Greetings. Welcome to the Fractyl Health six-month REMAIN-1 midpoint cohort. At this time, all participants are in listen-only mode. The question and answer session will follow the formal presentation. If anyone today should require operator assistance during the conference, please press star zero from your telephone keypad. Please note, this conference is being recorded. I'll now turn the conference over to Lara Smith Weber, Chief Financial Officer for Fractyl. Thank you. You may now begin.
Thank you. This morning, we issued a press release that outlines the topics we plan to discuss today. The release is available at www.fractyl.com under the Investors tab. Presenting today will be Dr. Harith Rajagopalan, Co-founder and CEO of Fractyl Health. Before I begin, I'd like to remind you that during this call, we make forward-looking statements which involve risks and uncertainties that may cause actual results to differ materially from our forward-looking statements. We provide a comprehensive list of risk factors in our SEC filings, including the quarterly report Form 10-Q, filed on November twelfth, twenty twenty-five, which I encourage you to review. Any forward-looking statements on the call are subject to substantial risks and uncertainties, speak only as of the call's original date, and we undertake no obligation to update or revise any of these statements, even if subsequent events cause the company's views to change.
It is now my pleasure to pass the call over to Harith.
Thank you, Lara. Good morning, everyone. Thank you for joining us. Today, we are thrilled to present prospective, randomized, double-blind, controlled six-month data from our REMAIN-1 midpoint cohort pilot study, in which we show that Revita continued to show weight maintenance six months after the discontinuation of GLP-1s. The data we're presenting today builds upon a set of evidence we have been generating over the past two years that together represent the beginning of what we believe is a new potential blockbuster therapeutic category in obesity, which is post- GLP-1 weight maintenance, a field that Fractyl is uniquely positioned to lead. Today's results are the continuation of a period of momentum and acceleration with multiple clinical weight maintenance data readouts and regulatory milestones this year, culminating in top-line pivotal data and potential FDA filing in the second half of this year.
Today's data also extend and substantiate what we first demonstrated in September, that Revita can meaningfully alter the trajectory of weight regain after GLP-1 discontinuation, and they do so at a critical six-month time point that aligns with the primary endpoint in our ongoing pivotal study. Let's start with the key takeaways from the trial. The REMAIN-1 midpoint cohort data are a compelling success at six months, providing strong evidence of sustained weight maintenance with excellent safety and tolerability. While the entire efficacy cohort demonstrated weight maintenance, results were particularly pronounced in patients with greater GLP-1-associated run-in weight loss, those who are at highest risk of rapid weight rebounds. These patients experienced a 70% reduction in post-GLP-1 weight regain with Revita versus sham, and importantly, these observations from the study reinforce our confidence in the design and execution of the ongoing pivotal study.
Taken together, they provide substantial and compelling evidence to support the potential safety, efficacy, and strategic positioning of Revita in post GLP-1 weight maintenance. Second, we are also thrilled to share that we've had a constructive and interactive dialogue with the FDA about Revita's favorable safety and tolerability. Given the output of these discussions, we requested FDA feedback on reclassifying Revita under the De Novo classification pathway versus the PMA category in which it is currently classified. This is huge because the De Novo pathway may enable a more efficient, risk-based regulatory review process, and we expect FDA feedback on this request in Q2 2026. Third, in light of our accelerating clinical and regulatory progress, we are advancing commercial readiness by turning our attention to reimbursement and commercial preparedness activities in the quarters ahead.
Key enablers of this preparation include the predictable pathways conferred by both FDA Breakthrough Device Designation and CMS Transitional Pass-Through statutory timeline and pathway. We are very excited about the anticipated catalysts ahead on the path to pivotal data, potential FDA submission, and commercial preparation over the coming quarters. We believe Revita can be viewed as a potential backbone therapy in obesity, and if it can succeed in this hardest to treat post GLP-1 weight maintenance category, we believe it has potential across the spectrum of obesity and metabolic disease. For those who are new to the story, Revita is a 1-time, less than one-hour outpatient endoscopic procedure designed to be like LASIK for obesity to address gut-level metabolic dysfunction. In prior clinical studies, we've seen up to two years of durable activity after a single treatment.
