GUTS - NASDAQ

Good afternoon, and welcome to Fractyl Health Fourth Quarter and Full Year 2025 Financial Results and Business Update Call. [Operator Instructions]. I'll now turn the call over to Brian Luque, Head of Investor Relations and Corporate Development at Fractyle. Brian, you may now begin.

Thank you. This afternoon, 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. Joining us on the call today are Dr. Hartih Rajagopalan, Chief Executive Officer; and Lara Smith Weber, Chief Financial Officer. 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 annual report on Form 10-K filed today, 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 the 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, Brian, and good afternoon, everyone. Millions of Americans are starting GLP-1 therapy. Most of them will stop within a year. Data show that when they stop, the weight comes back, approximately 10% of their body weight within 6 months and approximately 15% within 12 months. Every one of those patients faces a moment with no durable off-ramp, no alternative to either resuming chronic pharmacotherapy or accepting the risk of regain. Revita is being built for that moment. For those of you who are new to the Fractyl story, Revita is our lead asset. It's like LASIK for obesity, an endoscopic procedure designed to durably maintain weight loss after GLP-1 discontinuation. And Rejuva is our smart GLP-1 platform targeting long-term metabolic remission from a single dose. Today, I want to tell you where we stand in the development of Revita for post- GLP-1 weight maintenance, what we have learned since we last spoke to you about the clinical data and share new favorable feedback we have received from the FDA on our filing strategy. I'd like to start by naming something directly. In January, we reported 6-month data from the REMAIN-1 Midpoint cohort. The past several weeks of analysis have given us a level of precision about which patients benefit most from Revita and at what procedural profile that we did not have before. This clarity has strengthened our conviction in Revita and has helped us finalize the pivotal study's key design elements to ensure we are set up for regulatory and commercial success. Today, we will share what we now know and why the picture is both more precise and more compelling than the headline p-value initially suggested. Let me walk you through 4 key pillars that give us conviction in the opportunity in front of us. Number one, the clinical signal is real. Number two, the pivotal is built to succeed. Number three, the path from data to commercial value is clearer than ever. And four, we have the runway to get to the definitive pivotal data without any planned incremental capital raise. Now let's start by discussing the clinical signal. You will recall that the Midpoint Cohort was a pilot randomized, double-blind, sham-controlled study that enrolled 45 patients with obesity who were GLP-1 naive. They were started on tirzepatide to achieve at least 15% total body weight loss and then randomized 2:1 to Revita versus sham. This 45-patient study was designed as an interim read to validate the design and the powering assumptions for the REMAIN-1 pivotal study, not as a powered stand-alone efficacy study. Nonetheless, the 6-month Midpoint Cohort data did not look as strong as the 3-month data. Early analysis that we shared at the time of data release was that site level heterogeneity appeared to account for the attenuation of the clinical signal in some patients. Further investigation has revealed that the site level heterogeneity is, in fact, differences in ablation length or treatment dose at early clinical sites and that these differences in ablation length are a key driver of efficacy differences between patients. Critically, we have not identified site level operational issues. What we did find was even better, a strong dose response relationship between ablation length and weight maintenance after GLP-1 discontinuation. This is a strong positive signal for the Revita mechanism of action and for the potential success of the pivotal study. We have long understood from our work in type 2 diabetes that Revita's treatment effect is proportional to the extent of duodenal resurfacing. Our first-in-human feasibility and dose escalation pilot study in type 2 diabetes was published in Diabetes Care in 2016 and prospectively demonstrated a clear relationship between ablation length and glucose lowering. Since that time, we have been systematically optimizing the procedure profile across successive clinical studies to deliver longer ablation length from 9 centimeters in the first in human to over 16 centimeters on average in REMAIN, and have seen greater potency in our studies without compromising patient safety. And because of this experience, our pivotal study already prespecified an ablation length dose response secondary endpoint. When we applied this dose response analysis to the Midpoint Cohort 45 patients, we observed a statistically significant p less than 0.05 monotonic and clear relationship between ablation length and weight maintenance treatment effect at 6 months. Participants who received more than 14 centimeters of ablation regained approximately half the weight of sham, whereas those individuals with subthreshold ablations accounted for the apparent narrowing of