis. Our program is essentially the only fat inhibitor in any of the spaces that we're pursuing development, and it makes it rather unique.
If we talk about just MASH for a moment, we have a very strong body of data that shows through preclinical and clinical studies essentially the same thing, that Denifanstat inhibits and blocks fat, inflammation, and fibrosis directly and independently. And again, that makes it rather unique in the space. Everything else in MASH is really a fat burner of some type of mechanism, a fat oxidizer like an FGF or a THR or a fat mobilizer like a GLP. Those programs really rely on burning fat and hoping that fat burning translates into reductions in inflammation and fibrosis. And we've seen varying degrees of success in how well that works.
But our program specifically targets inflammatory cells within the liver as well as fibrotic cells, and that has really catapulted the program forward and translated into the type of results that some of you may be familiar with. In a phase II study that we announced in January of 2024, we showed that in the F2/F3 population within MASH that we had a really pronounced reduction in fibrosis. And that further played out in the F3 population specifically where we see a really unmatched reduction in fibrosis. We carried that a bit further, and we looked at a subpopulation within our phase II study that were digitally diagnosed as F4 patients or those that have cirrhosis or beginning cirrhosis.
We showed that, of the 13 patients in that study that were digitally diagnosed as F4s, 11 of the 13 had a one or two-stage improvement, which is really pretty unparalleled. It's great. It gives us a great deal of confidence as we move the program forward. We announced last May that we were initiating a study or our plans to initiate studies, specifically focused on F4s and cirrhotics, in combination with resmetirom. We have since completed a phase I study that we announced just before the holidays last year, showing that there was no safety signal. The drugs are incredibly compatible as we anticipated and really supports moving the program now into phase II. That's where we're currently at. We will start the phase II program in MASH later this year and really looking forward to getting that rolling.
Shifting over to acne just briefly, I know we're gonna talk about that in a bit more detail here shortly. But our partner in China, Ascletis, completed a phase II and a phase III study in moderate to severe acne patients using Denifanstat at the same dose as we're using in MASH, 50 mg orally once daily, and showed incredibly consistent results in both studies, roughly 20% reductions in lesion count, total inflammatory non-inflammatory lesions, and also of roughly about a 20% improvement in IGA. Based on the strength of their phase III data, they submitted an NDA to the NMPA, the Chinese FDA, and that NDA was accepted by the NMPA. So they are waiting for approval at this stage, which we anticipate or I should say they anticipate later this year, maybe the beginning of next year at the latest.
They just announced data from the extension part of their phase III study, which showed that from a safety perspective, Denifanstat was incredibly well tolerated through the course of a total of 52 weeks for most of the patients. And that was really well received. In addition, they also indicated and hinted at data that's going to be coming forth in a publication and presentation that patients continued to respond in terms of efficacy, achieving IGA scores of 0 or 1 and/or improvements of 1 or 2 rating points. So it works very effectively in this population. From our perspective, we're taking our next-gen molecule forward, that is a FASN inhibitor. It's a slightly more potent version of Denifanstat, and we're in phase I right now.
We're well on track to start the phase two in the second half of this year as we've communicated publicly. So maybe with that, I'll direct back over to you.
Great. Yeah. So, just because I think investors are generally less familiar with the acne portion of the story, and it's definitely of growing interest in an area that we have a lot of expertise in, wanted to just kinda drill into, you know, your views not just around the efficacy data for Denifanstat, but the similarities in comparisons to the sister compound, you know, that we can start to maybe hopefully draw a little bit of a straight line from Denifanstat over to the next compound.
Sure. Rob, you wanna tackle that?
Yeah. Thanks. Thanks for the question. So just taking a step back. So our partner, Ascletis, in China conducted a phase III acne program. Acne programs are 12 weeks. The endpoints are typically IGA success, which is our acne scoring score, total lesion count, inflammatory lesion, and non-inflammatory lesion. So in this phase III study that was 12 weeks long, 480 patients, all the primary and secondary endpoints met clinically significant efficacy. And so that was good. It was positive. It demonstrated that the 50 mg Denifanstat is an effective treatment for moderate to severe acne. The secondary endpoints were around safety, and the product demonstrated it was well tolerated. No significant adverse events came up. So very positive. So it's safe and effective, you know, well-tolerated product in phase III.
