10-K

Table of Contents

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2024

For the transition period from to

Commission File Number: 001-41942

Fractyl Health, Inc.

(Exact name of Registrant as specified in its Charter)

3 Van de Graaff Drive, Suite 200Burlington, MA 01803

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (781) 902-8800

Securities registered pursuant to Section 12(b) of the Act:

Title of each class TradingSymbol(s) (Name of each exchange on which registered)

Common Stock, $0.00001 par value per share GUTS The Nasdaq Global Market

Securities registered pursuant to section 12(g) of the Act:

None

(Title of class)

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☐NO☒

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. YES ☐ NO ☒

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. YES☒ NO ☐

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). YES☒ NO ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). YES ☐ NO ☒

The aggregate market value of the voting and non-voting common stock held by non-affiliates of the registrant based on the closing price of the registrant’s common stock as reported on The Nasdaq Global Market on June 28, 2024, was $144.4 million. Solely for purposes of this disclosure, shares of common stock held by executive officers, directors and certain stockholders of the registrant as of such date have been excluded because such holders may be deemed to be affiliates

As of February 21, 2025, the number of shares of the registrant’s common stock outstanding was 48,920,221.

DOCUMENTS INCORPORATED BY REFERENCE

None.

Table of Contents

TABLE OF CONTENTS

Page

Forward-Looking Statements iii

Summary Risk Factors v

PART I

Item 1. Business 1

Item 1A. Risk Factors 67

Item 1B. Unresolved Staff Comments 132

Item 1C. Cybersecurity 132

Item 2. Properties 133

Item 3. Legal Proceedings 133

Item 4. Mine Safety Disclosures 133

PART II

Item 6. [Reserved] 134

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 146

Item 8. Financial Statements and Supplementary Data 147

Item 9A. Controls and Procedures 147

Item 9B. Other Information 148

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 148

PART III

Item 10. Directors, Executive Officers and Corporate Governance 149

Item 11. Executive Compensation 152

Item 14. Principal Accountant Fees and Services 164

PART IV

Item 15. Exhibits and Financial Statement Schedules 165

Table of Contents

BASIS OF PRESENTATION

Except where the context otherwise requires or where otherwise indicated, the terms “Fractyl,” “Fractyl Health,” “we,” “us,” “our,” “our company,” “Company” and “our business” refer to Fractyl Health, Inc and its subsidiaries.

The consolidated financial statements include the accounts of Fractyl Health, Inc. Our financial statements have been prepared in accordance with generally accepted accounting principles in the United States, or GAAP. Our fiscal year ends on December 31 of each year. References to 2024 and 2023 refer to the year ended December 31, 2024 and the year ended December 31, 2023, respectively. Our most recent fiscal year ended on December 31, 2024.

Certain monetary amounts, percentages and other figures included in this Annual Report on Form 10-K have been subject to rounding adjustments. Percentage amounts included in this Annual Report on Form 10-K have not in all cases been calculated on the basis of such rounded figures, but on the basis of such amounts prior to rounding. For this reason, percentage amounts in this Annual Report on Form 10-K may vary from those obtained by performing the same calculations using the figures in our consolidated financial statements included elsewhere in this Annual Report on Form 10-K. Certain other amounts that appear in this Annual Report on Form 10-K may not sum due to rounding.

TRADEMARKS AND TRADENAMES

This Annual Report on Form 10-K includes our trademarks and trade names, including, without limitation, REVITA, REJUVA and our logo, which are our property and are protected under applicable intellectual property laws. This Annual Report on Form 10-K also contains trademarks, trade names and service marks of other companies, which are the property of their respective owners. Solely for convenience, trademarks, trade names and service marks referred to in this Annual Report on Form 10-K may appear without the ®, TM or SM symbols, but such references are not intended to indicate, in any way, that we or the applicable owner will not assert, to the fullest extent permitted under applicable law, our or its rights or the right of any applicable licensor to these trademarks, trade names and service marks. We do not intend our use or display of other parties’ trademarks, trade names or service marks to imply, and such use or display should not be construed to imply, a relationship with, or endorsement or sponsorship of us by, these other parties.

INDUSTRY AND OTHER DATA

This Annual Report on Form 10-K contains industry, market and competitive position data from our own internal estimates and research as well as industry and general publications and research surveys and studies conducted by independent third parties. Industry publications, studies and surveys generally state that they have been obtained from sources believed to be reliable. Our internal data and estimates are based upon information obtained from trade and business organizations and other contacts in the markets in which we operate and our management’s understanding of industry conditions. Management is responsible for the accuracy of our internal company research and believes such information is reliable and the market definitions are appropriate. The industry in which we operate is subject to a high degree of uncertainty and risk due to a variety of factors, including those described in Part I. Item 1A. Risk Factors. These and other factors could cause results to differ materially from these expressed in the estimates made by the independent third parties and by us.

Table of Contents

FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K contains forward-looking statements that can involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this Annual Report on Form 10-K, including statements regarding our future results of operations and financial position, our ability to continue as a going concern, business strategy (including our Strategic Reprioritization, as defined herein), prospective products, or product candidates, plans regarding or status of clinical trials or studies and their design, our plans for readouts of interim or final results, product approvals, research and development costs, future revenue, timing and likelihood of success, plans and objectives of management for future operations, future results of anticipated products and prospects, plans and objectives of management and the timing of any of the foregoing are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements.

In some cases, you can identify forward-looking statements by terms such as “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” or “would” or the negative of these terms or other similar expressions, although not all forward-looking statements contain these words. Forward-looking statements contained in this Annual Report on Form 10-K include, but are not limited to, statements about:

•

the timing, progress and results of preclinical and clinical studies for our current and future product candidates, including statements regarding the timing of initiation and completion of studies and related preparatory work, the period during which the results of the studies will become available and our research and development programs;

•

the timing, scope or likelihood of regulatory submissions, filings, clearances, certifications and approvals, including final regulatory approval certifications or clearance of our product candidates;

•

our ability to develop and advance product candidates into, and successfully complete, clinical studies;

•

our expectations regarding the size of the patient populations for our product candidates, if approved, certified or cleared for commercial use;

•

the implementation of our business model and our strategic plans for our business, product candidates and technology;

•

our commercialization, marketing and manufacturing capabilities and strategy, as well as our product development strategy;

•

the pricing and reimbursement of our product candidates, if approved or cleared;

•

the scalability and commercial viability of our manufacturing methods and processes, including our plans to maintain our in-house manufacturing facility, even after commercialization of any of our product candidates;

•

the rate and degree of market acceptance and clinical utility of our product candidates;

•

our ability to establish or maintain collaborations or strategic relationships or obtain additional funding;

•

our competitive position;

•

the scope of protection we and/or any future licensors are able to establish and maintain for intellectual property rights covering our product candidates;

•

developments and projections relating to our competitors and our industry;

•

our expectations related to the use of proceeds from our initial public offering (“IPO”);

iii

Table of Contents

•

our estimates regarding expenses, future revenue, capital requirements and needs for additional financing;

•

our ability to continue as a going concern;

•

the period over which we estimate our existing cash and cash equivalents will be sufficient to fund our future operating expenses and capital expenditure requirements;

•

the impact of laws and regulations;

•

our expectations regarding the time during which we will be an emerging growth company and smaller reporting company under the JOBS Act; and

•

the impact of adverse macroeconomic conditions, geopolitical events and potential future public health crises, including epidemics and pandemics.

We have based these forward-looking statements largely on our current expectations and projections about our business, the industry in which we operate and financial trends that we believe may affect our business, financial condition, results of operations and prospects, and these forward-looking statements are not guarantees of future performance or development. These forward-looking statements speak only as of the date of this Annual Report on Form 10-K and are subject to a number of risks, uncertainties and assumptions described in Part I. Item 1A. Risk Factors and elsewhere in this Annual Report on Form 10-K. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events or otherwise.

In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this Annual Report on Form 10-K, and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain and you are cautioned not to unduly rely upon these statements.

Table of Contents

SUMMARY RISK FACTORS

Our business is subject to numerous risks and uncertainties, including those described in Part I, Item 1A. Risk Factors. You should carefully consider these risks and uncertainties when investing in our common stock. The principal risks and uncertainties affecting our business include the following:

•

We have a limited operating history in developing medical devices and biopharmaceutical products, have not completed any pivotal clinical studies and have no products approved from commercial sale in the United States, which may make it difficult for you to evaluate our current business and predict our future success and viability;

•

We have incurred significant net losses since inception and we expect to continue to incur significant net losses for the foreseeable future and may never achieve or sustain profitability;

•

We will require substantial additional capital or must implement other business strategies to execute our operating plan and continue to operate as a going concern. If we are unable to raise such capital when needed, or on acceptable terms, we may be forced to delay, reduce and/or eliminate one or more of our research and drug development programs or future commercialization efforts;

•

The regulatory approval process of the U.S. Food and Drug Administration (the “FDA”), comparable foreign regulatory authorities and notified bodies, are lengthy, time-consuming and inherently unpredictable, and even if we complete the necessary clinical studies, we cannot predict when, or if, we will obtain regulatory approval or certification for any of our product candidates, and any such regulatory approval or certification may be for a more narrow indication than we seek;

•

Clinical studies are expensive, time-consuming, difficult to design and implement, and have an uncertain outcome. Further, we may encounter substantial delays in our clinical studies;

•

We currently conduct and may in the future conduct clinical studies for our product candidates outside the United States, and the FDA or comparable foreign regulatory authorities may not accept data from such studies;

•

We may not be able to file investigational device exemptions (“IDEs”) or IDE supplements or comparable documents in foreign jurisdictions to commence additional clinical studies on the timelines we expect, and even if we are able to, the FDA or comparable foreign regulatory authorities may not permit us to proceed;

•

We may not be able to submit investigational new drug applications (“INDs”) or IND amendments, clinical trial applications (“CTAs”) or comparable documents in foreign jurisdictions to commence additional clinical studies on the timelines we expect, and even if we are able to, the FDA or comparable foreign regulatory authorities may not permit us to proceed;

•

We are substantially dependent on the success of our lead product candidate, Revita, and if we are unable to obtain marketing approval or certification for and commercialize any of our current or future product candidates in a timely manner, our business will be harmed;

•

Our long-term prospects depend in part upon discovering, developing and commercializing product candidates, which may fail in development or suffer delays that adversely affect their commercial viability. We intend to identify and develop novel product candidates, which makes it difficult to predict the time, cost and potential success of our current product candidates, and other product candidates we may develop in the future;

•

Additional time may be required to develop and obtain regulatory approval or certification for our Rejuva gene therapy candidates because we expect them to be regulated as a combination product;

•

We cannot be certain that our Rejuva gene therapy candidates will successfully complete preclinical and clinical studies, or that they will not cause significant adverse events or toxicities. There can be no assurance that any development problems we experience in the future related to our Rejuva gene therapy candidates or

Table of Contents

any of our research programs will not cause significant delays or unanticipated costs, or that such development problems can be solved;

•

We may not be able to gain the support of leading hospitals and key thought leaders, or to publish the results of our clinical studies in peer-reviewed journals, which may make it difficult to establish the Revita DMR procedure and/or our Rejuva gene therapy candidates as a standard of care, if approved, and may limit our revenue growth and ability to achieve profitability;

•

We have not yet studied the ability of Revita to be used in repeated procedures. If we are unable to demonstrate the safety and efficacy of Revita for repeat use, it could have a material adverse effect on the clinical utility and commercial adoption of the device;

•

We have never obtained marketing approval for a product candidate in the United States and we may be unable to obtain, or may be delayed in obtaining, marketing approval for any product candidate in the United States;

•

We substantially rely, and expect to continue to rely, on third parties, including independent clinical investigators and contract research organizations (“CROs”), to conduct certain aspects of our preclinical studies, and clinical studies. If these third parties do not successfully carry out their contractual duties, comply with applicable regulatory requirements or meet expected deadlines, we may not be able to obtain marketing authorization of or commercialize our product candidates and our business could be substantially harmed;

•

If we decide to establish new collaborations in the future, but are not able to establish those collaborations on commercially reasonable terms, we may have to alter our development and commercialization plans;

•

We contract with third parties for the manufacture of sub-assembly components for Revita and for the materials for our Rejuva gene therapy platform for preclinical studies and our ongoing clinical studies, and expect to continue to do so for additional clinical studies and ultimately for commercialization. This reliance on third parties increases the risk that we will not have sufficient quantities of our product candidates or such quantities at an acceptable cost, which could delay, prevent or impair our development or commercialization efforts;

•

If we or our suppliers fail to comply with the FDA’s quality system and/or good manufacturing practice regulations, this could impair our ability to market our products in a cost-effective and timely manner;

•

We face the risk of product liability claims that could be expensive, divert management’s attention and harm our reputation and business. We may not be able to maintain adequate product liability insurance;

•

We rely on a variety of intellectual property rights, and if we are unable to obtain, maintain or protect our intellectual property, our business, financial situation, results of operations, and prospects will be harmed. If we are unable to obtain and maintain patent protection for our current product candidate, any future product candidates we may develop and our technology, or if the scope of the patent protection obtained is not sufficiently broad, our competitors could develop and commercialize products and technology similar or identical to ours, and our ability to successfully commercialize our current product candidate, any future product candidates we may develop and our technology may be adversely affected; and

•

If we are unable to establish sales or marketing capabilities or enter into agreements with third parties to sell or market our product candidates, we may not be able to successfully sell or market our product candidates that obtain regulatory approval.

Table of Contents

PART I

Item 1. Business.

