Great. Good morning, everyone. Thanks for joining us here at day three of the Leerink Partners Global Biopharma Conference. My name's Tom Smith, one of the senior biotech analysts here at Leerink, and it's my pleasure to introduce our next company, Sagimet, and their management team, led by CEO Dave Happel, Executive Board Chair George Kemble, and CMO Eduardo Martins. Gentlemen, thanks for joining us.
Thank you.
Looking forward to the presentation. Dave, why don't you take it away?
Very good. Thanks, Tom. Good morning. Thanks for taking a few moments from your day to listen to us. Greatly appreciate it. Really fortunate to be joined by my colleagues here and wanna thank Leerink for the opportunity to share with you our progress. Just really quickly, I'll go ahead and skip through that. So our approach really begins with understanding how overactivity of fatty acid synthase, or FASN, plays such a critical role in the development of a number of underserved diseases, and our primary focus being in NASH or MASH. But also we have really provocative data in acne and in certain solid tumors that are FASN-dependent, in order for disease progression to occur.
We solve for this overactivity of FASN, with the development of unique, first-in-class, FASN inhibitors led by our lead program, denifanstat, that really seek to target an underlying cause or a primary culprit that is common to all of these conditions, and that primary culprit is fat accumulation or lipogenesis. We have, as I mentioned, some really interesting data in, in oncology and acne, but we won't get to that today. We're gonna focus our attention on, on our key driver, of, valuation for the company, and that's our, development program in NASH where we've accumulated the greatest body of, of work.
I will say that denifanstat has demonstrated through all of the preclinical and clinical studies an overwhelming replication of results from biomarker improvement now all the way through biopsy improvement from our most recently released 52-week biopsy data that we shared in late January. The molecule is incredibly unique. It's arguably the only one that targets the three key drivers of NASH, being fat, inflammation, and fibrosis, and doing so directly and in parallel. The drug has been developed and exposed to over 700 patients at this stage. It's been proven to be very well-tolerated and generally safe. Therefore, we see no limitations to the treatment populations that we're pursuing development. With an eye towards commercialization and the payer landscape, we also have the unique ability to correlate potential on-target response with a predictive biomarker, a very nasty triglyceride called tripalmitin.
And we've been able to demonstrate historically that we reduce tripalmitin consistently, which correlates with biomarker improvement and now treatment response. So, as I indicated to our data in acne, I would encourage you all to, as I said, we're not gonna spend much time on it today, but I would encourage you to take a look at some results that were posted last May, from our Chinese partner, Ascletis, who ran a phase II study in 180 patients in moderate to severe acne and showed a highly statistically significant reduction in lesion count across all three doses. And with that data, they began a phase III study this at the end of last year, and they expect to see top-line results from that study at the end of this year and the beginning of 2025. Our patent estate is quite strong.
We have two primary patents that we're pursuing, one composition of matter, that expires and all of them are issued globally. Our composition of matter expires in 2032. We'll get five years of PTE on top of that. Our molecule's been in development for over 10 years, so it's a pretty straightforward calculation. But we also have a method-of-use patent that is quite interesting. Normally, not something that I would pin a lot of hopes on, but our IP counsel, Goodwin, is strongly and adamantly recommending that we use that patent to plug our PTE on top of because there has been no precedent for any FASN inhibitor in the development of NASH. So we do expect that that actually could hold, and that patent, plus the PTE would run until 2042. So, I think you all are probably familiar with the landscape in NASH. A lot of patients.
It's gonna grow exponentially over the next couple of decades. We see denifanstat as an oral small molecule, once daily, fitting very nicely into the F2 to F4 population. Once we have a chance to share all of the data at EASL this year, in June, I think you'll see that the likelihood of the impact of this drug in F4s is likely to be quite pronounced. And so we're highly confident that, as we work through our phase III program and then onto commercialization, that this drug will be used extensively in that population. So with that, I think I'll turn it over to Eduardo Martins.