Revita has breakthrough device designation from the FDA for post GLP-1 weight maintenance, and today's six-month REMAIN-1 midpoint pilot data support the potential durability of effect and provides increased confidence in the ongoing pivotal study. The REMAIN-1 midpoint cohort enrolled 45 adults with obesity and without type 2 diabetes who were GLP-1 naive, started on tirzepatide, and titrated to achieve at least 15% total body weight loss. Once they hit 15% weight loss, tirzepatide was stopped, and then these individuals were randomized 2-to-1 to Revita versus sham. In effect, we constructed a clinical study that allowed these people to become the world's hungriest humans and then randomized them to assess the effect of Revita versus sham.
And the study was initially designed as a three-month study, was not powered formally for hypothesis testing, and the P-values we present today are provided to describe the strength and consistency of the treatment effect.... In the midpoint cohort, of the 45 patients who were randomized, 29 were in the Revita arm versus 16 in the sham, with 98% retention through six months across multiple sites. All 45 randomized subjects are included in the safety analysis, and the efficacy analysis includes 40 participants who followed protocol-specified diet and exercise requirements through six months. Let's start with the six-month randomized top-line data. What you see on slide eight is the average body weight change at six months after tirzepatide discontinuation in the midpoint cohort.
In this full efficacy population, Revita-treated patients regained 4.5% of their body weight, compared to 7.5% in the sham arm, with a p-value of 0.07 one-sided. That represents a meaningful attenuation of post GLP-1 rebound, with weight regain in the Revita arm coming in at less than half of what's typically expected following GLP-1 withdrawal. Importantly, approximately 30% of Revita-treated patients either maintained their weight loss or continued to lose weight through six months. It's important to also remember that a p-value of 0.07 with an n of only 40 participants bodes very well for the pivotal study design with a sample size of 315 patients. Now, let's spend a moment talking about what we are seeing here.
We do not believe when we look closely at the data, that we are seeing a degradation of effect. Across all sites, the efficacy signal for Revita was robust compared to sham. At one site, we did observe an increase in weight in both the Revita and the sham arms, which we picked up through central statistical monitoring. This site is not contributing materially to the pivotal cohort, but it did contribute material to this pilot. Across all the other sites, the Revita effect remained remarkably stable, and average weight regain in those, in the Revita arm was less than 2.5%, which is very much in line with what we have already presented in December, with from the REVEAL-1 open label cohort of 1.5% and in line with what we expect to see in the ongoing pivotal cohort.
Remember, this is a small study with a small n, and we believe that what we are seeing is remarkably consistent across the study. We believe the pivotal study will be able to continue to demonstrate what we were expecting to see. Now, let's look a little bit deeper at the outcomes. Patients who do lose the most weight on GLP-1 therapy are also those who are at highest risk of rapid and substantial weight regain once drugs are stopped. That has been shown consistently across GLP-1 withdrawal studies, and REMAIN-1 was intentionally designed around this reality. We randomized patients only after they achieved at least 15% total body weight loss on tirzepatide, because that represents a population under the greatest biological pressure to regain weight. Remember, the world's hungriest humans.
Consistent with that design, we conducted an analysis of the impact of GLP-1 run-in weight loss on efficacy outcomes, allowing us to understand how the treatment effect varies across the rate of regain, the weight, the rate of run-in weight loss that people experience. What you see on the right graph is striking. In patients with above average GLP-1 induced weight loss in this study, Revita reduced post-GLP-1 weight regain by approximately 70% versus sham at six months, with a p-value of only 0.004. In absolute terms, sham patients in this subgroup had highest rates of weight regain, regaining about 13% of their body weight over six months, and Revita-treated patients regained only about 4%, representing a large and clinically meaningful separation at a highly relevant time point.
