10-K

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2025

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 30, 2025, was $49.6 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 March 1, 2026, the number of shares of the registrant’s common stock outstanding was 158,648,963.

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DOCUMENTS INCORPORATED BY REFERENCE

Portions of the definitive proxy statement for the registrant’s 2026 annual meeting of shareholders, which is to be filed within 120 days after the end of the registrant’s fiscal year ended December 31, 2025 are incorporated by reference into Part III of this Form 10-K, to the extent described in Part III.

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TABLE OF CONTENTS

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Forward-Looking Statements iii

Summary Risk Factors v

PART I

Item 1. Business 1

Item 1A. Risk Factors 61

Item 1B. Unresolved Staff Comments 129

Item 1C. Cybersecurity 129

Item 2. Properties 130

Item 3. Legal Proceedings 130

Item 4. Mine Safety Disclosures 130

PART II

Item 6. [Reserved] 131

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 143

Item 8. Financial Statements and Supplementary Data 143

Item 9A. Controls and Procedures 144

Item 9B. Other Information 144

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 145

PART III

Item 10. Directors, Executive Officers and Corporate Governance 146

Item 11. Executive Compensation 146

Item 14. Principal Accountant Fees and Services 146

PART IV

Item 15. Exhibits and Financial Statement Schedules 147

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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 (“U.S. GAAP”). Our fiscal year ends on December 31 of each year. References to 2025 and 2024 refer to the year ended December 31, 2025 and the year ended December 31, 2024, respectively. Our most recent fiscal year ended on December 31, 2025.

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 those expressed in the estimates made by the independent third parties and by us.

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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, 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, communications with or submissions to the U.S. Food and Drug Administration (the “FDA”), 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, the anticipated use of or impact of the net proceeds from the ATM Offering, the August 2025 Offering and the September 2025 Offering, 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:

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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;

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

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

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

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

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

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

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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;

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

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

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our competitive position;

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

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the status, breadth and strength of our intellectual property portfolio and its ability to protect our innovations;

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our ability to obtain patent coverage for our products;

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our ability to successfully defend litigation and other similar complaints and to establish and maintain intellectual property rights covering our products;

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developments and projections relating to our competitors and our industry;

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our expectations related to the use of proceeds from our financing activities;

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

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our ability to continue as a going concern;

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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;

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the impact of laws and regulations;

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

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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.

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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:

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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 for commercial sale in the United States (“U.S.”), which may make it difficult for you to evaluate our current business and predict our future success and viability;

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We have incurred significant net losses since inception, we expect to continue to incur significant net losses for the foreseeable future and may never achieve or sustain profitability, and we have identified conditions and events that raise substantial doubt about our ability to continue as a going concern;

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We 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;

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The regulatory clearance and certification processes 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;

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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;

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

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We may not be able to submit 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;

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We may experience delays, interruptions or additional costs in obtaining and maintaining government regulatory approvals, licenses, certifications or reimbursements as a result of federal government shutdowns, reduced staffing or funding lapses. Such delays or disruptions could adversely affect our ability to develop, commercialize or market our product candidates, or to receive payments or reimbursements in a timely manner;

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

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We are substantially dependent on the success of our lead product candidate, Revita®, and our lead gene therapy product candidate, RJVA-001, in the Rejuva® platform. If we are unable to obtain marketing authorization or certification for and commercialize any of our current or future product candidates in a timely manner, our business will be harmed;

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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;

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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;

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

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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;

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

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We have never obtained marketing authorization for a product candidate in the U.S. and we may be unable to obtain, or may be delayed in obtaining, marketing authorization for any product candidate in the U.S.;

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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;

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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;

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We contract with third parties for the manufacture and supply 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;

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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;

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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;

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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

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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 marketing authorization.

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PART I

Item 1. Business.

Our Company

We are a clinical stage metabolic therapeutics company focused on pioneering novel approaches to treat obesity and type 2 diabetes (“T2D”). Our Revita® and Rejuva® candidates are designed to target root causes of metabolic diseases, allowing us to advance metabolic disease treatment from chronic management towards prevention and reversion of the disease.

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 approximately 115 million people in the U.S. have prediabetes and/or are living with obesity, and an additional approximately 27 million people have T2D and are potentially 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 November 2025, approximately 12% of adults are taking glucagon-like peptide-1 (“GLP-1”) drugs (an increase of 6 percentage points from May 2024), translating to approximately 30 million patients potentially 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.

The Revita DMR System (“Revita”), our lead product candidate, is based on our insights surrounding the potential role of the gut in obesity. Revita is designed to remodel the duodenal lining via hydrothermal ablation (i.e. duodenal mucosal resurfacing) to reverse damage to intestinal nutrient sensing and signaling mechanisms caused by chronic high-fat and high-sugar diets that are a root cause of metabolic disease. Revita has U.S. FDA Breakthrough Device designation in weight maintenance for people with obesity who discontinue GLP-1 based therapy. We have received favorable FDA feedback on our De Novo classification request for Revita and anticipate submitting a potential De Novo marketing application in the late fourth quarter of 2026. We are evaluating Revita in the REMAIN-1 weight maintenance program, which is designed to evaluate Revita’s potential to maintain weight loss following GLP-1 based therapy discontinuation. The REMAIN-1 study includes three distinct participant cohorts that are conducted under a single IDE: the REVEAL-1 Cohort, the REMAIN-1 Midpoint Cohort and the REMAIN-1 Pivotal Cohort, which are designed to collectively establish the clinical and regulatory foundation for Revita in weight maintenance.

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The REVEAL-1 Cohort (n=22) is an open-label study in individuals with obesity who have lost at least 15% of their total body weight on a GLP-1 medication and who either need or choose to discontinue GLP-1 based therapy.

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The REMAIN-1 Midpoint Cohort (n=45) is a randomized, double-blind, sham-controlled pilot study to assess the potential of Revita to maintain weight loss after GLP-1 based therapy discontinuation.

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The REMAIN-1 Pivotal Cohort (n=315) is a randomized, double-blind, sham-controlled pivotal study to evaluate the safety and efficacy of Revita in maintaining weight loss.

The REMAIN-1 study was initiated in the third quarter of 2024. Enrollment of all three cohorts is complete and the REMAIN-1 Midpoint Cohort and REMAIN-1 Pivotal Cohort are fully randomized, as described further under “Ongoing REMAIN-1 Clinical Study” below.

We are also developing Rejuva, our novel and locally administered, adeno-associated virus (“AAV”)-delivered pancreatic gene therapy platform. Rejuva is designed to enable long-term remission of T2D and obesity by durably reprogramming

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pancreatic islet cells to endogenously produce metabolic hormones. Rejuva leverages advanced delivery systems and proprietary screening methods to identify and develop metabolically active gene therapy candidates targeting the pancreas.

