Shareholder Call Series: Part 2 — Advancing Pivotal Programs Toward Major Clinical and Regulatory Milestones

Dear Shareholders,

This post is Part 2 of 2 in our summary of Chairman and CEO David Hochman’s recent shareholder update call, which provided a detailed perspective on Orchestra BioMed’s progress through 2025.

In Part 1, we focused on the Company’s strengthened capital position and strategic partnerships. In this second installment, we turn to the clinical and operational progress that defines Orchestra BioMed’s execution across its two flagship programs - AVIM Therapy and Virtue SAB - both now the focus of pivotal-stage clinical trials that are actively enrolling patients.

Virtue SAB: Advancing a Differentiated Approach to Coronary Treatment

In late October, Orchestra BioMed announced that first patients were enrolled in the Virtue Trial, a U.S. pivotal IDE study evaluating the Virtue® Sirolimus AngioInfusion™ Balloon (Virtue SAB) against Boston Scientific’s AGENT™ paclitaxel-coated balloon for the treatment of coronary in-stent restenosis (ISR). Coronary ISR is a difficult-to-treat and serious complication of coronary stenting that increases the risk of life-threatening heart problems, affecting an estimated 100,000 patients in the U.S. annually.

The Virtue Trial marks a significant step toward U.S. regulatory approval for Virtue SAB and reflects a broader paradigm shift in coronary interventions toward “leave-nothing-behind” strategies that utilize drug delivery balloons and avoid using stents, permanent metal implants.

Virtue SAB stands apart from existing drug delivery balloons which are all drug-coated balloons. Virtue SAB was designed specifically to provide important, fundamental differentiating features:

• It delivers a large liquid dose of Orchestra BioMed’s proprietary SirolimusEFR™ formulation — designed for optimal arterial uptake and extended-release to achieve sustained therapeutic tissue levels of sirolimus, the proven “gold standard” drug used for many years on drug eluting stents, during the critical healing period following the interventional procedure.
• It enables drug delivery through our novel, patented, microporous balloon delivery system, meaning it is non-coated and avoids particulate embolization and drug loss during navigation while optimizing drug delivery at the time of inflation.
• It demonstrated best-in-class results in prior pilot data in coronary ISR (SABRE study), with a 12-month target lesion failure rate of only 2.8% and no reinterventions through 36 months.

The Virtue Trial will enroll approximately 740 patients at up to 75 U.S. centers, with enrollment completion targeted for mid-2027.

As Mr. Hochman noted during the call, Virtue SAB represents “…a fundamentally different, and we believe, superior approach to arterial drug delivery…We believe Virtue SAB is a very exciting pivotal-stage asset that offers a substantial future value creation opportunity, which we are driving toward from a position of financial, operational, and strategic strength.”

AVIM Therapy: Broadening Clinical Impact Through the BACKBEAT Study

AVIM (Atrioventricular Interval Modulation) Therapy continues to advance in the BACKBEAT global pivotal study, which is designed to evaluate its potential to treat uncontrolled hypertension in patients indicated for or recently implanted with dual-chamber pacemakers.

The therapy — delivered as proprietary firmware programming — is designed to substantially and persistently lower blood pressure while improving cardiac function in hypertensive heart disease.

Key 2025 milestones include:

• FDA Breakthrough Device Designation for the treatment of patients with uncontrolled hypertension who have elevated cardiovascular risk and preserved ejection fraction — encompassing an estimated 7.7 million patients in the U.S.
• Implementation of an FDA-approved protocol update nearly complete, expanding eligible patients and simplifying enrollment processes across sites, enabling faster recruitment and broader representation.
• Expanded collaboration with Medtronic, providing a pathway for potential integration of AVIM Therapy into future leadless pacing technology.

Recent peer-reviewed publications have also reinforced the therapeutic promise of AVIM Therapy as a potential treatment for hypertensive heart disease, a condition where heart muscles become damaged over time due to prolonged or chronic high blood pressure:

• JACC: Advances published data from the MODERATO II study, showing significant reductions in blood pressure and improvements in ventricular function in patients with diastolic dysfunction.
• JACC: Clinical Electrophysiology reported acute and chronic clinical results demonstrating sustained blood pressure reductions and improved cardiac function across multiple measures using standard and conduction system pacing methods.
• New data presented at HRX Live 2025 confirmed that AVIM Therapy’s effects in a pilot study were sustainable, reversible, and reproducible over multi-year follow-up — emphasizing its potential long-term clinical utility and safety profile.
  
