Good morning, everyone, and welcome to the Fractyl Health data call on the top-line results from the pivotal cohort of REMAIN-1. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentation. As a reminder, this call is being recorded and a replay will be made available on the fractylhealth.com website following the conclusion of the event. I'd now like to turn the call over to Brian Luque, Head of Investor Relations and Corporate Development at Fractyl Health. Please go ahead, Brian.
Thanks, Tara. 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 one to month six and in fact doubled between month three and month six. 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 cm 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 mg 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 two to three zeros consistent results. Just as important is the responder analysis. One in three Revita participants either maintained their GLP-1 weight loss or lost further weight even after stopping high-dose tirzepatide. One in two 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.
Revita was highly statistically significant with a growing effect size in the full mITT population, and the results look even better with longer lengths of ablation. Patients receiving at least 12 cm of treatment had 43% less weight regain than sham. Those in the highest ablation length cohort who received more complete treatment of the full duodenal mucosa had 53% less regain than sham and nearly 60% less than expected from historical GLP-1 withdrawal studies. The corresponding nominal P values here are 0.001 and 0.003 versus sham, respectively. These are consistent, substantial, clinically meaningful observed differences, and the pre-specified hypothesis in this study indicated that more complete ablation can produce a larger effect. We also now see that the procedural efficacy threshold for clinically meaningful improvement is lower than we previously observed in our pilot study.
Twelve centimeters of ablated length below the greater than 14-cm benchmark seen in the smaller midpoint cohort. What does it mean to ablate more mucosa in this procedure? Each ablation step covers 2 cm of the duodenum, and interventionalists move proximal to distal as they apply treatments to each segment. Each 2-cm ablation segment is roughly two minutes, so going from 14 cm- 20 cm is about six minutes of incremental procedure time. In this study, physicians took caution on their first cases, but as they grew comfortable over several procedures, all investigators increased the length of the duodenum that they consistently ablated and achieved therapeutic doses within the study. If cleared, we expect this longer length of ablation to become standardized in how physicians train and certify if approved.
We are confident from our technical success in the study and our safety profile that this is going to be part of the algorithm as we go forward. On this graph, you can see the weight regain trajectories from historical studies of semaglutide and tirzepatide withdrawal, and from our own pilot sham control. The open circles on the right show where we expect the sham to land at 12 months, with 60%-70% of weight regained by that time. The science around GLP-1 withdrawal is clear. Patients tend to regain nearly all of their pre-GLP-1 weight by 18 months, and the rate of regain is proportional to where the weight set point will be at 18 months.
You can see the sham arm in our pivotal regaining weight rapidly in the gray solid line, and historical experience suggests the sham should end up at 12 months where the prior data show. Further down, you can see how the Revita arms at various ablation lengths have performed through six months with a dose response as a function of ablation length and 85% of weight loss retained in the longest ablation cohort at six months. These Revita weight trajectories in the pivotal study are very much in line with our pilot experience, which overlaps through six months and plateaus at approximately 80% weight loss retained at one year. This plateauing of body weight regain is a very big deal. It suggests that Revita patients are trending toward a lower weight set point than where they were before they entered the study.
That is our core hypothesis, that Revita can deliver a fundamental reset to the body's abnormal weight set point. Turning to safety, there were no device or procedure-related SAEs. Serious treatment emergent events occurred in two Revita participants and four sham participants. None was independently adjudicated by a DSMB to be probably or definitely related to the device or procedure. Related side effects were predominantly mild, Grade 1 events. 94% of those Revita events occurred within seven days. The vast majority of them occurred on the day of the procedure alone. These are acute procedural events, not lingering effects. Common events included oropharyngeal pain, nausea, abdominal pain. The risk window here appears to be short and predictable.
When you consider that a major reason for GLP-1 drug discontinuation is the drug class's side effect profile, which is neither short nor predictable, we view the mild periprocedural pattern as highly encouraging for patient enthusiasm. On to patient adjudication. REMAIN-1 had excellent retention through six months, with 94% of participants attending the six-month visit. Sham participants were three times more likely to restart an anti-obesity medication than those in the Revita arm. That three times difference is a conservative estimate, and the observed sham effects potentially mask the true treatment effect of Revita. This high rate of restarts mirrors what we are seeing in the field with the latest GLP-1 drug studies. We anticipated this possibility, especially as GLP-1s have gone from a regulated market to a widely available consumer market where patients can effectively restart on demand.
