Hi, everyone. Sorry about the delays. I hope you're having a good afternoon. I'm gonna skip the little intro spiel and just go right into it. I'd like to introduce Harith Rajagopalan, who is the CEO and co-founder of Fractyl Health.
Thank you so much. That's the best pronunciation of my name I've had all year at investor meetings, so appreciate it. My name is Harith Rajagopalan. I'm the co-founder and CEO of Fractyl. We're developing breakthrough therapies for obesity and type two diabetes, and these are important spaces, and I wanna spend a moment talking about our differentiation. We ask a different question than I think a lot of the therapeutics developers in obesity and type two diabetes. The question that we ask is: how do we develop therapies that can have lasting benefits for patients? Therapies that do not rely on adherence and persistence to medicines, and yet will work for the long term for patients, even if they are unable to comply with or tolerate the medicines that are available today.
We're developing novel, game-changing therapies to treat the root causes of obesity and type 2 diabetes. We have two therapeutic assets in development. One of them is Revita, which is a device-enabled endoscopic procedure addressing a root cause of obesity and type 2 diabetes in the gut, which has multiple study readouts starting in the fourth quarter of twenty twenty-four. And we expect to enter the clinic next year for Rejuva, a one-and-done pancreatic gene therapy platform for obesity and diabetes. We are well-capitalized, having completed an IPO roughly seven months ago, and are excited to be able to share the upcoming catalysts that we think have the potential to transform the treatment landscape in obesity and type 2. There's an incredible unmet need, even in the face of extraordinarily potent drugs in the GLP-1 category.
Wegovy and Zepbound have been incredible advancements in the space, but what we're learning is that the drugs are not solving the biggest problem that exists in obesity today, which is the inability to maintain the weight loss that can now be achieved. A majority of individuals who start on obesity medicines stop taking them within six to 12 months, and weight rebound becomes the single biggest challenge in the space because the drugs are increasingly available, but people are not able to or choose not to stay on them for the long term. Many thought that people are just choosing to take a break from these medicines and would just restart them when they need them again.
But as it turns out, most people who stop taking GLP-1s for obesity do not restart and are at risk of rapid weight and metabolic rebound within weeks to months of stopping the therapy. We have technologies that are designed to address root causes of obesity and diabetes that can have long-lasting benefit because they target diseased organs in the gut and the pancreas with the intention to offer long-lasting benefit. Revita targets the duodenum. We identified that there's a pathological change in the lining of the gut when we started the company, in two thousand and eleven, that is dysfunction that causes an abnormal signal from the gut to the brain that drives obesity and diabetes. And we believe that we are able to reverse that disease by ablating the duodenal mucosa and allowing it to regenerate a healthy new lining in its place.
We are developing Rejuva, which will enter the clinic next year, which is a local AAV administered directly into the pancreatic parenchyma with GLP-1-based therapeutic transgenes that effectively allows a one-and-done GLP-1 for obesity and type two diabetes. We have a pipeline that is designed to end obesity because the therapies that we're developing are designed to be long-lasting, and Revita and Rejuva have multiple catalysts coming in the coming quarters. Revita is currently in two pivotal studies. One is in weight maintenance after the discontinuation of GLP-1 drugs. That's called the Remain-1 study. It has FDA Breakthrough Device Designation and will have a midpoint data analysis in the second quarter of 2025. There will be an open-label cohort followed alongside of that, called Reveal-1, which will have data updates starting in the fourth quarter of this year.
Revita is in a second pivotal study in type 2 diabetes and this is in type 2 diabetes, and it's called Revitalize-1. It also has breakthrough device designation, and we anticipate top-line primary endpoint data beginning for Revitalize-1 in mid-2025. While the Revita has two pivotal studies in obesity and type 2 diabetes in the U.S., it is already approved under a CE mark in Europe, has reimbursement authorization in Germany, where we are collecting real-world registry data. After having already treated over 300 patients in clinical trials, we are now collecting real-world evidence for Revita's impact in people with obesity and type 2 diabetes. We just presented one-year data on the initial cohort of patients in the real-world registry, showing profound improvements in glucose and weight, and we will continue to share quarterly updates on the progress in that registry.
Rejuva is the gene therapy program. We have nominated a candidate for type 2 diabetes. We are actively working on IND enablement right now, and we anticipate initiating a first-in-human study in the first half of 2025, and we are developing an obesity gene therapy candidate that and we intend to nominate a candidate for that program by the end of this year. Turning to Revita, it's the first procedure that can potentially durably reset metabolism in the body and has already demonstrated in over 300 clinical trial participants over two years of durable improvements in weight and blood sugar control. This is a device that has a CE mark and is reimbursed and marketed in Germany, and two breakthrough device designations. In Germany, after having completed 300-400 patients worth of clinical studies, we're now beginning to see the impact in the real world.