Our Company

We are a metabolic therapeutics company focused on breaking the pattern of treatment of metabolic diseases, including obesity and type 2 diabetes (“T2D”). Despite advances in treatment over the last 50 years, obesity and T2D continue to be principal and rapidly growing drivers of morbidity and mortality. According to the Centers for Disease Control and the International Diabetes Federation, approximately 100 million people in the United States have prediabetes and/or are living with obesity, and an additional 25 million people have T2D and are on medical therapy. Within the past two years, the unmet need in obesity has shifted rapidly from identifying treatments that can achieve short-term weight loss to identifying treatments that can enable durable weight maintenance. While highly potent drugs in the glucagon-like peptide-1 receptor agonist (“GLP-1RA”) class are now available to lower weight and blood sugar, these agents have high discontinuation rates that lead to a substantial risk of weight and metabolic rebound. According to a Kaiser Family Foundation Health Tracking Poll from May 2024, approximately 6% of adults are taking glucagon-like peptide-1 (“GLP-1”) drugs, translating to approximately 10 million patients on therapies that require chronic administration and do not correct the underlying disease of obesity. Despite the growing interest in these drugs, a Blue Health Intelligence brief from 2024 found that over 50% of patients discontinue GLP-1 drugs within three months of starting, long before patients can experience clinical benefit from these agents. Discontinuation of these agents typically leads to an immediate loss of metabolic benefit and weight rebound, as seen in Eli Lilly’s SURMOUNT-4 study with tirzepatide and Novo Nordisk’s STEP-1 extension study with semaglutide. For example, studies published in JAMA in 2023 found that patients lost approximately 20% of their body weight over 36 weeks while on tirzepatide. However, when patients discontinued the drug, they experienced approximately 14% weight regain in 52 weeks, approximately 5% of which was regained in the first three months after discontinuation. These high rates of drug discontinuation and weight regain demonstrate the need for new approaches that can enable durable maintenance of weight and metabolic health without requiring daily or weekly pharmacotherapy. Our goal is to develop durable disease-modifying therapies that are designed to provide lasting metabolic health by targeting root causes of obesity and T2D – without lifelong treatment.

Building on the growing recognition of the gut's role in metabolic disease, our founders designed novel, differentiated, disease-modifying therapies aiming to shift patient care from management to prevention and remission. The Revita DMR System, or Revita, our lead product candidate, is an investigational outpatient procedural therapy designed to durably modify duodenal dysfunction, a major pathologic consequence of a high fat and high sugar diet, which can cause obesity and T2D. The duodenum regulates the human metabolic response to food intake, and modern diets drive dysfunctional hyperplasia of the duodenal mucosa. This results in alterations to physiologic signaling that affect glucose control and satiety. The Revita DMR System is designed to enable durable and repeatable metabolic improvement via hydrothermal ablation of the dysfunctional duodenal mucosa to address duodenal pathology and consequent metabolic disease progression directly. Currently, our Revita clinical program is focused on patients living with obesity who want to maintain their weight loss after GLP-1 drug discontinuation. We have obtained Breakthrough Device designation from the FDA for the Revita DMR System, as an adjunct to diet and exercise, to perform hydrothermal ablation of the duodenal mucosa, or the Revita DMR procedure, for use in the maintenance of weight loss after discontinuation of GLP-1-based therapy. This designation may enable prioritized FDA review of any marketing application we may submit for Revita within the designated indication, as well as the potential for an early or accelerated decision on reimbursement by the Centers for Medicare & Medicaid Services (the “CMS”).

We are evaluating Revita in the REMAIN-1 pivotal study, which is designed to include two cohorts - an open label cohort referred to as REVEAL-1, and a randomized cohort, which includes both a midpoint analysis and a pivotal analysis. Patients who previously lost at least 15% of their body weight on a GLP-1 can qualify for the open label REVEAL-1 cohort. The data generated from the REVEAL-1 cohort will be used for open label reporting as the study progresses. The REMAIN-1 randomized cohort will enroll patients living with obesity and a body mass index (“BMI”) between 30 and 45 kg/m2 who are not currently on a GLP-1 drug. Patients will be prescribed tirzepatide and titrated to achieve at least 15% total body weight loss, at which time tirzepatide will be discontinued and patients will be randomized to Revita versus sham.

Table of Contents

Midpoint Analysis of Randomized Cohort:

The midpoint analysis of the randomized cohort will be performed at three months of follow-up on approximately 45 patients, allowing us to assess and report on safety and efficacy signals that could be anticipated in the pivotal analysis. These patients are distinct from those included in the pivotal analysis.

Pivotal Analysis of Randomized Cohort:

The pivotal analysis of the randomized cohort will be performed on approximately 315 patients (distinct from those included in the midpoint analysis) and will evaluate safety and efficacy in the first co-primary endpoint, which is weight regain from the time of tirzepatide discontinuation in Revita DMR versus sham patients at six months, with a primary objective of demonstrating a benefit of Revita DMR versus sham for weight maintenance after GLP-1 discontinuation. The second co-primary endpoint evaluates a responder rate among the Revita DMR treated group at one year to demonstrate the durability of the Revita DMR procedure for weight maintenance after discontinuation of a GLP-1-based therapy.

Secondary objectives will include evaluation of the effectiveness of the Revita DMR procedure on the change in blood glucose levels, cardiovascular disease (“CVD”) risk factors, body composition and pre-diabetes status. All patients enrolled in the study will receive diet and lifestyle counseling.

The REMAIN-1 study was initiated in the third quarter of 2024. In January 2025, we reported positive preliminary results from the REVEAL-1 open-label cohort of the REMAIN-1 study. Initial findings from the first patient, as of a cutoff date of January 13, 2025, showed successful weight maintenance at one month following GLP-1 drug discontinuation and Revita DMR procedure. Additional data from the REVEAL-1 cohort are anticipated to be presented in the first quarter of 2025. As of February 15, 2025 recruitment for the REMAIN-1 study has generated significant interest, with over 189 patients enrolled across 13 clinical study sites in six months since first site activation, reflecting strong engagement from both patients and physicians. We believe this momentum underscores the urgent need for effective post-GLP-1 weight maintenance solutions. In the fourth quarter of 2024, we completed enrollment of a sufficient number of patients for the midpoint analysis of the study, which is anticipated in the second quarter of 2025. Full enrollment in the study is expected in the summer of 2025.

On January 31, 2025, we announced a strategic reprioritization (“Strategic Reprioritization”) to focus Revita resources on the REMAIN-1 pivotal study, driven by the positive preliminary results from the REVEAL-1 cohort, strong patient and physician interest, and the urgent need for durable weight maintenance solutions after GLP-1 drug discontinuation. As part of this Strategic Reprioritization, we have paused investment in our Revita programs for T2D, including the REVITALIZE-1 pivotal study and the Germany Real-World Registry study.

We are also developing Rejuva, our novel, locally administered, adeno-associated virus (“AAV”) delivered pancreatic gene therapy platform, with a key near-term goal of advancing the lead product candidate in the platform, RJVA-001, into first-in-human studies, if allowed by the regulatory authorities to proceed. Rejuva is designed to enable long-term remission of T2D and obesity by durably altering metabolic hormone function in the pancreatic islet cells of patients with T2D and obesity. We nominated our first smart GLP-1 gene therapy candidate in the platform, RJVA-001, in January 2024. RJVA-001 is a locally administered AAV9 viral vector with a transgene designed to express human GLP-1 hormone from an insulin promoter in a nutrient-responsive manner. Based on preclinical data, we believe RJVA-001 has the potential for greater potency, greater durability, and greater tolerability over currently available GLP-1 therapies. These advantages are anticipated to enable a differentiated label and indication for use for RJVA-001 for the remission of metabolic disease, which chronically administered GLP-1 based medicines cannot offer.

In preclinical head-to-head studies, Rejuva gene therapy candidates demonstrated improved weight reduction in a disease-relevant diet-induced obesity (“DIO”) mouse model along with improvement in glycemic control, and delayed T2D progression in a disease-relevant db/db mouse model compared to chronic administrations of semaglutide (the active agent in Ozempic and Wegovy, which are FDA-approved). We believe these results highlight the potential benefits of metabolic treatment with a smart GLP-1 candidate designed to be nutrient-responsive at the locus of disease in the pancreas. We have completed key preclinical in vivo studies to support a CTA for RJVA-001, designed for the remission of T2D. We anticipate submitting the first CTA module to regulators by the first half of 2025, and if our CTA is authorized, expect to report preliminary data in 2026.

Table of Contents

In November 2024, we nominated our first smart GIP/GLP-1 pancreatic gene therapy lead candidate, RJVA-002, designed for the treatment of obesity. RJVA-002 is a locally administered AAV9 viral vector that expresses human GLP-1 and GIP hormones from a human insulin promoter. RJVA-002 is designed to activate both GIP and GLP-1 receptors, which play crucial roles in regulating blood sugar and body weight.

Prior to our Strategic Reprioritization we had been enrolling our pivotal REVITALIZE-1 study in patients with inadequately controlled T2D despite being on at least one antidiabetic agent (“ADA”) also referred to as a glucose lowering agent (“GLA”). Pursuant to our Strategic Reprioritization, we have paused this study. Patients with inadequately controlled T2D, who are on at least one GLA and previously randomized, will continue to be followed per protocol to 48 weeks. Patients randomized to the sham arm will be offered an opportunity to receive the Revita DMR procedure (crossover) once unblinded. Patients who crossover and undergo the Revita DMR procedure will be followed per protocol. We have paused REVITALIZE-1 pursuant to our Strategic Reprioritization due to outsized interest in the Revita weight maintenance pivotal study, REMAIN-1, and our decision to do so was not driven by any safety or efficacy concerns for Revita in T2D.

We have obtained Breakthrough Device designation from the FDA for the Revita DMR System to perform the Revita DMR procedure to improve glycemic control and eliminate insulin needs in T2D patients who are inadequately controlled on long-acting insulin.

In granting Breakthrough Device designation to the Revita DMR System, the FDA found the following: there is a reasonable expectation that Revita will provide for more effective treatment or T2D patients who are inadequately controlled on long-acting insulin therapy; Revita represents a breakthrough technology; Revita, if found to be safe and effective, could offer significant advantages over existing approved or cleared alternatives; and the availability of Revita, if found to be safe and effective, would be in the best interest of patients. We have observed the Revita DMR procedure to be generally well tolerated and to have demonstrated durable weight maintenance and blood glucose lowering for two years post-procedure in controlled studies of patients with T2D who are inadequately controlled despite already taking certain GLAs or ADAs, and receiving lifestyle counseling.

Revita has a CE mark for patients with inadequately controlled T2D in Europe. After securing reimbursement in Germany in the first half of 2022, we initiated our pilot commercial launch along with a Real-World Registry study. Although we have paused investment in this study, pursuant to our Strategic Reprioritization, we expect to continue to follow existing patients per protocol and continue to report on clinical, health economic, and patient-relevant outcomes from this study on an ongoing basis.

We believe Revita and Rejuva, if approved, have the potential to revolutionize treatment across the spectrum of obesity and T2D, align the clinical and economic interests of key stakeholders around the long-term regression of metabolic disease, and, at their fullest potential, significantly reduce the burden of metabolic disease globally.

Table of Contents

Our Development Pipeline

Our development pipeline for Revita and Rejuva pancreatic gene therapy (“PGTx”) candidates target large market indications in obesity and T2D and aim to transform treatment from chronic symptom management to disease-modifying therapies that target the organ-level root causes of metabolic disease.

The following table summarizes our development pipeline and potential clinical opportunities across the spectrum of metabolic disease, from obesity (with or without prediabetes) to advanced T2D.

*Revita has been granted Breakthrough Device designation for weight maintenance after GLP-1 discontinuation in patients living with obesity or who are overweight **Product candidates under our Rejuva gene therapy platform may undergo Phase 1, Phase 2 and/or Phase 3 clinical studies ***CTA = Clinical Trial Application.

1. The anticipated pipeline milestones are based on management’s current estimates and expectations. See Part I. Item 1A. Risk Factors for a discussion regarding Risk Factors to these and other estimates and expectations.

What Sets Us Apart

Our vision is to develop transformative therapies that can prevent and eliminate metabolic disease. We plan to achieve this by creating disease-modifying therapies targeting the gut and pancreas, driving broad adoption of our innovative approach, and improving real-world outcomes for patients and health systems. Our vision is supported by the following strengths:

Pioneering New Approaches Based on Deep Understanding of Metabolic Diseases

We are pioneering the development of disease-modifying therapies targeting the organ level root cause of metabolic disease. Our approach builds on over a decade of our research and the accumulation of independently published, supportive clinical evidence, all implicating the gut and pancreas as validated, untapped targets in obesity and T2D. We aim to restore and preserve the health of the key organs required for metabolic fitness and reduce the burden of metabolic disease for patients.

Developing Disease-Modifying Therapies that Provide Long-Term Metabolic Benefits and the Potential to Shift the Treatment Paradigm in Obesity and T2D

Our Revita and Rejuva programs are designed to target dysfunction in the duodenum and pancreas, respectively, to provide long-term metabolic benefits from a single administration. For this reason, we believe Revita and Rejuva offer the potential to address metabolic diseases in ways we believe current therapies do not, including the prevention and remission of the diseases. Specifically, Revita has the potential to support long-term, durable weight maintenance, while Rejuva offers the potential to drive T2D remission and achieve durable weight loss.

Table of Contents

Rigorous Approach to Clinical Development

The Revita clinical program is designed to advance the development of Revita as a foundational outpatient procedural therapy for obesity. By targeting duodenal dysfunction, Revita aims to provide durable weight maintenance solutions, addressing a critical gap in current obesity treatments. To date, we have evaluated Revita in over 300 patients across multiple clinical studies and we have observed over 500 patient-years of exposure data, favorable tolerability data, as well as favorable glycemic control and weight maintenance data. Our Rejuva platform with GLP-1 PGTx candidates has been evaluated in small and large animal models, as well as ex vivo murine and human islets. In preclinical head-to-head studies, Rejuva gene therapy candidates demonstrated weight reduction in a disease-relevant DIO mouse model, along with improvement in glycemic control and delayed T2D progression in a disease-relevant db/db mouse model compared to chronic administrations of semaglutide (the active agent in Ozempic and Wegovy). We are leveraging our extensive clinical experience with Revita to inform our clinical plans with our Rejuva PGTx candidates.

Aligning Interests of Key Stakeholders: Patients, Referring Physicians, Providers, and Payors

We believe Revita and Rejuva, if approved, have the potential to offer clinical and economic benefits while reducing the burden of disease management compared to the current standard of care in obesity and T2D. We believe both programs have the potential to broadly align interests across key stakeholders involved in the treatment of obesity and T2D, and may have the following benefits to these groups:

•

Patients. Improving weight loss maintenance, and glycemic control while reducing the number and burden of therapies required to adequately manage obesity and T2D.