Our lead candidate from the Rejuva platform, RJVA-001, is designed to be delivered to the pancreas via a single endoscopic intervention to enable pancreatic beta cells to express GLP-1 locally via nutrient-responsive control. This gene therapy approach enables physiologic GLP-1 secretion without the high circulating levels that contribute to side effects seen with systemic GLP-based drugs.

Our second candidate from the Rejuva platform, RJVA-002, is a dual GIP/GLP-1 gene therapy and is currently in preclinical development. RJVA-002 expands the Rejuva platform into obesity, targeting dual incretin biology with the goal of achieving durable, well-tolerated, weight loss from a single intervention.

Additional information regarding the Rejuva platform is described under “Rejuva Platform Description” and “Preclinical Data Overview: Rejuva Gene Therapy Platform” below.

We believe Revita and Rejuva 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.

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.

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 preclinical and clinical evidence, all implicating the gut and pancreas as validated, untapped targets in obesity and T2D. We

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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.

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 long-term obesity care. To date, we have evaluated Revita in over 500 participants across multiple clinical studies at sites in South America, Europe and the U.S., with favorable safety and tolerability, 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 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). We are leveraging our extensive clinical therapeutic endoscopy experience with Revita to inform our clinical plans with our RJVA-001 and RJVA-002 T2D and obesity candidates, respectively. We believe our clinical and preclinical programs are supported by a robust intellectual property position, including issued patents and pending applications, intended to protect core elements of our technology and assets and provide meaningful barriers to entry.

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:

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

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Referring Physicians. Preventing weight gain and lowering HbA1c for specific patient populations with a procedural therapy that reduces the workload in disease management and improves quality metrics associated with the disease.

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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.

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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 leadership team, combining product development know-how, therapeutic expertise and commercial readiness, has over 150 years of collective experience in therapeutic development. We are mission-driven to develop novel

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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, endoscopy and gene therapy.

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 marketing authorization will initially focus on patients with the highest unmet need in obesity, those who need to maintain weight loss after GLP-1 medication discontinuation and then progress to other unmet needs in the treatment and prevention of metabolic diseases, including T2D.

We believe our Revita clinical program, including our ongoing REMAIN-1 study, 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, which is designed to enable long-term remission of T2D and obesity by durably reprogramming pancreatic islet cells to endogenously produce metabolic hormones. Based on this mechanism, we believe Rejuva could be a potentially first-in-class, nutrient-responsive (“smart”), gene therapy that durably improves metabolic control. Our platform utilizes a novel investigational pancreatic delivery device to administer gene therapy candidates directly to the pancreas (body and tail). We believe that our approach allows for the precise mechanical and molecular confinement of targeted, low dose gene therapy medicines that can address many of the challenges that limit the use of gene therapy in the pancreas and systemic GLP-1-based drugs today.

Execute Targeted and Efficient Go-to-Market Strategy for Revita

If Revita is approved in the U.S. 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 learning 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 a center of excellence model, working closely with gastrointestinal (“GI”) endoscopist “early adopters,” with a dedicated interest in bariatric and metabolic endoscopy. In parallel, we plan to leverage our letter of intent (“LOI”) with Everself (formerly Bariendo) as this potential partnership will bring a scalable, physician-driven platform designed to deliver metabolic endoscopic solutions at the nation’s largest network of high-volume hospital and ambulatory endoscopy centers across the U.S. We intend to roll out a robust procedural training and support program for GI endoscopists, which we believe will ensure seamless integration into their workflow and practice. We will also work with CMS and private insurers to seek to establish coverage and reimbursement for procedures using our Revita product candidate, a key strategy to support the commercial viability of Revita with providers.

Broaden the Indication and Use of Revita

If Revita is approved for a weight maintenance indication in the U.S., 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 with the potential to significantly reduce the burden of obesity, T2D and prediabetes. As we expand the adoption of Revita, we may seek regulatory allowance to evaluate additional indications and uses of Revita, as well as partnerships and/or distributor relationships for its commercialization in other global geographies.

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

The Rejuva platform is modular and designed to enable local pancreatic production of key metabolic hormones important for proper beta cell function and incretin signaling. Our initial gene therapy candidates will include an AAV9 vector with a transgene that expresses GLP-1 (RJVA-001) and glucose-dependent insulinotropic polypeptide (“GIP”)/GLP-1 (RJVA-002) hormones from an insulin promoter. The modular nature of our platform can enable production of a number of additional metabolic hormones, including but not limited to, peptide YY (“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, cardiovascular disease (“CVD”), metabolic dysfunction-associated steatohepatitis (“MASH”) (formerly known as non-alcoholic steatohepatitis).

Whereas our ancestors lived 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 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 the 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, MASH, PCOS and certain types of cancer. The International Diabetes Federation estimates that there are over 800 million people globally today who suffer from obesity and prediabetes, with nearly 100 million people in the U.S. 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 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 that patients with obesity should initially be prescribed aerobic exercise and resistance training, a reduced calorie diet, and

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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-1 class of medicines have proven clinical efficacy in obesity. Wegovy (semaglutide), Saxenda (liraglutide), and Zepbound (tirzepatide) are GLP-1 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 CVD and no prior history of T2D. Current prescription trends suggest widespread usage of GLP-1s 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-1s. As with glucose control, GLP-1s 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.

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 approximately over 500 million adults worldwide, with nearly 1.3 billion people expected to be living with T2D globally by 2050. In the U.S. alone, approximately 27 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. Even though 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 preventive 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 (“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,

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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 U.S. 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 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 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. These critically important categories in obesity and T2D treatment cannot be addressed with current pharmacology. 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.

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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.

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 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:

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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 U.S. 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.

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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.

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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

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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, approximately over 25 million endoscopies are performed each year in the U.S., including over 600,000 advanced endoscopic procedures. Of the estimated 30 million people potentially on GLP-1s in the U.S. today, approximately 3 million will undergo an endoscopy this year. The Revita DMR procedure is designed to be a simple add-on procedure to-these, and other endoscopies already performed on patients living with obesity and T2D annually.

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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.

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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.

Overview of Rejuva

Rejuva is a novel, endoscopically administered, adeno-associated virus (“AAV”) pancreatic gene therapy platform designed to enable long-term remission of T2D and obesity by durably altering metabolic hormone production 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 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 metabolic disease. There are no therapies approved today that target the pancreatic islet in T2D or obesity.