treatment effect between month 3 and month 6 that we saw in our January data release. This finding is consistent with our prior evaluation of ablation length on patients with type 2 diabetes, and it makes sense biologically. The duodenum is lined with enteroendocrine cells that drive key metabolic signaling pathways. The density of that cell population is distributed along the length of the duodenal mucosa and duodenal dysfunction from high fat high sugar diet extends along the length of the entire duodenum in animal models. A longer ablation resurfaces a greater proportion of that signaling surface, producing a more complete metabolic effect, which is exactly what our dose response data confirmed. In the REMAIN-1 pivotal study, we trained physicians to ablate from the ampulla of Vater to the ligament of Treitz, which are anatomical landmarks toward the beginning and the end of the duodenum, respectively. Based on our work in type 2 diabetes, we aim for an ablation of at least 10 centimeters, but encourage physicians to ablate more if they deemed it appropriate. In the pivotal study, the mean and median ablation length are more than 16 centimeters, providing ample opportunity to demonstrate an enhanced clinical signal reflecting more complete duodenal ablation. Notably, all pivotal investigators were successfully trained to achieve more than 14 centimeters of ablation, confirming procedural scalability and feasibility across diverse operators and patient anatomies. So taking a step back, what we have is a clear monotonic dose response, which is exactly what you would expect to see from a true biological intervention. All drugs and all procedural therapies that work like drugs should show a dose response relationship. That's what biological activity looks like. And ablation dose is a specific, measurable, controllable and standardizable metric for repeatable outcomes in a broad population. So having established ablation length as a key procedural driver of Revita's potency, let's turn to patient selection. The scientific community has long understood that the magnitude of initial weight loss on GLP-1s is proportional to the magnitude and speed of weight regain upon discontinuation. So we designed REMAIN-1 with a greater than 15% total body weight loss threshold at run-in, specifically because we expect the treatment effect to scale with the degree of pre-randomization weight loss. Midpoint Cohort results at 6 months confirm this relationship. Participants with greater than 17.5% weight loss showed an early, sustained and compounding separation from sham through 6 months. The pivotal has enrolled a population that is built to capture a large effect size that scales to the magnitude of initial weight loss as well with a mean run-in weight loss of 18.3% in the Pivotal Cohort. So when we now consider the right dose in the right patient, we observed the signal to be strongest among participants with higher weight loss who received longer length of duodenal ablation. And in these individuals, Revita-treated patients experienced only 2.9% weight regain at 6 months compared to 9.9% in the sham arm, approximately a 70% reduction in post GLP-1 weight regain. Like ablation length, the treatment effect scale monotonically with the magnitude of weight loss as well. Another way to think about it is that in this optimized patient cohort in the midpoint study, patients retained about 88% of their body weight loss on tirzepatide compared to only about 60% in the sham arm at 6 months. We believe this degree of weight loss maintenance will be highly compelling to key commercial stakeholders. It is a prospectively definable, commercially significant population. It is the exact population that the pivotal study has enrolled and will enable efficacy endpoints in our pivotal study later this year. This is also classic translational pharmacology applied to a procedural therapy, identification of the right patients and the right dose to optimize the clinical profile and achieve a large treatment effect. Turning now to the pivotal study statistical analysis plan and operational progress. Our plan was always to analyze the 6-month Midpoint Cohort to inform our understanding of the key drivers of effect size and then to use this information to prespecify the Pivotal Cohort statistical plan. The pivotal SAP, which we will file with FDA shortly, incorporates these parameters as prespecified analyses, and this will enable clarity on effect size and durability as a function of treatment dose and patient selection in the pivotal study. I also want to provide clarity about our endpoint structure. REMAIN-1 has 2 co-primary endpoints. The first is percent body weight regain in the Revita arm versus sham at 6 months. This is the data we expect in early Q4. The second co-primary is the proportion of Revita-treated patients who maintain at least 5% total body weight loss at 1 year after GLP-1 discontinuation. Both co-primaries are required to be met at p less than 0.05 for overall study success and we believe the pivotal is well powered at over 90% to achieve that result even under conservative assumptions. In addition to these co-primaries, we will present a comprehensive set of secondary endpoints, including a dose response analysis, a high responder population analysis, cardiometabolic markers and patient-reported