•

Referring Physicians. Preventing weight gain and lowering HbA1c for specific patient populations with a procedural therapy that reduces the workload in disease management (i.e., rigorous patient medication, diet adherence) and improves quality metrics associated with the disease.

•

Providers. Straightforward, easy to train outpatient procedures, which we believe could be safely deployed at scale across a large patient population. Intended to seamlessly integrate into existing endoscopist workflows and provide a new, potentially profitable service line for hospitals with a patient-friendly therapeutic option for a significant portion of their patients.

•

Payors. Significant health economic benefits for payors who are currently struggling with the increasing expenses of obesity and T2D, driven primarily by unchecked disease progression and the lack of disease-modifying therapies.

Purpose-Built Leadership Team with Shared Mission to Advance Patient Care in Metabolic Disease

Our diverse team, combining marketing, product development and therapeutic expertise, has over 150 years of collective experience in therapeutic development. We are mission-driven to develop novel disease-modifying therapies that can potentially reverse metabolic diseases for patients and for health systems. Our team aims to continuously advance and expand upon our body of knowledge in order to establish and maintain a scientific leadership position in our therapeutic areas of focus. We do so by collaborating with expert advisors who are leaders in metabolic disease, weight maintenance, endocrine signaling and endoscopy.

Growth Strategies

Our mission is to develop transformative therapies that prevent and eliminate metabolic disease. To achieve this goal, we plan to employ the following strategies:

Establish Practice-Changing Levels of Evidence for Revita Across the Spectrum of Obesity

Our stepwise approach to regulatory approvals will initially focus on patients with the highest unmet need in obesity and then progress to other unmet needs in the treatment and prevention of metabolic diseases, including T2D.

Table of Contents

analysis. Patients who previously lost at least 15% of their body weight on a GLP-1 can qualify for the open label REVEAL-1 cohort. The data generated from the REVEAL-1 cohort will be used for open label reporting as the study progresses. The REMAIN-1 randomized cohort will enroll patients living with obesity and a BMI between 30 and 45 kg/m2 who are not currently on a GLP-1 drug. Patients will be prescribed tirzepatide and titrated to achieve at least 15% total body weight loss, at which time tirzepatide will be discontinued and patients will be randomized to Revita versus sham.

Midpoint Analysis of Randomized Cohort:

Pivotal Analysis of Randomized Cohort:

Secondary objectives will include evaluation of the effectiveness of the Revita DMR procedure on the change in blood glucose levels, CVD risk factors, body composition and pre-diabetes status. All patients enrolled in the study will receive diet and lifestyle counseling.

As announced on January 31, 2025, we have paused investment in the REVITALIZE-1 study, pursuant to our Strategic Reprioritization. Patients with inadequately controlled T2D, who are on at least one GLA and previously randomized, will continue to be followed per protocol to 48 weeks. Patients randomized to the sham arm will be offered an opportunity to receive the Revita DMR procedure (crossover) once unblinded. Patients who crossover and undergo the Revita DMR procedure will be followed per protocol.

We believe our Revita clinical program will provide comprehensive clinical evidence to support the potential of Revita as an investigational, potential disease-modifying procedural therapy for weight maintenance in obesity.

Rejuva Gene Therapy Platform to Enable Long-Term Remission of T2D and Obesity

To further our core strategy to treat and significantly reduce the burden of T2D and obesity, we are developing the Rejuva gene therapy platform. Our Rejuva gene therapy platform utilizes our novel investigational pancreatic delivery device to administer gene therapy candidates to target the dysfunctional pancreatic beta cells that are a root cause of insulin insufficiency in T2D. We believe that the precise mechanical and molecular confinement of targeted, low dose gene therapy medicines, can address many of the challenges that limit the use of gene therapy in the pancreas and the use of systemic GLP-1 drugs today. We have completed key preclinical in vivo studies to support a CTA for RJVA-001. We plan to submit the first CTA module to regulators by the first half of 2025, and, if approved to proceed, expect to report preliminary data in 2026.

Table of Contents

In December 2024, we unveiled promising preclinical data demonstrating the safety and feasibility of local delivery of RJVA-001 at the World Congress Insulin Resistance, Diabetes and Cardiovascular Disease (“WCIRDC”). Using an endoscopic ultrasound-guided system, we achieved safe and precise pancreatic delivery in Yucatan pigs at a low total viral dose with our proprietary Rejuva delivery catheter, closely mirroring the proposed route of administration in our planned first-in-human studies. Results showed therapeutically relevant GLP-1 expression within pancreatic beta cells with no adverse safety effects, reinforcing RJVA-001’s potential as a breakthrough approach for T2D. Based on these critical data, we are confident in our ability to advance toward first-in-human studies.

Execute Targeted and Efficient Go-to-Market Strategy

If Revita is approved in the United States, for a weight maintenance indication, we plan to execute an efficient “hub-and spoke” commercialization strategy to capitalize on the aligned incentives of key stakeholders and drive rapid adoption. Leveraging key learnings and insights from the Revita clinical program, and from the commercial pilot in Germany, we plan to assemble a targeted sales force initially focusing on centers of excellence with metabolically focused gastrointestinal (“GI”), endoscopists with a dedicated interest in bariatric and metabolic endoscopy, as we believe their familiarity with our product candidate may make them early adopters. We also intend to roll out a robust procedural training and support program for GI endoscopists, which we believe will ensure seamless integration into their workflow. We also plan to work with CMS and private insurers to seek to establish coverage and reimbursement for procedures using our product candidate, a key strategy to support the commercial viability of our product candidate with providers.

Broaden the Indication and Use of Revita

If Revita is approved for a weight maintenance indication in the United States, we plan to leverage our platform, technology, core capabilities and the data gathered from our prior clinical studies and the Revita clinical program to expand the indication and use of Revita within other unmet needs in the treatment and prevention of other serious metabolic diseases, including T2D.

Because of our broadly accessible and disease-modifying approach, we intend to make Revita a backbone procedural therapy that can potentially significantly reduce the burden of obesity, T2D and prediabetes. As we expand the adoption of Revita, we may seek regulatory allowance to evaluate potential indications and uses of Revita, as well as partnerships and/or distributor relationships for its commercialization in other global geographies.

Expand Application of Rejuva Platform to Other Metabolic Targets Beyond GLP-1

The Rejuva platform is modular and designed to enable local production of key metabolic hormones important for proper insulin production. Though our initial gene therapy candidate, RJVA-001, will include an AAV9 vector with a transgene that expresses GLP-1 hormone from an insulin promoter, our platform can enable production of a number of hormones, including, among others, glucose-dependent insulinotropic polypeptide (“GIP”), glucagon, peptide YY, or PYY and amylin. The versatility of the Rejuva platform has the potential to underpin a comprehensive, next-generation modality capable of targeting the root causes of various metabolic diseases.

Addressing Interlinked Metabolic Conditions: Obesity and T2D

Metabolic syndrome represents a spectrum of disorders that are primarily characterized by disturbances in the body’s ability to properly metabolize glucose, lipids, and other essential molecules. One of the most prevalent and ubiquitous manifestations of metabolic syndrome is obesity, a condition where excessive body fat accumulates to a degree that has the potential to adversely impact health. The presence of excess body fat in obesity helps predispose at-risk individuals to other manifestations of metabolic disease, notably T2D, CVD, metabolic dysfunction-associated steatohepatitis, or MASH (formerly known as non-alcoholic steatohepatitis).

Whereas our ancestors lived in and adapted over centuries to ensure adequate energy supply in environments with limited nutrition, many people now live in a modern world with abundant access to calories and levels of nutrition for which we believe our bodies were never designed. The mismatch between our ancestral genetics and modern diets that are

Table of Contents

high in fat and sugar is a primary driver of metabolic diseases in the recent past. Emerging scientific consensus links these high fat and sugar diets to dysfunction in key metabolic organs that increase the risk of the development of obesity and T2D, including the gut and pancreas. There is a high degree of overlap between obesity and T2D. Obesity is a key factor in poor metabolic function in patients with T2D, and weight loss is seen as a critical therapeutic goal for T2D patients. According to the American Diabetes Association Standards of Medical Care in Diabetes—2022, management of obesity is an important factor in the treatment of diabetes. According to the American Diabetes Association, even a 5% weight loss can improve blood glucose levels and reduce need for medication. Therapeutic strategies that can both lower blood glucose and help with weight management could have longer-term benefits in prevention and remission of metabolic diseases.

Our Market Opportunity in Obesity

Obesity is a disorder of altered metabolic setpoint and nutritional excess characterized by progressive weight gain and metabolic dysfunction that sits at the apex of a diverse range of negative health conditions, including T2D, CVD, and certain types of cancer. The International Diabetes Federation estimates that there are over 800 million people globally today, nearly 100 million people suffer from obesity and prediabetes in the United States alone. With new innovations achieving greater degrees of potency than earlier agents, the obesity market is poised for immense growth, with industry expectations of approximately $250 billion in drug sales by the end of the decade.

The human body has complex mechanisms to regulate weight, often compared to a thermostat that sets a "weight setpoint.” This setpoint is determined by a variety of factors, including genetics, environment, and behavior, and is regulated by a multitude of neural and hormonal signals originating in the intestine, pancreas, and adipose tissue, converging in the hypothalamus and other regions of the brain.

In individuals with obesity, the weight setpoint might be set or defended at a higher level, which is a key challenge in the management of this disease. When an individual with obesity loses weight (either by behavior changes or with medications, including GLP-1 drugs), the body perceives the weight loss as a state of calorie deficit and risk of starvation. For this reason, the brain triggers a set of compensatory mechanisms, including increased hunger and decreased energy expenditure to try to restore the previous, but higher weight setpoint. The potential correction of the body’s altered metabolic setpoint can enable lasting benefits and translate to superior real-world outcomes.

The Current Treatment Paradigm in Obesity

Guidelines today focus on addressing excess weight in obesity, rather than developing strategies to lower or reset the body’s altered weight setpoint. Initial interventions focus on dietary changes and lifestyle modifications. The American College of Cardiology (“ACC”) and American Association of Clinical Endocrinologists (“AACE”) recommend patients with obesity should initially be prescribed aerobic exercise and resistance training, a reduced calorie diet, and behavioral intervention. The AACE and ACC guidelines recommend that behavioral interventions be escalated for patients who do not achieve 2.5% weight loss within one month of beginning lifestyle modifications. If lifestyle modifications are not successful, treatment may move into therapeutic involvement and surgery. The AACE guidelines recommend that pharmacotherapy combined with lifestyle modifications be considered in individuals with a BMI of at least 27 kg/m2.

The GLP-1RA class of medicines have proven clinical efficacy in obesity. Wegovy (semaglutide), Saxenda (liraglutide), and Zepbound (tirzepatide) are GLP-1RA based therapies currently FDA-approved for obesity, with additional candidates in various development stages. In August 2023, Novo Nordisk’s SELECT trial demonstrated that treatment with semaglutide as an adjunct to the standard of care reduced the risk of heart attack, stroke, or heart disease-related death by 20% in overweight or obese individuals with cardiovascular disease and no prior history of T2D. Current prescription trends suggest widespread usage of GLP-1RAs in obesity, demonstrating extensive patient interest in access to this class of drugs.

A critical unmet need remains in obesity despite the potency of GLP-1RAs. As with glucose control, GLP-1RAs have a “rebound effect” in obesity, in which weight loss is not maintained once medication is stopped. A 2022 third-party study exploring weight regain and cardiometabolic effects after withdrawal of 2.4 mg of once-weekly semaglutide found that participants regained two-thirds of their prior weight loss one year after treatment discontinuation, with similar changes in cardiometabolic variables. In July 2023, results from Eli Lilly’s SURMOUNT trials for tirzepatide demonstrated similar results. We believe there remains a critical unmet need in obesity for a therapeutic option that provides long-term weight and metabolic benefit even after treatment discontinuation.

Table of Contents

In an era of potent but non-durable weight loss therapies, we believe goals for anti-obesity medications should be 1) weight maintenance, defined as minimal weight regain over the course of at least one year after the discontinuation of therapy, and 2) obesity remission, defined as achieving durable weight loss without the need for ongoing obesity-specific pharmacologic or surgical treatments. Therapeutic strategies that can achieve weight maintenance and obesity remission have the potential to provide a step change in outcomes for patients with obesity.

Our Market Opportunity in Type 2 Diabetes

The International Diabetes Federation estimates that diabetes currently affects over 500 million adults worldwide, with nearly 1.3 billion people expected to be living with T2D globally by 2050. In the United States alone, 25 million people live with T2D on medical therapy and 5 million people live with advanced T2D on insulin therapy.

The Current Treatment Paradigm in T2D

The current standard of care for T2D is defined by life-long symptomatic management, focused on blood glucose control instead of disease modification. Despite the fact that T2D affects a significant fraction of the global population, there has not been a novel modality introduced to treat T2D in over a decade. While therapeutic advances in T1D have led to the approval of Tzield (teplizumab-mzwv) for the prevention of progression of T1D in 2022, and novel cell-based approaches to replacing beta cells in T1D, there has been an absence of therapeutic strategies tackling the root cause pathology of T2D. This lack of innovation is evidenced by the stubborn persistence of inadequate T2D control in patients. There are no approved disease-modifying therapies that target the organ-level root causes of T2D today.

The standard initial therapy in T2D is preventative care: dietary and lifestyle interventions aimed at altering the risk factors that contribute to progression of disease. While alterations to lifestyle are important, even intensive diets have not demonstrated sufficiently durable effectiveness to favorably impact long-term health in most patients due to lack of persistence and adherence. The Look AHEAD trial, conducted by the National Institute of Diabetes and Digestive and Kidney Diseases, was a randomized controlled trial comparing an intensive lifestyle program to standard diabetes education in overweight and obese T2D patients to track the development of CVD over time. The trial was stopped for futility after a median follow-up of 9.6 years. Eventually, even with diet and lifestyle interventions, blood glucose often worsens as ongoing insulin resistance causes progressive failure of pancreatic beta cells. At this point, symptomatic therapy to manage hyperglycemia is needed and most patients advance to medications and the chronic-care therapeutic model we see today.