Our stats plan included a pre-specified framework for handling those events. Let's look ahead to the upcoming 12-month endpoint. The second co-primary evaluates the proportion of Revita patients who remain at least 5% below their starting body weight at 12 months against a 50% performance goal. Applying the endpoint methodology at six months, the model estimated responder rate was 97.2%, nearly double the 50% performance goal. The nominal P value at six months was less than 0.0001. If and when the second co-primary endpoint is also met at 12 months, then our pre-specified key secondary endpoints will also then be evaluated in sequence for formal statistical testing. This finding is robust to key sensitivity analyses, again, as we showed with co-primary endpoint number one. These findings give us substantial confidence as we approach the remaining assessment at 12 months in Q1 2027.
Today's results also allow us to advance the preparation of our potential De Novo submission. As we discussed previously, FDA's pre-submission feedback indicated that Revita's safety profile could be consistent with a Class II De Novo classification. That feedback is advisory with final determination dependent on the agency's review. That provides prioritized review, interactive engagement as we prepare this submission. How does Revita get paid for? There are three favorable developments underway for Revita in coding, payment, and coverage. First, on coding. On October 2, the AMA published Category III CPT code 1122T, a dedicated code for reporting the Revita procedure with submucosal lift and thermal ablation effective on January 1, 2027. Second, payment. CMS's Transitional Pass-Through, TPT, program for Breakthrough Devices supports our potential route to Transitional Pass-Through payment subject to applicable requirements.
If Revita qualifies as we expect it will, that could help hospitals recover catheter cost during the early launch period and support an economically workable service line with a positive contribution margin from day one. Third is coverage. RAPID is a Regulatory Alignment for Predictable and Immediate Device coverage pathway. CMS and FDA announced the RAPID Pathway in April, which may provide a national coverage determination issued the same day as FDA authorization for Breakthrough Devices with final coverage as soon as 60 days later for Class II devices like ours. In the proposed notice, CMS has explicitly requested feedback during an open comment period on a temporary process that could bring devices already under an IDE like Revita into the proposed RAPID Coverage Pathway. Clinical and patient communities are engaged.
The ASMBS, AGA, ASGE, individual physicians, and obesity patient advocacy groups have submitted comments supporting this pathway and Revita's candidacy. If codified by CMS, which is expected in early 2027, this could offer a materially better coverage position than we have been planning for under our base case assumptions and may create a substantial upside in our model. What we are building with Revita is highly relevant to CMS and CMS beneficiaries. The Medicare GLP-1 Bridge program began on July 1, expanding access to obesity medicines and creating a patient population within CMS that is highly relevant to the coding coverage and payment just described. With all of these advancing, together with our highly positive clinical findings, FDA Breakthrough Device Designation, De Novo pathway, they all strengthen the path from a successful procedure to an accessible and scalable business.
Stepping back, what could this mean for Revita's long-term role in obesity? We chose post-GLP-1 weight maintenance first because it is both the hardest test and the clearest near-term opportunity. It is an absolute stress test. Withdrawal of a highly potent appetite-suppressing medication in people with obesity, and today's six-month comparison is, in our view, the definitive central proof point and a turning point for our field. If Revita can change the course of weight after withdrawal of highly potent medication like tirzepatide, we expect that other less demanding clinical settings may show other compelling effects as well. The second compelling use case is adjunctive treatment. Given Revita's excellent safety and tolerability profile, it is complementary to other approaches.
We believe Revita could work alongside rather than compete against any of the vanguard therapeutic options to obesity care to either deepen therapeutic efficacy or enable superior results with less tolerability burden, fewer doses, lower doses, et cetera. That is what we mean by a potential backbone therapy, an intervention that could support patients at multiple stages of care. At our September 1st Investor Day, which I encourage you to go back and review, we reviewed that Revita, if cleared, could become a substantial business. The largest unmet need in obesity, a capital-efficient center of excellence launch, single-use catheter model, leveraging existing infrastructure, and extremely large patient pools within established metabolic practices. You will hear about that from Dr. Dan in just a minute.
