We're gonna get going here with our next company presenter at the B of A Annual Healthcare Conference. I am pleased to be introducing Fractyl Health and CEO and Co-founder, Harith Rajagopalan. So Harith, thanks so much for joining us, and for those on the webcast, my name is Jason Gerberry. I'm one of the mid-cap biotech analysts at B of A. But yeah, Harith, fresh off the IPO start of the year, and you guys are, I guess I'd characterize you as a hybrid company in terms of a device, but also a therapeutic play. So, unique from that perspective with your device now in pivotal stage testing with an important readout at the end of the year.
So maybe if you wanna just introductory remarks, but just thinking, how do you help frame investors through what Fractyl Health is, where—how you're trying to change the world, and help patients?
Thanks, Jason. It's a pleasure to be here. My name is Harith Rajagopalan. I'm the Co-founder and CEO of Fractyl Health, for those of you who are joining online. We started Fractyl with a simple but audacious goal, which is to eradicate metabolic diseases, including obesity and type 2 diabetes. I think that the word eradication is important because we think about chronic diseases as diseases that we're just succumb to managing for the rest of a person's life. But I was a physician in cardiology at the Brigham. I saw a lot of patients with coexisting type 2 diabetes, cardiovascular disease, and obesity.
I saw the effect that chronic disease has on people, and I thought, "It's just not sustainable for society to continue to chronically co-manage more and more conditions with more and more medicines." And we live in a world now where the obesity and type 2 diabetes landscape has been totally transformed by GLP-1 drugs. They're incredibly effective, and yet we're also beginning to see limitations. Limitations like you need to be on chronic therapy; it would seem like, for the rest of your life, in order to be able to continue to benefit. Thank you to Oprah for making that known to the entire public a couple of weeks ago on her special.
You also are seeing that when you discontinue the drug, you get a rebound in weight, you get a rebound in blood sugar, and you undo a lot of the benefits of having been on the drug. This is part of the reasons why payers are so resistant to paying for the medicines. And then third, perhaps most surprising, is that a majority of the people who start on GLP-1s stop them, often within the first one or two years. And so that, I think, is most shocking because you would think that if they're working for you and if you can afford them, then you would stay on them. But there's a lot of reasons why people stop them. It's not easily understood.
And so we're now living in a world where we can lower weight and we can lower blood sugar, but we need to figure out ways to keep it off for the masses. That's where Fractyl comes in. We have two technologies in development, Revita and Rejuva, that are both designed to offer long-term benefits after a single administration, both on glucose and on weight. And the way that we do that is by targeting very precisely the organs that become diseased in the body after a chronic exposure to high-fat, high-sugar diet, that are root causes of obesity and type 2 diabetes, and we aim to correct the changes that have taken place so the body can go back to managing its weight and its blood sugar at a normal level again.
We think that the highest aspiration for people with disease is to live a life that is free of disease, that is healthy. It's pretty clear that you can't call yourself healthy if you are reliant on medicines in order to maintain that and dependent upon them in order to maintain them for you. I don't think most people would call that true health. What we aim to do is to try to bend that curve with our two product platforms in development, to try to get people to a healthier state so that they can live a life that is more free of disease. That's what we're all about.
Got it. Okay. We'll start with your lead program, Revita, and maybe the simplistic description of it is organ remodeling, right? And so, what led you to go down this pathway? What, you know, inferences, what data gave you the confidence that this might be an approach that could improve an insulin-dependent diabetic's blood sugar, body weight, all the parameters that you wanna show improvement on in diabetes, and maybe lessen the treatment burden that you're currently undergoing?
Yeah, thanks. So we've known for 20+ years that bariatric surgeries that are targeting the gut, that change how nutrients are processed by the gut, can have very long-lasting effects on obesity and type 2 diabetes. But what we've learned in the recent past is that chronic exposure to high-fat, high-sugar diets cause changes to the lining of the gut and the way that the gut communicates with the brain in order to help the brain know how to regulate your weight and your blood sugar. So, when you bypass the duodenum, which is the first part of the small intestine, with a surgical procedure, you get an immediate improvement in blood sugar and in the ability of the body to control body weight, but doing a surgery on 30 million people with type 2 diabetes is unreasonable.