Thank you. Thank you, Dave. Good morning. So over the next few slides, I wanna share with you a little bit more on the mechanism, but most importantly, the results from the recently completed and highly successful phase IIb study, FASCINATE-2. So, as Dave alluded to the mechanism of action, so let's just dive in, in a little bit more detail. So this is our NASH cycle, and by the way, we are using the word NASH as and not MASH just because the trial started when it was still NASH. So in the center of this circle, we have fatty acid synthase or FASN, which is a key enzyme to metabolize the high inflow of sugars that come from the diet through a process called de novo lipogenesis or DNL. FASN is a key enzyme in that process and is the target for denifanstat.
As sugars come in through DNL, fat is generated, the highly lipotoxic, Triglyceride palmitate that, Dave mentioned, that accumulates in the hepatocytes, steatosis. Hepatocytes with that lipotoxicity in them, they start to balloon up and eventually they die. And that apoptosis, all those debris activate inflammatory cells, and that activation is also dependent on FASN and DNL, and that's where our mechanism starts to differentiate from everybody else. The continuous activation of inflammatory cells, release of inflammatory mediators, and the again, the debris from cells that die from that will lead to activation of stellate cells that try to repair the damage by depositing fibrosis, so scar tissue. This process goes on and on and on, and if left unchecked, it will progress to cirrhosis and eventually HCC. So denifanstat, as Dave mentioned, targets all the three key drivers.
It targets steatosis by impacting the de novo lipogenesis, downregulating the mechanism, all the downstream benefits of steatosis, but adding to that a reduction of inflammation and adding to that a reduction in fibrosis. So all three key drivers, not a fat burner, not an anti-inflammatory, not a fibrosis drug. It's everything. So very briefly, our phase IIa, I just wanna share with you, the safety data. As Dave alluded to, the drug is safe, well-tolerated. We did not see any serious AEs in the phase IIa, and the majority of AEs were grade ones, no drug-related grade three or higher. The FASCINATE-1 data were published in Gastroenterology a few years ago. So now let's go to the recently completed FASCINATE-2, the phase IIb trial. This is the schema of the study. It's a very simple trial.
Biopsy in the beginning, 52 weeks of treatment randomized to denifanstat 50 mg oral once daily or placebo. At the end of the 52 weeks, another biopsy, primary endpoints and key secondary endpoints, histology. We enrolled 168 patients, and this was a global study. All patients were F2 and F3. Excuse me. So moderate to advanced fibrosis. We did not enroll a single F1 patient by design. We wanted to go straight to the phase III population. Primary endpoints, as you see, those were agreed upon, actually suggested by FDA, NAS greater or equal to two points improvement and no worsening of fibrosis. And I think you're going to recognize the other one, which was one of the Madrigal endpoints in their successful phase III, NASH resolution plus NAS improvement of two or greater without worsening of fibrosis.
Now, when we designed the study, of course, we didn't know the results. We assessed all existing data, not only from NASH but from other chronic liver diseases. We know that to power a study for fibrosis, you need as a primary endpoint, you need hundreds and hundreds and hundreds of patients. Nevertheless, we made improvement in fibrosis without worsening of NASH one of the key secondary endpoints that have in the study. To complement the data from our central reader, we also did AI digital pathology. So the fibrosis findings were seen by the human but also validated by the AI pathology. Looking in at a qualitative way, categorical way from the human in a continuous way with the AI pathology. We had a number of other things and, of course, safety. The demographics, I'm not going to read through this.
This is your typical F2, F3 population. Middle age, we had mostly women, white. This is what you see in the studies, in particular, U.S, predominant studies. High BMI, over 60% diabetics, highly active disease, high NAS, elevated enzymes, and about 10%-13% of patients were on a GLP-1 stable when they were at baseline. And finally, we had two non-invasive markers of fibrosis, ELF, showing that the fibrosis was really there, visible in the biopsy and with the soluble markers as well. We continue to try to further the field in non-biopsy ways to diagnose, monitor treatment, and ultimately looking at success of treatment. Patients were not surprisingly on statins, hence the normal or even actually below the limit LDLs. So now let's go to the results.