We believe the results seen today strengthen our path toward building a profitable business with line of sight to potential cash breakeven within five to eight quarters of launch. Critically, these figures are our base case assumptions, which do not presume a national coverage determination via RAPID. Suffice to say, if RAPID applies to Revita, our launch numbers are conservative. Today, we have reported the pivotal six-month treatment comparison at the core of that strategy. We believe it is a transformative result for Fractyl and the future of obesity care. Here is what to watch for next. Potential De Novo submission later this year, 12-month co-primary results expected in the first quarter of 2027, and from there, FDA review, payer decisions, and if cleared, commercial execution. We are well on our way toward a large and compelling commercial opportunity. Let me bring the story together.
GLP-1s have changed what is possible in losing weight. Our ambition is to change what is possible in keeping it off durably to make Revita the GLP-1 off-ramp. Today's result is the clearest evidence yet that this ambition is within reach, and we believe it could reshape how obesity is treated after GLP-1 therapy. The results open the door to a new category of medicine, one-time outpatient procedures that durably improve metabolic health like [LASIK] for obesity, and we are striving toward that pathway toward durable metabolic health and freedom from obesity and metabolic disease without chronic medicines in the largest consumer market in healthcare. That is an opportunity ahead. I am pleased to be joined by Dr. Adrian Dan, Medical Director of the Weight Management Institute of Summa Health and Professor of Surgery at Northeast Ohio Medical University, and Director at Large of ASMBS.
I turn it over to you, Adrian.
Thank you, Harith. Thank you for that wonderful presentation and recap. I will start just by saying a few words about myself. You do not need to twist a surgeon's arm to speak about themselves for a little bit, but I want you guys to know who I am, and I am honestly honored and humbled to be a part of this. Not something I typically do, but it is my conviction and excitement about the data that we just received and the technology that inspires me to share my thoughts. I have been in practice just over 20 years, all at Summa Health in Akron, Ohio, and my practice consists of metabolic surgery, obesity medicine, and endoscopy. As a matter of fact, you are catching me today at the beginning of a busy endoscopy lineup here.
I did my general surgery training at Michigan State University and followed that with fellowship training in advanced laparoscopy and bariatric surgery at the Cleveland Clinic. I do have a passion for metabolic health. I hope you guys can sense that. I see patients. I have board certification in general surgery with additional focused practice designation in metabolic and bariatric surgery by the American Board of Surgery. Given the shifts in the landscape of obesity management, I went back and received my board certification in obesity medicine by the ABOM a few years back. I eat, I sleep, I breathe, and I live the management of obesity, diabetes, and cardiometabolic conditions. I am the director of our Weight Management Institute, which is morphing into a comprehensive metabolic health center, and years of service and advocacy have led to my election by my peers to serve.
I am humbled to serve as a board of directors of the American Society for Metabolic and Bariatric Surgery. I am not here to leverage that position. I am speaking with my own true convictions and excitement about this technology and the potential to offer this to patients. We are consistently one of the highest volumes in metabolic surgical procedures in our region, in a region that boasts some impressive institutions in Northeast Ohio. Also, in our center, we have five obesity medicine physicians, two APPs that do nothing but care for patients from a medical standpoint, and we also have five bariatric surgeons.
We are a very high-volume center, and we are seeing an inundation, a flood that is overwhelming our center of patients with long waiting lists, trying to get in for initial care as the folks who have already began GLP-1s and have achieved good results are flooding that ability for us to continue taking new patients in. I see this as a very compelling opportunity because the demand for something other than lifelong medications or some of the anatomy-altering procedures that are available, that demand exists on both sides of the equation. On the side of patients who are seeking it and the side of physicians who are excited about offering something that makes sense from a scientific standpoint. That creates a powerful combination where there is growing patient demand. The more patients succeed with GLP-1s, the more people will be looking for a way to lock in those accomplishments.