We view this as a compelling, biologically coherent enrichment signal, consistent with our understanding of Revita's mechanism of action and our understanding of those who are at greatest risk of post-GLP-1 weight rebound. We believe the data show that Revita is having its greatest impact exactly where the unmet need is highest, reinforcing both the therapeutic rationale and our confidence in the ongoing pivotal study. The effect of Revita on other endpoints that are secondary endpoints in the pivotal and exploratory endpoints in this pilot study include the cardiometabolic lipid profile and food craving patient-reported outcomes. These results are totally consistent with the emerging clinical understanding of Revita's impact on metabolic disease.
Starting with cardiometabolic parameters, at six months, Revita-treated patients demonstrated improvements in HDL cholesterol with a p-value of 0.01, and in triglyceride to HDL ratio with a p-value of 0.03 compared to sham. These are both well-established markers of improved insulin sensitivity and lipid handling, and we have seen improvements in the parameters in prior clinical studies of Revita as well. This is nice confirmation of what we've previously seen. Importantly, we also looked at patient-reported appetite and craving. We have heard anecdotally in prior studies and open label work that patients describe less food noise after Revita. Here, Revita-treated patients reported significantly reduced craving for sweet foods compared to sham, the p-value of 0.04. Clinically, sweet food craving is one of the earliest and most powerful drivers of post-GLP-1 rebounds.
Seeing the signal reduced at six months is consistent with Revita's proposed gut-brain mechanism and helps explain why Revita may help maintain a lower body weight set point. Now, turning to safety, I will be brief because the story here is very straightforward. There were no new related adverse events between the three-month and six-month follow-up, which reinforces the stability of the safety profile as we extend the duration of follow-up.... Taken together, the data continue to support Revita as a procedure that is well tolerated, is scalable, and appropriate for broader clinical use, which is critical as we advance toward pivotal readout and regulatory review. On the basis of everything we've just shown you, we believe that we are addressing the key risks in the REMAIN-1 pivotal study. We see excellent safety, tolerability, and importantly, signals of activity in the midpoint cohort.
The midpoint cohort also gives us confidence that the pivotal study is appropriately powered for success, and all of this is prelude to the observation that the pivotal cohort is proceeding very well and ahead of plan. We are very confident in what we are heading into later this year. Remember, the midpoint cohort was designed to mirror the design and execution of the pivotal cohort with the same inclusion and exclusion criteria, the same positions, and the same endpoints. In the pivotal cohort, we will measure the percent weight regain at six months, the responder rate at twelve months. I'd like to update that the study is fully enrolled. We have randomized approximately 95% of the participants. We expect to complete randomization in February and are on track for top-line pivotal data and potential FDA filing in the second half of 2026.
Now, turning to our regulatory path. We've had a very productive, interactive dialogue with the FDA regarding Revita's encouraging safety and tolerability data to date. In light of these discussions, we requested FDA feedback on potentially reclassifying Revita under the De Novo pathway instead of a PMA. We see the potential for the De Novo pathway to enable a more efficient, risk-based regulatory review process that has the potential to reduce our timeline to U.S. launch, if accepted, and to enable label expansion as we go in a much more straightforward manner than a PMA would offer. We expect to receive feedback from the FDA in the second quarter of 2026, but based on discussions we already have had, we feel very confident that this pathway will be granted. Now, turning to our regulatory and reimbursement milestones over the next two years.
We see an opportunity to leverage well-established FDA Breakthrough Device Designation and CMS Transitional Pass-Through mechanisms as we prepare for commercialization. We start with the observation that an FDA Breakthrough Device Designation in hand provides a well-defined regulatory path with an opportunity for ongoing interactive dialogue with the FDA, as we just described we're having. We just shared with you the exciting six-month randomized midpoint data, which we believe reads on the likelihood of success of the pivotal study later this year, and we also anticipate filing for a CPT code and completing our FDA submission in the back half of this year. We believe that CPT code may go into effect at around the same time as a potential FDA approval next year, and then immediately following FDA approval, we anticipate filing for CMS transitional pass-through payment for the Revita device.
