Fractyl Health IPO investment analysis

January 30, 2024

This is not investment advice. We used AI and automated software tools for most of this research. A human formatted the charts based on data / analysis from the software, prompted the AI to do some editing, and did some light manual editing. We did some fact checking but cannot guarantee the accuracy of everything in the article. We do not have a position in or an ongoing business relationship with the company.

Fractyl Health is developing therapies for type 2 diabetes (T2D) and obesity. The company leverages innovative strategies aiming to shift from symptomatic management to durable, disease-modifying therapies. Fractyl Health targets the root causes of these metabolic diseases, potentially offering long-term solutions beyond current pharmacotherapies' limitations.

The increasing prevalence of T2D and obesity poses a significant public health crisis, with around 100 million individuals affected by prediabetes, obesity, or T2D in the United States alone. Despite the efficacy of current treatments like GLP-1 receptor agonists (GLP-1RAs), limitations exist, notably in therapy adherence and long-term disease progression control. Fractyl Health addresses the critical unmet need for therapies that provide durable metabolic health maintenance without the necessity for lifelong daily or weekly pharmacotherapy.

Product Pipeline:

• Revita DMR System: Fractyl's leading product, Revita, is an outpatient procedure targeting duodenal dysfunction — a key pathological driver of T2D and obesity. The therapy uses hydrothermal ablation of the dysfunctional duodenal mucosa, presenting a novel approach to directly modify disease progression. Revita has received Breakthrough Device designation from the FDA for improving glycemic control and eliminating insulin needs in specific T2D populations. It is approved for certain T2D patients in Europe, with ongoing and planned pivotal studies to expand its indications.
• Rejuva PGTx Platform: A pioneering pancreatic gene therapy platform designed for long-term remission of T2D and obesity by modifying metabolic hormone function in pancreatic islet cells. Preclinical studies highlight its potential to outperform current GLP-1RA therapies, with IND-enabling studies for the first candidate, RJVA-001, targeted for the second half of 2024.

Risks and highlights

Valuation

We estimate the last private round valued the company at $190M. We estimated an IPO pricing range of $350-550 million. Due to the early-stage nature of the company, we did not conduct a DCF analysis or M&A comps analysis.

Revita procedure

Scientific background

Therapeutic Rationale for Revita in Insulin-Treated Type 2 Diabetes (T2D) and Weight Maintenance

Revita is an innovative outpatient procedure aimed at addressing duodenal dysfunction through a thermal ablation therapy. This dysfunction is seen as a critical player in the development of T2D and obesity, largely due to modern diets high in fats and sugars. Through a process that modifies the duodenal mucosa, Revita aims to reset the gut’s signaling mechanisms to improve metabolic health and potentially ameliorate T2D and obesity.

Scientific and Clinical Rationale:

• Targeting Duodenal Dysfunction: Chronic exposure to diets high in fats and sugars alters the structural and functional landscape of the duodenal mucosa, leading to disrupted nutrient sensing and signaling. Such disruption is a key contributor to systemic metabolic dysfunction, including impaired glucose control and altered satiety, both of which are pivotal in the development of T2D and obesity.
• Metabolic Improvement through Mucosal Renewal: By using a proprietary balloon catheter to ablate the dysfunctional mucosa and stimulate regeneration, Revita aims to restore the gut’s natural metabolic signaling. The regenerated duodenal lining is expected to improve systemic metabolic response, enhancing glucose control and promoting weight maintenance.
• Evidence from Clinical Studies: Clinical data suggest that Revita, combined with ongoing oral anti-diabetic agents and lifestyle counseling, can lead to meaningful reductions in HbA1c and weight in T2D patients. These improvements are indicative of restored metabolic function and have the potential to delay or prevent the progression of T2D and obesity-related complications.
• Therapeutic Advantages:
  • Durable and Repeatable Benefits: The procedure offers the prospect of long-term metabolic improvement, which is a significant advantage over conventional treatments that may lose efficacy over time or require strict patient compliance.
  • Tolerability and Patient Friendly: Revita is well-tolerated, allowing for rapid resumption of daily activities. It stands out as a less invasive option compared to bariatric surgery, with minimal post-procedure discomfort.
  • Broad Implementation Potential: The outpatient nature of Revita and its compatibility with existing endoscopic procedures make it a viable option for a wide range of patients, including those with advanced T2D or patients who seek an alternative to pharmaceutical interventions.
• Impact on Pancreatic Function: While primarily targeting the gut, the benefits of Revita potentially extend to improved pancreatic function. By resetting the metabolic signaling in the gut, there’s potential for enhanced GLP-1 signaling and improved beta-cell function, further contributing to metabolic stability and optimal glucose control.

The therapeutic rationale for Revita hinges on several scientific theories and clinical observations that are at the forefront of metabolic disease research. While promising, it's important to recognize that these concepts, especially those connecting specific gut modifications to systemic metabolic improvements, represent a relatively new and evolving area of study. Below, we address the extent to which the science is established, noting areas of uncertainty or ongoing debate, and assessing the overall level of evidence.

• Duodenal Dysfunction and Metabolic Disease Link:
  • Established Science: The concept that the gut plays a crucial role in metabolic regulation is well-founded. The existence of duodenal dysfunction in obesity and T2D has been documented, and the mechanisms through which the gut influences systemic metabolism, including the role of neurohormonal signals from the gut to the brain, are increasingly understood.
  • Areas of Uncertainty: The idea that ablating and regenerating duodenal mucosa can lead to long-term metabolic improvements is based on relatively recent research. While early clinical data are encouraging, more extensive longitudinal studies are needed to fully understand the durability of the benefits and the potential long-term risks or side effects.
• Clinical Efficacy of Revita:
  • Established Science: There is evidence from clinical trials that procedures targeting the gut, like Revita, can improve glucose control and support weight loss in the short to medium term. Similar mechanisms are proposed to underlie the benefits of certain bariatric procedures, which have more extensive evidence supporting their efficacy.
  • Areas of Uncertainty: Most of the clinical data on Revita come from controlled settings with relatively small sample sizes and short to medium follow-up periods. The extent to which these outcomes can be generalized and maintained in the long term across a broader patient population remains to be seen. Additionally, the optimal patient profile for this procedure, and how it fits with other T2D treatments over the long term, is still under investigation.
• Mechanism of Action:
  • Established Science: The underlying mechanisms involving nutrient sensing, hormonal signaling, and the potential for mucosal regeneration have a basis in established gastrointestinal physiology and pathophysiology. The impact of modern diets on gut health and the concept of metabolic surgery altering the course of T2D are supported by substantial evidence.
  • Areas of Uncertainty: The specific biological processes and cellular-level changes following the Revita procedure are an active area of research. The precise ways in which these changes translate to systemic metabolic improvements and the potential for unintended consequences or adaptations over time are not fully understood.
• Level of Evidence: The overall level of evidence supporting the therapeutic rationale of Revita in T2D and weight maintenance is emerging and promising but not yet definitive. There is a strong theoretical basis, supported by preclinical studies and early-phase clinical trials, suggesting that targeting duodenal dysfunction could be a novel pathway for treating metabolic diseases. However, larger and longer-term clinical trials are necessary to establish the safety, efficacy, and position of this therapy within the broader treatment landscape of T2D and obesity.

