Fractyl Health, Inc. Common Stock Canaccord Genuity's 46th Annual Growth Conference

Thanks for having me, Whitney.

Fractyl's focus is on developing therapies that offer the potential for durable metabolic benefit against obesity, type 2 diabetes, and related metabolic disease. The way that we aim to achieve durable metabolic benefit is by targeting the root causes of these disease in the body. Our lead asset, Revita, is a device that enables a one-time outpatient endoscopic procedure targeting a segment of the gut called the duodenum that we've discovered to be a root cause of the abnormal weight set point in obesity and abnormal glucose set point in diabetes. By targeting the duodenal mucosa by ablation, it allows a cellular regeneration of a healthy new lining of the duodenal mucosa that then allows the body to manage nutrient sensing and signaling mechanisms to normalize body weight and blood sugar without the need for ongoing medical therapy.

Our second asset, called Rejuva, is a one-time pancreatic infusion of a gene therapy candidate, RJVA-001, which is about to enter the clinic, which offers the potential for the pancreas to start making its own natural human GLP-1 on demand. What you see with Revita and Rejuva targeting the gut and the pancreas are one-time endoscopic treatments with the potential for very long-lasting benefit, which is fundamentally where we think the unmet need has now shifted in metabolic disease. There are great drugs out there. We all know their names. We see their advertisements every day. The problem is most people stop taking these medicines in less than 1 year and lose all of their hard-won benefit. Revita and Rejuva are both designed to help patients maintain lasting weight and metabolic benefit without the need for ongoing therapy. That is the differentiating advantage of our solutions.

Sure. Revita, again, it is the one-time endoscopic procedural therapy enabled by our device. It is performed by gastroenterologists. The origin story is actually a simple story in three parts. The first one starts with an accidental observation from bariatric surgery, performed millions of times, that shows that if you bypass the duodenum in people with obesity and type 2 diabetes, you can immediately reverse their obesity and their diabetes without patients having to change their behavior in any way. That observation, that duodenal bypass has this profound metabolic benefit, led scientists to try to understand what is it about the duodenum that is somehow magically allowing people to improve their obesity when food does not contact it anymore. What scientists discovered is that there are critical nutrient sensing and signaling pathways from the duodenum to the brain and the liver and the pancreas that help the body control metabolism.

Years and years of high-fat, high-sugar diets cause duodenal dysfunction, which is an abnormal structure of the duodenal mucosa causing abnormal nutrient sensing and signaling. Step one was this accidental duodenal bypass surgery. Step two was interrogating the root cause of that and then understanding duodenal dysfunction to be the mechanism. Step three was where we came in. How do you take that lesson and then develop a root cause targeted therapy that can enable millions of patients a year to be able to have the first true disease modification in obesity and type 2 diabetes in a scalable manner? That is the root cause story about- Okay where Revita came from.

Yeah. I am going to just answer the last part of your last question as I transition. For many years, we worked on developing duodenal resurfacing for type 2 diabetes, and we developed hundreds of patients and sham-controlled data in the type 2 diabetes patient population. About 2 and a half years ago, it became obvious to us that as effective as the GLP-1 therapies are, most people cannot or will not stay on GLP-1 therapies for life in order to manage their weight. Even though we were developing evidence in type 2 diabetes, we had this very interesting clinical signal in hundreds of patients followed for 1 and 2 years that after a single Revita intervention, patients were losing weight and then holding their weight flat for 2 years without patients changing anything about their diet or lifestyle or without even thinking about it.

That profile of a one-time intervention, early weight loss, and then sustained weight benefit without effort suddenly became incredibly relevant in an era where you have patients stopping GLP-1s and then regaining weight very rapidly. It occurred to us that Revita's value in a post GLP-1 weight maintenance setting could be incredibly compelling. Two years ago, we went to the FDA. We took our evidence from type 2 diabetes, and then we went straight into three different clinical trials in post GLP-1 weight maintenance. We made a hard push in this area because we saw extraordinary value because patients are completely compelled. Our customer physicians feel like this is the single biggest problem to solve in obesity, and health systems and payers are already balking at the cost of lifelong GLP-1 for their patients.

How do you deliver durable weight maintenance in a manner that overcomes the fact that most people will stop taking their medicines? That is why we went into this area, and that decision ended up being a very prescient one, because we now are sitting on 1-year data from two different studies, open label study called REVEAL-1, and then a randomized pilot, randomized double-blinded sham-controlled pilot study, called our Midpoint Cohort. We are now less than 3 months away from seeing the definitive evidence in a 300-patient prospective randomized sham-controlled pivotal study designed much like the pilot, but just 7 to 8 times the size.

What that means is it is very well powered, and if we just see the same thing we saw in the Midpoint Cohort, in the larger sample, in the definitive experiment, we could be less than 3 months away from the first registrable data set for a durable post GLP-1 weight maintenance solution. What we have seen from the two pilot studies that we have run, open label and randomized, very consistently, is excellent maintenance of weight loss in patients who have lost considerable weight on tirzepatide. They have lost 40 to 50 pounds. They are maintaining more than 80% of that weight loss at 1 year, compared to the sham arm or historical controls, which are regaining about 60% of their weight by 1 year. A very large difference. We are maintaining almost two-thirds of the weight that the sham arm is.

Oh, sorry, 3 times as much of weight as what the sham arm is maintaining. We believe that this is an incredibly compelling clinical profile. I am happy to go into any of that in more detail.