  

Investor Takeaway: Positioned for Value-Creating Milestones Ahead

With both Virtue SAB and AVIM Therapy now enrolling patients in pivotal studies, Orchestra BioMed is entering the last phase of clinical execution toward potential regulatory approvals and strategic value inflection. Key upcoming Company catalysts include:

• AVIM Therapy & the BACKBEAT Study: Completion of enrollment in mid- 2026, followed by primary endpoint data thereafter.
  • Notably, Orchestra’s strategic collaborator, Medtronic, is responsible for securing regulatory approval and commercializing AVIM Therapy devices for the pacemaker-indicated population and has a right of first negotiation for the broader treatment population with uncontrolled hypertension and increased cardiovascular risk.
• Virtue SAB & the Virtue Trial: Completion of enrollment in mid-2027.
  • Notably, Orchestra has broad strategic optionality to pursue business partnerships or strategic transactions related to the commercialization of Virtue SAB subject to the right of refusal it has granted Terumo with respect to certain Virtue SAB transactions in the coronary market.

As Mr. Hochman summarized:

“2025 has clearly been a successful and eventful year for Orchestra BioMed to date, with recent developments positioning us to operate on all cylinders for both of our pivotal-stage, high-impact programs…We are very well capitalized to achieve key clinical and regulatory milestones [and] we expect 2026 will be a landmark year for Orchestra BioMed, with target completion of enrollment in the BACKBEAT study and primary endpoint results data to follow thereafter, given that the primary efficacy and safety endpoints are measured at three months follow-up.“

For shareholders, this translates to clear visibility into the Company’s next two years of milestones — a period expected to define Orchestra BioMed’s trajectory as a pivotal-stage medtech innovator with two Breakthrough Device-designated programs moving toward market readiness.

— Team OBIO

Published November 2025

Forward-Looking Statements

Certain statements included in the content distributed by Orchestra BioMed Holdings, Inc. (the “Company”) to which this disclaimer relates (including, but not limited to, visual, auditory, or written statements accessible through the link included in the Company’s digital communication) (the “Content”) that are not historical facts are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements generally are accompanied by words such as “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “intend,” “expect,” “should,” “would,” “plan,” “predict,” “potential,” “seem,” “seek,” “future,” “outlook” and similar expressions that predict or indicate future events or trends or

that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements relating to the initiation, enrollment, timing, implementation and design of the Company’s ongoing pivotal trials and reporting of top-line results, the potential benefits of regulatory approvals or designations received from domestic and foreign regulatory bodies with respect to the Company’s product candidates and/or ongoing trials, the potential safety and efficacy of the Company’s product candidates, the ability of the Company’s partnerships to accelerate clinical development, the realization of the clinical and commercial value of the Company’s product candidates, the Company’s ability to achieve expected regulatory and business milestones and the Company’s ability to pursue business partnerships or strategic transactions related to the commercialization of Virtue SAB in light of the new Terumo agreement. These statements are based on various assumptions, whether or not identified in the Content, and on the current expectations of the Company’s management and are not predictions of actual performance. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as and must not be relied on as a guarantee, an assurance, a prediction, or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and may differ from assumptions. Many actual events and circumstances are beyond the control of the Company. These forward-looking statements are subject to a number of risks and uncertainties, including changes in domestic and foreign business, market, financial, political, and legal conditions; risks related to regulatory approval of the Company’s commercial product candidates and ongoing regulation of the Company’s product candidates, if approved; the timing of, and the Company’s ability to achieve expected regulatory and business milestones; the impact of competitive products and product candidates; and the risk factors discussed under the heading “Item 1A. Risk Factors” in the Company’s Form 10-K for the year ended December 31, 2024, and under the heading “Item 1A. Risk Factors” in our quarterly report on Form 10-Q for the quarter ended March 31, 2025. The Company operates in a very competitive and rapidly changing environment. New risks emerge from time to time. Given these risks and uncertainties, the Company cautions against placing undue reliance on these forward-looking statements, which only speak as of the date of the Content. The Company does not plan and undertakes no obligation to update any of the forward-looking statements made in the Content, except as required by law.