outcomes, including reduction in cravings for sugary foods. In February, we completed randomization in the full study of the Pivotal Cohort with over 300 participants across more than 30 sites and over 20 operators across the United States, making this the largest sham-controlled GI endoscopy pivotal trial ever conducted. Every operational metric that predicts pivotal success is tracking favorably. Retention exceeds 95%. Medication resumption rates are below our model assumptions. The blinded adverse event profile remains encouragingly consistent with what we have seen in prior studies. And we remain on track to deliver top line 6-month primary endpoint data in early Q4 2026. Turning now to regulatory progress. Earlier this month, we received favorable FDA feedback on our De Novo classification request. You may remember that we aim to get that feedback in Q2, but our most recent discussion with FDA revealed that they have reviewed safety data to date, and they acknowledge that Revita's safety profile is consistent with a Class II device classification or a moderate-risk De Novo device. With this positive feedback now in hand, ahead of schedule, we are on track for De Novo submission in late Q4 2026 with 6-month pivotal data in hand. There are several advantages to the De Novo pathway compared to the PMA pathway. It is a more capital efficient, faster and strategically superior path. So now let's turn to the commercial opportunity because the landscape is evolving in ways that reinforce the urgency of what we are building and the path from clinical data to commercial value is becoming clearer and nearer than ever. With an anticipated filing via the De Novo pathway at the end of this year, we're also preparing ourselves for our potential commercial launch. There is a large and growing population on GLP-1 drugs with estimates projecting over 30 million users in the next several years. We estimate that as newer agents become more effective, more than 50% of patients are expected to lose more than 17.5% of their total body weight on GLP-1s and more than half of these are likely to discontinue. As a result, the post-GLP-1 unmet need is intensifying rather than abating. A large study published in BMJ Medicine last week following over 330,000 patients showed that GLP-1 cardiovascular benefits erode rapidly after discontinuation with the authors coining the term metabolic whiplash. Resuming treatment did not fully restore lost benefits, underscoring the need for durable maintenance solutions. Meanwhile, the payer landscape is shifting. CMS has expanded Medicare coverage of GLP-1s, driving a massive increase in the addressable patient population, but also intensifying the economic pressure on payers who are now grappling with the long-term cost of chronic therapy. This creates an unprecedented window for Revita, the first FDA breakthrough device designed for post-GLP-1 weight maintenance as a potentially durable, cost-effective solution that gives people an off-ramp from chronic pharmacotherapy while preserving the metabolic benefits they work so hard to achieve. On reimbursement, we now have a clear and validated pathway. We plan to file a Category III CPT code application this summer with a code expected to be effective in the summer of 2027. The payment economics work for hospitals from nearly day 1. Transitional pass-through payment by a CMS provides a separate incremental mechanism to cover the cost of the Revita disposable device on top of the facility rate, ensuring that hospitals can maintain a positive contribution margin while offering the procedure to patients. Revita is the only potential procedural therapy in development for post-GLP-1 weight maintenance, and we believe the commercial infrastructure will be ready to move quickly upon clearance. Briefly, let's turn to Rejuva, our smart GLP-1 platform targeting long-term metabolic remission from a single dose. We submitted clinical trial applications for RJVA-001 in type 2 diabetes to regulators in the EU and Australia, and we anticipate regulatory feedback in Q2 2026, expect reporting first-in-human dosing and preliminary data in the second half of this year. The Rejuva program is advancing within a disciplined spending framework that does not compete with Revita for capital, and we will share more on the platform at an upcoming Investor Day. Let me frame the anticipated catalyst-rich path ahead before I hand it to Lara. In Q2, we will see 1-year REVEAL-1 open-label data and receive CTA regulatory feedback on RJVA-001. In Q3, we will see 1-year REMAIN-1 Midpoint Cohort randomized data, and we expect to be able to demonstrate continued compounding treatment effect and durability at that time in a randomized data set. In early Q4, we will anticipate seeing top line 6-month randomized data from the REMAIN-1 pivotal study. This is the single most important catalyst in our company's history. And in late Q4 this year, potential De Novo marketing application submission for Revita in post-GLP-1 weight maintenance. In the second half of this year, we will also see human dosing of RJVA-001, subject to CTA authorization and preliminary safety and PK data. Each of these milestones move us closer to delivering the first potential procedural therapy for maintenance and weight loss after GLP-1 discontinuation, and it is a catalyst-rich year ahead. Lara?

