Fractyl Health, Inc. Common Stock Study update

Good morning, everyone, and thank you for joining us. I'm Brian Luque, Head of Investor Relations and Corporate Development at Fractyl Health. Today we will review the positive six-month top-line results from the ongoing REMAIN-1 pivotal study of Revita in post-GLP-1 weight maintenance. Dr. Harith Rajagopalan, our Co-Founder and CEO, will discuss what these findings mean for patients, the remaining 12-month assessment, and how the results advance the regulatory and commercial strategy we outlined on our September 1st investor day. We will take questions after the prepared remarks. First, let me please turn to the legal disclaimer. During this presentation, we will be making forward-looking statements about future clinical results, regulatory submissions and authorizations, reimbursement, commercial launch, potential treatment populations, and for future catheter sales and other business opportunities. These statements reflect current expectations and involve risks and uncertainties that could cause actual outcomes to differ materially.

Please review the disclosures in this presentation and the risk factors in our SEC filings. We undertake no obligation to update these statements, except as required by law. Revita remains investigational in the U.S. The study is ongoing, and the top-line data remain subject to final validation. 12-month co-primary endpoint has not yet been assessed, and regulatory authorization, coverage, payment, and commercial outcomes are not assured. With that, I'll turn the call over to Harith.

Thank you, Brian, and good morning, everyone. We are thrilled to present the highly positive top-line six-month result from the REMAIN-1 pivotal study for Revita in post-GLP-1 weight maintenance. For years, it has been clear that unhealthy foods in our modern diets are causing dysfunction in the gut and in the duodenum in particular, and this duodenal dysfunction is a fundamental root cause of obesity and type 2 diabetes. Revita targets this gut dysfunction with the goal of preventing and reversing disease in a disease-modifying manner. The idea is to target the underlying physiology driving disease, aiming to provide a durable metabolic reset that offers the potential to reverse the pathology caused by modern diets. We believe the answer to a chronic disease epidemic driven by our food must involve repairing the root cause rather than simply relying on managing it with a lifetime of medication.

Toward this aim, we are starting with individuals who need to stop or want to stop GLP-1s without regaining weight. GLP-1 therapies have proven that dramatic weight loss is possible, improvements in weight, diabetes, cardiovascular risk, and even aging. There is a $100 billion market that has now been built around that proposition. But the Achilles' heel of the GLP-1 class is that the results only last as long as patients continue taking these medicines. The drugs do not change the underlying drivers of the disease. They only forestall disease progression as long as the drugs are in the body. There are currently an estimated 29 million U.S. patients on GLP-1s, and this month alone, over 1 million Americans will stop taking GLP-1s and be at risk of rapid weight regain and metabolic rebound. As such, there are only two choices today.

Either stay on the drugs indefinitely while struggling through side effects, tolerability, access, and cost issues, or lower dose, lower frequency, or discontinue and run the risk of metabolic rebound. That is a problem Revita is built to solve. The REMAIN-1 trial studies Revita in this hardest and highest unmet need market opportunity in obesity today, designed to evaluate Revita in patients who are at most risk of rapid weight and metabolic rebound to provide the most rigorous test of efficacy within the obesity category. Revita has FDA Breakthrough Device Designation for post-GLP-1 weight maintenance, a potentially efficient De Novo regulatory path, and favorable reimbursement tailwinds. We set out three goals in this pivotal study, and we hit on all three at the six-month co-primary endpoint. First, most important, the primary analysis in the MITT population was highly statistically significant with a P value of 0.0023.

80% of GLP-1 induced weight loss retained in the Revita arm versus 67% in the sham arm. Nearly a third of Revita patients maintained stable weight or lost weight after stopping a GLP-1, and this result at six months is catching the data at a moment in time. The treatment effect grew from month 1 to month 6 and in fact doubled between month 3 and month 6. Second, exploratory analyses showed the treatment works even better with longer ablation lengths, consistent with our observations from prior work in our pilot studies. When ablation of the full length of the duodenum is performed, we believe the weight maintenance result in the Revita arm is not only statistically significant but also highly clinically meaningful.

Third, we observed the same excellent profile through six months that we have come to expect from Revita, with no device or procedure-related serious adverse events and a generally mild periprocedural adverse event profile. REMAIN-1 is a first sham-controlled pivotal trial to show sustained weight maintenance after stopping obesity medications in this most rigorous setting. This is a category-defining moment and a potentially landmark result for the field of weight maintenance because it demonstrated through six months that ablation of the duodenum has the potential to reset the body's metabolic control set point. That is a totally new approach to targeting obesity and metabolic disease. You can think of Revita like LASIK for obesity.