Several classes of oral and injectable drugs exist for the management of hyperglycemia, and the sequential addition of medications on top of one another is directed by patient preference and payor pressure to minimize costs. Most patients with T2D will remain on an expanding list of medications to lower their blood glucose throughout the remainder of their lives. The sodium-glucose cotransporter-2 inhibitor, or SGLT2i (e.g., empagliflozin), and GLP-1RA (e.g., semaglutide), classes emerged over ten years ago as important new therapies in T2D with benefits beyond glucose lowering alone, including broader metabolic benefits on CVD and kidney disease risk. Guidelines call for patients to typically try SGLT2i and GLP-1RA if affordable before progressing to insulin therapy, helping to make the SGLT2i class an estimated $12 billion market and the GLP-1RA class an estimated $20 billion market in 2022. The significant market uptake of these drugs has come despite important shortcomings. SGLT2i and GLP-1RA medicines have a black box warning associated with significant safety risks, as well as tolerability challenges affecting medication adherence. For example, GLP-1RAs impact several physiological processes and result in a variety of side effects, including nausea, vomiting and diarrhea.

The advent of the GLP-1RA class of medicines for T2D has led to an explosion in prescriptions of these drugs due to their impressive potency, cardiovascular benefits, and favorable weight loss profile. According to a report by Trilliant Health, physicians signed more than nine million GLP-1RA prescriptions in the United States for Ozempic, Mounjaro and Saxenda in the last three months of 2022 alone. However, a retrospective study conducted by Polonsky et al. analyzing medical claims data between July 2012 and January 2019 demonstrated that a majority of patients on a weekly GLP-1RA (i.e., semaglutide, dulaglutide or exenatide extended release) discontinued therapy at 12 months (Polonsky et al. Diabetes Ther (2022) 13:175–187). Discontinuation of these agents typically leads to an immediate loss of metabolic benefit and weight rebound, as seen in Eli Lilly’s SURMOUNT-4 study with tirzepatide and Novo Nordisk’s STEP-1 extension study with semaglutide. This lack of persistence to therapy and subsequent loss of benefit in both blood glucose and weight suggests that these agents do not offer durable disease modification in the disease and help explain the increasing burden of T2D in society, even with the availability of these potent drugs.

We believe the current symptom-driven approach to T2D management is misdirected and unreasonable. It asks patients for dietary and lifestyle changes in the face of an altered physiologic set-point in the body, rigorous and lifelong

Table of Contents

patient adherence and persistence to medicines, and unquestioning willingness to accede to increasingly complex therapies. This burdensome approach to care is often unmanageable and may leave many patients at risk, potentially resulting in chronic elevations in blood glucose that increase the likelihood of microvascular and macrovascular complications of T2D, and even death. There are no therapies that are approved today in T2D that offer disease modification, which we define as ongoing and durable preservation of pancreatic insulin production capacity even after therapy is discontinued.

We believe the same attention toward disease modification should be applied to T2D as is now already evident in T1D therapeutic development with goals of 1) diabetes prevention, defined as whether the treatment delays progression of diabetes, and 2) diabetes remission, defined as achieving a blood glucose level below the diabetic range for at least one year in the absence of active pharmacotherapy or ongoing procedures.

Our Approach

We design and develop novel, differentiated, disease-modifying therapies that precisely target and alter the function of the diseased organs responsible for obesity and T2D. Despite the development of highly potent medicines that can improve glucose control and weight loss, significant unmet needs remain in these diseases due to high rates of drug discontinuation over time, the loss of metabolic benefit upon drug discontinuation, and the inability of medicines to arrest the progressive nature of these conditions. Our vision is to develop transformative therapies that have the potential to prevent and eliminate metabolic diseases.

Our product candidates have the potential to offer a major advance in healthcare because they are designed as disease-modifying treatments that provide long-term metabolic benefits from a single administration, and are therefore potentially positioned to target the prevention and remission of disease, critically important categories in obesity and T2D treatment that cannot be addressed with current pharmacology. In order to be maximally impactful, these therapies must also be delivered at a scale that can match the incidence and prevalence of metabolic disease around the world. We believe our product candidates are not only unique in their potential for disease modification, but also in their design for broad accessibility for large populations. Accordingly, we believe our candidates have the capacity to revolutionize treatment of obesity and T2D and, at their fullest potential, significantly reduce the burden of metabolic disease globally.

Our Solutions

We believe there is a significant market opportunity for disease-modifying treatments that provide long-term metabolic benefits across the spectrum of obesity and T2D and we are developing a suite of product candidates that will target different phases of these metabolic diseases.

Our Revita pivotal clinical study, REMAIN-1, is designed to evaluate Revita in a clinical study assessing the maintenance of weight loss after GLP-1 discontinuation.

We are also developing Rejuva to enable long-term remission of T2D and obesity by potentially restoring pancreatic metabolic function and boosting satiety in patients with these diseases.

Overview of Revita

Revita is an investigational outpatient procedural therapy designed to durably modify duodenal dysfunction, a major pathologic consequence of a high fat high sugar diet, which can initiate obesity and T2D in humans. The duodenum is the first segment of the small intestine and the first site of nutrient absorption within the body. The duodenal mucosa regulates the human metabolic response to food intake, and chronic exposure to modern diets high in fat and sugar drive a functional maladaptation of stem cells in the duodenum and lead to dysfunctional hyperplasia of the duodenal mucosa. These diet-induced changes to the structure and function of the duodenal mucosa disrupt physiologic nutrient sensing and signaling mechanisms from the gut to the brain, with resulting alterations to systemic metabolic activity that affect glucose control and satiety through multiple downstream organ systems. Emerging scientific consensus has identified this dysfunction in the gut as a root cause of obesity and metabolic dysfunction and therefore propose targeting gut dysfunction to address downstream metabolic diseases. There are no therapies approved today that target the duodenal mucosa for regeneration and renewal.

The Revita system is designed to enable durable and repeatable metabolic improvement by targeting duodenal dysfunction with an outpatient, endoscopic procedural therapy. Revita uses heat energy to ablate the dysfunctional duodenal mucosa, including the duodenal stem cells residing at the base of the mucosa, to enable regeneration and renewal of the

Table of Contents

duodenum and restore normal metabolic signaling from the gut. The Revita procedure provides thermal protection to the duodenum before ablating the superficial mucosa by (1) isolating the mucosa from the deeper muscle layer of the duodenum and then (2) hydrothermally ablating the superficial layer of the duodenal lining with a proprietary balloon catheter and control console. The procedure takes less than 45 minutes and can be conducted in an outpatient setting in a manner that allows immediate return to daily life for patients. In the days following the ablation procedure, the duodenal mucosa regenerates, which we believe leaves the duodenal lining revitalized and better able to properly coordinate the gut’s metabolic signaling mechanisms.

Revita is designed to treat patients ranging from those who are living with obesity and at risk of developing metabolic complications of obesity, such as T2D, to those who have advanced T2D and have exhausted medical therapies. For individuals with obesity and prediabetes, Revita is designed to address upstream metabolic dysfunction that puts them at risk for the progression of obesity and at risk for the development of T2D.

Potential Benefits of Revita

We believe that Revita’s unique individual features combine to provide a significantly differentiated solution to obesity, offering the following potential benefits:

•

Durable and Repeatable Benefit. Revita is designed to improve metabolic health, blood glucose levels, and weight in patients living with obesity and/or T2D. A pooled analysis of data collected on secondary endpoints assessing weight in our previously conducted controlled clinical studies across the United States and Europe demonstrated a 3.4% (n=100) mean reduction in total body weight loss at four weeks in patients with T2D on multiple ADAs after undergoing a single Revita DMR procedure and showed a sustained mean body weight loss of 4.0% (n=94) at 48 weeks. We believe this is an important and differentiated therapeutic profile in obesity management. In addition, we believe our Revita system has the potential to enable repeat Revita procedures over time.

•

Tolerability. In clinical studies to date, Revita has been observed to be generally well tolerated, with most patients resuming normal daily activities one day after the procedure and none requiring prescription pain medications. Our proprietary Revita technology is designed to provide thermal protection before ablation, enabling isolation of the mucosa from deeper tissue structures and sparing pain fibers in the muscle while reducing risk of tissue injury.

•

Broad Implementation. Revita is a modular system that can potentially be incorporated into the endoscopist workflow by leveraging familiar skillsets of advanced endoscopists. Revita is intended to fit into most endoscopy suites and typically requires fewer than four cases for the endoscopist to acquire proficiency. It is designed to be an outpatient procedure that can be performed by a trained therapeutic endoscopist in less than an hour. Today, over 20,000,000 endoscopies are performed each year in the United States, including over 600,000 advanced endoscopic procedures, by nearly 10,000 gastroenterologists. Of the estimated 10 million people on GLP-1s in the United States today, approximately 800,000 will undergo an endoscopy this year. The Revita DMR procedure is designed to be a simple add-on procedure tothese and other endoscopies already performed on patients living with obesity and T2D annually.

•

Real-World Outcomes. Because it is designed as a procedural therapy, Revita does not rely on perfect patient adherence or persistence to chronic therapy for its anticipated clinical effects. Unlike diet and lifestyle interventions or pharmacologic management, the benefits of Revita are intended to be conferred at the time of the procedure and not reliant upon ongoing therapeutic maintenance. This allows a shift in patient focus from escalating chronic disease management burden to ongoing health maintenance after the procedure.

•

Patient Friendly. Revita is designed to offer a straight-forward, outpatient experience requiring less than a half-day visit, and allowing patients to typically return to their normal daily lives the very next day. Furthermore, initial interim data suggest that the Revita DMR procedure has thus far been observed to be compatible with other current interventions for obesity in broad use, including diet and lifestyle, as well as existing and emerging pharmacologic therapies.

Table of Contents

Overview of Rejuva

Rejuva is a novel, locally administered, AAV-delivered PGTx platform designed to enable long-term remission of T2D and obesity by durably altering metabolic hormone function in the pancreatic islet cells of patients with T2D and obesity. Pancreatic islets are tiny clusters of cells distributed throughout the pancreas that play a crucial role in endocrine function and glucose metabolism. There are several cell types within the pancreatic islet, including alpha cells responsible for glucagon production and beta cells responsible for insulin production. Metabolic dysfunction in obesity and prediabetes can lead to progressive beta cell dysfunction and eventual failure, loss of insulin production and secretion, and the development of T2D. There are no therapies approved today that target the pancreatic islet in T2D for repair or replacement.

Our Rejuva gene therapy platform utilizes our novel investigational pancreatic delivery device to administer gene therapy candidates to target the dysfunctional pancreatic beta cells that are a root cause of insulin insufficiency in T2D. Rejuva is a modular, physiologic gene therapy platform with three key elements designed to enable successful pancreatic gene therapy: (1) a proprietary delivery catheter designed to enable local, low dose therapeutic delivery directly to the pancreas via endoscopic access, (2) vectors with tropism for the pancreatic islet to enable successful transduction and gene delivery with limited biodistribution via this route of administration, and (3) transgenes with tissue-restricted promoters and metabolically active peptides that can durably impact glucose and weight control. Rejuva is designed to directly administer a gene therapy into the body and tail of the pancreas via mechanical confinement of virus with local administration and molecular confinement of transgene expression with tissue-specific promoters. These peptides are intended to rejuvenate beta cell health and restore the body’s natural ability to produce insulin. The first gene therapy candidate for Rejuva is RJVA-001, a smart GLP-1, comprising a locally administered AAV9 viral vector that expresses a full-length GLP-1 hormone from an insulin promoter designed for the remission of T2D. The second gene therapy candidate for Rejuva is RJVA-002, a smart GIP/GLP-1, designed for the treatment of obesity. RJVA-002 is a locally administered AAV9 viral vector that expresses human GLP-1 and GIP hormones from a human insulin promoter. RJVA-002 is designed to activate both GIP and GLP-1 receptors, which play crucial roles in regulating body weight and blood sugar.

Potential Benefits of Rejuva

We believe that Rejuva’s individual features combine to provide a significantly differentiated solution to T2D and obesity, offering the following potential benefits:

•

A Compelling, Substantial Commercial Model in Gene Therapy. We believe the Rejuva platform, if approved, has the potential to provide a differentiated market offering within the gene therapy space. We believe this potential for differentiation could be enabled by a large patient population (approximately 27 million people are living with T2D in the United States; approximately 100 million people are living with obesity in the United States), low cost of goods (local delivery of a validated AAV capsid enables a cost of goods sold of potentially less than $10,000 per patient), and a development space where the high economic

Table of Contents

value is substantial and well understood (approximately $10,000 price per year under the Institute for Clinical and Economic Review (“ICER”) price benchmark).

•

Novel Approach to a Highly Validated Target. Our Rejuva platform candidates are being developed as an investigational pancreatic delivery device and local, AAV-delivered PGTx to durably improve islet health in the pancreas. Our first Rejuva PGTx candidate, RJVA-001, is intended to augment intra-islet GLP-1 receptor activation, leveraging well established biology on GLP-1 signaling and potentially leading to improved beta cell health and glucose control in patients with T2D. Our second Rejuva PGTx candidate, RJVA-002, a smart GIP/GLP-1, is designed for the treatment of obesity.

Human GLP-1 PGTx (RJVA-001) Therapeutic Mechanism of Action. 1)TheRJVA-001 transgene construct, consistingof a human insulin promoter and GLP-1sequences, is packaged into AAV9 vectors whichare taken up by the beta cell. 2) Vectorsenter the nucleus and release thetransgene, which is transcribed into GLP-1mRNA. 3) GLP-1 mRNA exits the nucleusand is translated into protein. 4) GLP-1proteins are packaged into secretoryvesicles with insulin. 5) GLP-1 with insulinrelease is triggered by nutrient stimulation.

Table of Contents

•

Precise Local Delivery. Our Rejuva gene therapy platform is designed to provide precise local delivery of gene therapy to the pancreas in a single endoscopic procedure. Our Rejuva platform leverages standard-of-care techniques for pancreatic tissue access and possesses key proprietary device elements and procedure steps, thereby reducing procedural risk. We believe our Rejuva gene therapy candidates will benefit from localized administration, potentially avoiding the risk of high dose systemic administration that has been observed with other gene therapy candidates or GLP-1 receptor analogs.