Also, there is physician interest in a scalable pathway to adoption for hospitals. It makes sense not having to build new care delivery networks and capital investments, and the infrastructure is already in place in every which way you look at it. With that, I will turn it over to you guys for any additional questions about how I see Revita fitting into clinical practice.
Yeah, great. Maybe I can start, and Harith, please feel free to jump in. Maybe talk about your interpretation about the clinically meaningfulness of this six-month data and how it could potentially affect your practice and how you may speak about Revita with patients if approved, cleared.
Well, the first thing I am going to say is that the results exceeded my expectations. I think this is wonderful that we have validation that the concept works. Patients are looking for something durable. They are looking for something minimally invasive, incisionless, and effective. I just look at the difference between patients that I see for surgery, before surgery, who are concerned, worried, nervous. I see my patients today on an endoscopy day where nobody is concerned about an endoscopic procedure. They are actually happy to be here and take a little nap and get a procedure and get a benefit out of it.
What's really exciting is that when looking at the data, there's actually. First of all, in patients that have had more than 20 cm of ablation, the 53% less weight gain with the statistical significance and clinical significance that I see with that amount of weight loss maintenance, that's fantastic. It tells us that with increased quality control, with increased refinement of the procedure, with increased education and appropriate credentialing, we can improve on that, and the greatest likelihood is that we'll improve. That ablation length dose dependence tells me that the concept is validated, that the science makes sense, and that the reset theory is something that I could explain and patients would understand. Also really great is the fact that a third of patients are continuing to lose weight or maintaining their weight loss. That is amazing. That's a win-win for the patients.
They get to come off their medications. They get to escape what they're looking to escape. Initially, patients are quite content to deal with that medication anchor, to deal with the cost of the medication, and the side effects as the dosages increase, because they're finally realizing that, hey, this isn't a choice, an act, or a behavior. This is a disease, and it's proven by the fact that it could be modifiable. After a while they ask, "What is next? What are my options?" I would present patients with all those options, but looking at this data, I can show them numbers. The outstanding safety profile also screams volumes to me. It's something that I can tell the patient, you're looking for something safe, you're looking for something minimally invasive, and the safety profile is frankly great.
When the adverse events, the few that do occur, they are very mild. They occur with procedure itself. I hope that answers that for you, Brian. That's how I see these results. Those are the most important things that jump out at me, and what's exciting is that those are things that I could put into terms that patients understand.
Fantastic. Thanks for that. Maybe a two-parter next. Help contextualize how a patient might think about Revita within its continuum of different treatment options available to the patient. A highly educated consumer market at this point within obesity. They know what's out there. They know what other medications are available. They know what medications are coming. Contextualize Revita within the landscape of pharmacotherapy, maybe juxtaposed to how they're thinking about surgery as the first part, and then second, maybe an abstraction of that. Maybe contextualize the potential patient volumes of maybe how many patients might be amenable to Revita within your practice and maybe more broadly.
Sure. I'll take the first one first. That conversation I alluded to earlier with the patients asking you, "What is next? Where do we go from here?" That's typically guided by the patient, and I think it's important to provide that comprehensive approach where you give the patient all the options. As I said before, initially, the weekly medications, the costs associated with the medications, the side effects are something that the patient is willing to accept. They're actually very excited about the results of their weight loss. But after a while, they're looking for the next step, and I would of course, provide my patients with all the options, and I would imagine, as with every choice we have in life, some will choose to continue the medication. Hey, it's worked. Let's continue to do it.
A few, and depending on their clinical severity of their obesity, may choose to proceed to surgery. But the main reason, Brian, that in the United States and worldwide, we are sorely undertreating the disease of obesity is because there's something missing. What's missing there is what patients are looking for. A minimally invasive, nonsurgical, durable, effective procedure. I think that market and that gap is enormous, and I would certainly provide my patients with all the options. I think patients oftentimes look for that best of both worlds option that currently does not exist, unfortunately, in the commercial sense. I will go to your next question, then. I think that was about where I see this going in terms of the number of procedures. Depends on the size of a center.
