Yeah.
Sorry.
All right, no problem. Thanks, everybody. Good morning. Good morning, Eduardo. Good morning, Dave. Thanks for joining us. Appreciate you joining us remotely. Obviously, lots going on, including many travel difficulties, so apologize, or while we would love to have you here with us, we're glad to actually have you remotely with us. I'm Seamus Fernandez, and welcome, everybody, to Guggenheim's second annual Healthcare Innovation Conference. The opportunity here is to really learn more about Sagimet. We have CEO Dave Happel with us, the CFO, my far right, who was already introduced, to my immediate right, Rob D'Urso, and then also Eduardo Martins with us as well. Dave, I just want to turn it straight over to you. Thanks for joining us today. Obviously, we're running a little bit behind time, but maybe you can just give us the lay of the land of Sagimet, just for starters.
Yeah, sure. Thanks, Seamus, and thank you for the invitation to present. Thrilled to be here. Sagimet, for those that are not interested, is a clinical stage biopharmaceutical company that is focused on the development of a target of a rather unique and ubiquitous enzyme in the body, and that is called fatty acid synthase, or FASN. FASN is responsible, when it becomes overactive, to be quite difficult in a number of different diseases or conditions. The conditions that we're focused on are MASH, acting in certain solid tumors that are absolutely dependent upon FASN for progression of disease.
To solve for this overactivity of FASN, we have developed a portfolio of novel FASN inhibitors, including our lead program, denifanstat, that targets fat accumulation or lipogenesis, which is a root cause that is common to all of the disease states that I mentioned that we are pursuing development. With denifanstat, it's a once-daily oral small molecule that offers a highly differentiated approach to treating these diseases.
If we look specifically at the diseases in which we have significant preclinical and clinical data, particularly in MASH and in acne, in MASH, we presented our results from our phase IIb biopsy study about a year and a half ago, in which we showed really pronounced effects of the molecule in reducing fat, inflammation, and fibrosis, particularly in fibrosis and particularly in later stage MASH patients, those that have F3 stage disease, in which we showed highly statistically significant reductions in one and two stage fibrosis, and really industry-leading data. In that data set, we also showed that patients were less than half as likely to progress into cirrhosis, which was also statistically significant and industry-leading.
We further emboldened that data set as we presented at the European Liver Meeting in May that for patients that were digitally diagnosed as having F4 stage or cirrhosis of the liver, that 11 of the 13 patients who were diagnosed had a one or two stage improvement. All of this has led us to the strong conclusion that we believe that the molecule will work very, very effectively in patients with F4 stage disease or cirrhosis. As a result of that, we have begun a phase I study in combination with resmetirom that we're about halfway through, and we expect to have results from this study in the first half of next year. It's a simple phase I study, a DDI study, PK.
We don't expect anything, any real surprises to come out of this, but it does provide us the springboard to be able to move into phase II next year in patients with cirrhosis. We are really excited about this program, and we think the combination will work, has the potential, I should say, to work very effectively. We presented data as a foundation for this study, preclinical data about a year and a half ago that showed that when looking at our combination of our FASN inhibitor with resmetirom, that while our FASN inhibitor was able to show greater improvements in fat reduction and inflammation and fibrosis, that when you combine the two molecules, that it had a magnified effect in reducing inflammation and fibrosis.
That's part of the basis for taking this program forward as a combination and pursuing a fixed dose combination, single tablet oral for these patients, which would be novel. It's really also an acknowledgment that combination therapy is likely going to be required for many of these patients with cirrhosis to be able to reach their treatment goals. I'll let Eduardo, I know you're going to ask several questions that focus on this program, so I'll let Eduardo go into greater detail. I just want to touch really briefly on the other indication that we have significant data with denifanstat, and that's in moderate to severe acne. This is a significant population that has not seen a novel mechanism of action in development or approved in the last 40 years, really since isotretinoin was approved back in the 1980s.
What our partner in China, Ascletis, has been able to show is that in two studies of phase II and phase III that were actually quite consistent with roughly 20% reductions in lesion count in these moderate to severe acne patients. In phase III, they showed roughly about an 18%-20% improvement in IGA score. This data set really is, although we have no head-to-head data, it compares very, very favorably to the options that patients have today. Again, this would be a single oral tablet that would be taken daily, and we expect it to work very, very effectively. Ascletis, our partner, is pursuing approval now. They've had pre-clearance meetings with the NMPA, the Chinese version of the regulatory agency, and they're prepared to submit their data set for approval.
We are taking our next-gen molecule, a FASN inhibitor, forward in moderate to severe acne, and we are in the middle of a phase I study with our next-gen molecule, and we expect to have results from that next year and also to start the phase II next year as well. I'll pause there and go from there.
Great. Perfect. Maybe we can just sort of drill into where denifanstat is fitting into the treatment landscape from your perspective as we go forward and help us understand a little bit better the choice of resmetirom as the partner product for denifanstat. Is that for that?