The Rejuva platform is modular and consists of three key elements designed to enable successful pancreatic gene therapy delivery and expression with limited off-target biodistribution: (1) a novel, proprietary, investigational endoscopic device designed to enable local, low-dose therapeutic delivery directly to the pancreas (body and tail), (2) vectors with tropism for the pancreatic islet to enable successful transduction and (3) transgenes with tissue-restricted promoters driving the expression of metabolically active peptides that can durably impact glucose and weight control.

These peptides are intended to rejuvenate beta cell health, restore insulin production, and activate incretin signaling pathways in a nutrient-responsive (“smart”) manner. The first gene therapy candidate, RJVA-001, is comprised of an AAV9 viral vector that expresses a human GLP-1 hormone from an insulin promoter designed for the remission of T2D. The second candidate, RJVA-002, is designed to treat obesity and is composed of an AAV9 vector that expresses both human GIP and GLP-1 hormones driven by an insulin promoter. Activation of both GIP and GLP-1 receptors may improve body weight and blood sugar regulation.

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:

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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 U.S.; approximately 100 million people are living with obesity in the U.S.), 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 value is

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

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Novel Approach to a Highly Validated Target. Our Rejuva platform candidates leverage well established and understood hormone signaling known to be central to metabolic regulation. Our platform’s endoscopic pancreatic delivery, pancreas-targeted AAV capsid, and insulin promotor driven transgene expression enables nutrient-responsive (“smart”) production of GLP-1 (RJVA-001) and GIP/GLP-1 (RJVA-002) from beta-cells. Unlike GLP-1-based drugs, Rejuva candidates allow for durable physiologic metabolic hormone signaling.

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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

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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.

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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.

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Rigorous Development Plan. We completed key preclinical in vivo studies to support a CTA for RJVA-001 and subsequently submitted CTAs for RJVA-001 in T2D to regulators in the EU (Netherlands) and Australia in the second half of 2025, advancing the program toward its anticipated first-in-human study. We expect to receive regulatory feedback in the second quarter of 2026 and, subject to CTA authorization, to initiate first-in-human dosing of RJVA-001 and expected reporting of preliminary data in the second half of 2026.

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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 in combination, 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 marketing authorization for these product candidates in the U.S., 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. An emerging consensus identifies the impact of modern diets on the gut as one of the body’s critical metabolic control systems as an important root cause of metabolic disease. The gut possesses the largest nervous system outside the brain, the largest hormone-producing endocrine system, a 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 a meal. These mechanisms work together to provide an early warning detection system that helps the body prepare for and respond to the food we ingest.

Diets have changed significantly over the past several decades, shifting from relatively calorie-poor, fiber-rich, natural foods to an inexpensive and abundant supply of ultra-processed foods high in simple fats and sugars. Our founders, along

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with several scientific groups around the world, have detailed the specific changes that these modern diets cause in the gut and the downstream impact on the body and brain. While the gut has long been recognized as an acute nutrient sensor, its role in regulating the body’s metabolic status over longer periods of time has been underappreciated. Recent advances have demonstrated that chronic exposure of the intestine to high levels of fats and sugars leads to structural and functional changes of the lining of the proximal gut that may signal a metabolic shift to the brain and body. These diet-induced changes are geographically confined to the upper small intestine, particularly the duodenum, an area directly accessible via routine upper endoscopy. This 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 underlying obesity and T2D.

Structural and functional changes in the duodenal lining

Studies analyzing the small intestine in diabetic patients and animal models have identified functional maladaptation of the intestinal mucosa after chronic dietary exposure to high concentrations of fat and sugar. 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). Aliluev and colleagues observed that high-fat, high-sugar diets alter intestinal stem cell homeostasis leading to hyperplasia of the duodenal mucosa (Aliluev et al. Nat Metab. 3(9):1202-1216). Studies in rodents chronically fed a high-fat diet have demonstrated up to a 50% increase in mucosal surface area compared with rodents fed a normal diet, illustrating diet-induced structural overgrowth over time. This finding of a nutrient-induced stem cell division process that causes structural and functional changes of the duodenal mucosa has been replicated by multiple independent groups in the U.S. and Europe, and across organism species and disease models. Michael Theodorakis et al. 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 (Theodorakis et al. Am J Physiol Endocrinol Metab 290: E550–E559, 2006).

Hyperplasia and dysfunction of the duodenum is associated with a greater surface area for nutrient absorption and altered neurohormonal signaling, changing the body’s metabolic response from the gut. According to Duca et al., enteroendocrine cells 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. The brain receives these neurohormonal signals and uses the integrated information to regulate blood glucose levels and weight. In a healthy state, intraduodenal lipids trigger satiety and suppression of blood glucose, but chronic high-fat diets impair this gut-brain feedback, leading to metabolic dysfunction (Duca et al. Cell Metab. 2015 Sep 1;22(3):367-80, Duca et al., Nat Commun. 2021; 12: 903).

We believe that this preclinical and clinical evidence demonstrates that abnormal neurohormonal signaling from the duodenum is an important contributor to metabolic dysfunction, broadening conventional wisdom that excess weight and physical inactivity are the sole drivers of T2D.

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

The pancreas is a hormone-producing organ in the retroperitoneum surrounded by the duodenum, immediately below the stomach, with functions related to the secretion of digestive enzymes (exocrine pancreas) and hormones including insulin and glucagon from pancreatic islets (endocrine pancreas). Within the 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.

Most people can compensate for metabolic dysfunction by increasing insulin production to maintain normal blood glucose levels. Patients who develop T2D eventually experience a gradual loss of beta cell function, driven by two principal causes: (1) exhaustion of beta cell function in the face of longstanding metabolic dysfunction and chronically elevated blood glucose, and (2) damage to beta cells from the toxicity of circulating lipids (lipotoxicity). By the time the diagnosis of diabetes is made, patients have lost over 80% of their beta cell function, making early and aggressive intervention essential.

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

GLP-1 is a potent hormone 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. The role of GLP-1 within the pancreatic islet in beta cell function and insulin production is one of the best understood hormonal mechanisms in medicine. The GLP-1 receptor is expressed in

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beta cells, where activation acutely stimulates insulin secretion in response to blood glucose elevations and chronically stimulates insulin gene transcription and islet cell survival. The GLP-1 receptor is also expressed in alpha cells, where activation regulates glucagon expression. Studies have shown impaired GLP-1 signaling in the pancreatic islet in T2D, and that increased GLP-1 signaling can compensate for impaired insulin secretion, preserve beta cell function and survival, and improve glucose homeostasis. The beneficial effects of GLP-1 on islet function have been further demonstrated by the GLP-1RA class of medicines.

