Q&A: Novel Therapy Holds Promise for Hypertension Treatment in Patients With Pacemakers

For patients with pacemakers, hypertension is a common comorbidity, and a significant proportion of patients globally with hypertension struggle to meet ideal blood pressure goals. Atrioventricular interval modulation (AVIM) therapy is a device-based treatment that holds potential to provide significant benefits to this population in conjunction with medical therapies.

The FDA recently granted an investigational device exemption (IDE) to begin a pivotal trial of an AVIM therapy (BackBeat CNT; Orchestra BioMed) for treating hypertension in patients with pacemakers, with the IDE based on findings from the phase 2 MODERATO II trial. The treatment is compatible with standard dual-chamber pacemakers.

David Hochman, CEO of Orchestra BioMed, detailed the intricacies of AVIM therapy and the implications of their studies thus far.

This transcript has been lightly edited for clarity and conciseness.

What are some of the different approaches to care that are necessary for patients with pacemakers and hypertension?

Generally, all medical therapies for hypertension or all interventional medical therapies are based on pharmaceutical intervention such as prescribing anti-hypertensive medications. The types of drugs that are prescribed for treating hypertension include diuretics that help patients to potentially dropped fluid—make patients pee—along with calcium channel blockers, beta blockers, ARBs, and ACE inhibitors. There’s a number of approved anti-hypertensive drugs that are used in stack therapies. These drugs can be effective, but it is harder to prescribe the right mix of drugs for older patients for a number of reasons. One, these patients tend to have comorbidities and may be on a range of other medications. Getting the right mix of medications that compounds with the full scope of medications for patients is difficult. Older patients tend to have stiffer blood vessels and, as a result of that, they tend to have systolic hypertension or elevated systolic blood pressure, but not necessarily elevated diastolic blood pressure. When you have high systolic and normal diastolic, it's referred to as isolated systolic hypertension.

What we've found is that as much as 80% of the patients we've treated have what's called isolated systolic hypertension, or ISH, and it becomes more difficult then to prescribe the right mix of medicines because the medicines tend to work on both systolic and diastolic blood pressures. The physicians is trying to get the right mix of medicines that lower systolic without reducing diastolic blood pressure too much. That's hard.

Probably the next biggest issue of medical therapy is compliance and adherence. These patients, as I mentioned, are likely on a range of medication for maybe a range of indications. It's tough for all of us to always stay to our prescribed regimen of medication. In hypertension, noncompliance and nonadherence is one of the biggest challenges for patients. They either can't tolerate the medicine because of side effects or it's just tough to stay on those medicines.

Medicines don't always work, they have side effects, it's hard to get the right prescriptions, it's hard for the patients to really stay and maintain those medical therapies and achieve long-term control of their blood pressure. AVIM therapy is potentially really compelling because, once again, it's running in the background in a device the patients already need. The clinical evidence to date suggests it has a meaningful effect on blood pressure. We've seen, in our trials, reductions in systolic blood pressure of over 10 millimeters of mercury sustained in terms of the most sensitive measure of blood pressure, which is 24-hour ambulatory systolic blood pressure. That means a patient's wearing a device that's monitoring their blood pressure all day, as opposed to just taking a blood pressure measurement in the office. We’re getting the whole blood pressure profile. That’s a significant drop in systolic blood pressure and it's doing that while the patient is still on their prescribed background medical therapy.

It works in conjunction with and complementary with the medical therapy that's being prescribed. And AVIM therapy is working kind of regardless of whether the patient is still in compliance with their prescribed medicines.

What is AVIM, and why is there a need for such a treatment?

AVIM therapy, or atrioventricular interval modulation therapy, is a bioelectronic treatment for hypertension that is delivered by a standard dual-chamber pacemaker. It’s really a pacemaker-mediated or pacemaker-based treatment that a wholly owned subsidiary of our company, Orchestra BioMed, developed from concept to stage. We developed all the intellectual property and both non-clinical and clinical data that's brought the therapy to this point.

The treatment is particularly exciting because hypertension is really the number one risk factor for death worldwide. It's a huge problem affecting over one billion patients. With this study, we're focused on our first patient population, and we think it's a particularly high-need patient population of hypertensive patients that are also indicated for a pacemaker.

Pacemakers have been around for a long time, over a million pacemakers are implanted every year worldwide and the largest market for pacemakers is the United States. I think that about 350,000 pacemakers are implanted every year in the United States. And the most common comorbidity in that population is hypertension. Pacemaker patients tend to be older, obviously they have a rhythm issue, which gives them the pacemaker indication. They tend to have other comorbidities, but the number one most common one is hypertension.

These patients are at higher risk for the morbid and mortal events that hypertension drives. Hypertension is a leading risk factor for heart attack, stroke, progression to heart failure, progression to end stage kidney disease, and has an insidious interaction with artery disease. It's very common in these patients.

Because AVIM therapy can be delivered by the same device that these pacemaker patients are already getting implanted, and patients may get more than one pacemaker over the course of their life, it’s an exciting therapy because the data we've generated shows that this potentially significantly lowers blood pressure, particularly in this population, with what appears to be a lower safety profile in terms of risk. Also, the patient really doesn't have to do anything. It's running in the background and of the device that they already need for another indication. We think it's a very compelling potential therapy for a big problem in an established patient already receiving implants and intervention. And this study, and in our collaboration with Medtronic—which is the global dominant leader in terms of providing pacemakers and cardiac-pacing therapies—makes this trial the next pivotal step towards making this therapy available to patients.