Yeah. Eduardo, do you want to go ahead and?
Sure. As Dave said, the potent antifibrotic effect that we have observed in the phase IIb, which is, of course, what is to be expected from a molecule that hits all three cell types in MASH, that effect in fibrosis leads us to pursue the most advanced patients, the ones in most need. Now, why resmetirom? It's actually a logical choice. The mechanism of action of both drugs, they are complementary. They are not the same. We impact, if we look just at the fat aspect of the equation, we, as in denifanstat, a potent defatting agent, works on the production of fat, so sugars going into fat, whereas resmetirom works on the beta oxidation, or as Dave puts always adequately, burning those fats. You make less, and whatever is there is burned.
Importantly, when you use drugs that induce lipolysis, in other words, burn the fatty acids, you actually upregulate FASN. FASN effect goes up when you are trying to burn lipids. This is a problem because although you are trying to eliminate them on one side, you are actually inducing a higher production. Denifanstat comes in and again brings the level of fat activity down to what is normal, and therefore you complement the mechanisms. Now, the other important aspect is how the drugs are metabolized, so how they are eliminated by the body. The metabolic pathways to get "rid" of the drugs, that is what the body does with any drug, be it aspirin, you name it, any drug, it is different between denifanstat and resmetirom, two different enzymes.
We expect that there should be no interaction between the drugs when it comes to the pharmacokinetic aspect, and we expect to see in people what we saw in the animals.
Great. Can you maybe just remind us the safety and tolerability profile that you've seen both in the FASCINATE study, but also maybe more broadly as denifanstat was explored in other settings like acne, what you've seen in other settings as well, and if there's any sort of validation or perhaps even a better safety profile that emerged?
Sure. Importantly, denifanstat has up to now been evaluated in over 1,000 patients across multiple disease states, as you said, with doses actually going up to 11 times the MASH dose when we use it for oncology. The drug has been well tolerated. Of course, let's remember it's an oral drug once daily, ideal profile for MASH. Now, when we look at the phase II, the FASCINATE-2 trial, importantly, we did not see any daily drug-induced liver injury with denifanstat, which is again to be expected, no cardiovascular signal, so no issues there, no bone signal. Let's remember when bone goes away, it doesn't come back as the normal bone that should have been there in the first place, no muscle wasting whatsoever, and gastrointestinal effects were comparable to placebo.
Now, aside from the FASCINATE-2, we had seen only two cases of hair thinning with 50 milligrams of denifanstat out of 340 patients with this dose, again in two different indications. You mentioned other indications, let me talk acne. In the phase III study that Dave mentioned before, there were no cases of hair thinning whatsoever in the denifanstat arm. Actually, there was one case in the placebo arm. If we look specifically again at the FASCINATE-2, only 7% of patients discontinued the study with treatment-related hair thinning. Let's recall treatment-related hair thinning is seen 7%-10% of patients on GLP-1. We can just look at the label of tirzepatide, for example. Now, back to denifanstat, importantly, when we paused the drug for a little bit, the effect was reversed. It was also reversed with down titration, and most of the events were grade 1.
Why was the FASCINATE-2 different? There may have been different factors that were not there in other studies. One, COVID. We ran the study during the Omicron wave, and then that subsequent wave, I call it the son of Omicron. We all remember that, not fondly. We had actually an instance of accidental overdose, bringing the dose up to cancer levels of patients. One thing that we did not anticipate before the study, just because it was not there, Paxlovid. Ritonavir in Paxlovid increases the concentration of multiple drugs. That is why it is in it in the first place. For now, studies from now on, any patient that is going to receive Paxlovid just stops denifanstat for five to seven days while Pax is being given, and we should not see a problem.
There were other factors, levothyroxine, GLP-1, and actually MASH in and of itself can lead to that. This is consistent with the two cases that we observed on placebo, as well as the cases that we observed during screening. We discussed this with dermatology KOL advisors, and importantly, we know what to do for the phase III. That is a number of different things, vitamin supplementation, especially biotins, scalp oils, and dose reduction if needed. In a nutshell, this is the safety profile of denifanstat, very favorable, consistent with the drug that can be, if approved, given to patients with MASH for a long period of time. Of course, we need to complete our phase IIIs and all that like any drug.
Great. If you don't mind, I'd like to just, because of the limited time, shift gears a little bit to the acne program. Rob, this might be an opportunity just to jump in on acne, your thoughts on the data that were in the Ascletis trial, the phase III data, and then how the team at Sagimet are advancing into acne at this point.
Yeah, I can give just a quick overview of the acne. Taking a step back, acne has four main steps in pathogenesis: increased level of sebum, hyperkeratinization, an increased level of P. acnes, or the bacteria that eat sebum, and ultimately inflammation. In our early phase I studies, what we found is that an oral FASN inhibitor actually has a direct impact on de novo lipogenesis, and it has the ability to reduce the level of sebum available on a patient's face and also has anti-inflammatory properties. Oral FASN can actually have two effects on the pathogenesis of acne. That's on the mechanism side. Our partner in China has successfully, and they've announced successful phase II and phase III studies, 12-week studies in moderate to severe acne patients, which is what the US FDA would expect.