They also previously had completed a phase II dose ranging with the 25, 50, and 75 mg. When we and why that's important is both of the studies had very similar results with the 50 mg. So their repeated efficacy endpoints came out very similar. So I think when we look at, you know, the Chinese population, the Chinese data, that is a reproducible efficacy endpoint, which is very positive. And our KOLs in the U.S. now are looking at that data as reliable and something that is compelling for them. In addition, they've started as or just completed the open-label study that Dave was just mentioning. That is a follow-on study that is a 40-week safety study, open-label. So the patients that completed the 12-week rolled into a 40-week extension.
So those patients either were dosed for 40 weeks or 52 weeks with Denifanstat, and the primary endpoints were safety. In that safety study, just two treatment-emergent adverse events came up over 5%, which were dry skin and dry eyes. Both of them are easily managed with moisturizers and some eye drops, and it's on-label or on-mechanism. So nothing that's surprising to us, and there were no treatment-emergent adverse events that were moderate to severe. One thing to note, I think it just because of the history of Denifanstat, we did have only one patient of the 360 patients that were treated with Denifanstat that had some hair thinning, and that hair thinning self-resolved. The patient stayed on medicine, and it resolved within, I believe, eight weeks from treatment. So, just as a thing to note in that.
So that's kinda where the, the product's efficacy and, and safety have been with the Chinese population. When we've looked at it with our KOLs, they've really looked at how does this study how does this data, fit into the market in the U.S.? And so, you know, I think what we've gotten feedback is that obviously, you there's been no head-to-head studies, but when they're looking at it with their current standard of care products, the efficacy is a compelling efficacy story. And because of the well-tolerated safety profile, they're, they're viewing this as a potential significant therapeutic option for them for moderate to severe acne patients in the U.S.
Right.
And maybe you can kinda put that in context of some of the changes that are occurring in the acne market today.
You know, so one of the things in our work that is becoming increasingly clear is the ADA guidelines or sorry, AAD guidelines changed, and are really directionally leaning away from utilization of antibiotics. You know, we've even seen a precipitous fall in antibiotic prescriptions in the wake of that. You know, what kind of a unmet need is now emerging versus comparisons to other product launches that we've seen occur in the space where with lots of old mechanisms?
Yeah. It's been an exciting time in acne in the last little bit with this antibiotic. And actually, the FDA this week came out with some guideline improvements with iPLEDGE as well. But let me take a step back. So acne in the U.S. has about 50 million people that are affected with acne, about roughly 85% of adolescents. At some point in all of our lives, we all had acne. So it's a very common condition. About 5 million people are currently seeking therapy for acne in the U.S., largely treated by dermatologists. When you think about an acne patient, you can kinda bundle them into three groups: mild, moderate, severe, and cystic. So the mild patient is that one zit, two zits. Those people are largely managing their products, you know, their condition through CVS, home care, things like that Proactiv.
Then on the other side, the cystic patient, they're being managed by dermatologists with isotretinoin or Accutane. If that's a brand name that's commonly associated with it, the product is gold standard. It's been around for about 40 years, but it has a significant challenge with safety. So it's managed through this program called the iPLEDGE REMS program that requires patients, doctors, pharmacists, distributors all to be registered. There's significant birth pregnancy controls in there, so that's really geared towards cystic acne patients. Our therapeutic area is moderate to severe. So this is of the 5 million patients seeking therapy, about 70% of them are going to dermatologists with moderate to severe patients. The dermatologists have a choice, and they typically are using a combination of topicals and orals to manage these patients concomitantly.
Right now in the market, it's a mix of branded, generics, generics, but it's largely a generic market. As you've mentioned about this oral antibiotic, the main oral products that are used are oral antibiotics, so minocycline and doxycycline. Their efficacy is a little bit, you could debate it if it's great or not. But the challenge is that after you've had a patient on it for a long time, there's a potential that they have antibiotic resistance. And so the CDC and the AAD have been pushing for a long time to reduce their reliance on oral antibiotics for acne therapies. Dermatologists are also using oral spironolactone off-label for female acne.
So I think the opportunity here and our KOLs have told us this is that with oral Denifanstat or an oral FASN inhibitor, the doctors will have another oral product with a novel mechanism of action because over the last 42 years, really, there's been very limited novel mechanisms coming to market in acne. And so an oral FASN inhibitor represents a novel mechanism that addresses sebum regulation, which every single acne patient has an elevated level of sebum, and it has a well-tolerated demonstrated safety effect over 52 weeks now.