Can you give some more insight into the mechanisms of AVIM therapy?

There are two mechanisms that we believe are core to how AVIM therapy works. First is the hemodynamic mechanism, where through the pacemaker were able to control and reduce the timing of atrial and ventricular contraction. That's really what we refer to as this AV interval or some physicians would know it as AV delay. When you reduce that timing, you reduce the amount of blood that fills the ventricle.

There's a well-known principle of cardiovascular function called the Frank Starling Law. Essentially, the more you stretch the muscles or fibers of the tissue—the heart—by filling the ventricle, the more contraction force that heart muscle responds to. By reducing AV time we reduce filling, reduce contraction force, and can materially lower blood pressure. That alone isn't going to be a sustainable therapy for her blood pressure. While you can reduce blood pressure acutely, the body has a lot of mechanisms and sensors, particularly baroreceptors. These are monitoring blood pressure and looking to maintain equilibrium: basically looking to maintain blood pressure at what the body perceives as normal, even if that “normal” is too high or unhealthy. It's what the body is used to.

When the body detects that drop in blood pressure, normally it's going to react and look to potentially stiffen up the blood vessels or increase what's called total peripheral resistance, going to look to increase increased sympathetic activity, maybe increase heart rate, and bring blood pressure back to what it perceives as normal. What we do as a secondary mechanism, and this is really key to making AVIM therapy work, is we then do short AV intervals, very short AV intervals, that lower blood pressure, but we have learned how to program the pacemaker to then insert or interpolate longer AV intervals in a sequence or in sequences, so that we essentially overcome that baroreflex response and overcome that autonomic response. The body doesn't really know that blood pressure has changed and doesn't react the way it normally would. We think over time it gets reprogrammed, modulated, trained to accept lower blood pressure as the new normal.

Since this is a therapy that's being delivered constantly by the pacemaker in the background—the patient doesn't feel it and doesn't know it's running—we're able to take that first mechanism and dial in a lower blood pressure and sustain that reduced blood pressure over long periods of time.

We've run two pilot studies: a single-arm and then subsequently a prospective, randomized, double-blind study. Both had two-year follow-up and were able to see sustained reductions in blood pressure through the study period. The mechanism is both hemodynamic and neuromodulatory. Most importantly, it's delivered by a device that has decades of history. Its value in terms of treating rhythm issues has an established paradigm of care, a large, already-treated population, a large population of physicians and care providers. It's one of the common procedures that happens in the hospital by electrophysiologist and implanting cardiologists and also as an established supportive health economic infrastructure. We’re able to focus on that population and hopefully both prove the therapy’s efficacy and safety through this trial while potentially garnering meaningful, rapid adoption for regulatory approval because we're entering the care continuum with a population that's already getting the devices and intervention, and commonly has hypertension.

So far, have you seen any risks associated with AVIM therapy, and how have those been mitigated the studies so far?

Fortunately, we really haven't. It's important to look at data from the second study I mentioned—the prospective, randomized, double-blind study. In that study, while it was a pilot study involving around 50 patients, the double-blind period ran for six months. We looked at the efficacy profile where we saw AVIM therapy drove a statistically significant superior effect—a superiority by over eight millimeters of mercury benefit for patients at six months during the blinded period—in terms of 24-hour ambulatory systolic blood pressure. We also looked at major adverse cardiac events, or what's referred to as MACE, in patients and were able to compare the event rate in the treatment group that received AVIM therapy along with medical therapy, versus the control group that only received their standard medical therapy without AVIM therapy. In that study, we saw zero MACE events in the AVIM therapy arm versus a rate of just under 10% in the control arm.

It's a pilot study, it wasn't powered to prove safety. But one of the largest drivers of adverse events in these patients is their elevated blood pressure. We think that's indicative—we certainly hope is indicative—of lower blood pressure in the treatment group and lower event rate. In the BackBeat pivotal study, we'll be looking at a primary safety endpoint of what's referred to as unanticipated, serious adverse device-related events. One of the things that is really interesting about layering on a novel, pacing-based therapy like AVIM therapy into this population is there's a 40-plus-year history of treating pacemaker-indicated patients with cardiac pacing therapy. This is a novel pacing therapy. What the medical community has accumulated as a whole profile of what are the anticipated serious adverse events with pacing, in this trial the primary safety point will be: do we see anything that is unanticipated given that long history of existing events.

To date, we've not seen anything that's unanticipated in any of our previous trials. That'll be the primary safety endpoint which our clinical steering committee and leaders in Orchestra BioMed, at Medtronic—our strategic collaborator—along with the FDA, agree as the right primary endpoint. We'll look at that at three months. That'll be the primary data point both for efficacy and for the safety endpoint. But we also will keep the study blinded through 12 months to accumulate additional information on the therapy, including additional information related to safety. In short, nothing so far that we have seen is unexpected; some trends are favorable, and we hope those trends continue. But we do think the BackBeat study is well powered and well designed to thoughtfully look at safety and efficacy, hopefully in support of a regulatory filing for approval after we conduct the study.

While AVIM therapy is currently only being tested for hypertension in patients with pacemakers, David noted the long-term goal of this therapy becoming widely available for treating hypertension at large.

Reference

Orchestra BioMed granted FDA approval of IDE to initiate BACKBEAT pivotal study of BackBeat CNT™ for the treatment of hypertension in pacemaker patients. News release. September 19, 2023. Accessed October 4, 2023. https://investors.orchestrabiomed.com/news-releases/news-release-details/orchestra-biomed-granted-fda-approval-ide-initiate-backbeat