In summary, while the science supporting the therapeutic approach of Revita is compelling and builds on well-established principles of metabolic disease, it remains subject to scientific evolution and debate. The potential for Revita to offer a novel treatment avenue is significant, but more research is essential to fully validate its long-term benefits and understand its role in comprehensive metabolic disease management.

Revitalize-1 study

Study Design Summary

ClinicalTrials.gov ID: NCT04419779

Sponsor: Fractyl Health, Inc.

Study Title: Evaluation of the Efficacy and Safety of Duodenal Mucosal Resurfacing Using the Revita® System in Subjects With Type 2 Diabetes on Insulin Therapy (REVITALIZE 1)

Design Overview:

• Objective: To evaluate the efficacy and safety of Duodenal Mucosal Resurfacing (DMR) using the Revita® System compared to a sham procedure in subjects with Type 2 Diabetes inadequately controlled with insulin therapy.
• Approach: Prospective, randomized, double-blind, sham-controlled, multi-center study.
• Participants: Estimated enrollment of 560 subjects with Type 2 Diabetes on insulin therapy.
• Interventions: Active Comparator (DMR treatment) vs. Sham Comparator (similar endoscopic procedure without hydrothermal ablation).
• Follow-up: Subjects receiving DMR are followed for 48 weeks post-treatment, while sham subjects are followed for 48 weeks, after which they are offered to crossover to receive DMR treatment and followed for another 48 weeks.
• Primary Outcome Measures: Focused on various criteria of hypoglycemic events and HbA1c changes from baseline to Week 24.

Critiques of the Study Design

• Double-Blind and Sham Control: The double-blind, sham-controlled methodology is an excellent approach for minimizing bias and placebo effects, crucial for evaluating new therapeutic interventions. However, the effectiveness of the sham procedure as a true placebo may be challenged by patients' perceptions and sensations during endoscopy, which could potentially unblind the subjects.
• Cross-Over Design: Offering the sham group a cross-over to the treatment arm at 48 weeks is ethically considerate but could complicate the interpretation of long-term efficacy and safety data. This design might confound results derived from subjects in their initial 48 weeks versus those post-crossover.
• Outcome Measures: The primary focus on incidences of hypoglycemic events and changes in HbA1c levels is appropriate and clinically meaningful. However, the study could be strengthened by including secondary outcomes that measure patient-reported outcomes, quality of life, or direct measures of insulin sensitivity and beta-cell function.
• Enrollment Size: With 560 subjects, the study appears adequately powered to detect significant differences; however, dropouts or uneven cross-over rates could potentially impact the power of the study. Attrition rates should be carefully monitored.

Operational and Technical Challenges

• Endoscopic Procedure Skill Variability: The DMR and sham procedures require a high level of endoscopic skill, and variability between practitioners could influence outcomes. Standardized training and certification for participating endoscopists can mitigate this issue.
• Blinding Efficacy: Maintaining effective blinding in interventional procedures particularly ones involving endoscopy, is challenging. Measures to ensure that neither the participants nor the outcome assessors can distinguish between the DMR and sham procedures are critical.
• Participant Follow-Up: Keeping subjects engaged for a 48-week follow-up (96 weeks for sham-crossover subjects) is challenging, especially in a population potentially experiencing procedural discomfort or adverse events. Strategies to enhance retention, such as frequent communication and flexible scheduling, will be vital.
• Data Collection and Integrity: Accurate and consistent data collection, particularly regarding hypoglycemic events and insulin dosages, requires diligent monitoring and verification to ensure the reliability of the study's findings.

Conclusion

While the study design of the REVITALIZE 1 trial for evaluating the Revita® system in Type 2 Diabetes appears robust and well-conceived, addressing the critiques and operational challenges will be crucial for the successful execution of the study and the validity of its findings.

The study design for evaluating the efficacy and safety of the Revita® system in individuals with insulin-treated Type 2 Diabetes (T2D) is subject to several considerations concerning its proof-of-concept potential, including the appropriateness of primary and secondary endpoints, inclusion and exclusion criteria, and reproducibility challenges.

Proof-of-Concept and Endpoints

The primary endpoints, focusing on incidences and event rates of hypoglycemic events along with reduction in HbA1c levels, are directly relevant to the intended outcome of improved glycemic control in T2D. These measures are well-recognized, clinically meaningful, and align with the goals of diabetes management, thus supporting the study's objective to provide proof-of-concept.

The inclusion of secondary outcomes, while not detailed here, should ideally encompass measures that address long-term complications of diabetes such as cardiovascular risk factors, renal function, and patient-reported outcomes like quality of life and adherence to treatment. These additional endpoints can provide comprehensive evidence of the therapeutic potential and safety profile of the Revita® system.

Inclusion / Exclusion Criteria

The eligibility criteria are designed to select a participant population that best represents the intended use case of the Revita® system, though they also introduce specific challenges:

• Age and Medication Criteria: The age range (21 to 70 years) and the requirement for insulin treatment with stable doses position the study to evaluate effects in a broad adult population but exclude elderly individuals who might also benefit from such treatment. The permissible use of non-insulin antidiabetic agents (ADAs) allows for a realistic representation of patient management but may introduce variability in glycemic outcomes.
• Glycemic Control and BMI Requirements: A HbA1c of 7.5-10% ensures participants have suboptimal glycemic control, which is necessary for evaluating the efficacy of intervention. The BMI criteria (>24 ≤ 40 kg/m^2) exclude both lean and severely obese individuals, potentially limiting the generalizability of the findings.
• Comprehensive Exclusion Criteria: The extensive list of exclusion criteria, while essential for ensuring participant safety and study integrity, might significantly limit the enrollment pool. Conditions like severe kidney or hepatic disease, acute cardiovascular events, or specific gastrointestinal disorders are common comorbidities in T2D, possibly hindering recruitment and affecting the study's external validity.