•

Preclinical Pharmacology and Toxicology Profile.In preclinical head-to-head studies, Rejuva gene therapy candidates demonstrated weight reduction in a disease-relevant DIO mouse model, and improvement in glycemic control and delayed T2D progression in a disease-relevant db/db mouse model compared to chronic administrations of semaglutide.

Table of Contents

•

In a preclinical proof-of-concept head-to-head comparison to chronic semaglutide (10nmol/kg daily) in a DIO model for obesity, after a single administration of a GLP-1 PGTx candidate, we observed:

•

A statistically significant decrease in total body weight of 25% (p<0.0001).

•

Further, at the four-week timepoint, mice who were previously administered chronic semaglutide were discontinued from the drug and re-randomized to receive either a vehicle or PGTx. These mice were followed for an additional four weeks. By the end of the eight-week experimental period, the semaglutide withdrawal plus vehicle group regained the body weight they had lost (only 2% decrease from the baseline) while the semaglutide withdrawal plus PGTx group maintained their lost body weight (22% decrease from baseline).

Table of Contents

•

In a preclinical proof-of-concept head-to-head comparison to chronic semaglutide (10 nmol/kg daily) in a db/db model for diabetes, after a single administration of a GLP-1 PGTx candidate, we observed:

•

statistically significant average reduction of fasting plasma glucose levels of 73% (p < 0.0001) compared to vehicle at four weeks;

•

statistically significant increase in fasting plasma insulin of 478% (p < 0.01) at four weeks; and

•

statistically significant decrease in total body weight of 14% (p<0.001) at four weeks.

Additionally, no adverse events related to the pancreas, liver or other tissues were observed in our rodent or large animal studies.

In December 2024, we unveiled promising preclinical data demonstrating the safety and feasibility of local delivery of RJVA-001 at the WCIRDC meeting. Using an endoscopic ultrasound-guided system, we achieved safe and precise pancreatic delivery in Yucatan pigs at a low total viral dose, closely mirroring our planned first-in-human studies. Results showed therapeutically relevant GLP-1 expression within pancreatic beta cells with no adverse safety effects, which we believe reinforces RJVA-001’s potential as a breakthrough approach for T2D. Based on these critical data, we intend to advance toward first-in-human studies. We plan to submit the first CTA module to regulators by the first half of 2025 and, if approved to proceed, expect to report preliminary data in 2026.

•

Building Upon Clinical and Real-World Experience with Revita. The gene therapy candidates from our Rejuva platform benefit from the extensive clinical and real-world experience that we have accumulated through our Revita program. Rejuva PGTx candidates can be delivered by the same treating physicians and in the same setting as the Revita DMR procedure, utilizing the same distribution network. Moreover, we believe the metabolic benefits of Rejuva PGTx candidates have the potential to be complementary to, and perhaps synergistic with, the Revita DMR procedure.

•

Rigorous Development Plan. We have completed key preclinical in vivo studies to support a CTA for RJVA-001. We plan to submit the first CTA module to regulators by the first half of 2025, and if approved to proceed, expect to report preliminary data in 2026.

•

Interchangeable Platform for Metabolic Therapy. The Rejuva platform enables selection of multiple metabolically active peptide hormones (GLP-1, GIP, PYY, amylin, glucagon, etc.), either individually or

Table of Contents

combinatorially, with the same local delivery and plasmid construct for differential therapeutic profiles over time.

By employing Revita and Rejuva to target the prevention and remission of obesity and T2D, we believe it is possible to provide a step change in outcomes for patients above and beyond the current chronic management strategies that exist today. If we are able to obtain approval for these product candidates in the United States, we believe these therapies will enable us to chart a course towards significantly reducing the burden of obesity and T2D globally.

Our Targets: the Gut and Pancreas

“All disease begins in the gut.”

- Hippocrates

The Role of the Gut in the Central Regulation of Metabolism

In recent years, there has been an increase in research tying gut health to diseases throughout the body – ranging from obesity to T2D to dementia. One aspect of this research is the emerging consensus that an important root cause of metabolic disease is the impact of modern diets on the gut, one of our body’s critical metabolic control systems. Advances in our understanding of integrative organ physiology has begun to reveal the complex role that the gut plays in interfacing with the food we eat and coordinating the body’s response to that food. The gut possesses the largest nervous system outside the brain, the largest hormone producing endocrine system, a huge and complex microbiome, and the largest immune system in the body. Different segments of the intestine have different endocrine producing cells and different neurohormonal effects on the brain’s response to the meal. These mechanisms work together to provide a defensive barrier and an early warning detection system to help the body prepare for and deal with the food we ingest.

Diets have changed a great deal over the past several decades, with a shift away from relatively calorie poor, fiber rich, natural foods, to the inexpensive and abundant supply of ultra-processed foods that are very high in simple fats and sugars. Our founders, along with several scientific groups around the world, have begun to detail the specific changes that these modern diets cause on the gut and the impact these changes exert on the body and brain. While the gut has long been recognized as an acute nutrient sensor with signaling mechanisms to the other metabolic organs of the body, its role in regulating the body’s metabolic status over longer periods of time has been underappreciated. Recent advances have demonstrated that the chronic exposure of the intestine to high levels of fats and sugars lead to structural and functional changes of the lining of the proximal gut that may signal a metabolic shift to the brain and body. These insights provide a window into the adaptive role of the intestinal mucosa in helping to define metabolic parameters within the body—informing the metabolic regulation of insulin resistance versus sensitivity, hunger versus satiety, energy utilization versus energy storage, and protection from hypoglycemia versus protection from hyperglycemia. Moreover, these diet-induced changes are geographically confined to the upper small intestine, particularly the duodenum, an area of the body that is directly accessible via routine upper endoscopy via the mouth. This new research provides, for the first time, an accessible potential target of pathology within the gut that sits at the apex of the complex metabolic changes throughout the body underlying metabolic diseases, including obesity and T2D.

Structural and functional changes in the duodenal lining occur in response to high fat, high sugar diets, and can lead to obesity and T2D

After food passes through the stomach, it moves to the duodenum, which is approximately the first 25 cm to 30 cm of the small intestine, where nutrient absorption first begins in the body. The lining of the duodenum, known as the mucosa, is composed of several cell types, including absorptive cells called enterocytes and hormone-producing enteroendocrine cells, or EECs (comprising approximately 1% of the cells of the mucosa). EECs sense the presence or absence of nutrients in the duodenum and send chemical signals via the bloodstream and direct connections to nerve cells in the gut to the brain and body to help mediate glucose control, as depicted below.

Table of Contents

EECs in Duodenal Lining Send Neurohormonal Signals to Brain and Body

Studies analyzing the small intestine in diabetic patients and animal models have identified functional maladaption of the intestinal mucosa after chronic dietary exposure to high concentrations of fat and sugar similar to the composition of modern diets. Geltrude Mingrone (a consultant to the Company), et al. showed in 2010 that a high fat diet in rats can cause overgrowth of the duodenal mucosa. Working with colleagues at King’s College London, we extended these observations to show that mucosal overgrowth may occur in the duodenum and proximal jejunum but does not extend to further segments of the intestine, such as the ileum (West et al. bioRxiv preprint doi: https://doi.org/10.1101/822122). Further, Aliluev and colleagues observed that high fat, high sugar diets alter intestinal stem cell homeostasis leading to an overgrowth (i.e., hyperplasia) of the duodenal mucosa (Aliluev et al. Nat Metab. 3(9):1202-1216). The figure on the left demonstrates that chronic exposure to these diets may lead to the development of a dysfunctional duodenal lining. The image below on the right depicts the effect of a high fat diet on the growth of the mucosa in a rodent chronically fed a high fat diet, which led to a 50% increase in mucosal surface area over time, relative to a normal diet-fed rodent.

High Fat and Sugar Diets May Cause Overgrowth and Dysfunction of Duodenal Mucosa

This finding of a nutrient-induced stem cell division process that causes structural and functional changes of the duodenal mucosa has now been replicated by multiple independent groups in the United States and Europe, and across

Table of Contents

organism species and disease models. Michael Theodorakis et al. have demonstrated similar observations in diabetic humans, showing through duodenal biopsies that the mucosa in the duodenum of patients with T2D becomes thickened and exhibits changes to the hormone-producing cell populations in the duodenum (Theodorakis et al. Am J Physiol Endocrinol Metab 290: E550–E559, 2006).

Hyperplasia and dysfunction of the duodenum is associated with more mucosal cells, a greater surface area for nutrient absorption, and in turn more EECs for neurohormonal signaling, altering the body’s response to the metabolic signal from this region of the gut. The greater surface area of the duodenal lining accelerates nutrient absorption and nutrient sensing and signaling from EECs in the proximal intestine. Multiple downstream mechanisms have been implicated in the role of this gut dysfunction in causing metabolic dysfunction. According to Duca et al., EECs in the duodenum respond to ingested nutrients by secreting hormones, including GLP-1 and cholecystokinin, which enter the circulation and trigger local nervous system activation on the basolateral surface of those cells. In this way, the brain can receive neurohormonal signals from the gut and uses this integrated information to regulate blood glucose levels and weight by impacting glucose metabolism and energy metabolism throughout the body (Duca et al. Cell Metab. 2015 Sep 1;22(3):367-80, Duca et al., Nat Commun. 2021; 12: 903). In a healthy state, intraduodenal lipids triggers satiety and suppression of blood glucose levels through these mechanisms, but chronic high fat diets impair this gut-brain feedback in lipid sensing and signaling, leading to metabolic dysfunction (as depicted in the image below).

Source: Duca et al., Nat Commun. 2021; 12: 903; http://creativecommons.org/licenses/by/4.0/

We believe that, taken together, this recent preclinical and clinical evidence demonstrates that abnormal neurohormonal signaling from the duodenum to the rest of the body is an important contributor to metabolic dysfunction, which can increase the risk of obesity and T2D. This insight extends the conventional wisdom that excess weight and physical inactivity are the sole drivers of T2D by highlighting the important role of the duodenum in metabolic control.

Avoiding Nutrient Contact with the Duodenum can Reduce Insulin Resistance in T2D

Not only is there evidence that changes in the duodenum and duodenal nutrient sensing may directly and/or indirectly cause insulin resistance, but independent studies in animals and humans show that preventing or disrupting nutrient contact with the duodenal mucosa can ameliorate insulin resistance and its downstream clinical consequences. Metabolic surgeries that bypass the stomach and duodenum, originally intended for weight loss, have emerged as a treatment approach in T2D with superior metabolic benefits compared to the current standard of care. There is abundant and compelling surgical experience (performed in hundreds of thousands of patients with millions of patient-years of follow-up) showing significant and durable metabolic improvements that come from bypassing the duodenum in people with obesity and T2D. These surgeries have now firmly positioned the duodenum as a validated novel target for metabolic disease and an organ whose function can be safely and effectively altered for metabolic improvement.

Table of Contents

The Role of the Pancreas in Metabolic Control

The pancreas is a hormone producing organ in the retroperitoneum surrounded by the duodenum, immediately below the stomach. It has functions related to the secretion of digestive enzymes into the duodenum to help process food for absorption (exocrine pancreas) and functions related to the secretion of hormones into the bloodstream to help maintain glucose control (including insulin and glucagon) from pancreatic islets distributed throughout the pancreas. The figure below shows cells within a pancreatic islet: alpha cells secrete glucagon into the bloodstream and beta cells secrete insulin. Glucagon and insulin are counter-regulatory hormones that act in opposite directions to raise or lower blood glucose levels, respectively.

Pancreatic Islet Cells Produce Glucagon and Insulin

Most people can compensate for their bodies’ metabolic dysfunction by increasing the amount of insulin they produce in the beta cells of their pancreas to keep blood glucose levels within normal ranges. Patients who go on to develop T2D eventually experience a gradual loss of beta cell function, leading to reduced insulin production and insulin secretion over time. There are two principal causes for the loss of beta cell function in most people with T2D: (1) exhaustion of beta cell function in the face of longstanding metabolic dysfunction and chronically elevated blood glucose levels, and (2) damage to beta cells from the toxicity of circulating lipids (i.e., lipotoxicity) that are directly tied to metabolic dysfunction. By the time the diagnosis of diabetes is made, people have lost over 80% of their beta cell function, which we believe makes it essential that the physician intervene aggressively with therapies known to prevent or correct known pathophysiological disturbances in beta cell function.

Increasing GLP-1 Levels in the Pancreas Can Improve Islet Metabolic Function

GLP-1 is a potent hormone that is produced in the distal intestine and secreted into the circulation in response to nutrient intake and also produced in the pancreatic islets by alpha cells, acting within the islet to regulate metabolic control. The role of GLP-1 hormone within the pancreatic islet in beta cell function and insulin production is one of the best understood hormonal mechanisms in all of medicine. The GLP-1 receptor is expressed in beta cells of the pancreas, where receptor activation has multiple acute and chronic actions on beta cell function: acutely, GLP-1 immediately stimulates insulin secretion in response to elevations in blood glucose; chronically, GLP-1 stimulates insulin gene transcription and islet cell survival. The GLP-1 receptor is also expressed in alpha cells of the pancreas, where receptor activation regulates glucagon expression to help control blood glucose levels. Studies have shown that there is impaired GLP-1 signaling in the pancreatic islet in T2D, and increased GLP-1 signaling can compensate for impaired insulin secretion, preserve beta cell function and survival, and therefore improve glucose homeostasis in T2D. The beneficial effects of GLP-1 on pancreatic islet function have been further shown by the effects of the GLP-1RA class of medicines, which have demonstrated meaningful improvements in insulin production and pancreatic responsiveness to blood glucose.

Revita and Rejuva are designed to treat obesity and T2D by directly targeting the gut and pancreas, respectively. Both therapies focus on addressing root causes of metabolic diseases within these organs.

Table of Contents

By leveraging our expertise in developing novel, differentiated, disease-modifying therapies, and our insights into the biology of the gut and pancreas, we believe our therapeutic approaches, if approved, have the ability to alter the paradigm for treating obesity and T2D by remediating the most fundamental causes of the disease.