A large center like ours, we have a very large volume of patients, probably in the thousands, which are continuing to get chronic medical therapy, office visits every three to six months to follow- up on their progress. I would imagine as this becomes available commercially, we would begin with a few cases before we ramp up. Obviously, as the demand increases from word of mouth and people hearing about the options, and our patients today are highly educated and very wise to what is available out there. Just as a reference, there are a few other endoscopic procedures that are available today that patients ask about all the time. We just don't see that excitement on the physician side because of the cumbersome nature of those operations or procedures, and frankly, the lack of standardization of those procedures and results.
But something like this has the potential of having the patients be very interested. How many can we do? I think the demand is going to be wide. I think if you think about endoscopy centers, I've just happened to look at our board here today. There are endoscopists that do 20, 30 colonoscopies or upper GI endoscopies in a day. They are very quick turnover procedures. There's no need for closure of incisions. There's no need for extensive recovery. Many endoscopy centers, including the one that I happen to be at today, do more than 10,000 procedures annually. So this is something that an endoscopist, the bariatric interventionalists, can add to their practice and be quite efficient about performing 10, 15 of these procedures in a day. Hopefully for centers like mine, hundreds in a month. I fully believe that's conservative estimates.
If you just look at the number of patients with overweight, obesity, morbid obesity, severe obesity that exists in the United States, there's a potential for hundreds, thousands of these being performed annually within the United States.
Excellent. Well, thank you. Thank you for those remarks, Dr. Dan. With that, I think it makes sense for us to open it up to the live Q&A operator. Please begin.
Great. Yes, thanks, Brian. We'll be conducting a question and answer session with our speakers. Please hold for a brief moment while we poll for questions. Our first question comes from Mike DiFiore at Evercore. Please go ahead, Mike.
Hi, guys. Thanks so much for taking my question. Congrats on the data. Two from me, just regarding the higher drug restart rate on Sham, how does the six-month difference look if those patients' weights are kept in under a treatment policy approach? Which estimate do you expect FDA to focus on in the De Novo review? My follow-up question is, the midpoint data was framed around complete ablation length above 14 cm, and it would be helpful to see how that pre-specified group looks in these pivotal data at 6 months. How do you settle on the 12- 18 cm versus 20 cm cuts for today? Thank you.
Yeah. Thank you, Mike. We've been very clear, and we've been working with the FDA on defining the efficacy estimate as the primary evaluation metric in this trial. It's largely because of changes in the field where there are known GLP-1 restarts in placebo arms in a number of different drug studies and device studies that have preceded us. We know this is an issue that the FDA is well aware of. On the second question, with respect to greater than 14 cm, as I mentioned, that is a key secondary endpoint in our pivotal and through our gated hierarchy for statistical control, we will evaluate that formally at the second key primary endpoint, which will come with the 12-month data. You can please stay tuned for that.
Now that we have many more patients in whom we have done the full ablation, what we provide to you is a clear signal with far greater resolution that greater than 12 cm of ablation achieves clinically meaningful results. I believe that that would be what physicians would tell one another is what the minimum that should be done, and I think that more is clearly better at six months, as evidenced by the data here. I think that's going to inform how folks like Dr. Dan and the societies will certify and train their folks. It also goes to show, given the absence of any observed adverse effect level at that level, that we are just in the early innings of profile optimization.
We chose greater than 12 cm because that is the amount of ablation where we're beginning to see clear evidence of efficacy, and we chose 20 cm because that is generally the full length of the duodenum in most individuals. You will see the greater than 14 cm, when we have it at 12 months.
Great. Thank you.
Thanks for the questions, Mike. Our next question comes from Whitney Ijem at Canaccord. Please go ahead, Whitney.
Hey, you guys. Congrats on the data, and thanks for taking the questions. I guess first for Dr. Dan, maybe, we're starting to see more data in the weight maintenance setting from non-incretin-based therapeutics. Just curious your thoughts on the data we're starting to see there and maybe thinking about the Revita data in the context of that and how you might think patients would respond to different non-incretin-based options, including Revita, in an ultimate commercial setting, based on some of the early efficacy we're seeing so far. That's first question. Then second question, just to follow up on the 20% of Sham patients who restarted weight loss drug.