Yeah. So let's talk a little bit about the, you know, the sister compound. So you're advancing TVB-3567. You know, and again, it is structurally distinct from Denifanstat. You know, why not move Denifanstat? Maybe help us understand that. But also, you know, as we think about what needs to be proved with this compound, what do you feel needs to be proved with the compound? And then, you know, when's our opportunity to really sort of learn that?
Yeah. So from a commercial standpoint, it's, you know, adds a little bit of complexity if you had Denifanstat for acne in the U.S. and Denifanstat for MASH in a fixed-dose combination. There's pricing challenges. There's, you know, just substitution issues. So from a commercial standpoint, it'll be a little bit easier to have two molecules on the market.
Yeah.
And the IP landscape or portfolios of both of the molecules are somewhat optimized for each one: Denifanstat for MASH and 3567 for acne. So there's a commercial rationale for it. Clinically and scientifically, basically, Sagimet developed a library, and we own a library of FASN inhibitors. And so in that development pathway, we've done DMPK, CMC, TOX work on all these molecules. And these two molecules have basically led to the lead molecules of those. And so our choice to take 3567 forward instead of Denifanstat is more as a commercial decision. However, scientifically and clinically, that'll be proven out, you know, to date that they work very well. The PK and PD profiles look very similar. We've initiated a phase I program, as Dave was saying, with 3567.
that is ongoing right now, and that will give us really the confirmation that TVB-3567 and Denifanstat behave the same way in human subjects.
Okay. Great. And maybe just remind us, what are the kinda points of focus? Obviously, any phase I study, the focus is gonna be on safety, but what can we learn from the phase I study as it relates to potential kinda clinical activity, clinical endpoints?
Yeah. So standard phase I, you have your single and multiple dose ascending, you know, groups. So the goal of our phase I program, like anyone, will find a therapeutic dose or doses that will get us into a phase II, dose ranging clinical study. So that is the primary goal of the phase I study. Eduardo can elaborate that if you have additional questions. I think what's unique about our program is that in addition to the standard SAD/MAD studies, we have a part D, which is a 28-day MAD cohort that will be in moderate to severe acne patients. And in there, we have the opportunity by using a sebum meter and a sebum tape, very dermatology test, to study the composition of sebum before and after 28 days with 3567 and also the quantity of sebum.
Why that's important is sebum is the key driver in what we affect in acne patients. So if we can show a reduction and a change in the sebum, we feel really confident that the product's gonna work. Now, obviously, that is not a go-no-go decision for us. We're gonna find a therapeutic dose in the phase one and move into phase II, you know, a dose ranging study in phase two. This 28-day cohort just gives us additional comfort, additional knowledge, additional, you know, understanding of the mechanism and our direct effect on sebum.
Okay. Great. And I know that I think the bar is incredibly low on the sebum measurement side of things just because it hasn't necessarily been utilized that.
There's a lot of variation too. So I think it's a good biomarker, a good directional thing, but it's not, if you reduce by 20%, you're gonna have efficacy at 20%. It's not as black and white as that. I wish it were, but it's not.
Right. So I mean, the punchline here is that, you know, very similar molecule to what Denifanstat, to Denifanstat. Denifanstat has demonstrated a very clear, clinical benefit in, a relevant moderate to severe patient population in China. It's been replicated in China, two times with Denifanstat. And the reality is, is that the market is being left with an entire category that, physicians are being encouraged to no longer use.
Yeah. I mean, Seamus, I've been in dermatology for 25 years. I've watched multiple acne programs. Having engaged with these dermatologists that are KOLs in acne for that for that long, having the opportunity to show them this data and specifically this mechanism, it's been amazing to hear the feedback from these doctors of their excitement, their commitment to the program, and their understanding of how the mechanism relates directly to acne and how in China, that has already translated to clinical outcomes and how that clinical outcome translates to the U.S. population. I think it's a very easy story, you know, from our side of communicating. And now it's just, you know, clinical operations, clinical execution to get it to the next steps as we go.
Right. The breadcrumbs are there, so.
Yeah. Exactly.
Yeah. I think it's really neat, right? I mean, you know, in the extension study, I know I hinted at continuing efficacy. And you think, well, if you're on a medication for a longer period of time in acne, that shouldn't most patients continue to respond. But in reality, that's not the case. After about 12, 13 weeks, most patients start to plateau.
Right.
That's not what happened here. They've continued to have more and more lesion reduction and an improvement in IGA. It makes it really exciting.
Yeah.
It's gonna be very well received once we get to.
As a once-daily pill, the compliance is easy. It's a twice-daily topical product.