Reproducibility Challenges

The strict inclusion and broad exclusion criteria can pose significant reproducibility challenges. By excluding a wide range of comorbid conditions and concomitant medications, the study might generate results that are highly specific to a relatively narrow population of individuals with T2D, thereby limiting the applicability of the findings to the broader T2D population:

• Generalizability: The rigorous criteria may yield a study population that does not fully represent the diversity of people with T2D, particularly those with multiple comorbidities, which is more common than not in real-world scenarios.
• Recruitment and Retention: The complexity and specificity of the criteria may make recruitment challenging and potentially prolong the study timeline. Furthermore, the stringent criteria could lead to higher dropout rates as participants may develop excluded conditions over the course of the study.
• Application to Clinical Practice: The proof-of-concept provided by this study may be difficult to translate into clinical practice if the selected patient population does not accurately represent the target demographic.

In conclusion, while the study design and eligibility criteria aim to optimize safety and efficacy assessment of the Revita® system for insulin-treated T2D, careful consideration of the generalizability and practical application of the results will be necessary to ensure the findings can inform clinical practice effectively. Researchers should be prepared to address the reproducibility challenges posed by these criteria in subsequent trials or broader post-market evaluations.

Revitalize-2 study

The Revitalize-2 study for Revita aimed at treating patients with insulin-treated Type 2 Diabetes (T2D) outlines a comprehensive and phased approach to evaluating the effectiveness of the Revita DMR Procedure. Below is a summarized version of the study design, followed by critiques and a discussion of potential operational and technical challenges.

Summary of Study Design

• Type of Study: A randomized, double-blind, sham-controlled, multi-center pivotal clinical study.
• Stages: Two-stage approach.
  • Stage 1: Open-label, single-arm study for each site to gain experience with the DMR procedure. Sites with previous experience will enroll one patient, while naïve sites will enroll two patients. Additional enrollments can be recommended to ensure proficiency.
  • Stage 2: The primary study phase with up to 400 patients, after a maximum of 110 patients in stage 1.
• Sites: Approximately 35 in the US and 20 internationally, with over 50% of patients from the US.
• Population: Patients with T2D inadequately controlled on two or three Antidiabetic Agents (ADAs) but not yet on insulin.
• Endpoints:
  • Primary: Change from baseline of HbA1c at 24 weeks.
  • Key Secondary: Percentage of patients achieving an HbA1c of ≤7% without insulin rescue therapy at 24 weeks.
• Follow-up: Blinding maintained through 48 weeks for safety and effectiveness assessments.
• FDA Interaction: Feedback sought for primary endpoint and durability assessment at 48 weeks.

Critiques

• Complexity and Length: The study's two-stage design, involving initial open-label participation before the main blinded trial, adds complexity and extends timelines. This might impact patient recruitment and retention.
• Operational Challenge of Site Proficiency: Ensuring all sites reach a satisfactory level of proficiency with the DMR procedure, especially those new to the procedure, could present significant logistical challenges and potentially introduce variability in the treatment application.
• Blinding: Maintaining blinding for 48 weeks poses a considerable operational challenge, especially for interventions involving procedures where sham controls are used. This aspect requires meticulous planning to preserve the study’s integrity.
• Sample Size: The plan to enroll up to 510 patients might not suffice to detect differences in secondary outcomes or subgroup analyses, given the study's ambitious objectives and the complex nature of T2D treatment landscapes.

Operational and Technical Challenges

• Training and Standardization: Ensuring all participating sites, particularly those new to the DMR procedure, are adequately trained and execute the procedure consistently to minimize variability.
• Patient Recruitment and Retention: Recruiting a sufficient number of eligible patients who are inadequately controlled on ADAs but not yet on insulin, and retaining them throughout a lengthy study period, could prove challenging.
• Blinding Mechanism: Implementing an effective sham procedure that convincingly mimics the DMR treatment to maintain patient and investigator blinding, without compromising patient safety.
• Regulatory Approval Pathway: Navigating the regulatory landscape, especially with the FDA’s indication for a 48-week effectiveness assessment, poses a potential challenge in aligning study outcomes with regulatory expectations for durability and long-term efficacy.

In conclusion, while the Revitalize-2 study design attempts to rigorously assess the Revita DMR Procedure’s efficacy and safety in a well-defined patient population, the complexity of the study’s design and operational challenges need careful management to ensure the study's success and compliance with regulatory expectations.

Given the stated objectives and design of the Revitalize-2 pivotal clinical study for the Revita procedure in patients with Type 2 Diabetes (T2D) inadequately controlled on two or three antidiabetic agents (ADAs) but not yet on insulin, it aims to serve as a proof-of-concept for extending the use of Revita into a specific subset of T2D patients. Below are considerations regarding the study's potential proof-of-concept, endpoint appropriateness, inclusion/exclusion criteria, and reproducibility challenges.

Appropriateness of Primary and Secondary Endpoints

• Primary Endpoint: The selection of HbA1c change from baseline at 24 weeks as the primary endpoint is both clinically relevant and appropriately rigorous for assessing the immediate impact of the Revita DMR Procedure. This measure aligns well with regulatory standards and clinical benchmarks for effectiveness in T2D management.
• Secondary Endpoint: Evaluating the percentage of patients achieving an HbA1c of less than or equal to 7% without insulin rescue therapy at 24 weeks is an important secondary endpoint that will provide insight into the practical benefits of the procedure in reducing dependency on insulin therapy among patients.

Both endpoints are well-suited for assessing the efficacy of Revita in managing T2D and could substantiate a proof-of-concept if the outcomes demonstrate significant improvements.

Inclusion/Exclusion Criteria

• Inclusion Criteria: Targeting patients inadequately controlled on two or three ADAs and not yet on insulin may help in identifying a subset of T2D patients who could benefit the most from early intervention. This stratification ensures that the study population is at a critical point in the progression of T2D where the Revita DMR Procedure could potentially delay or prevent the need for insulin therapy.
• Exclusion Criteria: While not explicitly detailed in the summary, it is presumed that standard exclusion criteria would apply, such as excluding patients with significant comorbidities, those who are pregnant, or those with a history of bariatric surgery, which could confound the study outcomes. Specific to this study, the exclusion of patients already on insulin therapy helps in creating a homogenous study population more likely to exhibit a uniform response to the intervention.