Sorry if I missed it, but at what time points, or do you have any more data on those patients, and do you have or are you planning to run an analysis on the patients who did not restart weight loss drug relative to the Revita arm? Thanks.
I'll take the first one. Thank you, Whitney, for the question. I would imagine that you're referring to some of the other endoscopic therapies, balloons, suturing procedures.
Probably the other drugs, Adrian, the other drugs that are coming out now.
Yes. If you're referring to the other drugs, yes, the efficacy of GLP-1 and incretin-based therapy and non-incretin-based therapy are continuing to improve. That is without a doubt, and beyond the scope of going into great detail in this answer. However, the more people succeed with them, the more people will be looking for a way to lock in those accomplishments, to lock in those health benefits. As we all know, it does not take more than 15%-20% of total body weight loss to get some amazing health benefits, including sleep apnea resolution and improvement of diabetes, if not resolution of diabetes and so many other things. I think that, in a nutshell, the GLP-1 therapy is creating the success that Revita will help lock in and secure for patients, and I think that's a powerful thing for them.
I'll take the second question, that folks resume GLP-1s at various points in time in follow-up, and you can sort of infer when those were based on the ends at each of the time points. Some patients clearly became extremely hungry two to three weeks after the discontinuation of the GLP-1 in the randomization, right after randomization, and restarted early. Some restarted a little bit later. Per our pre-specified analysis, we censor all data post GLP-1 or anti-obesity medicine resumption and then take the last weight beforehand in the efficacy estimate. That's how this is done. That's how the field's handling these issues today.
Got it. Very helpful. Thank you.
Thanks, Whitney. Our next question comes from Nick Mattiacci at Craig-Hallum. Please go ahead, Nick.
Good morning. This is Nick on for Chase Knickerbocker. Thanks for taking our questions. If you guys could talk about your confidence that the De Novo review clock can begin before the submission of the 12-month data on the second co-primary, and if you could also discuss your best and worst case timelines around how you see the review and potential approval timeline for Revita.
I would assume that the clock will begin when we announce our second co-primary endpoint success, and that is expected to occur in Q1. I think that we will get this process started, but I don't think that the FDA review clock could be expected to begin before then. That's an active topic of conversation, and that means a few month delta between end of this year and in Q1, but less than a quarter.
Got it. The second one is, how do you guys think physicians will think about the placebo-adjusted effect size versus absolute weight regain data for Revita? That same question's for how payers might think about that.
Yeah. I think, number one, the placebo-adjusted effect size is growing. I don't think we'll know where it lands actually until we're at 12 or 18 months, but you look at the historical controls and where the sham is likely headed, and you look at where Revita is headed, especially in the longer ablation cohorts relative to the midpoint, we feel very confident in that effect size being robust. I think that when a doctor talks to a patient about this in a consumer market, they're not talking about placebo-adjusted effect size. What we have done here with this study is we have clearly, in a prospective manner, established the efficacy of Revita versus a sham in the most rigorous test of immediate and complete discontinuation.
Now that that question is addressed and disposed, I think when a doctor talks to a patient about this, the doctor's going to say, "Here's what you can reasonably expect to happen to you." But I would love Dr. Dan to weigh in and share his perspective.
No, Harith, I completely agree with you on that. I think patients are looking for very simple answers to, how will I be able to maintain my weight loss? I think that's the conversation you're going to have with them rather than the other mentioned points.
How compelling is this notion that one in three patients might maintain their body weight or lose further weight even after stopping a GLP-1 in the absence of ongoing therapy? How would that resonate? If you've talked to patients about Revita, maybe an opportunity to just say as a potential solution, what you've kind of heard from them.
Yeah, I think patients would welcome that. I think patients would be very satisfied with maintaining their weight loss. The possibility of additional weight loss, especially as we begin to understand what cohort of patients is likely to continue to have weight loss is the cherry on top, so to say.
Great. Thanks for taking the questions.
Yeah, thanks.
Thank you, Nick.
Yes, thanks for the questions, Nick. Our next question comes from Chi Fong at Bank of America. Please go ahead, Chi.