Primary endpoints, NAS worsening, the NAS improvement without fibrosis on the left, the NASH resolution plus NAS without worsening of fibrosis on the right. As you can see, the drug, denifanstat, was highly statistically superior to placebo with very high numbers, 52% versus 20%, a 32% delta, and 36% versus 13%. So highly significant primary endpoints. In addition, these results were also positive and in an intent-to-treat analysis with a two-sided p-value, and you're going to be seeing more data as the year goes by, in particular at the big conference. So no matter how we looked at the data, the data were highly statistically significant and positive. Now, let's go to the key to the crux of the disease. Actually, to the crux of any chronic liver disease, fibrosis determines prognosis. Our endpoint improvement in fibrosis without worsening of NASH was highly statistically significant.
That goes back to what I mentioned in the beginning, the hundreds of patients needed to prove that. Well, as it happens with the effect of the drug, we didn't need hundreds of patients. We had 41% of the patients on denifanstat having a response versus just 18% on placebo. This is industry-leading for trials of the same duration. Like the primary endpoints, these secondaries were also positive, in the ITT analysis, highly statistically significant on a two-sided p-value. Now, on the right, NASH resolution without worsening of fibrosis, and again, that pattern repeats itself, a highly statistically significant response when the results from denifanstat are compared to placebo. Importantly, those two endpoints are verbatim the ones in the FDA draft guidance from 2018 for registration. So past all endpoints, highly stat sig.
Now, I mentioned AI pathology, and this is the HistoIndex methodology, second generation harmonic, and the output is called qFibrosis. And this continuous variable analyzed by the model also showed the significant improvement in fibrosis, thus confirming the findings of the human pathologist. So human and machine both pointing in the same direction, both positive, both highly statistically significant. Now, let's look at GLP-1. As I said, we had about 10%-13% of patients with a stable GLP-1 at baseline. One comment here, we anticipate that in phase III, this number will jump quite considerably to 50%, perhaps 50%+ regardless. This is not a problem. Actually, if anything, we increase the effect of GLP-1, be it on the fibrosis side with NASH resolution, be it the other way around, NASH resolution without worsening of fibrosis, zero with placebo.
So our data are consistent with what has been seen with GLP-1 analogs, but the GLP-1 effect is magnified by denifanstat. So we are also well-positioned to the reality of treatment of the patients in the future. So briefly, FAST score and LFA, non-invasive markers of fibrosis. FAST score is FibroScan-based, in my opinion, the most important of them, highly statistically significant, and it gets better as time goes by, really showing the proper directionality, which I believe with things going beyond one year, this would get better and better. Of course, we don't biopsy the patients all the time, but if we did, I believe we would see an even greater response when comparing the drug against placebo. On the right-hand side, LFA. LFA is important because it is a prognostic factor.
What we did is we looked at patients with LFA greater than 9.8%, and that cutoff is when problems start. Patients with 9.8% and above are the ones at highest risk. Of course, the N comes down, but regardless, positive result, not statistically significant here, but a massive increase when compared to placebo. Oh, sorry, decrease when compared to placebo. Now, MRI PDFF, again, that way of trying to further things on the field, collaborating with others to get good non-invasive markers. MRI PDFF has been shown to be a good to have a good correlation with fibrosis, and our data confirmed that. 30% reduction or greater, these are paired drops from baseline. These are the numbers that correlate with fibrosis well, 65% versus 21%, highly statistically significant, highly consistent with our histology data.
On the right, the change from baseline, and the importance here is just to show how potent the drug is. You already see a massive effect halfway through the treatment. Now, liver enzymes, any primary care practitioner has access to, ALT, AST, are good surrogate markers of inflammation and to a certain degree fibrosis as well. And what we saw was, again, a statistically significant better response when compared to placebo. Like other markers, you see already an effect in the halfway point, and that gets better at the 52 weeks. So again, that continuous improvement, which gives us confidence in the long-term effect of the drug. LDL cholesterol, we did show a reduction, not statistically significant, but remember, the majority of the patients had normal LDL cholesterol at baseline.