Reproducibility Challenges

• Generalizability: The strict inclusion criteria, while beneficial for study clarity, can limit the general applicability of the study findings to broader T2D populations, especially those already on insulin therapy or those with varied ADAs backgrounds.
• Practical Implementation: Ensuring consistent adherence to inclusion and exclusion criteria across multiple sites, especially in multinational studies, can be challenging. Differences in healthcare practices and patient populations may influence patient selection and enrollment consistency.
• Evolution of T2D Management: The rapidly evolving landscape of T2D management, including the introduction of new ADAs, may affect the relevance of the inclusion/exclusion criteria over time and potentially affect the reproducibility and applicability of the study findings in future settings.

Revita-2 study

The Revita-2 clinical study, initiated in March 2017, was aimed at assessing the safety and efficacy of the Revita DMR Procedure in 108 patients across Europe and Brazil. These patients had type 2 diabetes (T2D) which was sub-optimally controlled despite being on oral antidiabetic drugs (OADs) and/or metformin. The study was randomized, double-blind, crossover, and sham-controlled.

Endpoints:

• Primary: Change in HbA1c at 24 weeks and absolute change in liver fat quantified by MRI-PDFF at 12 weeks in the modified intention-to-treat (mITT) population.
• Secondary: Changes in HOMA-IR (insulin resistance), weight loss, and MRI-PDFF in specific patient groups at designated times.

Patients underwent a 4-week run-in period before being assigned to either the DMR or sham procedure, keeping medication doses constant until week 24. Assessments were made at weeks 4, 12, 18, and 24.

Findings:

• The DMR group showed greater reductions in HbA1c and MRI-PDFF compared to the sham group.
• Statistical analysis revealed differences between European and Brazilian populations, prompting separate analyses.
• No severe adverse events (SAEs) or device-related SAEs were reported; adverse events were similar between DMR and sham arms.

Critiques of the Study Design

Operational and Technical Challenges:

1. Population Heterogeneity: The significant differences between European and Brazilian populations highlight the challenges in maintaining consistency across international sites. Such variability can affect the generalizability of findings.
2. Sham Control Application: Effectively blinding a sham procedure in interventional studies like this is crucial but challenging, as it requires the sham procedure to be convincingly similar to the actual treatment without providing therapeutic benefits.
3. Compliance and Monitoring: Ensuring medication compliance and consistent nutritional counseling across sites can be challenging, especially in a long-term study. Variations in these factors can influence study outcomes.
4. MRI-PDFF as a Biomarker: While MRI-PDFF is a validated biomarker for quantifying liver fat, its sensitivity and specificity in the context of T2D improvements need careful consideration, especially when comparing across different populations with potential variations in liver fat distribution and metabolism.

Operational or Technical Challenges Specific to This Study Design

1. Blinding and Sham Procedure: Implementing a convincing sham procedure that matches the invasiveness of the DMR procedure poses technical and ethical challenges. Blinding success is crucial for minimizing bias in subjective outcome assessments like pain or quality of life.
2. Cross-Over Design Complexity: Managing the crossover component adds complexity to data analysis, especially with the potential for carry-over effects, which can confound interpretations of treatment efficacy.
3. Multi-Site Coordination: Coordinating between multiple international sites adds logistical complexity, particularly with ensuring adherence to protocol, uniformity in clinical practices, and data collection standards.
4. Sample Size and Statistical Power: The subdivision of the population for separate analyses, particularly for the Brazilian cohort, might lead to reduced statistical power to detect significant differences, necessitating caution in interpreting these results.

In summary, while the Revita-2 clinical study design is comprehensive and addresses both safety and efficacy, it confronts standard challenges seen in international, multicenter trials, including maintaining consistency in treatment delivery and assessment across diverse populations, ensuring effective blinding in sham-controlled designs, and handling the complexities introduced by the crossover design.

The study design for evaluating the Revita procedure in insulin-treated type 2 diabetes (T2D) patients incorporates well-defined inclusion and exclusion criteria aimed at producing a specific, high-risk patient group likely to benefit from the intervention. These criteria are essential for establishing proof-of-concept validity and ensuring the relevance of primary and secondary endpoints to the target population.

Appropriateness of Primary and Secondary Endpoints

• Primary Endpoints: The primary endpoints focus on significant T2D management metrics: HbA1c levels and hepatic fat content as measured by MRI-PDFF. These are appropriate and widely accepted measures that directly relate to the disease's metabolic impact and the risk of related complications, making them highly relevant for this patient population.
• Secondary Endpoints: Secondary endpoints, including changes in insulin resistance (HOMA-IR), weight loss, and specific MRI-PDFF improvements, complement the primary endpoints well. They offer a broader view of metabolic improvements and potential benefits on cardiovascular risks and NAFLD/NASH, which are common co-morbidities in T2D patients.

Inclusion / Exclusion Criteria

• Inclusion Criteria: The criteria are set to include individuals within a specific age range (21-70 years) who are actively managing their T2D with insulin and up to three non-insulin antidiabetic agents. This focus ensures the study population is relevant to a significant portion of the T2D population struggling with disease management. The inclusion of specific medications and a range of HbA1c values targets a population that stands to benefit the most from the procedure.
• Exclusion Criteria: The extensive list of exclusion criteria is designed to minimize potential confounding factors, such as other health conditions that could affect glucose metabolism or the interpretation of study results. While this approach enhances the study's internal validity, it may limit the generalizability of findings to the broader T2D population.

Potential Reproducibility Challenges

• Limited Generalizability: The strict inclusion/exclusion criteria, while necessary for establishing a clear proof-of-concept, may result in findings that are not easily generalizable to all T2D patients, especially those with co-morbid conditions excluded from this study.
• Complexity of Criteria: The detailed and numerous exclusion criteria might make recruiting patients challenging, increasing the time and resources needed to reach the desired sample size. Furthermore, this complexity could pose challenges in reproducing the study in different settings or populations, as the specific mix of included and excluded conditions might not be consistent across different geographic or demographic contexts.
• Adherence to Criteria: Ensuring strict adherence to these criteria across multiple study sites can be challenging and might introduce variability in patient selection, potentially affecting the reproducibility of the study results.

In summary, the study design for the Revita procedure in insulin-treated T2D seems well-constructed to provide proof-of-concept. The inclusion and exclusion criteria are appropriately stringent to ensure a specific patient population is studied, though these criteria might pose challenges for patient recruitment and limit the generalizability and reproducibility of the findings. Increasing transparency around criteria adherence and possibly considering multi-phase studies to gradually broaden the inclusion criteria could mitigate some of these concerns.