Thank you, Harith. Research and development expenses were $16.5 million for the quarter ended December 31, 2025, compared to $20.3 million for the same period in 2024. The decrease was primarily due to our strategic reprioritization in Q1 2025, resulting in lower personnel-related costs and reduced costs associated with the pausing of the REVITALI

Thank you, Lara. Before we open Q&A, I want to address capital strategy directly and remove any ambiguity. We have closed our ATM facility, and we do not have plans to raise capital before we have pivotal data in hand. Our runway extends into early 2027. This is a deliberate commitment grounded in conviction. We expect the pivotal data will be positive, and we will operate with discipline within our existing capital envelope as a signal of management's alignment with shareholders through a key moment. A few final comments. First, we believe the clinical signal is real with a strong dose response and a clear GLP-1 responder target population. Second, the pivotal is built to win with strong powering on the full cohort and enrichment in an optimized cohort of patients with high running weight loss and longer ablation lengths. Third, we see a clear path to commercial value with favorable De Novo feedback and a large, defined and growing market opportunity. And lastly, we are funded to the key pivotal value inflection point without planned incremental capital raise between now and then. We have the science, the runway and the team to prove it. We look forward to sharing more data this summer and into the fall. I want to express my deep gratitude to our employees whose dedication and focus through a challenging year has been nothing short of extraordinary, to the physicians and investigators who believe in the science and bring it to patients with skill and care to the patients who trust us with their health and their hope and to you, our shareholders, whose conviction fuels everything we do. Operator, we are ready to take questions.

[Operator Instructions]. And our first question comes from the line of Whitney Ijem of Canaccord Genuity.

This is Angela on for Whitney. Can you guys just remind us how the ablation length is determined again, is that it's after the patient is already like during the procedure, right? And so yes, I guess like how is that length determined? And then it sounds like 16 centimeters is the cutoff now like going forward, is that the target minimum ablation length?

Yes. Great question, Angela. Happy to clarify this point because it's important to how we think about standardizing this procedure as we go forward and how we are going to analyze the pivotal data as well. When we looked at the type 2 diabetes patient population, we saw a dose response where ablation was defined as the length of the total amount of duodenum that was ablated. When we did our first-in-human study, we saw that about 10 centimeters of ablation had more glucose lowering efficacy than 3 centimeters. We are seeing the same thing now in obesity, but at higher lengths of ablation. Our ablation balloon is 2 centimeters long. In the procedure, we count the number of ablations that are performed longitudinally along the length of the duodenum, and that allows us to calculate the ablation length. What is clear is that the ablation length for weight effects is greater than or equal to 16 centimeters. That will be our operating standard going forward and will be built into the key secondary endpoints in our pivotal study. And in those patients, we see a clinically meaningful and compounding treatment effect in the Midpoint Cohort. We believe this to be the reason for heterogeneity that we saw back in January, and we're very gratified to have the data to be able to give us clarity on the precision of what is needed in order to deliver benefit to patients.

Great. Maybe just a quick follow-up. I guess, does this impact how doctors are going to be trained in the future in terms of length of ablation? And was it -- were they conducting less ablation because they were less comfortable with it? Or if you could just provide more color around that?

Well, in the pivotal study, we advise patients -- doctors to ablate at least 10 centimeters and from the anatomical landmark at the beginning of the duodenum towards the end of the duodenum. But it was less to the physician's discretion how much ablations to perform. In that study, everyone was trained to be able to successfully perform greater than 14 centimeters of ablation across the board. And so we believe that we can easily train physicians to do that consistently now that we have the data to support that length being the efficacious dose.