Oh, hey, guys. This is Chi on for Jason Gerberry. Thanks for taking our questions. The first one is for the company, I guess. Harith, what's your confidence level for the 12-month co-primary endpoint based on the six-month data and trajectory of the curve separation? Along the same lines for that one-year endpoint, in addition to maintaining at least 5% of total body weight loss relative to the pre-tirzepatide weight, can you clarify whether Revita would need to be statistically different than sham arm on the weight maintenance at that one-year time point? Then I have a follow-up.
Okay. Highly confident based on where we sit today. We do not have any pre-specified Revita versus sham analysis at 12 months in the SAP. We will, of course, do exploratory looks, but there is nothing defined.
Got it. My second question is for the doctor. Curious what proportion of your current GLP-1 patients want to off-ramp from pharmacotherapy? Of those, how many of them do you see them getting a Revita procedure?
That's a great question, Chi. Thank you. As usual things, you could do the exact same procedure, same drug on 100 different people and get 100 different results because it's really the physiology that makes that difference. It really depends. The most compelling reason to consider the off-ramp is typically because of cost, because of the inconvenience of weekly medications, and of course because of the side effects as the dosage increase to get better efficacy. I could tell you that I have a conversation about one of those things in the large majority of my patients who have been on GLP-1s for a year or two and have achieved the types of results that we have in our run in numbers, in REMAIN-1. One of those things will come up.
After a couple of years, the concept of moving on to something else, looking for a different way to lock in the results is quite prevalent. We have thousands of patients in our centers. There are thousands of centers across the country. I don't know that I could put an exact percentage on it, but the conversation is quite common and, I think that is what gives me the conviction that the interest will be quite high.
In year one, how many Revita procedures might you do per month?
Year one, Harith, I would imagine is something that we would be ramping up, but I think I'd have no problem, with coverage, being able to do 50- 100 per month between myself and my partners in the average metabolic center.
And then ramping up from there?
I think ramping up from there, it could be in the thousands. If you just look at an endoscopy center, again, tens of thousands of procedures done a year. This is something that is very high turnover, very effective, very efficient in terms of getting the procedures done. With the complex anatomy altering operations, it is not the same.
Thank you, Chi.
If I may squeeze in a follow-up for the doctor. How important is the safety profile to you? Curious of thought. There is efficacy part-
Yeah
-of the equation, but how much is it just simply, if you were to have a safety device, how much is it, why not? Let's give it a try. If it works, great. If it doesn't, then we can look for alternative, but at least you can try it. Just curious how much safety, as an important component, as you think about a device like Revita.
Yeah. Chi, that's a wonderful question. As a clinician, that's incredibly important. That's why I chuckle a little bit because, I'm a bariatric surgeon, and we have improved the safety of those procedures tremendously. However, patients do not see it that way. We love the complex procedures, patients do not, and the biggest hurdle is for patients to realize that the risk-benefit calculus is very favorable to them. That's the most likely reason that a patient should say, "Sure. Let's go ahead and proceed with this therapy." We see that difference between taking a pill or a shot in surgical interventions. We have 30 million. That's the most conservative estimate I've heard in a long time. 30 million patients that we know of that are on GLP-1s in the United States because people want that low-risk approach.
For reasons I don't want to get into, there's so much that the patients just don't feel that anything high risk is something that they want to, that they have, no pun intended, appetite for or is palatable to them. That is incredibly important to be able to point to that data and show them the low severity of the adverse events have been meticulously collected and the data has been meticulously put together. But for patients to see that they're so mild and they occur in the first few days after a procedure, that is something that is incredibly important to me as a clinician to be able to have the patient get excited about it, and really focus on the benefits more than the potential risks.
Thank you.
Thanks, Chi. Our next question comes from Jeff Cohen at Ladenburg. Please go ahead, Jeff.
Good morning, and thank you for taking our questions. I guess firstly, for Harith and/or Dr. Dan, could you talk about the responder rate of 12 months and hypothesize with us what that might look like and the treatment effect upon the different duration, different length effect of 12, 14 or 20 cm?