Yeah. And the AE profile there, you know, I know there was, you know, one I think one case of hair thinning, but then it resolved. So it, it seems like that's not that meaningful of a, an AE at this point.
No.
We've had in both acne studies, we've had 2 cases out of 284 on Deni, 1 case on placebo.
Yeah.
Incidentally, the one case on placebo, it took eight months for it to resolve. So there's a certain level of randomness here, it seems. But, you know, we've only seen hair thinning in one of our four major studies. And it happened to be our II-B MASH study, which was conducted during COVID, which I'm sure Eduardo can comment on. But, you know, and, and in fact, COVID was the largest AE in as a matter of fact in that study, not, not hair or skin. And, and so it just, it seems to be the anomaly right now.
Great. So, you know, wow, we really don't have a lot of time. And there's a whole other side of the company to talk about.
Sorry. I got excited.
That's okay. But I think it's worthwhile, right? It's, you know, where your next catalyst is.
Yeah.
It's kinda the next key proof points for the company and drawing this mechanism into a new space. Now, you know, I know it may not make sense to investors or, or some folks that, you know, like, okay, well, you have a dermatology group and an endocrine endocrine, group or a hepatology group that you would be targeting here. But again, I think the message is, is it's on mechanism.
For sure.
Maybe bring us back to the sort of MASH opportunity, and, you know, what you are hoping to prove with your F4 data, as you move forward.
Sure. Just one quick comment on mechanism. Spironolactone that is used for acne is a diuretic that we use for patients with advanced liver disease and ascites. So, same rationale. Now, for the F4 trial, our goal is to regress fibrosis. So to make those patients, turn those patients that are F4, in other words, cirrhotics, into F3s or F2s. So changing that, sorry, let me put it the other way around. When you go from F2 or 3, but in particular from 3 to cirrhosis, things change dramatically. It's not just a simple stage. There is a significant impact on liver function, blood flow, and all that.
Now, what we want to show, we actually have seen evidence of that, excuse me, in a subset of patients in our phase IIb trial, the FASCINATE-2 trial, in which there were 11 patients that by AI digital pathology were seen as F4 or as the platform labeled them qF4. And of those 11 patients.
13, 11.
Sorry. Thank you. 11 are the responders.
Yes.
MASH is not the specialty of the house. Out of those 11, 13 regressed to F3 or F2. So, and this was with Deni monotherapy. With our planned combination with Deni and resmetirom, the goal is to utilize the two non-overlapping mechanisms of action to increase efficacy. And Deni being, as Dave said, direct and indirect inhibitor of fat inflammation and fibrosis, and resmetirom as being a potent defatting agent. Although defatting is not enough in F4, it does play a role. So, in very broad terms, this is where we plan to be.
This really builds off of the preclinical data that we had with Deni in combination with resmetirom. We presented that at ESLD about a year and a half ago, where it showed that Deni was better at reducing fat inflammation and fibrosis, not surprisingly. But when you add the two together, there is an additive effect in inflammation and fibrosis reduction. So, combining the two mechanisms, fat inhibitor, fat burner, should be very responsive for patients.
Great. And, you know, Dave, maybe I know we have limited time to go through more of the program here, but, you know, just in terms of the potential next steps, phase II design, how you're gonna approach the phase II, maybe you can just also lay out the timelines for, you know, the overall program, but also if there's a potential for interim looks at data?
Yeah. So we expect to start the phase II study in MASH later this year. We're looking at, we're gonna propose that the FDA accept a non-invasive measurement for treatment response at 52 weeks. We'll see how they go about that. They've certainly aligned on that in the F2, F3 population. It will be prepared to take it to 96 with biopsy if we need to. And we'll start that study, as I said, by the end of this year. It'll take, you know, roughly 12-18 months to enroll this study, as a standard for most of the patients and studies in F4s. And so we should see a 26-week biomarker readout in the first part of 2028, first half of 2028, and then a 52-week interim readout in the second half of 2028.
Okay. Great. Maybe just to wrap us up, cash on hand, and, you know, how far out does that take us?
Yeah. So we reported in our Q3 earnings that we had roughly $125 million. That gives us about 2 years of cash to roughly the end of 2027. That allows us to get a phase II efficacy readout, proof of concept readout in acne, with the next-gen molecule by the end of next year. And it should get us to pretty much near completion of enrollment of the MASH program.
Great. Well, that's thanks so much for taking the time. Thanks for joining us here. We're looking forward to all the progress in the next 18 months.
Likewise.
for the company.
Thank you.