Patients with obesity, advanced type 2 diabetes, on up to three different glucose-lowering agents at baseline, underwent Revita and then got diet and lifestyle counseling afterwards. These are people who are 62 years of age. Their BMI is 32, which is not particularly heavy for an obese patient population, but consistent with advanced diabetes, and had very poorly controlled disease, with a median baseline HbA1c of 9.6%. You can see that at the end of 1 year, patients are experiencing over 13% total body weight loss, something that is very hard to achieve in an advanced, mostly male, type 2 diabetes patient population, and over two percentage points improvement in hemoglobin A1c.
Admittedly, this is from a very high baseline, but what is particularly interesting is that the twelve-month results in HbA1c are very stable over time, and in weight, actually continue to improve from three to six to twelve months, even though there's no ongoing active chronic management to explain the improved weight loss at that period of time. So who is the ideal patient with obesity for Revita? There are two distinct patient populations. There are those who are already on GLP-1 drugs. We know that more than 50% of them are likely to stop taking them within one year, and they currently have no off-ramp from GLP-1s. There's no way to say that they can stop taking these drugs without being at risk of violent and rapid hunger and weight regain.
There's a second group of people, which is even larger, which is that two-thirds of patients with obesity do not even wish to start a GLP-1 drug because they do not want to be committed to chronic medical therapy to manage the weight for the rest of their lives. We believe that people who, if they are offered an off-ramp from GLP-1s, would be intrigued by the prospect of a short course of therapy with a GLP-1-based drug in order to get weight loss, and then a Revita procedure in order to help maintain that weight loss for the long run. So the Remain-1 pivotal study in weight maintenance is now underway, and the trial design is intended to demonstrate Revita's superiority to a sham procedure in maintaining weight loss after stopping GLP-1-based drugs.
We're looking at obese individuals with a BMI of 30 or greater, who do not have type 2 diabetes and are GLP-1 drug naive. We will be giving them tirzepatide. We've already started this, enrolling in multiple centers in the United States in August, and titrating the tirzepatide to achieve at least 15% total body weight loss, and then discontinuing the tirzepatide and randomizing patients two to one to undergoing the Revita procedure or a sham, and then following them at six months and one year. We have a primary endpoint, which is principally on showing a separation in weight regain between the Revita group and the sham group. Prior studies of tirzepatide show that patients regain roughly 70% of their body weight that they lose within a one-year period of time.
Suggestions are that they're regaining almost all of their fat mass and not regaining the muscle mass, which is critical for metabolic health. And so what Revita aims to do is to demonstrate a meaningful improvement in the proportion of patients who are able to retain clinically meaningful weight loss, which most patients who stop these drugs are not able to maintain, thereby raising the question of whether all of their effort at the weight loss in the first place was all for naught if they're only gonna regain most of that fat mass within the next year. We plan a midpoint data analysis in Q2 of 2025, after 45 participants have been randomized and followed for at least 12 weeks, which should give us early good visibility into the separation between the Revita arm and the sham arm at that time.
In addition to this pivotal study in weight maintenance, which we think has the potential to solve a really important problem in obesity, we're also developing Revita for type two diabetes, where the goal is to demonstrate glucose control, weight maintenance, and reduced glucose medication requirement in an inadequately controlled type two diabetic patient population. This is a straightforward study assessing blood sugar improvement at six months, assessed by a hemoglobin A1C, comparing Revita to sham, and we'll have top-line data in mid-2025 from this study.
There are roughly twenty-five million Americans with type two diabetes who are taking glucose-lowering medicines, who are at risk of disease progression, and Revitalize-1 would be an appropriate treatment strategy for patients who are looking to improve glucose control without escalating medicines, particularly to provide an alternative to patients who do not want to start on insulin therapy. Turning to our second program, Rejuva, our potential solution for the durable remission of obesity and type two diabetes. The idea behind Rejuva is to imagine what a best-in-class incretin could look like and wondering how you would deliver that. A best-in-class incretin, to our mind, would be a one-time therapeutic administration with very long duration benefit and potency, and we believe that we can deliver that with our pancreatic gene therapy platform.
We think that if you engineer the pancreatic islets to produce GLP-1, you can offer differentiated benefit over all of the incretins that exist or are currently in development. Why is that? Because we can leverage the pancreatic beta cell, the cell that makes insulin, to produce nutrient-stimulated hormones and to secrete the hormones when the body needs it and not when the body doesn't. We think that this effect can be very long-lasting because the beta cells are terminally differentiated. When you're at thirty years old, you've got all of the beta cells you're gonna have for the rest of your life. So successful delivery of AAV into the pancreatic beta cell should have very long-lasting effects.