So when you start looking at those that are over 100 mg per dL, we see that they get better, but the numbers go down, hence not statistically significant. There is a small increase in triglycerides associated with the drug. We know this. We've seen this before. There is one important differentiator here, however, not all triglycerides are made equal. What denifanstat does is to change the composition of those triglycerides from nasty saturated fats, George likes to call it, the butter triglycerides, to the extra virgin olive oil, polyunsaturated, fatty acid triglycerides. And that is important because it may have cardiovascular benefits. So again, not all fats, not all triglycerides are made equal. We have published the data from the phase IIa.
We have other data, and as soon as the final results from the FASCINATE- 2 analysis of the lipids are ready, we're also going to present that. Now, safety, the safety was very consistent with what we have seen before. There are really no limitations for the drug. It is well tolerated. We do see a few more AEs with the drug. There was a combination of things, including those that led to discontinuation. There was a mishmash of events that were not drug-related, such as complications from a bronchoscopy that the patient had an incident, one was hospitalized, and all that. There were some other events, eye skin disorders, and we know that. Some dry eye comes with the drug and some dry skin, so easy to take care of. Actually, I have dry eye.
Any moisturizer that you buy at Target CVS or your preferred vendor, and any eye drops that you buy at Target CVS and your preferred vendor. And finally, no deaths, no SAEs related to the drug. So in short, these are the top-line data of the study. And with that, I'll pass on to George, but Dave, where are we with?
Do we have questions or do we keep going? Do you want to?
So I have a few questions. I don't know if George, you have a if you want to.
I would say why don't we go to the questions? This is a little bit about what's next, probably getting there.
Yeah. So, you mentioned, and I think people are looking forward to seeing more data at EASL in June. Maybe just walk us through sort of the additional analyses that you're expecting.
Obviously, this is the curtain raiser on the entire dataset,
But in seven minutes?
Yes.
Okay.
Abstract. Abstract. Abstract.
No, you're going to see more detail on those primary endpoints. There will be more details on the lipid analysis, more details on subsets. So we're going to look at, in particular, the hard-to-treat patients. The AI, this is the first set of results. We're going to have much more in a more granular event. So, we have already submitted some abstracts to EASL. The primary results are going to go as a late breaker, and we are going to be submitting a couple of other abstracts as well. So do expect more from the clinical results, and do expect more from the more exploratory things such as the change in those triglycerides from butter to extra virgin olive oil.
I would just offer that we'll show mITT as well as ITT on all the data, and we hit on everything. So it's, I mean, that's probably not much of a surprise when you look at the mITT and you change the denominator to the total number of patients. It's pretty straightforward calculations. So, we'll share that as well. We have additional data that we're going to share, combining, as we are the only FASN inhibitor and GLP fat burners, we are continuing to look at data not only in combination with GLPs but other fat burners. And we're going to be pleased to share that at EASL as well, from a rather prominent fat burner that is on the table in the next, say, day or so.
Got it.
I have a question on that, but before we get to that, you highlighted the efficacy in combination with GLPs. Can you just talk through, I guess, if, as you've analyzed the safety tolerability, was there any differences in patients who were on background GLP?
No. No. Again, small Ns, but we did not observe any difference, probably because they were stable on GLP. So these were the ones that survived that first year and then dropped from the GLP. So they had all the GI events already, and we did not add anything other than efficacy.
Got it. That makes sense. If you could just remind us on the biopsy review methodology, how many pathologists did you use, and how does that tie in with the AI quantitative fibrosis analyses?