I'll take that. You can tell that we are trending towards an extremely high responder rate already, just based on 97% at six months and then, how those curves are going. I have obviously no concern about crossing the 50% threshold. I can't pin for you exactly where those numbers are going to land yet, but it's looking very favorable. When I look at the trajectories of the different ablation lengths, I see something very reassuring there in how clean that is, again, with the larger end than we had in our midpoint cohort. I think you can reasonably overlay what we're seeing from the pivotal with what we have already seen from the longer ablation cohort in the pilot. That I think is going to give you some sense for where we think things are going.
Got it. Secondly, could you talk about participants and where you think you'll end up at 12 months? I know that you're at 176 and 74 in the sham
Yeah, retention remains high. Adjudication of intercurrent events is really one question that is going to be. That's really the only question that I don't have an answer for you yet. We've had excellent study execution, excellent follow-up, data collection, timeliness. We'll report all of that to you soon.
Perfect. Thanks for taking our questions.
Thanks, Jeff. Our final question comes from Joe Pantginis at H.C. Wainwright. Please go ahead, Joe.
Hey, everybody. Thanks for taking the questions, and very nice data. I apologize if my question has a little bit of a longer setup, but this is targeted to Dr. Dan, please. These data today are highly statistically significant. The forest plots clearly favor Revita in each assessed characteristic. I guess my question is, surrounding the chart of the weight regain for both arms, I think there may be some misperceptions out there about Revita's weight gain as well. Despite the positive data here today, can you discuss the importance of the endpoint of the 5% hurdle, that you would not gain 5% or more of your original baseline weight, and why that's important to patients? Thank you.
Harith, do you want me to take that, or do you want to start?
Sure. I think this all boils down to clinical meaningfulness and use, ultimately, Adrian. Please, you take it.
Yeah. Especially with some of the bariatric procedures, there's a misconception that people need to lose all of their excess weight in order to see clinical benefits. We see clinical benefits with as little as 5%-10% excess weight loss, let alone total body weight loss or slightly different measurements. But I think that's a very appropriate threshold. I think that's an important point that you can make to the patient, is you can maintain this and maintain the benefits that you've already achieved, and you can lock them in. Am I covering the whole question, Joe, or was there something else?
No, I guess that's really it. I think, again, it's just focusing on the misperceptions of the charts and the regains and that what is clinically meaningful. I think you really did hit that even 5% weight loss following stopping of, say, tirzepatide, is beneficial to your patients. Not looking to parrot back your answer, but I'm just looking to confirm that.
Yeah. A few things I would mention is that we see in a third of patients, they continue to lose weight. So that gives us the potential for further weight loss, and there's quite a substantial amount of data and evidence that the amount of weight that it takes to gain clinical benefits, decrease in heart attacks, strokes, resolution of diabetes, improvement of diabetes, all those, is in that magnitude. So that's why I think that would be something that patients will embrace because it'll be enough for them to maintain the benefits.
I'm glad you mentioned the one in three, because that was part of my second point here, and I guess more for the company. This study here, and before we get the 12-month data, this is all based on improving procedures, and by the time, hopefully, it gets approved, the procedure and the ablation lengths will be even more optimized to hopefully raise that one in three metric there. Hopefully, that's a safe projection.
That's exactly what I wanted to bring up, is the fact that we have to be purists. We have a methodology, and we have to stick to it and look at the data as a whole. But if you compare the sham to the optimal ablation length population group, that's what I envision future results will show that and then some as we refine the procedures. That's a real comparison that we need to make. We will continue to refine this. I'm excited about that as a clinician, and it will continue to get better. That's my theory looking forward. So I'm glad you brought that up. The ablation length dose dependence I think is extremely important.
We've said all along that complete ablation is going to deliver fantastic results, and it is. We're getting high statistical significance in the full ITT population. That clears an extraordinarily important hurdle. We have no safety signals, and yet excellent efficacy at more complete ablations, which is exactly what we had indicated. So I feel like we have a huge win here.
Thank you for the added color.
Thanks for the questions, Joe. At this time, this concludes our Q&A session and the overall event. We thank you for joining, and you may now disconnect. Have a great day.