Both studies came back that all efficacy endpoints were statistically significant, so very positive data, which we like to see. Also from a safety standpoint, the product was very well tolerated and no adverse events popped up that we were not expecting. From an efficacy and safety standpoint, oral FASN has demonstrated in moderate to severe acne that it is compelling and is a good value prop. Because we have a library of oral FASN molecules, what we have chosen to do in the US is we have taken a sister molecule, TVB-3567, and moved that product into phase I. In June, we announced that we were taking that product into phase I. Our rationale for that is very simple.
Denifanstat has a great IP portfolio for MASH and for those indications, and TVB-3567 has the ability to have a very strong IP protection and portfolio for the acne indication. From a commercial standpoint, we think it's good to have both molecules in development in the U.S., and that's how we're progressing. Ultimately, that phase I study has kicked off, and we've communicated that we'd like to initiate a phase II acne program sometime in 2026 once we have the data and also have the ability to engage with some regulatory bodies.
Got it. Dave, maybe back to you before we're out of time. I wanted to just ask you to cover the plan of advancing acne and advancing your programs in MASH simultaneously, as well as just sort of the catalysts as you see them advancing over the next, let's call it 12 to 18 months or so.
Yeah, sure. First of all, the next milestones for MASH are completion, and we're highly focused on completing the phase I PK study with REZ. We would kick off the phase II biopsy study next year. That's the plan. We have enough cash to be able to move that program forward for a couple of years. Also, to complete the phase I with our next-gen molecule for acne sometime, hopefully in the first half of next year, and then also begin the phase II program for acne at the next stage and next year, second half.
Great. Maybe just to provide a little bit of a relative context for the size of each of these markets from your perspective, how do you see the size of the MASH market evolving? We've seen the good, robust launch of resmetirom so far. We'll get more context from Novo in terms of their launch, more so in 2026. How are you thinking about just sort of the absolute size of the MASH market? On a comparable basis, the acne market sort of on a go-forward basis, how do you see your own molecule playing into that opportunity and how big of an opportunity do you see that in terms of the total addressable market?
Yeah, I think it's really interesting, right? The MASH market has exploded, and certainly Madrigal has done a terrific job in establishing the potential for treating patients who are in need. The market with Novo and potentially Eli Lilly and other players coming in with high resources, the market is expected to triple, if not quadruple in size over the next decade or two, and really approach a cardiometabolic blockbuster-type market that includes treatment of type 2 diabetes, dyslipidemia, hypertension, and MASH should be included in that as well as a cardiometabolic disease. I think the anticipation from everyone is that it's going to be a high-need, high-treatment area that's going to require multiple medications and multiple mechanisms to be able to treat these patients. We're thrilled, frankly, to have the only fat inhibitor in the world of fat burners, right?
Everything outside of Denifanstat at this stage of development is really a fat-burning mechanism of some type, a fat oxidizer, fat mobilizer, but they really rely on burning fat in order to have downstream improvements in inflammation and fibrosis. As we've seen, there have been varying degrees of success with that approach, whereas our molecule that targets the three drivers of the disease independently and simultaneously can have a pretty impactful result. Not only do we feel that Denifanstat can play very well as a monotherapy, even for cirrhotic patients at the level of an FGF molecule or better, combining it with, as Eduardo so eloquently described, combining it with a fat oxidizer like THR should have a really magnified effect. We are really excited about the MASH program and how we look in terms of where it fits in the treatment algorithm.
Again, as the only fat inhibitor, it makes it a highly, highly attractive program, especially with the side effect profile being so relatively clean. With acne, the acne market in the United States is significant. 50 million patients have acne today. About 10% or 20% of those, I'm sorry, have moderate to severe acne, but only about half of those are seeking treatment. And it's largely because there isn't really an effective, broad systemic treatment for those patients that they can use. So many patients rely on home remedies or OTC products, and they get very dissatisfied and therefore don't really get into the dermatologist's office like they should.
We fully anticipate that the launch of our molecule in this space is going to be very, very similar to what we have observed with the atopic dermatitis markets and the psoriasis markets that were very, very similar to the acne market before the large molecules really launched and invaded those spaces with the JAK inhibitors and the IL-413s in atopic derm and the TNFs and IL-17, IL-20s in psoriasis. They completely changed the value proposition for those markets, and we fully expect the same thing to happen in acne.
Great. Thanks everybody for joining us. Unfortunately, we are up on time. It's an abbreviated opportunity, and I apologize for those who participated in the webcast for the late start. Can't control the government shutdown, but hopefully we're moving past that. Again, Dave, Eduardo, thanks so much for joining us and to the team here in Boston. Hopefully, we'll see you soon in the Boston area as flights take off again.
Thanks.
Thanks again.
Thank you very much.