Revita Product Description

Device Overview

Revita is comprised of (i) the Revita console that houses our proprietary technology and software, and (ii) a single-use Revita DMR catheter. The console’s touchscreen-based graphical user interface is designed to provide ease-of-use and clear guidance on the performance and progress of the procedure for the physician. The console is designed to control the temperature of the ablative and cooling fluid, vacuum suction, facilitate the delivery of saline for the submucosal lift and the pressure and flow rate of water during the ablation cycle. In addition, the console houses sensors that are designed to monitor temperature, pressure and procedure status. We believe the console enables a targeted ablation process by enabling a proprietary safety mechanism that reduces penetration of heat to deeper tissues during the hydrothermal ablation procedure, and potentially reduces the risk of physician error by automating certain steps of the treatment process by guiding the physician step-by-step through the procedure. The image below depicts a prototype rendering of the modular Revita console with the proprietary Revita catheter. The catheter and graphical user interface are currently being used in our REMAIN-1 clinical study and in our REVITALIZE-1 clinical study, but the Revita console hardware below is not. We plan to seek approval from the FDA of a supplemental PMA for this console design modification. The Revita DMR catheter is comprised of three outward-facing ports on the exterior of our novel ablation balloon with a control handle on the proximal end. Each port on the catheter has an opening whose size and shape is designed to enable suction to selectively pull mucosal and submucosal tissue into the port, while preventing the deeper muscularis tissue from being pulled in. In addition, the catheter is thin, flexible and narrow, and is designed to be deliverable and trackable across the stomach into the small intestine over a standard endoscopic guidewire or the Revita procedurally optimized guidewire. In the first quarter of 2025, we began offering the FDA 510K cleared Revita Guidewire to principal investigators to support ongoing Revita

Table of Contents

clinical studies. The Revita Guidewire is designed specifically to enable ease of delivery for the Revita DMR catheter and procedure.

Modular Revita Console Powered by an Intuitive Touchscreen User Interface

Procedure Overview

The Revita DMR procedure is designed to be a minimally invasive, outpatient, endoscopic procedural therapy using a proprietary balloon catheter that is uniquely designed for the duodenal mucosa in a procedure that typically lasts less than an hour. Revita is designed to target the mucosal surface for ablation and induce intestinal stem cell-mediated regeneration. The procedure is performed by a trained endoscopist while the patient is under conscious sedation or general anesthesia. With the help of the Revita console, certain steps of the procedure are designed to be highly automated, which we believe minimizes the risk of physician error.

The procedure involves inserting the distal end of the single-use Revita catheter through the mouth over a guidewire past the stomach and into the duodenum, using fluoroscopy to assist placement. The catheter is then positioned distal to the ampulla of Vater (i.e., the hepatopancreatic duct where bile salts and pancreatic enzymes enter the GI tract) under direct endoscopic visualization. The procedure then involves a repeated sequence of thermal safety and hydrothermal ablation steps.

Table of Contents

Thermal Safety. Our proprietary thermal safety procedural step involves an automated, circumferential instillation of saline into the submucosal space of the duodenum. This step is initiated through the user interface of the console and enables the lifting of the mucosa away from the underlying muscle layer. The catheter balloon is expanded with fluid to allow the catheter to engage with the mucosa and a vacuum connected to the console draws the mucosa into each of three injection ports on the catheter. The user interface of the console is then used to initiate saline delivery to the submucosal space via needles within the vacuum ports. This procedure step is designed to create a thermal barrier between the mucosa and the underlying muscular layer in order reduce the risk of discomfort or unintended thermal injury, and to enable repeated procedures by ensuring that the mucosa can be safely lifted before performing thermal ablation.

Designed to Create a Protective Thermal Barrier for a Well Tolerated Procedure

Hydrothermal Ablation. After the thermal safety step is completed in a region of the duodenum, hydrothermal ablation is initiated through the console user interface. The ablation cycle involves the introduction and recirculation of water within the balloon. We believe this sequence of steps provides a controlled, uniform, “thin layer” ablation of the mucosa and superficial submucosa and potentially further reduces the risk of injuring deeper tissues. The first step fills the balloon with cold water to cool the duodenal tissue below body temperature prior to ablation. The second step is intended to deliver a precise dose of hydrothermal energy to the tissue to create a controlled coagulative ablation. The third step is intended to remove any residual heat from the tissue and to prevent unintended conduction of heat within the tissue.

The thermal safety and hydrothermal ablation steps are continued sequentially along the length of the duodenum, extending from just beyond the ampulla of Vater and proceeding distally until the full length of the duodenum is treated. The sequential thermal safety and hydrothermal ablation steps are designed to ensure the spatial and temporal alignment of the ablation within the previously lifted region before the thermal protective saline barrier dissipates. We have designed Revita’s hydrothermal ablation to be coagulating, where the proteins in the tissue are denatured but the tissue remains in place. In addition, our ablation procedure is designed to prevent bleeding and to allow overlapping ablations without excessive depth of ablation.

Upon completion of the procedure, the guidewire, catheter and endoscope are removed, leaving no long-term implant in the GI tract. The patient is typically discharged on the same day and is prescribed a graduated post-procedure diet, starting with liquids and progressing to pureed foods and soft foods. Similar to other routine upper-GI endoscopic procedures, if Revita is approved, we anticipate that patients will resume normal activities the day after their procedure, which is supported by our observations to date.

Table of Contents

Clinical Data Overview: Revita

We have evaluated the Revita DMR procedure in over 300 patients in multiple clinical studies across numerous sites in South America, Europe and the United States. To date, we have observed the Revita DMR procedure, when added to certain ADAs and lifestyle counseling, to be generally well tolerated and demonstrated durable blood glucose lowering and weight stabilization in patients for two years post-procedure. We are currently evaluating the Revita DMR procedure in the REMAIN-1 pivotal study. Pursuant to our Strategic Reprioritization, we have paused investment in Revita for T2D, which includes the REVITALIZE-1 study and the Germany Real-World Registry study. In the REVITALIZE-1 study, patients with inadequately controlled T2D, who are on at least one GLA and previously randomized, will continue to be followed per protocol to 48 weeks. Patients randomized to the sham arm will be offered an opportunity to receive the Revita DMR procedure (crossover) once unblinded. Patients who crossover and undergo the Revita DMR procedure will be followed per protocol. We expect to continue to follow the existing patients per protocol in a real-world setting and continue to report on clinical, health economic, and patient-relevant outcomes from this study on an ongoing basis in the Germany Real-World Registry study. Based on the data observed in our previously conducted clinical studies, we believe that the Revita DMR procedure has the potential to treat the organ-level root cause of metabolic diseases, such as obesity and T2D.

The table below summarizes our ongoing, paused and completed clinical studies for the Revita DMR procedure.

Study and Status Study Design Primary Objectives Milestones

Ongoing

Paused due to Strategic Reprioritization

Table of Contents

Study and Status Study Design Primary Objectives Milestones

Completed

* p-value represents the chance that the observed results occurred by chance alone. A p-value of less than 0.05 is considered statistically significant.

Key Metrics

The outcomes of our clinical studies are evaluated by a number of well-known validated glycemic metrics, including:

•

Total Body Weight Change. A physical measurement from baseline weight identifying alteration in weight due to caloric excess or deficit. Total body weight change can include weight gain (from energy excess) or weight loss (from energy expenditure exceeding caloric intake).

•

Glycosylated Hemoglobin (HbA1c %). HbA1c reflects average levels of blood glucose over the previous two to three months and is the most widely used clinical test to estimate mean blood glucose and monitor glycemic control.

•

Fasting Plasma Glucose (mg/dL or mmol/L). FPG measures the serum glucose concentration after an overnight fast of at least eight hours providing an instantaneous measure of glucose homeostasis.

•

Oral Glucose Tolerance Test. A oral glucose tolerance test, or OGTT, evaluates beta cell function after a patient ingests a fixed glucose solution. To perform the test, blood glucose is measured immediately prior to consumption and typically every 30 minutes two hours after consumption. Area under the curve, or AUC, OGTT is the calculation of the total excess of blood glucose measured during the course of the OGTT.

Revita Clinical Program Insights

Our Revita clinical program design has been informed by our prior clinical studies and expertise in the field of metabolic diseases, including obesity and T2D. We are evaluating and/or have evaluated the Revita DMR procedure in over 30 clinical centers and it has been performed by more than 30 different endoscopists. We have followed most Revita-1 and Revita-2 patients beyond 12 months post-procedure to observe the long-term safety of the Revita DMR procedure, including its effects on glucose homeostasis and weight, and, in all, we have observed over 500 patient-years of Revita

Table of Contents

DMR procedure exposure data using Revita. Based on these experiences, we believe the Revita DMR procedure has the potential to:

•

enable weight maintenance in patients living with obesity;

•

reduce the risk of developing diabetes in patients with high-risk prediabetes;

•

improve glycemic control in T2D patients on insulin; and

•

improve glycemic control in T2D patients on one or more ADAs who are not yet on insulin.

We are focused on developing Revita to treat patients ranging from those who are living with obesity and at risk of developing metabolic complications of obesity, such as T2D, to those who have advanced T2D and have exhausted medical therapies. For individuals living with obesity and prediabetes, Revita is designed to address upstream metabolic dysfunction that puts them at risk for the progression of obesity and at risk for the development of T2D.

Ongoing REMAIN-1 Clinical Study

We are evaluating Revita in the REMAIN-1 pivotal study, which is designed to include two cohorts - an open label cohort referred to as REVEAL-1, and a randomized cohort which includes both a midpoint analysis and a pivotal analysis. Patients who previously lost at least 15% of their body weight on a GLP-1 can qualify for the open label REVEAL-1 cohort. The data generated from the REVEAL-1 cohort will be used for open label reporting as the study progresses. The REMAIN-1 randomized cohort will enroll patients living with obesity and a BMI between 30 and 45 kg/m2who are not currently on a GLP-1 drug. Participants will be prescribed tirzepatide and titrated to achieve at least 15% total body weight loss, at which time tirzepatide will be discontinued and patients will be randomized to Revita versus sham.

Midpoint Analysis of Randomized Cohort:

Pivotal Analysis of Randomized Cohort:

We gained FDA approval for the IDE in the first quarter of 2024 to initiate the pivotal REMAIN-1 study. In July 2024, we obtained Breakthrough Device designation from the FDA for the Revita system, as an adjunct to diet and exercise, to perform hydrothermal ablation of the duodenal mucosa, or the Revita DMR procedure, for use in the maintenance of weight loss after discontinuation of GLP-1-based therapy on patients who cannot tolerate long-term GLP-1 therapy and who are not candidates for endoscopic remodeling procedure or bariatric surgery. In September 2024, the FDA approved an amendment to the clinical study protocol for the REMAIN-1 study of our Revita device, which aligns the co-primary endpoint with a weight maintenance indication for Revita and adds a midpoint analysis at three months allowing us to analyze and report on approximately 45 randomized patients. In the third quarter of 2024, we initiated REMAIN-1.

In January 2025, we reported positive preliminary results from the REVEAL-1 open-label cohort of the REMAIN-1 study. Initial findings from the first patient, as of a cutoff date of January 13, 2025, showed successful weight

Table of Contents

maintenance at one month following GLP-1 drug discontinuation and Revita DMR procedure. Additional data from the REVEAL-1 cohort are anticipated to be presented in the first quarter of 2025. As of February 15, 2025 recruitment for the REMAIN-1 study has generated significant interest, with over 189 patients enrolled across 13 clinical study sites in six months since first site activation, reflecting strong engagement from both patients and physicians. We believe this momentum underscores the urgent need for effective post-GLP-1 weight maintenance solutions. In the fourth quarter of 2024, we completed enrollment of a sufficient number of patients for the midpoint analysis of the study, which is anticipated in the second quarter of 2025. Full enrollment in the study is expected in the summer of 2025.

The table below depicts the REMAIN-1 clinical study design.

Germany Real-World Registry Study

In April 2023, we initiated the Germany Real-World Registry study, a prospective, post-market, clinical follow-up study to evaluate the Revita DMR procedure in patients with inadequately controlled T2D. Our inclusion criteria included patients ages 18 and over, with a baseline HbA1c between 7.0% and 10.0%, a BMI of less than or equal to 45 and on at least one ADA. The study assessed change in HbA1c, change in number of ADAs, safety and tolerability, quality of life and patient reported outcomes, and healthcare utilization expenditure over five years in patients with T2D after receiving the Revita DMR procedure in a real-world setting.

On January 31, 2025, we announced that pursuant to the Strategic Reprioritization, we have paused investment in the Germany Real-World Registry study. We expect to continue to follow the existing patients per protocol and continue to report on clinical, health economic, and patient-relevant outcomes from this study on an ongoing basis.

As of February 15, 2025, we have treated 39 patients with Revita DMR and enrolled 34 patients in the Real-World Registry study with 12-month follow-up data from 17 patients. At baseline, prior to Revita DMR procedure, these patients (n=17) were a mean age of 61 years, with obesity and advanced T2D, a mean body weight of 106 kilograms (234 pounds; BMI 34 kg/m2) and mean baseline fasting blood glucose (FBG) and HbA1c of 181 mg/dL and 9.1%, respectively, despite using up to three GLAs. Approximately 65% of these patients were male. At three months, patient mean weight was reduced by 7.2 kilograms (16 pounds) and this reduction was maintained through 6 and 12 months post-procedure (see the table below for absolute values). Nearly all patients lost weight with 65% and 29% losing >5% and >10% of their body weight at 12 months post-Revita DMR procedure, respectively. Weight loss was observed as early as one-month post-Revita DMR procedure, and weight loss was generally maintained through one year of follow-up, further underscoring in a real-world setting the potential for a single Revita DMR procedure to be a compelling and durable weight maintenance solution.

Table of Contents

FBG and HbA1c also improved, with mean decreases of 50, 47, and 49 (n=17) mg/dL and 1.0, 1.0, and 1.2% (n=17), at 3, 6, and 12 months, respectively. In addition, at 12 months post-procedure, 82% of patients stabilized or reduced their GLA usage in addition to losing weight and improving their hyperglycemia (n=17). Patient reported outcomes (PROs) revealed that Revita was valued by patients and improved T2D management. At 12 months post-procedure, 94% of participants reported they would undergo the Revita DMR procedure again and 100% would recommend the procedure to a family member or friend (n=17). Revita scored a 9.7 and 9.3 (1-10, 10 highest) for its ability to improve T2D management and quality of life, respectively (n=17). To date, no device or procedure-related serious adverse events have been reported.

