Fractyl Health, Inc. Common Stock Morgan Stanley 24th Annual Global Healthcare Conference

Sure. My name is Harith Rajagopalan. I'm the co-founder and CEO of Fractyl. Thanks for having us, Mike. We are developing Revita duodenal mucosal resurfacing for post-GLP-1 weight maintenance. We have pivotal data coming in early Q4, just several weeks away, for potentially the first therapeutic option that has the potential to deliver a durable metabolic reset for people with obesity and type 2 diabetes. What that means is the potential for long-lasting clinical benefits in both weight and metabolic parameters, even in the absence of ongoing medical therapy. The reason this matters so much is because, as everyone knows, GLP-1s have totally transformed the treatment landscape in obesity, diabetes, and metabolic disease. We have nearly 30 million Americans on GLP-1s, but 1 million people discontinue GLP-1s each month, and then when they do, lose the benefits that they had worked so hard for.

The fundamental question in obesity, I think, has now shifted from how do you achieve weight loss, which we're doing very well with drugs, to how do you maintain that weight loss for the long term? That's where we believe Revita comes in with the first potential option in the space. Revita has Breakthrough Device designation from the FDA and has a potential De Novo registrational filing pathway. With pivotal data in hand in early Q4, we anticipate a potential regulatory filing later this year. So it's an exciting time with key pivotal, potentially practice-changing data just around the corner.

Yeah. Revita targets a portion of the gut called the duodenum. It is like the hunger center of your gut. The reason that that is important is because the duodenum is the first place where nutrients are absorbed in the body. In people with obesity and type 2 diabetes, nutrient sensing and signaling is abnormal. It does not work properly. We believe that this is the very first thing that goes wrong in people when they develop obesity, and it is the reason why people have obesity and diabetes in the first place.

What we have developed is an approximately 1-hour outpatient endoscopic treatment with a proprietary catheter-based delivery system that targets this dysfunctional duodenum with ablation, which is targeted energy delivery directly to this diseased tissue to allow the removal through ablation of that unhealthy tissue and the potentially healthy regrowth or regeneration of a new lining that aims to restore the normal nutrient sensing and signaling mechanisms in the body so that people can go back to maintaining a healthier weight, even in the absence of ongoing medical therapy. We believe that unlike pharmacology, which can be very effective, but only works as long as you take it, Revita can actually be a durable metabolic reset by fixing whatever abnormal signaling mechanisms are causing people to have obesity in the first place.

That is why we see a lot of potential for it for the million patients a month who are going to stop a GLP-1 and be at significant risk of weight and metabolic rebound. Beyond the patients, we think that this answers a problem that physicians have when their patients are asking them, "Okay, I have lost weight on a GLP-1," or, "I am having side effects on my GLP-1. I want to stop. I need to stop, but I do not want to regain all of my weight.

What do I do?" I think it answers a question for health systems that recognize the importance and the value of treating obesity, but are struggling with drugs that only work as long as people take them, and the majority of people stopping them within such a short amount of time that the long-term health benefits are not actually realized in the real world. I think Revita can be a very compelling answer for all the patients, the physicians, and the health systems.

Yeah. Revita is purpose-built to have a very selective ablation of the mucosa without damaging deeper structures. The way we do this is that we first put saline into the wall of the submucosa in order to create a thermal barrier between the mucosa that we wish to ablate and the muscle layer that we do not want to damage, because that is where the pain fibers reside, and the structural integrity of the duodenum as well. Our ablation is designed to ablate the mucosa and the superficial submucosa, but to prevent injury to the underlying muscle. As a consequence, in recent randomized trials, we have seen that Revita has essentially the same treatment-emergent adverse event profile as patients who undergo a sham procedure. Most patients do not experience any symptoms at all.

Those who do have mild procedure-related symptoms, maybe abdominal discomfort or throat discomfort lasting one or two days, self-limited, resolving on its own. We think it is a mild peri-procedural profile that potentially supports very broad outpatient use, because you have got to think about this as a transoral upper endoscopic procedure, and we are doing millions of these types of procedures in endoscopy suites across the country today. What I think is compelling is that the safety profile and the scalability of the technique can actually meet the need of the very large population of potential GLP-1 discontinuers.

Yeah. We have done studies in type 2 diabetes for many years. We have collected data out to 2 years in type 2 diabetes, where patients who have undergone a single Revita procedure have had 2 years of durable glucose improvement, metabolic benefit, and weight maintenance for that 2-year period of time. We have just begun to see this summer 1-year data from our post GLP-1 weight maintenance setting. We saw that in two different patient cohorts that we have been following. One is an open label cohort called REVEAL-1, roughly 20 patients. The other is in a randomized controlled setting called REMAIN-1 Midpoint, where that is roughly 45 patients in whom roughly 30 were in the Revita arm. Collectively, we now have about 50 Revita patients with 1 year of follow-up, and the results, I must say, are very encouraging.

Approximately 80% of the GLP-1 weight loss has been retained across these cohorts at 1 year. That is a very impressive number because when you think about what happens in natural history or in the control arm in our own trials, patients are regaining 55%-60% of that weight, continuing to regain weight at 1 year. Maintaining 80% weight, instead of giving up less than 20% of that weight loss, is clinically meaningful, better than what we can see from other pharmacological approaches in maintenance, and we think will be very highly compelling if the pivotal trial continues to show what the pilots have already demonstrated.