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

Revita Product Description

Revita Device Overview

Revita comprises (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 flow, pressure and temperature of the ablative and cooling fluid, vacuum suction, facilitate the delivery of saline for the submucosal lift. 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 commercial console and catheter. The catheter and graphical user interface are currently being used in our REMAIN-1 and REVITALIZE-1 clinical studies, but the Revita console hardware below is not. We plan to seek FDA clearance of the proposed commercial system as part of our FDA De Novo process. The Revita DMR catheter comprises 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 only the mucosal and submucosal tissue into the port. The catheter 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

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Guidewire to principal investigators to support ongoing Revita clinical studies. The Revita Guidewire is specifically designed for ease of delivery of the Revita DMR catheter.

Modular Revita Console

Revita 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.

Thermal Safety. Our proprietary thermal safety procedural step involves an automated, circumferential injection of saline into the submucosal space of the duodenum. This step is initiated through the user interface of the console and enables the

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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

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 patient will resume normal activities the day after their procedure, which is supported by our observations to date.

Clinical Data Overview: Revita

We have evaluated the Revita DMR procedure in over 500 participants across multiple clinical studies at sites in South America, Europe and the U.S. 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 weight maintenance program, which is designed to evaluate Revita’s potential to maintain weight loss following GLP-1 based therapy discontinuation.

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Pursuant to our Strategic Reprioritization, announced on January 31, 2025, we paused investment in Revita for T2D, including the REVITALIZE-1 study and the Germany Real-World Registry study. Our decision to pause these studies was not driven by any safety or efficacy concerns. We continue to follow existing participants per protocol and report outcomes on an ongoing basis for these studies. For additional detail on REVITALIZE-1, see our Annual Report on Form 10-K for the fiscal year ended December 31, 2024. For additional detail on the Germany Real-World Registry study, see “Germany Real-World Registry Study” below.

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

Study and Status Study Design Primary Objectives Upcoming Milestones

Ongoing

Paused due to Strategic Reprioritization

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.

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Key Metrics

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

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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).

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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.

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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.

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Oral Glucose Tolerance Test. A oral glucose tolerance test (“OGTT”), evaluates beta cell function after a participant 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, 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 500 participants, 30 clinical centers, with the procedure performed by more than 30 different endoscopists. We have followed most Revita-1 and Revita-2 participants beyond 12 months post-procedure to observe the long-term safety of the Revita DMR procedure, including its effects on glucose homeostasis and weight. Based on these experiences, we believe the Revita DMR procedure has the potential to:

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enable weight maintenance in patients living with obesity;

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

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improve glycemic control in T2D patients on insulin; and

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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 weight maintenance program, which is designed to evaluate Revita’s potential to maintain weight loss following GLP-1 based therapy discontinuation. The REMAIN-1 program includes three distinct participant cohorts that are conducted under a single IDE:

The REVEAL-1 Cohort (n=22): an open-label study in individuals with obesity who have lost at least 15% of their total body weight on a GLP-1 medication and who either need or choose to discontinue GLP-1 therapy. After stopping the GLP-1 based therapy, participants receive Revita treatment in an open-label setting and take part in a structured diet and lifestyle program. REVEAL-1 is designed to provide early, real-world insights on how Revita performs after GLP-1 discontinuation.

The REMAIN-1 Midpoint Cohort (n=45): a randomized, double-blind, sham-controlled pilot study to assess the potential of Revita to maintain weight loss after GLP-1 based therapy discontinuation. Participants with obesity who have not yet taken GLP-1 drugs, are initiated on tirzepatide at the time of enrollment, and treated with the drug to achieve at least 15% total body weight loss. Participants then discontinue tirzepatide and are randomized to undergo either Revita or a sham procedure with a 2:1 treatment randomization. The key efficacy endpoint is total body weight change in Revita versus sham

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at 3 months. The randomized Midpoint Cohort serves as an important early randomized readout to assess Revita’s potential to maintain weight loss after GLP-1 based therapy discontinuation. All participants enrolled in the study will receive diet and lifestyle counseling.

The REMAIN-1 Pivotal Cohort (n=315): a randomized, double-blind, sham-controlled pivotal study to evaluate the safety and efficacy of Revita in maintaining weight loss after GLP-1 based therapy discontinuation. Participants with obesity who have not yet taken GLP-1 drugs, are initiated on tirzepatide at the time of enrollment, and treated with the drug to achieve at least 15% total body weight loss. Participants then discontinue tirzepatide and are randomized to undergo either Revita or a sham procedure with a 2:1 treatment randomization. The first co-primary endpoint is defined as the percent of total body weight regain from the time of tirzepatide discontinuation in Revita versus sham participants through 6-month follow up. The primary objective is to demonstrate a benefit of Revita versus sham for weight maintenance after GLP-1 based therapy discontinuation. The second co-primary endpoint evaluates a responder rate among the Revita treated participants at 1 year to demonstrate the durability of the Revita procedure for weight maintenance after discontinuation of a GLP-1 based therapy. The responder rate is defined as the percentage of participants who received the Revita procedure who maintain at least 5% total body weight loss from pre‐tirzepatide (week -21) to week 52. 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 participants enrolled in the study will receive diet and lifestyle counseling.

Enrollment of all three cohorts is complete. We completed randomization of 307 participants in the REMAIN-1 Pivotal Cohort in February 2026, with topline six-month data anticipated in the early fourth quarter of 2026. In March 2026 we received pre-submission feedback from the FDA in which it acknowledged that the safety profile of the Revita DMR System, based on clinical data from over 300 procedures, is consistent with a Class II device classification. We anticipate submitting a potential De Novo marketing application in post-GLP-1 weight maintenance in the late fourth quarter of 2026.

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 participants. In the third quarter of 2024, we initiated REMAIN-1.

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 participants who cannot tolerate long-term GLP-1 therapy and who are not candidates for endoscopic remodeling procedure or bariatric surgery.

We gained FDA approval for the IDE in the first quarter of 2024 to initiate the pivotal REMAIN-1 study.

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

REVEAL-1 Cohort:

In December 2025, we announced 22 participants had been treated in the REVEAL-1 cohort, with up to six months of follow-up data available for 17 participants. As of December 2, 2025, no safety or tolerability concerns were reported, consistent with Revita’s safety profile observed in prior clinical experience. Participants maintained stable weight after a single Revita procedure, with a mean total body weight change of 1.5% ± 1.3% (SEM; n=17) at 6 months. Published

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third-party studies report ~10% weight regain by this time point after GLP-1 withdrawal alone. Minimal change in HbA1c levels was observed after the Revita procedure (0.04% ± 0.08%; SEM; n=17), compared to the ~0.4% increase in HbA1c seen post-GLP-1 based therapy discontinuation in the STEP-1 trial extension of GLP-1 withdrawal. These results indicate the potential for Revita to help stabilize cardiometabolic parameters beyond weight loss alone. Mean body weight and HbA1c curves showed a stable and durable trajectory over time, consistent with prior Revita clinical study and real-world experience. No procedure-related serious adverse events were observed; 8 of 22 participants (36%) experienced mild treatment-emergent adverse events which were transient, and self-limited; all consistent with prior Revita experience and similar to routine upper endoscopy findings.