The table below reflects the Germany Real-World Registry study Weight and Blood Sugar Data Over Time Post-Revita DMR procedure.

Endpoint Baseline 3 Months 6 Months 12 Months

Mean values shown. Company data on file, n=17. NCT06256497. HbA1c=glycated hemoglobin.

REVITALIZE-1 Pivotal Clinical Study

In March 2021, we commenced REVITALIZE-1 (formerly known as REVITA-T2Di), a randomized, double-blind, crossover, sham-controlled, multi-center pivotal clinical study in patients with inadequately controlled T2D despite being on up to three ADAs and 20 to 100 units of insulin daily. In June 2024, the FDA approved an amendment to the protocol of the REVITALIZE-1 study of our Revita device, which expanded eligibility to patients with T2D who are inadequately controlled on any GLA, including GLP-1 drugs and/or insulin. On January 31, 2025, we announced that pursuant to the Strategic Reprioritization, we have paused investment in REVITALIZE-1. Patients with inadequately controlled T2D, who are on at least one GLA and previously randomized, will continue to be followed per protocol to 48 weeks. Patients randomized to the sham arm will be offered an opportunity to receive the Revita DMR procedure (crossover) once unblinded. Patients who crossover and undergo the Revita DMR procedure will be followed per protocol.

The table below depicts the REVITALIZE-1 clinical study design.

Table of Contents

Rejuva Platform Description

Rejuva is a modular, physiologic gene therapy platform with three key elements designed to enable successful pancreatic gene therapy: (1) a proprietary delivery catheter designed to enable local, low dose therapeutic delivery directly to the pancreas via endoscopic access, (2) vectors with tropism for the pancreatic islet to enable successful transduction and gene delivery with limited biodistribution via this route of administration, and (3) transgenes with tissue-restricted promoters and metabolically active peptides that can durably impact glucose and weight control. Rejuva is designed to directly administer a gene therapy into the pancreas with both mechanical and molecular confinement of the therapeutic candidate with local administration and tissue-specific promoters. In the first quarter of 2024, we nominated the first candidate in our gene therapy platform, designated as RJVA-001, designed for the remission of T2D. RJVA-001 is a locally administered AAV9 viral vector with a transgene that expresses a GLP-1 hormone from an insulin promoter. In the fourth quarter of 2024, we nominated our first smart GIP/GLP-1 pancreatic gene therapy lead candidate, RJVA-002, designed for the treatment of obesity. RJVA-002 is a locally administered AAV9 viral vector that expresses human GLP-1 and GIP hormones from a human insulin promoter. RJVA-002 is designed to activate both GIP and GLP-1 receptors, which play crucial roles in regulating blood sugar and body weight.

Rejuva Device Overview

The Rejuva catheter leverages (i) the Revita console that houses our proprietary technology and software, and (ii) a single-use Rejuva PGTx catheter. The console’s touchscreen-based graphical user interface is designed to provide ease-of-use and clear guidance on the performance and progress of the procedure or the physician. The console houses sensors that are designed to monitor volume, pressure and flow rate of the delivery of the gene therapy candidates. We believe the console enables a targeted delivery process by enabling a proprietary safety mechanism that controls the parameters of delivery that are required to ensure minimal disruption to the pancreatic tissue, and potentially reduces the risk of physician error by automating certain steps of the treatment process by guiding the physician step-by-step through the procedure. The Rejuva catheter is composed of a narrow-gauge needle catheter that can be delivered through the working channel of a standard endoscopic ultrasound in which needle size, bevel shape, and aperture are designed to minimize risk of injury to the pancreas upon needle insertion.

Table of Contents

Rejuva Drug Overview

The Rejuva drug platform is designed to be a modular, interchangeable platform composed of delivery vectors with high tissue tropism for the pancreatic islet and tissue-restricted promoters confining metabolically active transgene expression to islet cells. In the first quarter of 2024, we nominated RJVA-001, our first clinical candidate to emerge from the Rejuva platform for the remission of T2D. RJVA-001 combines a novel, proprietary Rejuva catheter for delivery, an AAV9 serotype vector, and a proprietary transgene construct, which features a modified human insulin promoter and a proprietary coding sequence that enables secretion of active human GLP-1. We have completed key preclinical in vivo studies to support a CTA for RJVA-001. We plan to submit the first CTA module to regulators in the first half of 2025 and, if approved to proceed, expect to report preliminary data in 2026.In the fourth quarter of 2024, we nominated our first smart GIP/GLP-1 pancreatic gene therapy lead candidate, RJVA-002, designed for the treatment of obesity. RJVA-002 is a locally administered AAV9 viral vector that expresses human GLP-1 and GIP hormones from a human insulin promoter. RJVA-002 is designed to activate both GIP and GLP-1 receptors, which play crucial roles in regulating blood sugar and body weight. Our GLP-1 PGTx candidates are designed to express GLP-1 specifically in beta cells in a manner that will allow beta cells to produce, package, and secrete GLP-1 hormone in a similar method to insulin. In this way, the GLP-1 transgene product can act within the pancreatic islet on adjacent alpha and beta cells to augment local GLP-1 receptor activation and signaling. Because of this local expression, our GLP-1 PGTx candidates are designed to improve beta-cell health and function and thereby provide durable weight loss and glycemic control while minimizing the side effects of systemic exposure to GLP-1 We believe our GLP-1 PGTx candidates will be a single administration with the potential to provide long-term metabolic benefits, even after therapy is discontinued, because the turnover rate of human beta cells is thought to be very low in adults. As such, AAV has already demonstrated durable transgene expression in the pancreas of rodents beyond a year.

Delivery Overview

Our Rejuva PGTx candidates are locally administered using a proprietary needle catheter that is uniquely designed for pancreas delivery in an outpatient, endoscopic procedure that may last less than thirty minutes. The procedure is performed by a trained endoscopist while the patient is under conscious sedation or general anesthesia. With the help of the Revita console, certain steps of the procedure are designed to be highly automated, which we believe minimizes the risk of physician error.

The procedure involves inserting the distal end of the single-use Rejuva catheter through the working channel of an endoscopic ultrasound imaging device and into the stomach. Ultrasound will be used to direct needle placement through

Table of Contents

the stomach wall into the body and tail of the pancreas after identifying the pancreatic duct and other key anatomical structures. The needle is then advanced into the distal pancreas. The physician will confirm needle placement before enabling a precise dose of the drug candidate to be delivered into the pancreas by an automated syringe pump system in the console. During the administration, the console will measure the pressure and flow rate of the delivered fluid to prevent injury to the tissue and monitor the volume of delivery to control the precise dose of administration. A favorable benefit-risk profile of the delivery device can be enabled by directing the needle toward the body and tail of the pancreas, where a majority of pancreatic islets reside, and by avoiding the pancreatic duct in the head of the pancreas, where the risk of procedural pancreatitis would be higher.

Preclinical Data Overview: Rejuva Gene Therapy Platform

We have evaluated potential GLP-1 PGTx candidates in large and small animal studies. In survival studies in over 100 large animals, we have observed 100% technical success with our Rejuva device using our proposed clinical route of administration with no device-related adverse events observed thus far. In small animal pharmacology studies, we observed that our potential GLP-1 PGTx candidates were generally well tolerated, reduced weight, improved glycemic control, and delayed T2D progression compared to vehicle or control and semaglutide. Given the data observed in our preclinical studies thus far, we believe that our Rejuva gene therapy candidates have the ability to provide clinical benefit in T2D and people living with obesity who currently have limited treatment options that provide long-term benefit even after treatment discontinuation.

Preclinical Studies: Proof-of-Concept

We have conducted multiple proof-of-concept studies with GLP-1 PGTx candidates consisting of AAV-delivered transgenes carrying an insulin promoter driving GLP-1RA sequences in in vitro, ex vivo human islets, ex vivo mouse islets, and in vivo survival studies in a db/db mouse model of T2D and obesity. In db/db mice 10 weeks after a single administration of a GLP-1 PGTx candidate, we observed dose-dependent expression of the GLP-1RA protein in whole pancreas explants and in isolated islets from animals sacrificed at that time point. Isolated pancreatic islets from treated mice grown ex vivo demonstrated increased insulin content and improved glucose-stimulated insulin secretion (“GSIS”) (as depicted in the image below), a hallmark of improved beta cell function.

Table of Contents

In the human EndoC-BH5 beta cell line, a GLP-1 PGTx candidate demonstrated dose-dependent increases in GLP-1RA secretion into the cell supernatant and improved GSIS. The improvement in GSIS was blocked by the administration of a GLP-1 receptor antagonist (exendin-9), demonstrating that improvements to beta cell function by the GLP-1 PGTx candidate were achieved through GLP-1 receptor binding and activation (as depicted in the image below).

In ex vivo human islets, a GLP-1 PGTx candidate demonstrated dose-dependent transduction of up to 25% of beta cells within islets along with a doubling of GSIS. Taken together, we believe the results from EndoC-BH5 and healthy (non-diseased) human islets indicate that GLP-1 PGTx candidates have the potential to successfully transduce human beta cells and improve beta cell function even in healthy, non-diseased islets.

In proof-of concept preclinical in vivo studies in a db/db mouse model, we evaluated escalating doses of GLP-1 PGTx candidates in glucose lowering potency compared to vehicle. We observed dose-dependent improvements in FPG that were sustained for 64 days after a single administration of a GLP-1 PGTx candidate compared to vehicle control, along with sustained increases in fasting insulin at the same time point. We believe these results indicate that GLP-1 PGTx candidates have the potential to improve glucose control and beta cell insulin production and secretion in a durable manner.

In a head-to-head preclinical in vivo study in a db/db mouse model, we evaluated a GLP-1 PGTx candidate compared to semaglutide. By four weeks post treatment, we observed a statistically significant average reduction of FPG of 73% (p <0.0001), a statistically significant increase in fasting insulin of 478% (p < 0.01), and a statistically significant decrease in total body weight of 14% (p <0.001) relative to vehicle treated mice after a single administration of a GLP-1 PGTx candidate. Based on these data, we believe this study suggests that a single administration of a GLP-1 PGTx

Table of Contents

candidate can achieve greater improvements in blood glucose control and weight loss and delayed T2D progression in db/db mice compared to semaglutide (as depicted in the images below).

In a head-to-head preclinical in vivo study in a DIO mouse model, we evaluated weight loss after a single administration of GLP-1 PGTx candidate compared to semaglutide 10 nmol/kg daily. At 28 days after administration, we observed a statistically significant reduction of total body weight of 27% for the GLP-1 PGTx candidate compared to 21% for semaglutide (p < 0.05 for the difference between GLP-1 PGTx candidate and semaglutide). Semaglutide-treated animals were then randomized on day 29 to withdrawal of semaglutide or a single administration of the GLP-1 PGTx candidate, and both groups were followed for an additional 4 weeks. On day 57, we observed weight loss of 25% in the obese rodents initially treated with the GLP-1 PGTx candidate, compared to weight gain of 4% in vehicles. Animals withdrawn from semaglutide regained weight to a net 2% body weight loss on day 57, while animals who crossed over from semaglutide to a single dose of the GLP-1 PGTx candidate maintained body weight loss on day 57 with 22% weight loss from baseline. Based on this data, we believe that a single administration of a GLP-1 PGTx candidate can achieve greater improvements in weight loss than semaglutide at the tested dose, durable improvements in weight loss compared to vehicle control, and can

Table of Contents

offer a potential weight maintenance therapeutic solution to prevent weight regain after semaglutide discontinuation (as depicted in the image below).

In vivo studies of GLP-1 PGTx candidates in DIO and db/db mice have demonstrated high specificity of transgene expression for the pancreatic islets with no detectable transgene expression in off-target tissues (e.g., the exocrine pancreas). Quantification of GLP-1RA immunoreactivity in mouse islet beta cells indicates that potent efficacy can be achieved with only a small fraction (< 10%) of beta cells expressing GLP-1RA (as depicted in the image below).

We observed that promoter and regulatory element optimization in GLP-1 PGTx candidates demonstrated the potential for a broad dynamic range of transgene protein production at eight to nine weeks after a single administration of a

Table of Contents

GLP-1 PGTx candidate (as depicted in the image below). We believe these results indicate that GLP-1 PGTx candidates have the potential to provide durable metabolic benefits after a single administration with limited systemic exposure.

No abnormal findings were observed in animal behavior or clinical chemistries. Histopathologic analysis showed no evidence of inflammation, pancreatitis or pancreatic cancer (as depicted in the image below).

Preclinical Studies: Feasibility and Toxicity

Feasibility and toxicity studies were conducted in Yucatan pigs because their GI and pancreas anatomy is similar to that of humans, enabling a similar route of administration. In preclinical survival studies in Yucatan pigs, we

Table of Contents

demonstrated the feasibility and technical success of the Rejuva device and proposed clinical route of administration for local delivery of Rejuva PGTx candidates.

We evaluated dose-dependent AAV-transgene expression in the pig pancreas by using green fluorescent protein, or GFP, in our AAV vector. At a dose of 1.5 x 1014, we observed 41.2% islet cell transduction of GFP and a 3.5 vector copy number, or VCN. The FDA recommends that the VCN should be less than five copies per genome.

Biodistribution analysis demonstrated a 5.1x greater VCN in the pancreas as compared to the liver with our proposed clinical route of administration. According to a study done by Li et al., the same viral vector administered intravenously demonstrated a 0.005x VCN in the pancreas as compared to the liver (Li et al. Physiol Genomics 54: 261–272, 2022). We believe this reflects a 1000-fold liver de-targeting with our proposed route of administration as compared to intravenous administration.

We observed no evidence of abnormal adverse events to the pancreas, liver or other tissues after administration of a beta-cell restricted Rejuva PGTx candidate.