This would allow us to begin commercialization at hospital-based centers of excellence, where we already have excellent relationships, with payment to be established for those centers via the TPT mechanism. Taken together, the pathway is for a targeted and efficient commercial model at Revita Centers of Excellence. We believe that Revita can be delivered in endoscopy suites across the U.S., if approved. There are approximately 2,000-4,000 of these endoscopy suites in the U.S. alone, with an estimated capacity of up to 1,200 procedures annually at each of these centers, meaning we believe there's capacity to perform between two to four million new procedures annually using existing infrastructure in the United States as it exists today. And all of this creates the potential for a capital-efficient launch, leveraging existing infrastructure and existing patient flow through the healthcare system. Now, turning to our anticipated near-term catalysts.
We see a catalyst-rich year ahead, starting with today's presentation of our randomized six-month data. Next, we anticipate completing randomization in the pivotal cohort in February. We expect both FDA feedback on our potential De Novo pathway and one-year data from the REVEAL-1 cohort in Q2, one-year randomized data from the REMAIN-1 cohort in Q3, and in the second half of the year, six-month primary endpoint data and potential FDA filing very much on track. So in closing, we see a path to positive pivotal data, potential FDA submission, and robust commercial readiness. The key elements are pivotal study execution, regulatory progress, and commercial readiness. Thank you very much. Operator, we are now ready to take questions.
Thank you. We'll now be conducting a question-and-answer session. If you'd like to ask a question at this time, you may press star one from your telephone keypad, and a confirmation tone to indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment for our first question. Our first question is from the line of Jason Gerberry with Bank of America. Please proceed with your question.
Hey, team. Good morning. This is Phi for Jason. Thanks for taking our questions. I presume, if I may, but the first one is, can you talk about your expectations for the pivotal six-month readout based on today's results? Today, you reported about 40% difference in weight regain profile at month six between the two arms within the pre-specified efficacy population. And can you contextualize the five subjects that were excluded in the pre-specified population? I'm curious, were those same exclusion criteria pre-specified? And if you were to do the pivotal cut, would you expect the same exclusion criteria to be applied to the primary analysis in the pivotal cohort? And a couple of follow-up.
Sure. So based on the enrollment in the pivotal study, where patients have slightly higher weight loss in the run-in period than what we're seeing here, we expect to see a 50% reduction in weight regain in Revita versus sham, and we expect to see an enrichment for even greater effects in those patients with greater weight loss, based on what we are seeing today and our understanding of the biology. And so we are feeling quite confident, based on the data that we are seeing, that we are very well powered for success against that metric with 315 patients, and everything that we're seeing suggests that we're very much on track for that.
The 5 patients who were excluded were excluded due to a pre-specified exclusion in this small pilot study of non-adherence, you know, successive non-adherence to diet and lifestyle recommendations over at least three visits. In the pivotal study, we will have a sensitivity analysis that would look at this population as well.
Okay. And my second question is: Can you contextualize today's data relative to the regulatory bar? I recall the agency may have wanted to see a certain effect size between the Revita arm and the sham arm. I think it's 50% less regain in one year. Can you talk about that?
Yeah. So there's only... Just to be very clear, the FDA only, our conversation with the FDA leaders believe all we need is a p-value of less than 0.05, two-sided at, six months in the six-month co-primary endpoint. And in addition, we need at least 50% of Revita patients to have maintained at least 5% of the weight that they had lost on tirzepatide at one year. And we are incredibly well on track for those regulatory milestones. So the core question is like, do we see data that is sufficient for Revita to be approved? Absolutely, we are confident that we do. Do we see data that is sufficient for Revita to be utilized? We absolutely do, and we are very confident that we're heading towards something that is not only going to be approved, but also used.
Got it. Thanks for correcting me. And just one last one for me. I may have missed this from this slide, but I don't see a time lapse with the three-month and the six-month data together. Can you talk about the kinetics of the weight regain profile between the Revita arm and drug arm? Quite honestly, I'm working with imperfect data, but I am seeing a different weight regain profile between Revita arm and drug, Revita arm and sham arm between month three and month six, potentially more weight regain from the Revita arm than the sham arm. Are you going to catch up in the weight regain from Revita arm between month three and month six? Can you talk about that? Thanks so much.