In June 2025, we announced positive 3-month data from the REVEAL-1 Cohort. As of June 23, 2025, 22 participants had been treated in the REVEAL-1 Cohort, with 3-month follow-up data available for 13 individuals. The profile of the REVEAL-1 Cohort closely mirrors that of the REMAIN-1 Midpoint and Pivotal Cohorts, with an average age of 49 and a gender distribution of 11 women and 2 men. All participants had previously been treated with a GLP-1 therapy for durations ranging from approximately 5 months to 3 years, with a median total body weight (“TBW”) loss of 20.9% while on therapy. Fifteen percent of participants had pre-diabetes at baseline. At 3 months, 12 of 13 participants either lost or maintained their weight after GLP-1 based therapy discontinuation and a single Revita procedure. Notably, 6 of 13 experienced further weight loss. Median weight remained stable through 3 months (TBW change of 0.46% / ~ 1 pound was within the margin of error for daily weight measurement), compared to the typical 5-6% (10–15 pounds) rebound seen in other third party clinical studies such as SURMOUNT-4. Only one participant experienced weight regain similar to that seen after tirzepatide withdrawal. Early signs also point to excellent weight stability following Revita procedure, with essentially no weight change between 1 and 3 months (median weight gain at 1 month: 0.43% and 3 months: 0.46%). Consistent with prior studies of Revita, the procedure was well tolerated, with no unanticipated or serious adverse effects reported. No new safety concerns were observed.

In April 2025, we announced additional positive early data from the REVEAL-1 Cohort. As of April 1, 2025, 15 participants had been treated with Revita, with 1-month follow-up data available for the first 7 participants. There were not any safety or tolerability concerns reported in the 15 participants treated to date, consistent with Revita’s favorable safety profile from pooled data across more than 100 treated participants. At 1-month post-procedure, 7 participants experienced an average weight regain of just 1.2%, compared to the ~3% typically observed at this time period after GLP-1 based therapy discontinuation based on prior clinical studies.

In January 2025, we reported positive preliminary results from the REVEAL-1 open-label cohort. Initial findings from the first participant, as of a cutoff date of January 13, 2025, showed successful weight maintenance at one month following GLP-1 based therapy discontinuation and Revita DMR procedure.

REMAIN-1 Midpoint Cohort:

In January 2026, we announced 6-month randomized data. As of January 29, 2026, across the prespecified efficacy population (n=40, with five participants excluded per protocol due to diet and lifestyle noncompliance and only included in the safety population), Revita-treated participants experienced a 4.5% weight regain vs 7.5% in the sham arm at 6 months (p=0.07, one-sided), consistent with meaningful and sustained attenuation of the expected post-GLP-1 rebound trajectory. An exploratory analysis of participants who achieved above median weight loss during GLP-1 run-in (n=20) showed that Revita-treated participants experienced 4.2% weight regain versus 13.3% with sham at 6 months, corresponding to an approximately 70% relative reduction in post-GLP-1 weight regain (LS mean difference -9.1%; p=0.004, one-sided). As expected, treatment-by-run-in weight loss interaction terms suggested a meaningful relationship between degree of GLP-1-associated weight loss and the magnitude of Revita benefit. Further post-hoc analysis in March 2026 demonstrated a statistically significant correlation between ablation length and weight maintenance in the Revita arm and that more complete duodenal ablation drives greater treatment effect (n=29; p=0.048). Putting both together, in participants with above median GLP-1-induced weight loss who received greater than 14 cm duodenal ablation, Revita participants retained 88% of GLP-1 induced weight loss at six months compared to only 60% in sham participants. Revita continued to demonstrate favorable safety and tolerability results through six months, with no treatment-emergent serious adverse events related to the device or procedure, and no study discontinuations due to adverse events No new related adverse events were observed between 3- and 6-month follow up.

In September 2025, we announced positive 3 -month results from the randomized REMAIN‐1 Midpoint Cohort (n=45), demonstrating Revita’s potential to maintain weight loss after discontinuation of GLP-1 based therapy. Enrollment for this cohort had been previously completed, and as of September 26, 2025, all participants had been treated. The study met its 3-month efficacy endpoint with strong statistical significance (p=0.014), delivering 2.5% further weight loss with Revita (n=29) even after stopping tirzepatide, versus 10% weight regain in sham-treated participants (n=16). These results are

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clinically and statistically significant and provide randomized, blinded evidence that drug-free, durable weight maintenance is possible. No Revita-related SAEs or Grade II+ AEs were observed. Side effects were infrequent, mild, and transient, consistent with prior Revita clinical study experience.

In the fourth quarter of 2024, we completed enrollment of the 45 participants of the randomized REMAIN-1 Midpoint Cohort.

REMAIN-1 Pivotal Cohort:

We completed enrollment of the REMAIN-1 Pivotal Cohort in July 2025. We completed randomization of the REMAIN-1 Pivotal Cohort in February 2026, with topline six-month data anticipated in the early fourth quarter of 2026. In March 2026 we received favorable FDA feedback on our De Novo classification request for Revita and anticipate submitting a potential De Novo marketing application in Post-GLP-1 weight maintenance in the late fourth quarter of 2026.

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 participants with inadequately controlled T2D. Our inclusion criteria included participants 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 participant reported outcomes, and healthcare utilization expenditure over five years in participants 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 participants per protocol and continue to report on clinical, health economic, and participant-relevant outcomes from this study on an ongoing basis.

As of October 31, 2025, the first 30 participants with 1 year of follow-up had, at baseline, a mean age of 60 years, a mean weight of 102 kg (225 lbs; BMI 33 kg/m2), and a mean HbA1c of 8.8%, despite being on up to three glucose-lowering agents (“GLAs”).

After a single Revita procedure, these 30 participants achieved a mean total body weight loss of 8.0% with weight decreasing from 102 kg to 94 kg at 3 months, a result that was sustained throughout 1 year post-procedure (94 kg) (Table 1, Figure 3). Notably, 28 of 30 participants lost weight, 20 of 30 participants experienced at least a 5% weight reduction, and 12 of 30 participants saw weight reductions of 10% or more. In parallel, mean HbA1c decreased by 1.0% at 3 months, from 8.8% at baseline to 7.7%, and this improvement was sustained throughout 1 year post-procedure (7.9%) (Table 1) with 83% (25/30) of participants on stable or reduced GLAs. In this cohort, weight loss and glucose improvements began as early as one month after the Revita procedure and were sustained through 1 year of follow-up (Table 1).