So what we hypothesized when we started the company is that perhaps you can ablate the duodenal mucosa to reverse the pathological change, allow the body to regenerate a renewed mucosa that may normalize the gut-brain signals that will help the brain be able to regulate blood sugar and body weight again. And this is a device that we've developed in order to enable us to safely and effectively, hopefully, ablate the mucosa. It's in a pivotal trial to test exactly that question in type two diabetes, called the Revitalize One study, which is nearing the end of enrollment and will have top-line data at the end of the year. And it's intriguingly also showing results in the ability to help people maintain a lower body weight for a prolonged period of time.
And that's become super interesting when, like we just said, GLP-1s can help you lose weight, but they don't seem to be very effective in helping you keep it off. We were approached to ask by, by several players in the field whether Revita may be able to enable you to maintain body weight loss for people who are stopping GLP-1s. And it seems like the duodenum is like the hunger center of your intestine, and if you can reverse that pathology, you may be able to reverse the hunger that's driving people to regain weight. That's what the REMAIN-1 study is intending to investigate.
Okay. And with the first study, the Revitalize-1 study, I believe the goal, the primary endpoint, is the sham-adjusted 1% A1C improvement. Correct me if I'm wrong.
The regulatory threshold is a statistically significant improvement in hemoglobin A1c-
Okay
- compared to a sham of at least about 0.3%.
Okay. And then the clinically meaningful threshold in your view is?
I think a home run would be 1%, because-
Okay.
The reason I would call it a home run is because these are patients who are very severely advanced in their diabetes. They've exhausted all other medical therapies. If you were evaluating like a cancer chemotherapy, you would be calling it a fourth-line type of a therapy.
Okay.
I don't think we need that. Because if you look at what we're seeing in the real world in Germany, which will complement our efficacy studies, we're seeing in open label, real-world experience, really meaningful hemoglobin A1C improvements and weight loss. That gives us encouragement that we'll get. We have the chance to get good effectiveness once it's implemented in the clinic.
Yeah, so talk about that, your observations from that German data, clinical observations, some of which have had to be maybe benchmarked against historical control. Some of it has been controlled data, but, how you piece all that together and what sort of underpins the confidence on your registration endpoint, which is ultimately for investors, you know, where the focus begins, and then you kind of branch out to the other benefits of the therapeutic.
Of course. A lot of the pilot studies of Revita were conducted in Europe, and we have a CE mark in Europe, and we are also now reimbursed by the German government, where we've opened up a single-center real-world registry and been accumulating data there. We just reported on Monday data from the first 14 patients who've gone through that real-world experience, and we shared that patients' hemoglobin A1C improved from 9.2% to 7.6%, body weight loss of over 8%, total body weight loss, in a population of people with type two diabetes who are, have had disease for 13 or more years, are on multiple glucose-lowering agents, who are being treated in exactly the same way from a procedure standpoint as they are in the Revitalize-1 study.
And what we're seeing is that they lose body weight and blood sugar by month 1, and they're seeming to sustain that through 6 months so far. That is the registrational endpoint.
Mm-hmm.
of hemoglobin A1C that's relevant in Revitalize-1, and that's what gives us some confidence that it reads on the anticipated outcomes from the pivotal trial.
Okay. And so single pivotal trial, positive, what would be the sort of the next steps to getting that to market?
So this is regulated as a device by the FDA. It's a PMA process, and so we will have three components to that, like a device module, which describes the device and its design. Sorry, a design module, a manufacturing module that describes how we assemble our device, and then the clinical module, which will incorporate the data from the single pivotal trial.
Mm-hmm.