Subsequently, RJVA-001 (6e13 vector genome (VG)) was evaluated in non-diseased Yucatan pigs using ultrasound guided endoscopy with a custom needle integrated with a proprietary fluid delivery system to enable transgastric infusions of RJVA-001 into the targeted splenic lobe of the pancreas. Serum lipase, as a surrogate marker of pancreatitis, was assessed on days -14, 0, 4, 7, 21, and 34 post-delivery to establish early and longer-term procedural safety. Animals were necropsied at day 34 post-procedure and punch biopsies were taken from 20 locations across the pancreas to establish vector copy number (VCN), transgene ribonucleic acid (RNA) and protein expression as indicators of vector transduction efficiency and RJVA-001-driven GLP-1 production. All animals tolerated the delivery procedure well with serum lipase

Table of Contents

levels remaining within the upper limit of normal (ULN) at all timepoints evaluated from day -14 pre-procedure to day 34 post-procedure.

Transgastric delivery of RJVA-001 resulted in increased AAV9 transduction, GLP-1 transgene transcription, and subsequent active GLP-1 protein expression within the targeted splenic lobe of the pancreas. Active GLP-1 protein was five-fold greater in RJVA-001 treated animals compared to untreated controls. Pancreatic vector copy number (VCN), and RJVA-001 transgene RNA levels were positively correlated (r=0.85, p<0.0001). Likewise, RNA levels correlated with RJVA-001 islet-driven GLP-1 protein levels (r=0.85, p<0.0001).

Clinical Development Overview: Rejuva Gene Therapy Platform

We have completed key preclinical in vivo studies to support a CTA for RJVA-001. We plan to submit the first CTA module to regulators by the first half of 2025 and, if approved to proceed, expect to report preliminary data in 2026.

Table of Contents

In addition, in the fourth quarter of 2024, we nominated our first smart GIP/GLP-1 pancreatic gene therapy lead candidate, RJVA-002, designed for the treatment of obesity. RJVA-002 is a locally administered AAV9 viral vector that expresses human GLP-1 and GIP hormones from a human insulin promoter. RJVA-002 is designed to activate both GIP and GLP-1 receptors, which play crucial roles in regulating blood sugar and body weight.

Commercialization Strategy

The Revita DMR System is approved in Europe as a medical device under a CE Mark and has received reimbursement authorization through NUB in Germany for the treatment of T2D. After securing reimbursement for Revita in 2022, in the first half of 2023 we initiated a limited commercial pilot in a single center in Dusseldorf, Germany, along with a Germany Real-World Registry study, designed to evaluate real-world evidence of Revita’s safety and effectiveness in people with inadequately controlled T2D. We have paused investment in this commercial pilot, as well as in the Germany Real-World Registry study.

In the United States, we have obtained Breakthrough Device designation from the FDA for the Revita DMR System, as an adjunct to diet and exercise, to perform hydrothermal ablation of the duodenal mucosa, or the Revita DMR procedure, for use in the maintenance of weight loss after discontinuation of GLP-1-based therapy on patients who cannot tolerate long-term GLP-1 therapy and who are not candidates for endoscopic remodeling procedure or bariatric surgery. Breakthrough Device designation provides certain benefits to device developers, including more interactive and timely communications with FDA staff, use of post-market data collection, when scientifically appropriate, to facilitate expedited and efficient development and review of the device, opportunities for efficient and flexible clinical study design, and prioritized review of premarket submissions but does not alter or confer any advantage in the regulatory review or approval standard for medical devices

We intend to submit a Premarket approval (“PMA”) for Revita after we complete the REMAIN-1 study, including the patient follow-up through 52 weeks. If approved, we believe longer-term follow-up studies beyond 52 weeks will likely be performed as part of a post-approval study, or PAS, including potentially studying the safety and effectiveness of repeat procedures, should they be necessary. Based on regulatory precedent, we believe a PAS may be conducted in parallel with the commercial launch of Revita. If approved, we intend to execute a targeted, efficient go-to market strategy for Revita, driven by a stepwise approach that will build brand awareness, position Revita as a novel procedural therapy alternative to ongoing maintenance use of GLP-1s, and ultimately expand procedure volume as an attempt to validate Revita in endocrine and endoscopy communities as a durable and potentially repeatable option for patients living with obesity, prediabetes and other metabolic diseases.

As we progress our Revita clinical program and generate clinical evidence in support of Revita, we will invest in building a U.S.-based direct salesforce to support our U.S. launch to prepare for Revita’s potential FDA approval. We will seek to strategically recruit representatives with strong backgrounds and experience in the management of weight maintenance, obesity and prediabetes, as well as those with a deep understanding of the endoscopist workflow. We expect to grow our field force over time to accelerate broad market adoption of Revita, building on the foundational brand awareness we aim to achieve through our initial educational efforts.

As we generate additional clinical data and insights through our Revita clinical program, we plan to carry out an organized medical education effort to inform endocrinologists around the compelling solution provided by our product candidates, as we believe they will serve as the primary prescribing physicians. We believe that the clinical evidence generated from our program will continue to support our messaging to key leaders in the field of metabolic endocrinology and gastroenterology.

If Revita is approved, we intend to commercially launch with the PMA approved console design and plan to submit a supplemental PMA for our next generation commercial console design shortly thereafter. We plan to execute an efficient “hub-and spoke” commercialization strategy to position Revita as a novel procedural therapy to treat obesity and T2D and drive its rapid adoption. Leveraging key learnings and insights from our Revita clinical program, we plan to have a targeted sales force initially focusing on centers of excellence with metabolically focused GI endoscopists with a dedicated interest in bariatric and metabolic endoscopy. We plan to initially target participating physicians from our clinical studies, as we believe their familiarity with our therapies will make them early adopters. Our multi-channel commercialization strategy will include direct marketing campaigns to raise awareness amongst patients for a compelling new treatment alternative in weight maintenance and obesity.

Table of Contents

We also plan to roll out a robust procedural training and support program for GI endoscopists, ensuring seamless integration of Revita into their workflow. These education and training efforts will be critical in building an installed base in metabolic endoscopy that will begin with providers at large hospitals and expand to outpatient endoscopy centers over time.

Our initial approach will be to focus on people living with obesity who desire an off-ramp from GLP-1 drugs, and progress to other unmet needs in the treatment and prevention of metabolic diseases, including T2D. Once we are established in obesity and prediabetes through clinical validation, medical education and training, strong procedure volumes and a robust installed base, we plan to leverage our foundational platform, technology and core capabilities to expand indications to other metabolic diseases, CVD, and others.

As we expand the adoption of Revita, we will evaluate potential partnerships and/or distributor relationships for its commercialization in other global geographies. Given the high prevalence and rapidly growing incidence of obesity and prediabetes in international markets, we believe there is a significant unmet need for a scalable, disease-modifying therapy globally. We plan to pursue regulatory approvals and geographic expansion into international markets with reimbursement and a need for procedure-based solutions in obesity and prediabetes, as part of our long-term growth strategy.

Because Rejuva is designed to leverage the same console system, physicians, skill sets and same commercialization footprint of Revita, we believe that a successful launch of Revita will enable a more rapid commercialization of Rejuva into that same channel, if both products are approved in the United States.

Research and Development

We have an experienced research and development team with the scientific, engineering, software, operations and clinical talent that we believe is required to grow our business. We have committed, and expect to continue to commit, significant resources to improve product candidate performance and reliability and reduce costs. As of February 15, 2025, our research and development team was comprised of 79 employees. For the years ended December 31, 2024 and 2023, we incurred research and development expenses of approximately $70.5 million and $38.0 million, respectively. Major components of the research and development expenses included salaries and benefits, engineering, preclinical and clinical study expenses.

We continuously seek to improve Revita, the DMR procedure and our Rejuva gene therapy platform, including improvements in our technology and its accessibility. We believe that technical advantage is important to achieve or sustain a competitive advantage, and therefore our research and development efforts are focused on the continued enhancement of Revita, the DMR procedure and Rejuva. We are dedicated to ongoing innovation with respect to Revita, the DMR procedure, Rejuva, and to expanding our pipeline of product candidates and their applications to treat obesity, T2D and other metabolic diseases.

Competition

The medical device and biopharmaceutical industries are characterized by rapid advancement of novel technologies, significant competition and a strong defense of intellectual property rights. While we believe that our product candidates and scientific expertise provides us with competitive advantages, we face competition from multiple sources, including larger and better-funded medical device and biopharmaceutical companies, academic institutions, lifestyle and diet service centers, hospitals, surgical centers, governmental agencies and public and private research institutions. Any product candidates that we successfully develop and commercialize will compete with currently approved therapies, services and procedures, including lifestyle and diet services, bariatric surgeries, in particular gastric bypass surgeries, and new therapies that may become available in the future. Key factors that would affect our ability to effectively compete with other therapeutics include safety, efficacy, ease of administration, pricing, brand recognition and availability of reimbursement and coverage by third party payors.

There are a number of new classes of agents and combination agents in development for obesity and T2D, such as oral GLP-1s, other nutrient-stimulated hormones and novel mechanisms, which may offer evidence of significant weight loss and broad metabolic benefit. Pharmaceutical companies are heavily invested in their existing and future product platforms for obesity and T2D. They have strong relationships within the clinical community and with prescribing physicians in particular.

Table of Contents

Intellectual Property

Our ability to obtain and maintain intellectual property protection for our product candidates and technology is fundamental to the long-term success of our business. We rely on a combination of intellectual property protection strategies, including patents, trademarks, trade secrets, confidentiality policies and procedures, non-disclosure agreements, invention assignment agreements and technical measures designed to protect the intellectual property and commercially valuable confidential information and data used in our business.

As of February 15, 2025, we own: 29 issued U.S. patents; 29 pending U.S. non provisional patent applications; five pending U.S. provisional patent applications; six patent cooperation treaty, or PCT, applications that have not entered national stage; 71 issued foreign patents in Australia, Brazil, Canada, China, Europe, Israel, Japan, Korea, and Russia; and 34 pending foreign patent applications in Australia, Canada, China, Europe, Israel, India, Japan, and Korea. The subject matter covered by our owned patents and patent applications include: Revita and components thereof, methods of using Revita, Rejuva and components thereof, methods of using Rejuva, and other exploratory product candidates. Excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable: our owned issued U.S. patents are expected to expire between January 2032 and May 2036; our owned issued foreign patents are expected to expire between January 2032 and September 2038; any patents that may issue from our owned pending U.S. patent applications are expected to expire between October 2034 and December 2045; any patents that may issue from our owned pending foreign patent applications or PCT applications are expected to expire between January 2032 and January 2045.

With respect to Revita, as of February 15, 2025, we own: 22 issued U.S. patents; 21 pending U.S. patent applications; two pending U.S. provisional patent applications; one PCT application that has not entered national stage; 61 issued foreign patents in Australia, Brazil, Canada, China, Europe, Israel, India, Japan, Korea, and Russia; and 23 pending foreign patent applications in Australia, Canada, China, Europe, Israel, Japan, and Korea. The issued patents and any patents that may issue from our pending patent applications related to Revita are expected to expire between January 2032 and November 2045, excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable.

With respect to Rejuva, as of February 15, 2025, we own: four pending U.S. patent applications; three pending U.S. provisional patent applications; three PCT applications that have not entered national stage; and eight pending foreign patent applications in Australia, Canada, China, Europe, Japan and Korea. Any patents that may issue from our pending patent applications related to Rejuva are expected to expire between February 2042 and December 2045, excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable.

The term of individual patents depends upon the legal term for patents in the countries in which they are granted. In most countries, including the United States, the patent term is 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country. In the United States, a patent’s term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common inventor and having an earlier expiration date. We cannot be sure that our pending patent applications that we have filed or may file in the future will result in issued patents, and we can give no assurance that any patents that have issued or might issue in the future will protect our current or future products, will provide us with any competitive advantage, and will not be challenged, invalidated, or circumvented.

We intend to pursue additional intellectual property protection to the extent we believe it would be beneficial and cost-effective. Our ability to stop third parties from making, using or commercializing any of our patented inventions will depend in part on our success in obtaining, defending and enforcing patent claims that cover our technology, inventions, and improvements. With respect to our owned intellectual property, we cannot provide any assurance that any of our current or future patent applications will result in the issuance of patents in any particular jurisdiction, or that any of our current or future issued patents will effectively protect any of our product candidates or technology from infringement or prevent others from commercializing infringing products or technology.

Our commercial success depends significantly on our ability to operate without infringing, misappropriating or otherwise violating the intellectual property rights of third parties. The medical device industry is subject to rapid technological change and substantial litigation regarding patent and other intellectual property rights. Numerous third-party patents exist in the fields relating to our product candidates, and it is difficult for industry participants, including us, to

Table of Contents

identify all third-party patent rights relevant to our product candidates and technologies. We are aware of third-party patents, and patent applications that if issued, may be construed to cover our product candidates or technologies, including Revita.

In addition to our reliance on patent protection for our inventions, products and technologies, we also seek to protect our brand through the procurement of trademark rights. As of February 15, 2025, we own 46 registered trademarks and five pending trademark applications for FRACTYL, FRACTYL HEALTH, FRACTYL HEALTH LOGO, REVITA, REVITA DMR, REJUVA and other product related brand names in the United States and certain foreign jurisdictions. Furthermore, we rely on trade secrets, know-how, unpatented technology and other proprietary information, to strengthen our competitive position. We have determined that certain technologies, including certain aspects of our software, are better kept as trade secrets. To mitigate the chance of trade secret misappropriation, we enter into non-disclosure and confidentiality agreements with parties who have access to our trade secrets, such as our employees, consultants, advisors and other third parties. We also enter into invention assignment agreements with our employees and consultants that obligate them to assign to us any inventions they have developed while working for us. We generally control access to our proprietary and confidential information through the use of internal and external controls that are subject to periodic review.

Although we take steps to protect our proprietary information and trade secrets, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. As a result, we may not be able to meaningfully protect our trade secrets. For further discussion of the risks relating to intellectual property, see Part I. Item 1A. Risk Factors—Risks Related to Our Intellectual Property.

Manufacturing and Supply

GUTS US Equity

GUTS · 10-K · period ended 2024-12-31

Item 1. Business.

GUTS US Equity☆

GUTS · 10-K · period ended 2024-12-31

Item 1. Business.

GUTS US Equity