Table 1. Germany Real-World Registry Study Weight and Blood Sugar Data Post-Revita Procedure (n=30)

Endpoint Baseline 3 Months 6 Months 1 Year

Mean ± standard error of the mean (“SEM”) values shown. Fractyl Health internal data.

Of these 30 participants, 14 have now been followed for 2 years post-procedure. These 14 participants had a mean age of 62 years, mean weight of 104 kg (229 lbs; BMI 34 kg/m2), and a mean HbA1c of 9.1%, despite being on up to three GLAs. These 14 participants achieved a mean weight loss of 7.9% at 1 year with weight decreasing from 104 kg to 95 kg, an improvement that was maintained through 2 years post-procedure (94 kg) (Table 2). Mean HbA1c reduced by 1.2% at 1 year, from 9.1% at baseline to 7.8%, and this improvement was sustained throughout 2 years post procedure (7.4%) (Table 2), with 86% (12/14) of participants on stable or reduced GLAs.

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Table 2. Germany Real-World Registry Study Weight and Blood Sugar Data Post-Revita Procedure (n=14)

Endpoint Baseline 3 Months 6 Months 1 Year 2 Years

Mean ± SEM values shown. Fractyl Health internal data.

Figure 1: Germany Real-World Registry Study Total Body Weight Change from Baseline

Medication use was recorded at baseline and each follow-up visit. Changes were categorized as initiation or discontinuation of any GLA or anti-obesity medication class. In this Germany Real-World Registry study, treatment adjustments reflected routine clinical management and were not protocol-mandated. At baseline, participants were on up to 3 GLAs prior to treatment with Revita with inadequately controlled T2D.40% of participants were already receiving a glucagon‐like peptide-1 receptor agonist (“GLP-1RA”) for glucose control and remained inadequately controlled despite treatment. During follow-up, 14 of 30 (47%) participants remained on stable GLAs through their last follow-up period, 11 of 30 (37%) participants decreased the number of GLAs from baseline, and only 5 of 30 (17%) participants increased the number of GLAs from baseline. Analyses of weight and HbA1c were stratified by the change in the number of GLAs from baseline to account for the potential confounding effects of concomitant pharmacotherapy.

When stratifying for medication adjustments post-baseline, participants who were on either stable or reduced medications (n=25) had similar effects on weight and HbA1c at 1 year and 2 years post-procedure compared to the entire cohort. Those participants on stable or reduced medications had a mean weight reduction of 8.4±1.3% and 8.8±2.2% compared to 8.0±1.2% and 8.9±1.9% for the entire cohort (Figure 1 above) at 1 year and 2 years post-procedure, respectively. Likewise, participants on stable or reduced medications had a mean HbA1c reduction of 0.9±0.3% and 1.7±0.4% compared to 0.8±0.3% and 1.7±0.4% for the entire cohort at 1 year and 2 years post-procedure, respectively. Thus, the sustained improvement in weight and HbA1c observed after Revita occurred despite a substantial reduction in average GLA use and cannot be attributed to new medication use during the Germany Real-World Registry study follow up period.

Participant-reported outcomes (“PROs”) revealed that Revita was valued by participants and improved T2D management. At 1 year and 2 years post-procedure, 97% and 93% of participants, respectively, reported that they would undergo the Revita procedure again, and 100% and 93% of participants, respectively, would recommend the procedure to a family member or friend (n=30 at 1 year; n=14 at 2 years post-procedure). Revita received a mean score of 9.8±0.1 and 10±0.0 (1-10 scale, 10 highest) for its ability to improve T2D management. Revita’s ability to improve quality of life was scored a mean of 9.6±0.2 and 10±0.0 by Germany Real-World Registry study participants at 1 and 2 years post-procedure, respectively.

No device- or procedure-related serious adverse events have been reported to date.

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Collectively,these findings highlight the potential of a single Revita treatment to deliver durable weight maintenance, glucose improvement, and reduction in medication utilization without significant adverse events in a real-world setting out to 2 years post-procedure. Parallel PROs demonstrate durable participant-perceived value and improvement in T2D management.

As of February 15, 2025, we had treated 39 participants with Revita DMR and enrolled 34 participants in the Real-World Registry study with 12-month follow-up data from 17 participants. At baseline, prior to Revita DMR procedure, these participants (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 participants were male. At three months, participant 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 participants 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.

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 participants stabilized or reduced their GLA usage in addition to losing weight and improving their hyperglycemia (n=17). PROs revealed that Revita was valued by participants 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). As of February 15, 2025, 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

We obtained Breakthrough Device designation from the FDA for the Revita DMR System to perform the Revita DMR procedure to improve glycemic control and reduce insulin needs in T2D patients who are inadequately controlled on long-acting insulin. In granting Breakthrough Device designation, the FDA found the following: there is a reasonable expectation that Revita will provide for more effective treatment of 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.

On January 31, 2025, we announced that pursuant to the Strategic Reprioritization, we paused investment in REVITALIZE-1, and our decision to do so was not driven by any safety or efficacy concerns for Revita in T2D. At that time, enrollment was paused and on July 24, 2025 FDA agreed to and approved the final study revision converting the study to safety only and reducing the overall size to those participants already enrolled, establishing participant follow-up to 24 weeks post Revita procedure. Participants previously enrolled and randomized were those with inadequately controlled T2D, and who were on at least one GLA. Participants randomized to the sham arm were offered an opportunity to receive the Revita DMR procedure (crossover) once unblinded. Participants who elected to crossover and undergo the Revita DMR procedure are being followed per protocol.

In June 2024, the FDA approved an amendment to the protocol of the REVITALIZE-1 study of our Revita device, which expanded eligibility to participants with T2D who are inadequately controlled on any GLA, including GLP-1 drugs and/or insulin.

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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 participants with inadequately controlled T2D despite being on up to three ADAs and 20 to 100 units of insulin daily.

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.

Rejuva Device Overview

The Rejuva catheter leverages a single-use Rejuva PGTx catheter with a pressure-regulated and flow rate-controlled automated delivery mechanism. We believe the catheter 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 fluid delivery mechanism. The Rejuva catheter is further composed of a narrow 27-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.

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.

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.

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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.

Rejuva 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 lasts approximately twenty minutes. The procedure is performed by a trained endoscopist while the patient is under conscious sedation or general anesthesia. With the help of the Rejuva catheter handle, 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 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 catheter handle will control the pressure and flow rate of the delivered fluid to prevent injury to the tissue and regulate 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.

