AVIM Therapy: A Purpose-Built Solution for a Large, Underserved Patient Population

Fellow Shareholders:

Earlier this week at CSI Frankfurt 2025, Daniel Burkhoff, M.D., a key opinion leader in heart failure research and therapeutic innovation as well as a scientific advisor to Orchestra BioMed, presented key clinical insights into the unique role OBIO’s investigational AVIM therapy has the potential to play as novel hypertension therapy purpose-built for a high-risk, underserved patient population with hypertensive heart disease.

A large population with few effective options

Hypertensive heart disease isn’t a singular diagnosis — it’s a complex, progressive condition that can develop after years of uncontrolled hypertension and increases overall risk of major adverse cardiac events, especially in older patients. As blood pressure stays elevated for prolonged periods of time, the heart stiffens, loses its ability to relax properly (known as diastolic dysfunction), and can eventually progress to heart failure.

Over 7.7 million people in the U.S. are estimated to fall into this high-risk group - most of them older, prescribed multiple medications,

and many of them requiring pacemakers.

Existing therapies were designed for the broader hypertension population and are not necessarily optimized for the medical needs of older patients with elevated risk factors, leaving a clear gap in treatment. AVIM therapy was designed specifically to address this treatment gap for this high-risk patient population, providing major potential market and therapeutic differentiation.

As Dr. Daniel Burkhoff summarized in his CSI presentation:

“AVIM therapy directly targets the heart’s structural and functional changes caused by long-term high blood pressure — offering a highly tailored approach for these high-risk patients.”

AVIM therapy is designed specifically for this patient group

AVIM therapy is designed to directly impact the biomechanical mechanisms that drive hypertensive heart disease. Rather than simply adding more medication, AVIM is designed to leverage an implanted pacemaker to exert precise electrical timing adjustments between heartbeats to lower pressure inside the heart and throughout the body, reduce cardiac workload, and improve ventricular relaxation. AVIM therapy targets both blood pressure and heart function at the same time.

Because AVIM therapy is programmable and delivered automatically by the implanted device, it has the potential to provide an “always on” treatment that does not rely on patient adherence and compliance, which is a critical challenge for antihypertension medications.

Breakthrough Device Designation reflects the scale of the opportunity

Earlier this year, AVIM therapy received Breakthrough Device Designation (“BDD”) from the U.S. FDA — an important regulatory milestone that recognizes both its potential clinical impact and the large unmet need it can serve.

• Over 7.7 million U.S. patients meet the FDA’s BDD criteria: uncontrolled hypertension and increased cardiovascular risk despite the use of antihypertensive medications.
   
• Many of these patients are already receiving or are eligible for pacemakers, providing a natural delivery platform for AVIM therapy.

The BDD not only validates the innovation behind AVIM therapy but may also enable important regulatory and reimbursement advantages as the therapy advances through clinical development into regulatory reviews.

Encouraging data reinforces AVIM’s differentiated approach

In prior pilot studies, AVIM therapy demonstrated:

• A greater than 11 mmHg average reduction in 24-hour ambulatory systolic blood pressure at 6 months following treatment activation
• A greater than 12 mmHg average reduction in office systolic blood pressure at 6 months following treatment activation
• A greater than 17 mmHg average reduction in office systolic blood pressure at 2 years following treatment activation
• Statistically significant improvements in diastolic function and heart remodeling — addressing a core dysfunction driving heart failure risk in these patients
  
  

Pivotal global trial actively enrolling

OBIO is now conducting the BACKBEAT global pivotal study in collaboration with Medtronic. This randomized, double-blind trial will evaluate the efficacy and safety of AVIM therapy in pacemaker-indicated patients who remain hypertensive despite medical therapy.

As Avi Fischer, M.D., Orchestra BioMed’s SVP of Medical Affairs and Innovation, emphasized:

“AVIM therapy was purpose-built for this specific high-risk population, fitting naturally into existing pacemaker procedures and targeting the mechanisms that traditional therapies simply don’t address.&rdquo

In short: AVIM therapy represents a highly targeted solution for millions of patients who remain poorly served by current hypertension treatments. With FDA Breakthrough Device Designation, growing clinical evidence, and a global pivotal trial underway, and a strategic partnership with Medtronic, the global leader in cardiac pacing therapies, we believe AVIM therapy has the potential to become a major value driver for Orchestra BioMed and all of our stakeholders.

Orchestra BioMed is just getting started. Stay tuned.

- Team OBIO