Sure. You know, I did mention that we did observe that there is one site where there is high degree of variability in weight regain. This was actually picked up through central statistical monitoring. The site is not actively contributing to the pivotal cohort as a result, and when you back that site out, there is an expanding difference in treatment effect between Revita and sham between month three and month six. And so we do—we are in a situation where one site is contributing materially here. We do not expect them to contribute materially in the pivotal, and what we are seeing in the remaining sites is very consistent with an expanding treatment delta, which we would expect to see going forward as well.
Okay, thanks so much.
Thank you.
Our next questions are from the line of Michael DiFiore with Evercore ISI. Please proceed with your question.
Hi, guys. Thanks so much for hosting this call and for taking my call. Just two for me. This analysis had five less patients versus the three-month analysis, obviously, due to noncompliance. Just how much weight did these five patients initially lose on tirzepatide? And I have a question follow-up.
These five patients, we didn't see any relationship between. They were across the spectrum. There was nothing specific about them in terms of their weight loss on tirzepatide.
Okay. Also, in the exploratory analysis, you know, I noticed that the Revita-treated patients regained roughly the same amount of weight compared to the overall analysis. I think it was around 4.5%. Could, could this be the norm for what we might see in the pivotal cohort, where, like, 4.5% could, could be expected, or is it too early to tell?
You know, it's just, it's too early to tell, but one thing I will tell you is that the main objective here in the pivotal study is to be able to demonstrate a difference between Revita and sham. And whether you look at the full cohort analysis or you look at the this and this other end, this exploratory cohort, we are very, very confident that we are seeing a difference between Revita and sham. I think that the REVEAL open label cohort gives really good visibility into what one might expect to see in the real world. It's why we have two complementary data sets. And we also, as I mentioned before, have one site in this pilot that's not contributing meaningfully in the pivotal, that is driving the average weight regain much higher than the other sites.
So we actually expect that the weight regain in the pivotal arm in Revita will be lower than what you're seeing here.
I see. Thanks so much.
Thank you.
Our next questions are from the line of Mike Ulz with Morgan Stanley. Please proceed with your question.
Morning, and thanks for taking the question. Maybe just to follow up, I guess versus the six months open label data you shared previously, you know, versus today's data, looks like you're seeing more weight gain over that period. Just curious, any thoughts on what's specifically driving that? Is that related to the site issue you've mentioned, or is there other things going on there? And I have a follow-up.
It's related to the site issue, because if you back it out, it looks remarkably similar to what we saw at the, in the open label cohort. Now, one site... This is a small study. Remember, it's 45 patients. As you know, we enrolled the first centers that opened up for enrollment are the ones that contributed here. One site contributed meaningfully to the pilot cohort, not to the pivotal, and that site had higher than expected regain across both arms, though there was clear Revita effect. And I think that's why we're seeing. Look, at the end of the day, what we're seeing is clear evidence of efficacy, a slightly higher regain number in the Revita arm than what we would like to see, and we believe that that's unexplained and controllable.
That's the benefit of having done this pilot study in order to help make sure that we're on track to have a really compelling profile in the back half of this year.
Gotcha. And then maybe since you're seeing, you know, greater delta in those patients that lost more weight on GLP-1, are you considering maybe, you know, exploring that further in the future?
That is absolutely already the intent, and it always has been the intent to do so, because it is well known that patients who lose more weight on GLP-1 are at greater risk of rapid weight rebound. It's why we selected 15% as a cutoff for entry into the randomization phase. We fully expected from the start of the study that patients with more weight regain will be at greater risk of rebound. I think the way to understand this is like if you've lost a little bit less weight, you might be able to control your diet and lifestyle better because you're not so far away from your metabolic set point.
But the people who've lost 28+% of their total body weight, as we're looking in this study, in this population, it is very hard for them to control their food noise and very hard for them to control their, or prevent weight regain, and that's where Revita really shines.
Understood. Thank you.
Thank you.
The next questions are from the line of Whitney Ijem with Canaccord Genuity. Please proceed with your question.