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 potential to provide superior 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

RJVA-001:

The lead product candidate from this platform, RJVA-001, is being advanced for patients with inadequately controlled T2D. RJVA-001 is designed to durably reprogram pancreatic beta cells to locally produce GLP-1 under nutrient-responsive

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control, potentially enabling physiologic hormone secretion without the high circulating levels that contribute to side effects seen with systemic GLP-1 drugs.

In the second half of 2025, we completed preclinical chemistry, manufacturing, and controls activities and lot release for our RJVA-001 drug product, as well as key preclinical in vivo studies to support a CTA. During the same period, we submitted CTAs for RJVA-001 in T2D to regulators in the EU (Netherlands) and Australia, advancing the program toward its anticipated first-in-human study. We expect to receive regulatory feedback in the second quarter of 2026 and, subject to CTA authorization, to initiate first-in-human dosing of RJVA-001 and expected reporting of preliminary data in the second half of 2026.

In June 2025, we presented new preclinical data from Rejuva at the American Diabetes Association’s (“ADA”) 85th Scientific Sessions. We demonstrated that a single dose of GLP-1 PGTx was well-tolerated in healthy normal weight mice and prevented weight gain and hyperglycemia following a switch to a high-fat diet. Importantly, these data highlight Rejuva’s distinct mechanism of action. The Smart GLP-1TM design of Rejuva enables nutrient-responsive secretion, exerting minimal physiologic effect under healthy metabolic conditions and only activating in the presence of metabolic stress. This targeted activity, which mimics the body’s endogenous GLP-1 physiology, highlights the potential for Rejuva to offer superior potency and tolerability.

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In May 2025, we presented new preclinical data from Rejuva in an oral session at the American Society of Gene and Cell Therapy 2025 Annual Meeting. These data showed that a single-dose RJVA-001 led to durable, dose-dependent metabolic improvements in a well-established mouse model of diabetes (db/db). Additionally, these data highlight the platform’s potential to deliver durable, nutrient-responsive GLP-1 secretion from pancreatic beta cells, mimicking natural hormone regulation with low circulating levels of GLP-1, offering a potentially profound mechanistic advantage over pharmacologic GLP-1 drugs.

Rejuva Shows Nutrient Responsive, Dose-Responsive GLP-1

Expression and Secretion in Transduced Human Beta Cells

Rejuva GLP-1 Improves Metabolic Control in db/db/ Mice

Dose-responsive improvement in body weight, blood glucose, and insulin levels

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In a porcine route-of-administration safety model, RJVA-001 also showed strong efficacy, targeted delivery, and a favorable safety profile with no serum, biodistribution, or histopathologic findings of concern reinforcing its readiness for first-in-human studies.

Rejuva AAV Effectively Delivered to Pancreas Via Targeted ROA

Transgene DNA, RNA, active GLP-1 protein enriched in targeted pancreatic splenic lobe

No Toxicity Observed Following Rejuva Treatment

No serum, biodistribution, or histopathologic findings of concern

In the first quarter of 2025, we achieved alignment with European authorities on a patient population and study design for the RJVA-001 first-in-human study. The upcoming Phase 1/2 first in human study is designed to be an open-label, multicenter, single ascending dose study evaluating the safety, tolerability, and preliminary efficacy of RJVA-001 in adults with inadequately controlled T2D despite use of multiple glucose-lowering agents, including GLP-1 receptor agonists. Participants will undergo a standardized medication run-in and GLP-1 washout before receiving RJVA-001 delivered via endoscopic ultrasound-guided intrapancreatic infusion utilizing our investigational delivery device. The preliminary study design comprises three escalating dose cohorts (up to 3 participants each) which will be followed by an optional expansion cohort of up to 20 additional participants treated at the selected optimal dose. Participants will be monitored for 12 months for safety, glucose control, immune response, and GLP-1 expression, and enrolled in a long-term follow-up study for up to five years. Primary endpoints include safety and tolerability. Secondary endpoints include change in HbA1c, fasting plasma

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glucose, and time-in-range as measured by continuous glucose monitoring. Exploratory endpoints assess beta-cell function, metabolic biomarkers, cardiovascular risk markers, and transgene expression.

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”), a hallmark of improved beta cell function.

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, and demonstrating the potential for pharmacologic agents that block the GLP-1 receptor to abrogate the effects of RJVA-001.

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.

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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 candidate can achieve greater improvements in blood glucose control and weight loss and delayed T2D progression in db/db mice compared to semaglutide.

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 offer a potential weight maintenance therapeutic solution to prevent weight regain after semaglutide discontinuation.

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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.

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 GLP-1 PGTx candidate. 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.

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No abnormal findings were observed in animal behavior or clinical chemistries. Histopathologic analysis showed no evidence of inflammation, pancreatitis or pancreatic cancer.

RJVA-002:

The Company’s second candidate from the Rejuva platform, RJVA-002, is a dual GIP/GLP-1 gene therapy and is currently in preclinical development. RJVA-002 expands the Rejuva platform into obesity, targeting dual incretin biology with the goal of achieving durable, well-tolerated, weight loss from a single intervention.

In October 2025, we announced new preclinical potency data from RJVA-002 at the 2025 Cell & Gene Meeting on the Mesa. These data expand the potential of the Rejuva platform from the durable treatment of T2D to obesity. In this ongoing preclinical study, male mice engineered to express a humanized GIP receptor (“Biocytogen”) were fed a 60% high-fat diet (“HFD”) to induce obesity and were then randomized into one of four treatment cohorts: vehicle control, RJVA-001 mid-dose, RJVA-002 mid-dose, and RJVA-002 high-dose (n=7 per group). A single administration of RJVA002 led to approximately 30% weight loss over five weeks in a translational obesity model in male mice, with weight loss not yet plateaued and no observed adverse effects. In this preclinical trial, all mice were continued on HFD for the duration of the study. Treatment with RJVA-002 resulted in a robust, dose dependent reduction in body weight compared to vehicle control. By day 35, mice in mid- and high-dose cohorts had lost a mean of 18% (p<0.01) and 29% (p<0.0001) of their body weight after a single dose of RJVA-002, respectively. These findings highlighted the potential for a durable, one-time gene therapy approach to obesity that could match or exceed best-in-class chronic drug therapy. Results from this ongoing study at longer time points and with associated metabolic measurements will be presented at an upcoming scientific congress.

Clinical Development Overview: Rejuva Gene Therapy Platform

We completed key preclinical in vivo studies to support a CTA for RJVA-001 and subsequently submitted CTAs for RJVA-001 in T2D to regulators in the EU (Netherlands) and Australia in the second half of 2025, advancing the program toward its anticipated first-in-human study. We expect to receive regulatory feedback in the second quarter of 2026 and, subject to

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CTA authorization, to initiate first-in-human dosing of RJVA-001 and expected reporting of preliminary data in the second half of 2026.