What we can do, because we're leveraging the beta cell machinery, is amplify islet GLP-1 signaling, secreting GLP-1 when the body needs it, but not secreting it when it doesn't, in order to provide physiologic, autoregulated GLP-1 to the body on an as-needed basis. I'm unable to advance my slides. We have nominated the Rejuva-001 candidate for type 2 diabetes, which we think can really solve a lot of the problems that are left behind after semaglutide and tirzepatide, because we can offer something that has a one-time administration with nutrient-responsive GLP-1 expression. The design of this product is an AAV9 vector that delivers the human GLP-1 transgene, expressed via the insulin promoter and regulated via the insulin promoter, and delivered locally to the pancreas via an endoscopic needle.
The advantage of the local delivery is our proprietary automated endoscopic delivery device, which enables this procedure to be done in about ten minutes in an outpatient setting. A needle delivers AAV directly into the pancreatic parenchyma via direct endoscopic ultrasound visualization by a gastroenterologist. We can deliver a low dose of virus because we're delivering it locally into the pancreas, and we've demonstrated in pilot biodistribution studies, limited systemic virus exposure. So we get a lot of pancreas transduction of these of the viral vector, but limited exposure to the circulation. Islets are actually readily accessible in this manner via already established routine upper endoscopy, which is a procedure that is performed hundreds of thousands of times each year in the United States already.
We’ve done some things to the device and the procedure to further mitigate any risk, and have now tested this in over 60 survival animals, using the Yucatan pig as our model, in order to be able to show that we can successfully deliver gene therapy in a dose-dependent manner directly into the pancreas, be able to transduce and express the genes of interest within the pancreatic beta cell, and regulate the expression of those genes of interest in exactly the way that you’d expect the beta cell to perform. We’ve taken a prototype of our Rejuva-1 candidate and compared it to semaglutide in the db/db mouse model, which is a standard regulatory model for type two diabetes drug development.
You can see in the red a single injection of the gene therapy vector or a vehicle versus chronic administration of semaglutide in this rodent model, which is the relevant rodent model for the development of semaglutide and tirzepatide and other drugs for type 2 diabetes. When you look at panel A, you can see that the vehicle control animals become very hyperglycemic over an eight-week period of time after the start of the study. Semaglutide can prevent that blood sugar increase by about 200 milligrams per deciliter, but requires chronic administration, and the gene therapy, shown in red, more than doubles the potency of what semaglutide achieves in this model.
As one would expect in this model, which is losing the ability to make insulin, which is why blood sugar is going up, semaglutide can increase insulin production, but the gene therapy can increase the insulin production more, explaining why it has greater effects on blood sugar than semaglutide does, and surprisingly and intriguingly, we saw a pretty substantial difference in weight loss, which is almost impossible to achieve in the db/db model, which raised really interesting questions about the gene therapy's potential in obesity, so we then pursued a study of the prototype against semaglutide in the diet-induced obese model, which is a standard obesity model for the development of drugs in the obesity space. Here, again, doing a single injection of the gene therapy vector, comparing it to daily administration of semaglutide, but with a twist.
At the end of one month, we stop the semaglutide, and we randomize those animals to either getting a vehicle control, now coming off of Sema, or to getting a one-time administration of the gene therapy, and the results are beautifully, exactly like you would expect. Vehicles maintain their body weight over a period of one month. Semaglutide loses a little bit over 20% body weight. Gene therapy arm, in red, loses nearly 30% of the body weight. But look what happens when you stop the semaglutide and then give these mice a vehicle, is their body weight rebounds very rapidly back to where it was at baseline, unless you switch them over to the gene therapy and then maintain these benefits.
This is how we anticipate using our Rejuva gene therapy platform in obesity and type two diabetes, is to use the dose titration period on the GLP-1 drug to be able to establish safety and tolerability, to achieve a clinically meaningful effect, and then transition patients to the gene therapy for lasting benefit that does not require ongoing administration in a group of individuals where we already know that the GLP-1 is having desired clinical effects. So in summary, on Rejuva-1, our nutrient-responsive GLP-1, it utilizes our proprietary intrapancreatic delivery system. It's designed for improved potency and tolerability compared to other approaches. We've seen now efficacy in both the DB/DB and the DIO mouse models, and seen superiority to chronic semaglutide in those models. We've achieved regulatory alignment on the key IND-enabling studies for type two diabetes, first in human study.
Those IND-enabling studies are underway, and we anticipate in nominating a Rejuva-002 candidate in before the end of the year, as we start moving the Rejuva-1 candidate into the clinic next year. And so with that, I think even though we started a little bit late, ending on time, and I really thank you all for your patience when we got started today. Thanks so much.