Clinical trial overview

The Remain-1 clinical study for Revita is designed to assess the weight maintenance capability of the Revita DMR Procedure in patients with obesity who have successfully lost at least 10% of their total body weight using GLP-1RA therapy and are seeking to discontinue this therapy without regaining the weight. The study is structured into two parts: an open-label cohort known as Reveal-1 and a randomized, double-blind, sham-controlled cohort. It aims to enroll up to 100 patients in the Reveal-1 cohort and 300 patients in the randomized cohort, dividing the latter into 200 patients for the DMR arm and 100 for the sham arm. The study's primary objective is to assess the effectiveness of the Revita DMR Procedure in maintaining weight at 24 weeks post-discontinuation of GLP-1RA therapy, with secondary objectives focusing on changes in blood glucose levels, cardiovascular disease risk factors, and body composition. All participants will receive diet and lifestyle counseling.

Critiques of the Study Design

• Open-label vs. Double-blind Design: The initial part of the study being open-label could introduce bias, as patients and researchers are aware of who receives the treatment. This design might affect the subjective components of secondary outcomes, such as lifestyle modifications and adherence to diet counseling.
• Enrollment Criteria: The requirement for patients to have lost at least 10% of their body weight on GLP-1RA therapy before enrolling could introduce selection bias. Patients who respond well to GLP-1RA therapy may have different physiological or behavioral characteristics compared to the general population with obesity.
• Primary Objective Measurement Timing: Measuring weight maintenance at 24 weeks after discontinuation of GLP-1RA therapy might not be sufficient to gauge the long-term effectiveness of the Revita DMR Procedure.
• Comparison Challenges: Comparing the results across the open-label and the randomized cohorts could present challenges, given the differences in blinding and potentially in patient behavior or characteristics.

Operational or Technical Challenges

• Patient Recruitment and Retention: Enrolling patients who have successfully lost weight and wish to discontinue their effective GLP-1RA therapy could be challenging. Retention over the study period could also pose a challenge, especially for those randomized to the sham arm, who might seek alternative treatments.
• Consistency in Lifestyle Counseling: Ensuring the same quality and impact of diet and lifestyle counseling across multiple centers in the U.S. and Europe could be complex, influencing the study's secondary objectives.
• Sham Procedure Ethics and Execution: Implementing a sham procedure that is ethically acceptable and convincingly similar to the actual DMR procedure could be technically and operationally challenging. The sham procedure must ensure patient safety while also being credible enough to maintain the study's double-blind design.
• Regulatory Approvals: Navigating the varying requirements for clinical study approval across different countries and regulatory bodies could complicate the study setup and timeline. Any delays in obtaining approval could affect the planned start date of the study.
• Monitoring and Compliance: Ensuring adherence to the discontinuation of GLP-1RA therapy and accurately monitoring weight maintenance and secondary outcomes across diverse clinical settings could prove challenging, particularly in a long-term follow-up scenario.

In conclusion, while the Remain-1 clinical study offers a promising exploration into weight maintenance post-GLP-1RA therapy discontinuation, its success will depend on effectively managing inherent design limitations and operational challenges. Addressing these concerns through meticulous planning and execution will be critical for obtaining reliable and generalizable results.

The potential of the Remain-1 clinical study to provide proof-of-concept for the use of Revita in weight maintenance is significant, given the targeted patient population and the study design. The primary and secondary endpoints and inclusion/exclusion criteria seem appropriately designed to test the effectiveness of Revita DMR Procedure in maintaining weight loss, which is a critical issue for individuals with obesity who have managed significant weight loss through GLP-1RA therapy.

Primary and Secondary Endpoints

Primary Endpoint: Focusing on weight maintenance at 24 weeks after discontinuation of GLP-1RA therapy (tirzepatide or semaglutide) is a straightforward and meaningful measure of the Revita DMR Procedure’s success. It appropriately matches the primary concern of patients and clinicians regarding the potential for weight regain after stopping GLP-1RA therapy.

Secondary Endpoints: Including changes in blood glucose levels, cardiovascular disease (CVD) risk factors, and body composition as secondary endpoints is smart. These factors are key health metrics that are likely to influence a patient's overall metabolic health and are pertinent concerns for the target population. Moreover, improvements in these areas can strengthen the case for the Revita DMR Procedure beyond mere weight maintenance, highlighting its potential metabolic benefits.

Inclusion / Exclusion Criteria

The inclusion criteria - targeting patients with obesity who have lost at least 10% total body weight on GLP-1RA therapy and wish to discontinue their medication - is well-chosen. It clearly defines a specific patient group that would have a keen interest in a novel intervention to maintain their weight loss achievements. Furthermore, this criterion ensures that the study population has demonstrated responsiveness to weight loss interventions, potentially increasing the likelihood of a discernible effect from the Revita DMR Procedure.

Potential Reproducibility Challenges

• Specific Patient Population: The inclusion criteria may limit the wider applicability of the study results. By focusing on patients who have achieved significant weight loss with GLP-1RA therapy, the findings might not be generalizable to all individuals with obesity, especially those who have not undergone or not responded to GLP-1RA therapy.
• Variability in GLP-1RA Response: There is inherent variability in how patients respond to GLP-1RA therapy in terms of weight loss and metabolic changes. This variability can introduce confounding variables into the study, potentially affecting the reproducibility of the results.
• Diet and Lifestyle Counseling Compliance: The requirement for all patients to receive diet and lifestyle counseling introduces a variable that relies heavily on patient compliance and the effectiveness of the counseling provided. Differences in implementation and adherence could affect the study outcomes and pose challenges in reproducing the study results.

To mitigate some of these reproducibility challenges, the study could incorporate stringent standardized protocols for diet and lifestyle counseling across sites and ensure that the patient selection criteria are thoroughly documented and followed. Additionally, follow-up studies could aim to include a broader patient population to test the applicability of the Revita DMR Procedure across different segments of the obesity spectrum.

In summary, while the Remain-1 clinical study is well-positioned to provide valuable proof-of-concept data on the Revita DMR Procedure for weight maintenance, attention to the reproducibility challenges posed by the specific inclusion/exclusion criteria will be crucial in validating and extending the applicability of the study findings.