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 ongoing enrollment in the Germany Real-World Registry study.

In the U.S., 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 market authorizations but does not alter or confer any advantage in the regulatory review, approval, or clearance standard for medical devices.

We intend to submit a De Novo classification request with FDA for Revita after we complete the REMAIN-1 study, including participant follow-up through 52 weeks. If our De Novo request is granted, we believe longer-term follow-up studies beyond 52 weeks will likely be performed as part of a post-market study, which may include studying the safety and effectiveness of repeat procedures, should they be necessary. Based on regulatory precedent, we believe such post-market studies may be conducted in parallel with the commercial launch of Revita. If our De Novo request is granted, 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 sales force to support our U.S. launch to prepare for Revita’s potential FDA marketing authorization. We will seek to strategically recruit representatives with strong backgrounds and experience in the management of obesity and metabolic disease, as well as those with a deep understanding of therapeutic GI endoscopy. 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 gastroenterologists and endoscopic surgeons around the compelling solution provided by our product candidates, as we believe they will serve as the primary customers for our therapies. We believe that the clinical evidence generated from our program will continue to support our messaging to key leaders in the field of metabolic endoscopy. In parallel, we plan to leverage our LOI with Everself (formerly Bariendo) as this potential partnership will bring a scalable, physician-driven platform designed to deliver metabolic endoscopic solutions at the nation’s largest network of high-volume hospital and ambulatory endoscopy centers across the U.S.

If Revita receives marketing authorization, we intend to commercially launch with our next generation commercial console, which has been designed for scalability and ease-of-use. 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 learning 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 and surgical endoscopists with a dedicated interest in bariatric and metabolic endoscopy. We plan to initially target participating physicians from our clinical

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studies, as we believe their familiarity with our therapies will make them early adopters. Our multi-channel commercialization strategy will include a focus on patients directly with GI endoscopy suites and practices, as well as direct marketing campaigns to raise awareness amongst patients for a compelling new treatment alternative in weight maintenance and obesity.

We also plan to roll out a robust procedural training and support program for GI and surgical 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 authorizations, 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 patient referral pathways, physicians, skill sets and commercialization footprint of Revita, we believe that a successful launch of Revita, if authorized will enable a more rapid commercialization of Rejuva into that same channel, if both products receive marketing authorization in the U.S.

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 March 1, 2026, our research and development team was comprised of 73 employees. For the years ended December 31, 2025 and 2024, we incurred research and development expenses of approximately $74.5 million and $70.5 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. We also may face competition from companies developing endoscopic and other procedure-based metabolic interventions, including duodenum-targeted therapies. 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.

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There are a number of new classes of agents and combination agents approved or 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.

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 March 1, 2026, we own: 36 issued U.S. patents; 34 pending U.S. non provisional patent applications; five pending U.S. provisional patent applications; two patent cooperation treaty (“PCT”), applications that have not entered national stage; 51 issued foreign patents in Australia, Brazil, Canada, China, Europe, Israel, Japan, Korea, and Russia; and 26 pending foreign patent applications in Australia, Canada, China, Europe, Israel, India, Japan, and Korea. Patent counts reflect the patents we maintain. We may allow patents and applications that are not material to our business to lapse. 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 January 2041; our owned issued foreign patents are expected to expire between January 2032 and October 2040; any patents that may issue from our owned pending U.S. patent applications are expected to expire between January 2032 and February 2047; 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 March 1, 2026, we own: 34 issued U.S. patents; 27 pending U.S. patent applications; one pending U.S. provisional patent applications; one PCT application that has not entered national stage; 51 issued foreign patents in Australia, Brazil, Canada, China, Europe, Israel, India, Japan, Korea, and Russia; and 17 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 July 2046, 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 March 1, 2026, we own: six pending U.S. patent applications; six pending U.S. provisional patent applications; one PCT application that has not entered national stage; and nine 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 February 2047, 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 U.S., the patent term is 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country. In the U.S., 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

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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 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 March 1, 2026, we own 44 registered trademarks and three pending trademark applications for FRACTYL, FRACTYL HEALTH, FRACTYL HEALTH LOGO, REVITA, REVITA DMR, REJUVA and other product related brand names in the U.S. 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

We currently perform final assembly and acceptance testing of Revita at our headquarters in Burlington, Massachusetts. We rely upon third-party suppliers for the manufacture of sub-assembly components, the sterilization of final components of the Revita system, the device component of the Rejuva product and the Rejuva gene therapy candidates. We do not have long-term supply agreements with any of our suppliers, some of which are single- or sole-source suppliers. Our purchase order arrangements are terminable at will. We have not yet identified and qualified second-source replacements for many of our critical single-source suppliers. Thus, in the event that our relationship with any of our single- or sole-source suppliers terminates in the future, we may have difficulty maintaining sufficient supplies of key components of our product candidate. Where practicable, we are currently seeking, or intend to seek, second-source manufacturers for our single-source components. We believe that our existing facilities and those of our third-party suppliers are adequate to meet our current manufacturing needs.

Manufacturing facilities that produce drug products, medical devices or their component parts are subject to regulation and periodic unannounced inspection by the FDA and other domestic and international regulatory agencies. In the U.S., we and some of our sub-assembly component manufacturers will be required to manufacture any products that we sell in compliance with the FDA’s Quality Management System Regulation (“QMSR”), and the FDA’s current good manufacturing practices (“cGMPs”), which cover the methods used in, and the facilities used for, the design, testing, control, manufacturing, sterilization, labeling, quality assurance, packaging, storage and shipping of our product candidates. In international markets, we and some of our sub-assembly component manufacturers are and will be required to obtain and maintain various quality assurance and quality management certifications, and are and will continue to be periodically inspected by international regulatory authorities for certification purposes. Our manufacturing operations, and those of our suppliers, are designed to be in compliance with applicable regulations of the FDA or other applicable regulatory authorities.

Government Regulation

Our product candidates and our operations are subject to extensive regulation by the FDA and other federal and state authorities in the U.S., as well as comparable authorities in foreign jurisdictions. For example, certain of our product candidates are subject to regulation as medical devices in the U.S. under the Federal Food, Drug, and Cosmetic Act (“FDCA”), as implemented and enforced by the FDA, and other product candidates we intend to develop are regulated as

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biologic-device combination products subject to regulation by the FDA under the FDCA and the Public Health Service Act (“PHSA”), and comparable foreign laws and regulations.

United States Regulation of Medical Devices

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