Sure. We used one central pathologist, Pierre Bedossa, global, well-renowned, been over the decades reading countless studies. This was agreed upon with FDA enough to take us to the end of phase II meeting. We have seen in other studies, perhaps Intercept's the best example, a single pathologist a panel doesn't make much of a difference. Phase III, we will have a panel as FDA recommends and really wants to see. Now, AI pathology. AI pathology gives you a lot of information. I always like to say that, the human looks at the blueprint of a room like this. It can only say it's a room of, and has four walls and all that. The AI pathology gives you the details. There are tables here, chairs, some pushed here, some there.
But importantly, it validates the human, but it also gives you an idea of how things are progressing with the drug beyond just seeing, "Oh, yeah, those fibrous septa are improving. Where in the liver?" That gives you guidance also for future studies with combination.
That makes sense. I also wanted to ask about you mentioned a potential strategy around tripalmitin as a biomarker, and just how are you thinking about incorporating that into future development plans?
Yeah. So we've obviously in our two-way study done a lot of preliminary work to look at this thing. And the way we start to see it emerging is you could give this drug to a patient for, say, 4 weeks-8 weeks, take a blood draw, measure it, and then the patient and the physician can have a discussion.
If that marker is moving in the right direction, then there's a lot of enthusiasm for compliance and to keep that patient on the drug. Obviously, we'll be validating those responses in the phase IIb and moving them into the phase III. Again, not to select a patient per se, but simply to understand, can it be used in a commercial setting, to help the patient and a physician have a discussion about either maintaining, increasing, you know, modulating the dose, what it takes. But I think it's a, you know, we don't see it as a requisite. You must have this, in order to take the drug, but simply as a informative tool, to help the patient, physician, and I'm the payer as well, garner enthusiasm about continued dosing with the drug.
Got it. That makes sense. And you alluded to the potential approval of a fat burner, hopefully.
Yes. Tomorrow, hopefully.
Maybe if we could just walk through your expectations based on the data that you've seen, expectations for the label. Obviously, there's still some debate among investors regarding whether or not biopsy may be required in the label, but would just love to get your views on resmetirom expectations.
It's a good question. We all hope no biopsy is on the label. I am part of a team that thinks there will be no biopsy on the label because in the day-to-day in the clinic, that doesn't happen. So, the FDA is attuned to those things. We'll have to see the label, of course, but that's our belief. We also believe that it has a very high likelihood of being approved.
I think we're all hopeful.
Yeah.
And then just in terms of taking that a step further, in the real world, what's your, I guess, your feedback been, from payers and, I guess, their likelihood or willingness to implement a biopsy requirement or not?
We haven't heard of any payers looking to require a biopsy. I think they're going to follow the label, right? And I think that that's a pretty traditional path for payers. So, I think we're all anxious to find out tomorrow, right? And, but I don't expect it now. I, there are so many patients that are identified now that can receive treatment that I think will benefit from it. So I think that's a real plus.
Yep. That makes sense.
Just in the last 30 seconds that we have, maybe if you want to talk about sort of the path forward, upcoming catalysts, and just remind us on cash balance, operational cash runway.
Yeah, sure. So right now, after our last financing, after the release of our phase IIb results, we have a little over $200 million in cash. We obviously need a bit more than that to complete a phase III study, but we can certainly begin the trial. For NASH, we have an end-of-phase II meeting in mid-May, that the FDA has granted us. And then we expect to launch the phase III study, by the end of this year. So first patient enrolled should be into the program by the end of this year. And, you know, that's, kind of where we sit. We would like to get our acne program going.
We have great data from our partner in China, and we'd like to launch a phase I study with our lead backup molecule, which we currently have ready to go, ready to roll. And given the fact that they will be presenting phase III data in acne by the end of this year, it should have a very nice carryover effect for us. Very large population, be the first oral drug in acne in 40 years, and it seems to work quite, quite well.
Excellent. All right. Well, unfortunately, we're up against time. We'll have to leave it there. But thank you to the Sagimet team for presenting. And we'll stay tuned. Fingers crossed for tomorrow. And looking forward to EASL.
Thank you, Tom.
Thank you.
Thank you, Tom.
Thanks, everybody.