Revitalize-1 study

The clinical data supporting Revita in insulin-treated Type 2 Diabetes (T2D) comes from the ongoing Revitalize-1 pivotal clinical study, which was initiated in March 2021. This study is aimed at patients with inadequately controlled T2D despite being on up to three anti-diabetic agents (ADAs) and 20 to 100 units of insulin daily. It is designed as a two-stage, randomized, double-blind, crossover, sham-controlled, multi-center trial across approximately 35 sites in the United States and the European Union.

The study plans to enroll up to 140 patients in the first stage and up to 320 patients in the second stage, with the primary endpoint set at 24 weeks and a 48-week follow-up period. The first stage is an open-label, single-arm study to familiarize each site with the study protocol and the duodenal mucosal resurfacing (DMR) procedure. The primary goal of Revitalize-1 is to assess the change in HbA1c levels (DMR vs. sham) at 24 weeks, with the option for sham patients to crossover to the DMR arm at 48 weeks. All patients are evaluated in the clinic post-procedure at specified intervals (4, 12, 24, and 48 weeks).

Enrollment completion is expected in the first half of 2024, with top-line data from the randomized phase anticipated in the fourth quarter of 2024. If successful, a Pre-Market Approval (PMA) filing is planned for the first half of 2025, presenting 24-week primary endpoint data and detailed follow-up through 48 weeks, in alignment with FDA discussions.

Regarding interim data from the stage 1 drug washout (REVITA-T2Di) cohort, among the first ten patients enrolled, nine were treated with Revita following a drug washout period. Their inclusion criteria included HbA1c levels of 7.5% to 9.5%, fasting plasma glucose (FPG) levels of 180 mg/dL to 270 mg/dL, and concurrent use of metformin, long-acting insulin (20 to 60 units/day), and up to two additional ADAs. Their treatment post-procedure began with empagliflozin, adjusted to the maximum tolerated dose within 15 days.

Outcomes at 48 weeks for the seven patients who completed the study displayed a median HbA1c reduction of 1.6%, median FPG reduction of 77 mg/dL, median insulin dose reduction of 44%, and a median weight reduction of 9.3%. Device- or procedure-related adverse events were minimal and similar to those that might occur with routine endoscopies. It's noted that one patient discontinued the study due to euglycemic ketoacidosis, a complication attributed to empagliflozin use, rather than the Revita DMR Procedure.

This summarized clinical data suggests that the Revita system, through its DMR procedure, can potentially improve glycemic control in inadequately controlled T2D patients on insulin therapy, with an acceptable safety profile based on preliminary data. Further results from the ongoing pivotal study are awaited to strengthen these findings.

For a novel therapeutic approach like Revita in insulin-treated Type 2 Diabetes (T2D), the U.S. Food and Drug Administration (FDA) and similar regulatory bodies typically require robust evidence of safety and efficacy. The clinical endpoints and studies needed for approval depend on demonstrating a significant impact on disease management, improving patient outcomes, and ensuring safety. Based on scientific and clinical literature, as well as regulatory guidelines and data from competing or similar drugs, here's an overview of possible approvable endpoints, necessary clinical studies, and patient enrollment estimates:

• Approvable Endpoints
  • HbA1c Reduction: A primary endpoint almost universally required for T2D therapies is a statistically significant reduction in HbA1c from baseline compared to control or sham treatments. A drop of 0.5% or more is generally considered clinically meaningful.
  • Fasting Plasma Glucose (FPG) Reduction: Another common endpoint is the reduction in fasting plasma glucose levels, reflecting better controlled blood glucose levels over time.
  • Weight Loss: For T2D treatments, especially those targeting patients with obesity, weight loss can be a significant secondary endpoint, due to the strong link between obesity and T2D.
  • Insulin Dose Reduction: In insulin-treated T2D, the ability to reduce the daily dose of insulin needed while maintaining or improving glycemic control is a valuable endpoint.
  • Safety Endpoints: Adverse events, serious adverse events, and specific safety concerns (e.g., hypoglycemia events) are crucial for approval. Safety data helps in understanding the risk-benefit profile of the therapy.
  • Quality of Life and Other Patient-reported Outcomes: Improvements in quality of life, patient satisfaction, and other patient-reported outcomes are increasingly valued, particularly if the therapy introduces lifestyle changes.
• Clinical Studies for Approval
  • Pivotal Phase 3 Trials: After initial Phase 1 and 2 studies determine safety and preliminary efficacy, at least one large, randomized, controlled Phase 3 trial is typically required by regulatory agencies. This study should demonstrate a clear benefit in the chosen endpoints when compared to current standard of care or a placebo/sham procedure.
  • Long-term Follow-up Studies: Post-market or as a condition of approval, long-term studies may be required to monitor ongoing safety and efficacy, including the durability of the treatment effect and the long-term impact on diabetes complications.
• Estimated Number of Patients
  • Pivotal Phase 3 Trials: The size of pivotal trials can vary widely depending on the magnitude of the expected treatment effect, variability in response, and the primary endpoint's nature. For T2D, studies often enroll several hundred to a few thousand patients. For instance, to detect a difference in HbA1c with a power of 90% and a significance level of 0.05, studies might need anywhere from 300 to 800 patients per treatment arm, considering dropout rates and the need for subgroup analyses.
  • Long-term Follow-up Studies: The size can vary, often depending on initial sample sizes, expected event rates, and regulatory requirements. They might continue to follow the original cohort from pivotal trials or enroll additional patients in a registry.

Given Revita's innovative approach, the exact patient numbers will depend on discussions with regulatory bodies, interim study results' strength, and whether the technology demonstrates clear benefits over current therapies. The exact requirements may also evolve based on ongoing clinical data from Revita and competing therapies, regulatory feedback, and the changing landscape of T2D management.

Germany Real-World Registry

The Germany Real-World Registry is a prospective, post-market clinical follow-up study focused on assessing the effectiveness and safety of the Revita DMR Procedure in real-world settings for patients with inadequately controlled Type 2 Diabetes (T2D). The study criteria include patients aged 18 and older, with baseline HbA1c levels between 7.0% and 10.0%, a BMI of 45 or less, and those who are on at least one anti-diabetic agent (ADA). The main objectives are to monitor changes in HbA1c levels, alterations in the use of ADAs, safety and tolerability, impacts on quality of life and patient-reported outcomes, and healthcare utilization over a span of five years post-Revita DMR Procedure.