Our next question comes from the line of Michael DiFiore of Evercore ISI.

One on the De Novo pathway. It seems that you're increasingly more confident that the FDA could accept your De Novo submission based on early feedback. And I guess my question is, to what extent does efficacy play in the final determination here? Or is it all about safety? And then I have a follow-up.

Well, I think the De Novo pathway determination versus, say, a PMA determination is principally a safety consideration because what the FDA is thinking about is whether this is a moderate risk device in De Novo versus a high-risk device in a PMA. And then the efficacy threshold for PMA and De Novo are also nuanced -- have nuanced differences. The efficacy threshold for PMA is valid scientific evidence, whereas the efficacy threshold for a De Novo is reasonable assurance of safety and effectiveness.

I see. That's helpful. And then just back on the ablation length. I think I and a lot of other folks were under the impression that this was already standardized. But now you made it clear that in the pivotal studies, physicians were instructed to ablate at least 10 centimeters. And I guess my question is in the real world, based on the average patient, is 16 centimeters readily achievable? Or is the average patient's anatomy more conducive to less centimeter ablations?

In the Pivotal Cohort, mean and median ablation length was greater than 16 centimeters and is readily achievable by all of the investigators that we've trained, and we believe that will be translatable to the broader population.

Our next question comes from the line of Jason Gerberry of Bank of America Securities.

This is Chi on for Jason. Maybe a follow-up on the ablation length. Can you provide more color on the post-hoc analysis for the midpoint data set? More specifically, can you remind us the ablation length and GLP-1 induced weight loss from the Midpoint Cohort and how that compares to the metrics you provided for the Pivotal Cohort? And secondarily, how much variability in the ablation length you saw in the Midpoint Cohort compared to the Pivotal Cohort? And I guess, ultimately, how does this post-hoc analysis impact your confidence for the pivotal readout later this year?

Well, this is a post-hoc analysis in the Midpoint Cohort. It was already a prespecified analysis in the pivotal study and is consistent with prespecified studies we've conducted on dose in type 2 diabetes in the past. In the Midpoint Cohort -- sorry, in the Pivotal Cohort, mean and median ablation length are greater than 16 centimeters and the average ablation length is longer than it was in the Midpoint Cohort. And we feel confident that we can train physicians to perform longer ablations in the pivotal. All of this translates to a high degree of conviction in the pivotal study. Number one, we are very well powered at well over 90% for the full cohort, and we have key secondary endpoints that we have prespecified that will interrogate patients who receive more than 16 centimeters of ablation and in patients who receive -- who have more running weight loss on the GLP-1. And we are confident that each of those independently and collectively will drive larger and compounding treatment effects in the pivotal study and will provide clarity on how Revita can be used in which patient and at what dose in order to achieve a clinically meaningful signal that can translate to commercial utilization.

Got it. So the ablation length for the Pivotal Cohort is what you have observed is longer than the ablation length in the Midpoint Cohort?

That's right.

Okay. And given you have already fully randomized the Pivotal Cohort, basically, is it fair to assume that all the ablation had already occurred and you're talking about ablation length you have observed for all the procedures that conducted?

Yes, that's locked. And I think we're saying that we're more than 1 month out from the last randomization now. And the safety signal in our blinded analysis continues to be very encouraging. And so we feel quite confident that the efficacy is the question in the pivotal study and the data that we're sharing with you today meaningfully increase the probability of success on the efficacy angle as well.

Our next question comes from line of Mike Ulz of Morgan Stanley.

And maybe just another one related to ablation. Just curious how long it takes to sort of train these physicians to be able to do the procedure to ensure adequate ablation. Is that something that's fairly quick? Or how much experience does it take to kind of make sure that they're hitting that mark?