In conversations with regulators, we believe that this single pivotal trial, if it reads out favorably, should be sufficient for a PMA filing, which we would move to as soon as we read out our data. Then the PMA review process will take roughly a year, maybe expedited, because Revita has breakthrough device designation in the United States, and that would then set the stage for us to think about launching.
Yeah. Okay. And then, you know, we've been talking to you for a while now, you know, even at the time, the company was private, and you talked about GLP-1s, and I think the clinical program for Revita has evolved with GLP-1 therapy. So maybe just talk about how you're kind of evolving the clinical program in step with how the market's evolving.
Sure. So when we first talked to regulators about running a pivotal trial, we were... You know, the consideration that was put on the table, not by us, was to exclude patients on GLP-1s because the GI side effects might confound the anticipated safety profile of Revita. That clearly was a non-starter, especially now that we're hearing that one in four people with type two diabetes has tried a GLP-1, and it's a standard of care. That's changed so dramatically just in the past couple of years, and so now the Revitalize-1 study enables patients who are coming in on a GLP-1.
One of the interesting observations there is we think about GLP-1s and their efficacy, but a substantial proportion of the patients who are coming into our trial are on GLP-1s and yet still inadequately controlled with their diabetes, suggesting that it's not enough just to expect that GLP-1s are gonna solve the problem, and Revita may be an, a great solution for those patients. In addition, as we talked about a little bit earlier, there's a lot of people who are starting GLP-1s, and there's a lot of people who are stopping them. And I think it's becoming pretty clear that with the high discontinuation rates that we're seeing, we need to figure out an off-ramp from GLP-1s that allow people to keep the weight off without the rebound in hunger and weight gain that we're seeing.
So we're excited about our new REMAIN-1 pivotal study. Just in the time that we've gotten to know you, Jason, we've made a huge push in order to accelerate our engagement with the agency on that. The agency, we were able to work very collaboratively with key stakeholders in order to be able to get this study approved. I think the reason that that was happening is because people are realizing how important of a disease obesity is, and that we can't just rely on chronic pharmacology for the rest of people's lives to manage it. So if Revita can offer durable weight maintenance after people stop GLP-1, we think that's a massive opportunity.
Yep.
And we're excited to see how the data will. We'll be seeing open-label data from the REVEAL-1 cohort and then randomized data thereafter.
How important will it be, the weight loss signal in Revitalize-1, to reading across to REMAIN-1 and, you know, different scenarios of weight reduction, how that'll impact, you know, how you approach REMAIN-1 and willingness to run that trial through? If you don't see a signal versus if you do see a signal, you just stay the course.
There's so many things going on in an advanced Type 2 diabetic, who, where medicines are being adjusted and glucose is being lowered. We do expect, as we've seen in prior studies, to see weight loss in Revitalize-1. But weight loss in a Type 2 diabetes patient population that's advanced, even with GLP-1 drugs, is extremely modest relative to weight loss in an obese patient population. So I think a signal of efficacy would be highly informative, but we'll be looking at the REVEAL-1 open-label cohort in order to really give us a sense for the anticipated success of REMAIN-1, 'cause it's a different patient population.
Got it. We have a little less than a minute, but just Rejuva, the high points here. When you expect to start, be able to dose patients initially? I imagine it'll be in a staggered manner as you kind of dose patients, observe safety, and then get more leash from regulators to dose more patients.
Right. So just very briefly in the last 30 seconds. Rejuva is a pancreatic gene therapy platform that we've developed. It's critically enabled by the local administration of AAV directly into the pancreas with a catheter that we've developed. Our first product candidate, Rejuva 001, is anticipated to be a one-and-done GLP-1 for the treatment of Type 2 diabetes. We've got some incredible proof of concept data compared to semaglutide head-to-head in diabetes and obesity models, and we're anticipating a first in human to begin in the first half of next year.
All right, great. Well, thank you so much for joining us at the conference, and best of luck with the rest of your meetings.
Thank you so much, Jason. Appreciate it.