As of January 16, 2024, the registry had enrolled 21 patients, and interim data had been collected from 14 patients at three months post-procedure. The early outcomes from these 14 patients indicate a median reduction in HbA1c from 9.2% to 7.3% (a change of -1.9%), along with a median weight loss of 17.6 pounds (from 244.7 pounds to 227.1 pounds). Notably, two of these patients were able to discontinue all their previously prescribed anti-diabetic medications.

These preliminary results from the Germany Real-World Registry hint at significant metabolic health improvements in patients with inadequately controlled T2D following the Revita DMR Procedure. The reduction in HbA1c and weight loss both represent crucial outcomes for the management of T2D, potentially leading to a decrease in the risk of diabetes-related complications and improvement in overall health. Discontinuation of ADAs in some patients further suggests an enhanced glycemic control that could reduce dependency on pharmacological interventions.

The ongoing enrollment and continued follow-up across several centers highlight the commitment to gathering comprehensive data on clinical outcomes, health economics, and patient-reported metrics. This real-world evidence will be vital in understanding the long-term impact and utility of the Revita DMR Procedure in the management of T2D, supporting its potential role in clinical practice.

For a groundbreaking therapy like Revita, aimed at treating insulin-treated Type 2 Diabetes (T2D), achieving regulatory approval is contingent upon demonstrating significant clinical benefit through well-defined endpoints in rigorous clinical studies.

Based on the scientific and clinical literature, as well as data from competing or similar interventions, here is an overview of potential approvable endpoints, necessary clinical studies for regulatory approval, and projections on patient enrollment numbers.

• HbA1c Reduction: A key indicator of long-term glucose control in T2D patients. Regulatory agencies like the FDA often look for a clinically significant reduction in HbA1c levels, typically by at least 0.5% compared to the control group for drug interventions. For device-based interventions like Revita, the expected reduction might be higher due to the invasiveness and risks associated with procedures.
• Weight Loss: Given the strong association between obesity and T2D, significant weight loss could serve as an adjunct endpoint to directly support the primary glycemic control endpoints.
• Insulin Dose Reduction: For patients on insulin, reducing or eliminating the need for insulin can significantly impact quality of life and reduce the risk of hypoglycemia, making this an important potential endpoint.
• Improvement in Insulin Sensitivity: Measured through indices like HOMA-IR, changes in insulin sensitivity could provide evidence of the underlying physiological impact of the Revita procedure.
• Cardiovascular Risk Reduction: Given that T2D is associated with increased cardiovascular risk, surrogate markers of cardiovascular health (e.g., changes in lipid profiles, blood pressure) could serve as secondary endpoints.
• Safety Endpoints: These would include assessing the incidence of adverse events, serious adverse events, and procedure-specific complications.

• Pivotal Randomized Controlled Trials (RCTs): The cornerstone of regulatory approval, these studies must be designed to convincingly demonstrate efficacy on the approvable endpoints and assess safety. For Revita, this would likely necessitate at least one large, multicenter, controlled Phase 3 trial comparing the Revita DMR Procedure against standard of care or a sham procedure.
• Long-term Follow-up Studies: To monitor the durability of the treatment effect and long-term safety, especially in terms of cardiovascular health and potential procedure-related late adverse events.

• Pivotal Phase 3 Trial: The exact number would depend on the expected effect size, the variability in responses, and statistical power considerations. For a device like Revita, a sample size ranging from several hundred to over a thousand patients might be required.
• Long-term Follow-up Studies: These generally involve continued observation of the Phase 3 cohorts, so no additional enrollment is needed, but continued engagement and tracking are essential.

The design of these studies would need to consider comparator groups carefully, especially if a sham procedure is ethically and practically feasible, to meet the standards for medical device approval processes which can vary slightly from those for pharmaceuticals.

In summary, robust trials with clearly defined, clinically meaningful endpoints that reflect both glycemic control and broader health benefits are essential to the approval process for Revita in insulin-treated T2D. The successful demonstration of safety and efficacy through these trials, with sufficient numbers of participants to ensure statistical power, will be key to gaining regulatory approval.

Revita FIH study and Revita-1 study data

The clinical data supporting Revita in insulin-treated Type 2 Diabetes (T2D) come from two key studies: the Revita First-in-Human (FIH) clinical study and the Revita-1 feasibility study. Here's a summary of the clinical outcomes observed in these studies:

• Revita FIH Clinical Study
  • Study Design: An open-label feasibility study conducted in Santiago, Chile, involving 39 T2D patients with specific inclusion criteria related to age, HbA1c levels, BMI, pancreatic function, and the duration of diabetes diagnosis. The study aimed to evaluate the safety and feasibility of the Revita DMR Procedure over variable lengths of the duodenum.
  • Outcomes:
    • Patients were divided into long-segmented ablation (LS-DMR; mean length ablated: 9.3 cm) and short-segmented ablation (SS-DMR; mean length ablated: 3.4 cm) groups.
    • A significant decrease in HbA1c was observed 12 weeks post-procedure: LS-DMR recipients saw a 2.5% reduction, and SS-DMR recipients saw a 1.2% reduction (p < 0.05).
    • By 24 weeks, reductions in HbA1c averaged 1.4% for LS-DMR and 0.7% for SS-DMR, with an overall significant reduction of 1.2% in the full cohort (p < 0.001).
    • Early and sustained improvements in FPG were noted, indicating the procedure's potential for glycemic control.
    • Most gastrointestinal symptoms were mild and transient, with three cases of duodenal stenosis requiring endoscopic balloon dilation, but no severe hypoglycemia or significant adverse device effects were reported.
• Revita-1 Feasibility Study
  • Study Design: An open-label, multi-center feasibility study across Europe and South America involving 46 patients, designed to assess the safety and effectiveness of the Revita DMR Procedure on various glycemic endpoints.
  • Outcomes:
    • The study observed a statistically significant reduction in mean HbA1c of 0.9% at 24 weeks in the per-protocol (PP) population, with further analysis showing a 0.8% reduction in dual-catheter and a 1.0% reduction in single-catheter patients (p ≤ 0.001 for both).
    • At 48 weeks, the PP population showed a statistically significant absolute mean HbA1c reduction of 1.0% (p ≤ 0.001).
    • Secondary endpoints included reductions in FPG, insulin resistance (measured by HOMA-IR), and weight. Significant mean changes in these metrics were observed up to 24 and 48 weeks.
    • The long-term follow-up at 24 months confirmed statistically significant improvements in HbA1c, FPG, and weight, despite some patient drop-offs.
    • The device was well-tolerated overall, with few device-related adverse events, and ten serious adverse events (SAEs) were reported, only one of which was considered procedure-related but not device-related.