Hey, guys. Thanks for fitting me in. So I guess just to follow up on that last question then, the analysis of patients in the kind of who had more median weight loss, those patients, is that prospectively designed in the stat plan of the phase III, or are you saying you're gonna be adding that in?
It is, it is prospectively defined in the stat plan for the SAP. We are waiting FDA feedback on that stat plan, but we are absolutely, it is absolutely in the intent. It is absolutely in the design.
Okay, got it. And then you also just mentioned kind of some of the changes or observations in this cohort kind of are controllable and kind of can inform the phase III. So are there any other changes, I guess, happening to the phase III based on this data, stat plan or otherwise?
I think it validates things that we're doing in the phase III, like a statistical, analysis plan that you just mentioned and the central statistical monitoring that we have in place. It validates the things that we're otherwise already doing.
Got it. Okay. And then just last one for me. You mentioned that the FDA just wants kind of the p-value at six months and wasn't looking for a particular, delta. Is that also true of payers, or how have payers been thinking about what they want to see at six months?
I think payers are focused on demonstrating efficacy at six months, like what we just talked about with the FDA. And then I think they're also gonna care about how does this perform in the real world, compared to what you might expect from GLP-1 withdrawal. And so in that case, I think that we're really shining. So I think we have a very compelling argument to payers. I would point out that CMS TPT pathway is statutory, and it's very much tied to the FDA approval. So when you ask about payers, I'm referring more to commercial, whereas Medicare is more of a statutory process.
Got it. Thanks very much.
Thank you.
Our next question is in the line of Joseph Pantginis with H.C. Wainwright. Please proceed with your question.
Hey, everybody. Thanks for taking the questions and all the details you've provided so far. Most of my questions have been answered, but I'm just curious, when you consider the long-term profile of Revita, how have today's data provided any evolution to your thinking about future retreatment prospects?
Yeah, great question. I, I think that the... When I look at the totality of the data from this, from today, combined with what we have seen before, we continue to feel confident that we're gonna see two years of durable efficacy in from the Revita procedure, in even in this patient population. We, we think we see that in the majority of the sites, that the patients are heading towards a very stable trajectory, like what we saw in the REVEAL open-label cohort. And with all of that, in view, we do think that this is a procedure that may be repeated after a couple of years or more, but we continue to have confidence in the durability that would be sufficient for this to be a very compelling, marketable product.
Thank you.
Our next question is from the line of Jeffrey Cohen with Ladenburg Thalmann. Please proceed with your questions.
Hey, good morning. Thanks for taking our questions. Two quick ones, Harith. Firstly, as far as the steps with the agency on de novo versus PMA, what will we hear about, and when will we hear that? What steps are left from your side?
Well, I think we've already filed a reclassification request, and you're gonna hear about FDA feedback in Q2.
Okay, got it. And then when you talk about the above median weight loss in the subset, any metabolic signals that you've seen as far as biomarkers for those patients that stand out in particular, or that was just a pure % loss?
% total body weight loss. You know, it's very. It stood out in the prospective statistical analysis like a sore thumb, that the magnitude of the weight loss really, really correlates to the magnitude of the risk of weight regain and the delta between Revita and Sham. And so we feel like this is a very clear signal. It's biologically grounded, it's highly rational. It's what anyone would have predicted based on what they know about GLP-1 rebound risk. And so we feel very confident that we've enriched for that population in the pivotal cohort, and we look forward to those results later this year.
Perfect. Thanks for taking our questions.
Thank you.
Thank you. At this time, I'll turn the floor back to Harith for closing remarks.
Well, thanks, everyone. You've seen the data. We walked you through what we're observing and why we believe that we have substantially de-risked the pivotal study. The next steps are clear. We're gonna continue to drive towards pivotal cohort top-line data and potential FDA submission later this year. We believe that Revita has tremendous potential to solve the single biggest problem in obesity today, and we're gonna look forward to updating you on our progress with the catalyst-rich year ahead. Thank you very much.
Thank you. Ladies and gentlemen, thank you for your participation. This does conclude today's call conference. You may now disconnect your lines, and have a wonderful day.