This training that we've built is -- works very well. It takes less than 3 to 4 cases to train a physician to perform ablations. The shorter length of ablations that we sometimes see in the Midpoint Cohort and the Pivotal Cohort are often reflective of the first couple of cases that the physician is performing and yet very soon, they get very comfortable with it and then are consistently delivering longer ablations. The huge advantage of a prospectively defined dose response in the pivotal is that it allows us to standardize the treatment -- the training regime and the treatment recommendation in commercial use. And I think that's going to help standardize real-world outcomes.

Our next question comes from the line of Jeffrey Cohen of Ladenburg Thalmann & Company.

Sorry to be redundant. So on the -- in Q3, when we see the 1-year remain Midpoint Cohort, will we see further analysis by length as far as the data that you're reading out?

Yes.

Got it. And then could you talk a little bit about the energy delivery and the temperatures involved? Has anything changed as far as the delivery from the generator between the Midpoint Cohort and the Pivotal?

No, nothing has changed. And I think one point that you should take confidence in is that even though we went from a small number of sites in the midpoint to a much larger number of sites and operators and patients, the treatment that we've been able to train physicians to perform has been remarkably consistent and standardized over the course of time. The only difference that we are sharing with you now is that we can give specific guidance on what length of duodenum to aim for in obesity. And that is very useful information. We're glad to have it.

That's helpful. And then can you talk about the CPT code. So as I understand it, if you file during the midpoint somewhere in 2027 that, that could or would take effect January 1, '28. Are you also suggesting that it's possible that you'll have a T code that would take effect sometime in 2027?

We're anticipating filing for the Category III CPT code in June of this year. It's reviewed in September and should go into effect in the summer of '27, July 1. And we are also intending to file for a transitional pass-through payment through CMS immediately upon FDA authorization, and that's a quarterly review cycle. So that can go into effect very quickly upon launch. That's why we said that there was essentially no daylight between potential clearance authorization in the United States and reimbursement authorization for hospitals to begin to use it.

OOkay. And I'm assuming you'll also take on payer discussion late this year, commencing late this year as far as payer discussion?

That's right. And when you think about it, we will have a fully formed clinical profile by early Q4. 12-month randomized data from REMAIN-1, 12-month open-label data from REVEAL-1, 6-month randomized data from the full Pivotal Cohort of 300 patients. That's a fully derisked clinical package that we could then use to inform our payer discussions and drive towards our regulatory submission calendar.

Our next question comes from the line of Joe Pantginis of H.C. Wainwright.

So my first question is shorter, but maybe a more complex answer. So first, with the De Novo filing positive feedback, how would we view the totality of regulatory submissions over the next -- over the next year or so with regard to is it a multistep process? Or is it similar to a rolling BLA? Or how should we view it?

There are 3 main packages to the regulatory submission. There is a design history file, which is the device design. There's a manufacturing file, which reflects how we manufacture our systems. and then there will be clinical data. We will have a full package of 6-month data by the end of this year. There's -- we will also be ready to submit 12-month data in the first quarter of 2027, should that be necessary.

That's great. And then if I heard you correctly, correct me if I'm wrong, it sounded like you're going to be filing the SAP relatively soon. So with regard to the ablation length that we've been discussing today, and it's very intriguing data, by the way, how would you look at -- and you mentioned it's a prespecified population. How would that factor into the statistical analysis plan and also the role of the secondary endpoints that you mentioned and the hierarchy of them?

Great question. Obviously, details on the hierarchy are going to be pending our conversation with the FDA, and we'll share that with you when we have it. I would make 2 points right now. Number one, the sweet spot of the enrollment and randomization of the pivotal study are exactly the patients in whom Revita appears to be working best. The mean ablation length was more than 16 centimeters, which is where Revita's efficacy is very clear based on the midpoint cohort. And the mean run-in weight loss was over 18% total body weight, which is where Revita's efficacy is also very clear. So the right down the middle of the fairway of our pivotal enrollment is exactly the sweet spot of where we are seeing efficacy. And so we're confident in that. And we have designed key secondary endpoints in order to be able to demonstrate that very clearly.

Thank you. I'll now like to turn the call back to Dr. Rajagopalan for closing remarks.

Well, thank you, everyone. The science is working. The pivotal is on track and we look forward to delivering the definitive data this fall. Thank you all very much.