Conclusion

The clinical data derived from these early-stage studies of the Revita DMR Procedure in patients with T2D suggest that the treatment may offer a promising approach to improve glycemic control and reduce HbA1c levels, alongside potential benefits in weight management and insulin resistance. Safety outcomes indicate the procedure is generally well-tolerated, with manageable adverse events. Further studies, particularly larger, randomized controlled trials, would be necessary to confirm these findings, evaluate long-term outcomes, and fully characterize the safety profile of the Revita DMR Procedure in a broader T2D population.

In the realm of insulin-treated Type 2 Diabetes (T2D), both pharmaceutical and device-based therapies have been the focus of rigorous clinical evaluation. For a novel therapy like the Revita DMR Procedure, approvable endpoints and the design of required clinical studies are critically influenced by regulatory expectations, clinical and scientific precedents, and the unique mechanism of action of the intervention. Below is an exploration of these aspects based on existing literature and data from both competing and similar interventions.

• Approvable Endpoints for Revita
  • HbA1c Reduction: A cornerstone endpoint for T2D therapies is the reduction of HbA1c, representing improved long-term glycemic control. Regulatory bodies like the FDA typically require a statistically significant reduction in HbA1c from baseline compared to placebo or standard of care.
  • Weight Loss: Given the association between obesity and T2D, weight loss is a relevant secondary endpoint, especially if the therapy’s mechanism suggests potential weight reduction benefits.
  • Reduction in Insulin Dose: For therapies targeting insulin-treated patients, decreasing the required daily dose of insulin while maintaining or improving glycemic control could be a compelling endpoint.
  • Improvements in Other Metabolic Markers: This might include reductions in fasting plasma glucose (FPG), improvements in lipid profiles, or reductions in markers of liver function (e.g., ALT, AST) where applicable.
  • Quality of Life Measures: Patient-reported outcomes related to quality of life, treatment satisfaction, and T2D management burden, can be important, especially if the treatment offers advantages over standard insulin therapies in terms of convenience or side effect profiles.
  • Safety and Tolerability Endpoints: These are crucial for all therapies, with a focus on adverse events, serious adverse events, device-specific complications, and hypoglycemia incidents for insulin-treated populations.
• Clinical Studies for Approval
  • Pivotal Phase 3 Randomized Controlled Trial (RCT): This is the essential study for regulatory approval, demonstrating the efficacy of Revita on the primary and secondary endpoints vs. standard of care or placebo. Given the device nature of Revita, a sham procedure might be considered for the control arm to maintain blinding.
  • Long-term Extension Studies: To assess the durability of the treatment effect and long-term safety, especially concerning metabolic control, device integrity, and potential late-onset adverse effects.
  • Post-Market Surveillance: Studies designed to monitor real-world safety and effectiveness, critical for evaluating rare adverse events and long-term outcomes in a more diverse patient population.
• Estimated Number of Patients Required
  • Pivotal Phase 3 RCT: Typically requires a few hundred to several thousand participants. For example, considering dropout rates and the need for robust data, a study aimed at demonstrating a significant HbA1c reduction might need anywhere from 300 to 1000 patients per study arm.
  • Long-term and Post-Market Studies: The number can vary greatly but must be sufficient to detect rare adverse events and confirm the durability of benefits. These studies often enroll thousands of patients, given the broader and longer-term nature of their objectives.

Clinical trial data

The Revita-2 clinical study is pivotal in evaluating the safety and efficacy of the Revita DMR Procedure in patients with sub-optimally controlled Type 2 Diabetes (T2D), despite being on oral antidiabetic drugs (OADs) and/or metformin. This study was carried out across multiple sites in Europe and Brazil, involving 108 patients, and aimed at assessing the changes in HbA1c and liver fat content among other secondary outcomes. Here's a summary of the findings:

• Overall Study Observations
  • The study reported a reduction in HbA1c of 1.0% in the DMR group compared to a 0.7% reduction in the sham group.
  • MRI-Proton Density Fat Fraction (PDFF) reductions, which indicate liver fat content, were 5.4% in the DMR group versus 2.9% in the sham group.
  • Analyses were separated between the Brazilian and European populations due to significant variations in outcomes and adherence to study protocols.
• European Population Results
  • The DMR procedure showed a statistically significant reduction in HbA1c (-0.60% in the modified intention-to-treat (mITT) group and -0.8% in the per-protocol (PP) group) compared to the sham procedure at 24 weeks.
  • There was a significant reduction in liver fat as measured by MRI-PDFF in both the mITT and PP DMR groups compared to the sham at 12 weeks.
  • Secondary outcomes like the median reduction in MRI-PDFF among patients with NAFLD or NASH, reduction in insulin resistance (measured by HOMA-IR), and weight loss at 24 weeks post-procedure also showed significant improvements in the DMR groups compared to the sham.
• Brazilian Population Results
  • While the Brazilian population showed greater reductions in HbA1c, HOMA-IR, and weight in the DMR arm compared to sham, these were not statistically significant due to the small sample size and discrepancies found during site audits.
  • The results from the Brazilian cohort are advised to be interpreted with caution following an audit that identified inconsistencies in medication documentation and glucose monitoring practices.
• Safety and Tolerability
  • The DMR procedure was generally well-tolerated with no unanticipated adverse device effects (UADEs) or device-related serious adverse events (SAEs) reported.
  • Adverse event rates related to the study were comparable between DMR and sham arms, with specific adverse events of special interest (AESIs) being similarly reported across groups. In the Brazilian population, 11.8% of the DMR randomized patients experienced SAEs all considered related to the study procedure and not the device itself.
  • There were no reports of malabsorption, anemia, pancreatitis, biliary complications, or infection associated with the procedure.
• Conclusion

  The Revita-2 clinical study demonstrates the potential of the Revita DMR Procedure as a therapeutic option for patients with T2D, highlighting its efficacy in reducing HbA1c and liver fat content. The significant reductions observed in HbA1c and MRI-PDFF outcomes, particularly in the European cohort, affirm the superiority of the DMR procedure over the sham. Moreover, the study's safety profile supports the well-tolerated nature of the DMR procedure, with no significant device or procedure-related adverse outcomes reported.

  These results indicate that the Revita DMR Procedure could play a meaningful role in managing T2D, especially considering the added benefits of reduced liver fat content and improvements in insulin resistance and weight loss. However, disparities between regional cohorts and the importance of strict adherence to study protocols underscore the need for caution in interpreting the broader applicability of these findings.