The differentiating value proposition here is that Revita is a single outpatient procedure, takes about an hour with no incisions, no stitches, and nothing left behind in the body, and is designed to deliver lasting results for patients. In the context of post GLP-1 weight maintenance, the idea is to enable Revita to help lock in the weight loss that patients have worked so hard to achieve. Through our clinical studies, we've developed a standardized training program that allows reproducible delivery of the technology. Physicians were advised to ablate at least 10 centimeters of the duodenal mucosa, but to aim for the full length and to get the designed full effect of the procedure. This improvement in procedure execution, as physicians grew comfortable with Revita, is standard for medical devices, and it offers a potential for compounding profile optimization with more physician experience.

The long lengths of duodenal ablation, combined with a clean safety profile, even at the longest lengths of the ablation, give us confidence that we are in the early innings of exploring the potential of this platform. We knew post GLP-1 weight maintenance would be a hard problem to tackle in the absence of ongoing medical therapy. We were among the first to see that the unmet need in obesity was quickly shifting from weight loss to weight maintenance, and decided to design the most rigorous stress test conceivable for Revita's ability to prevent weight and metabolic rebound. The REMAIN-1 study is that randomized, double-blind, sham-controlled test. The study enrolled adults who had not previously received GLP-1 therapy. They first got tirzepatide, lost 15% of their total body weight before entering the randomized phase.

The medication was withdrawn, which is known to trigger a profound hunger and food noise response in patients discontinuing GLP-1s. At that point, patients were randomized two to one to Revita versus sham. The first six-month co-primary endpoint compared weight regain in Revita to sham. We've shared those results today. The second will assess weight loss maintenance at 12 months in the Revita arm alone against a pre-specified performance goal. At least half of the Revita patients staying 5% or more below their starting weight. We will formally evaluate our key secondary endpoints only after we have evaluated both of our co-primary results at study completion, and we expect to share those results Q1 2027. 308 U.S. participants were randomized and evaluated in our MITT population used to assess the primary endpoints. Baseline demographics were balanced across both study arms.

The enrolled patient population is consistent with prior Revita studies in weight maintenance and representative of the broader GLP-1 treated population with obesity in the U.S. A majority female, BMI of 30 at the time of randomization, and 66% with at least one weight-related comorbidity. The mean run-in weight loss on tirzepatide was 18.3% with a GLP-1 run-in duration of 25 weeks, and half the patients enrolled reached the maximum 15 milligram dose of tirzepatide, creating the rigorous conditions for this stress test of Revita's effect. In the pivotal six-month co-primary endpoint, Revita significantly reduced weight regain versus sham at six months with a highly statistically significant P value of 0.0023, with 80% of GLP-1 weight loss retained at six months in the Revita arm. Just as important, the treatment effect grew over time.

The arms separated at every visit from month. This treatment arm separation gives us confidence in the potential findings at 12 months, especially given the historical comparator 12-month results after GLP-1 withdrawal, shown at the top right of the graph in front of you. This first co-primary endpoint provides the randomized clinical evidence supporting the longstanding hypothesis that we have held that endoscopic ablation can change post GLP-1 weight maintenance. This is potentially practice-changing, and it points to an entirely new category of weight maintenance therapy for the millions of patients who face weight regain when GLP-1 treatment stops. Revita's effect versus sham in the primary MITT population was robust across all pre-specified analyses, including effect size evaluations at a run in weight loss of 20%, at the population mean of 18.3% with ANCOVA rather than MMRM, and in observed means.

All analyses yielded highly statistically significant P values with 2 to 3 zeros consistent results. Just as important is the responder analysis. One in 3 Revita participants either maintained their GLP-1 weight loss or lost further weight even after stopping high-dose tirzepatide. One in 2 maintained at least 80% of their GLP-1 weight loss, and the corresponding nominal P values versus sham are 0.02 and 0.0078. Obesity is a consumer market now. Results in the MITT population, with one-third of patients either maintaining or losing further weight, help us translate statistical significance to potential clinical meaningfulness as it facilitates the conversation a physician will have with a patient about Revita and what patients may expect if cleared. Another key finding relates to the dose-dependent effects of Revita as a function of ablation length. Remember, pilot studies indicated Revita outcomes were even better in patients with longer lengths of duodenal ablation.