Years after a setback to its clinical program, Medtronic plc‘s Symplicity brand renal denervation (RDN) system appears to be firing on all pistons. The Dublin-based company said this week that it will begin enrolling patients in a pilot study to assess the safety and efficacy of its newer-generation Symplicity Spyral using a targeted procedural approach with fewer radiofrequency (RF) ablations. The company is also slated to present data this spring on a pivotal trial evaluating the ability of Symplicity Spyral to control high blood pressure in the absence of antihypertensive medications.

Specifically, the SPYRAL DYSTAL study will analyze whether using fewer ablations in the distal main and first order branches of the renal artery is as effective as the more extensive procedural approach outlined in the SPYRAL HTN clinical trial protocol. The single-arm study is expected to enroll 50 patients at up to 15 sites in the U.S. and Europe.

“As we strive to build upon the rigorous renal denervation studies within the SPYRAL HTN clinical program, the DYSTAL study will help inform how we can fine-tune the procedure and continue to address the unmet need in hypertension measurement,” said Dave Moeller, vice president and general manager of the coronary and renal denervation business, within Medtronic’s Cardiac and Vascular Group.

Roughly 77.9 million U.S. adults, or 1 in 3, have hypertension, but only half of those have their condition under control, according to the American Heart Association. The annual toll in health care-associated costs is about $131 billion. Renal denervation is a one-time, minimally invasive, RF-based procedure designed to improve hypertension control by regulating nerve activity in the kidneys.

Growing body of evidence

In November 2018, Medtronic launched the Spyral HTN-OFF MED trial to offer clinical data for renal denervation that’s comparable to what has been reported for FDA-assessed drug candidates. The international, multicenter, 2:1 randomized, sham-controlled study has a primary efficacy endpoint of 24-hour ambulatory blood pressure at six months. The primary safety endpoints include major adverse events at one month and new renal artery stenosis at six months. An earlier trial, SPYRAL HTN-ON MED, aims to gauge more clearly the actual patient population that doctors treat.

Data from the OFF-MED study is set to be presented at the American College of Cardiology annual scientific sessions in March, and Larry Biegelsen, senior analyst with Wells Fargo, calls it the “most noteworthy” trial to watch. “The fact that the trial is on the program implies that the interim analysis was positive,” he wrote in a research note. “At this point, the main question, in our view, is how does the magnitude of the blood pressure lowering with RDN in the full trial compare to what was seen in the pilot trial.”

In May 2019 at the EuroPCR annual meeting in Paris, investigators reported three-year data from the Global SYMPLICITY Registry of Medtronic’s RDN systems in a real-world setting in patients with uncontrolled hypertension. Renal denervation resulted in significant and clinically meaningful reductions in both office and ambulatory blood pressure (16.5 mm Hg OSBP and 8.9 mm Hg 24H systolic ABPM) that were sustained over three years post-procedure. The improvements were consistent across high-risk subgroups, including people with diabetes, isolated systolic hypertension, chronic kidney disease, resistant hypertension and those 65 years of age and older.

Lessons learned

The tide of promising news comes six years after the SYMPLICITY HTN-3 trial, which used the earlier version Symplicity Flex, failed to hit its primary efficacy endpoint. The disappointing result caused Medtronic to suspend enrollment in other SYMPLICITY trials around the globe.

Since then, the company has made changes to the technology, procedure and the study protocol aimed at overcoming the earlier issues and getting Symplicity back on track. HTN-3 was “highly informative to future clinical studies as it brought to the forefront patient medication adherence as a complex, and significant, confounding factor,” Joey Lomicky, a Medtronic spokesperson, told BioWorld. “Addressing this factor has resulted in dramatically contrasting results in the SPYRAL HTN trials as compared to HTN-3.”

Specifically, by measuring and better controlling for drug adherence, the company has reduced variability in blood pressure outcome parameters, making it easier to demonstrate the effect of RDN in the OFF-MED study, he said.

Medtronic has also tweaked the procedure in the SPYRAL HTN program, building on its own and independent anatomical, histological and preclinical data that underscored the importance of distal vessel treatment in the branches in optimally targeting the sympathetic nerves. And it given Symplicity Spyral a highly flexible design and one uniquely suited to treating the distal renal branches and accessory vessels.

As for when Symplicity might be available in the U.S., Medtronic isn’t saying. “We continue discussions with the FDA, and making submissions per our jointly agreed plan,” Lomicky said. “The OFF-MED pivotal trial is but one part of the broader SPYRAL HTN global clinical program, a multi-phased clinical study strategy aimed to establish the safety and efficacy of renal denervation. We envision this package of data will ultimately support the approval submission.”

Big potential in resistant hypertension

The system is currently approved for commercial use in more than 50 countries, including CE marking in Europe. Along with the U.S., it remains investigational in Japan and Canada.

Biegelsen estimated the U.S. market for resistant hypertension alone could be as high as $35 billion. “Although there are still some areas of uncertainty, we believe RDN will be a meaningful incremental commercial opportunity for MDT that is not reflected in most sellside models,” he wrote. “Assuming a mid-CY2021 U.S. approval, we forecast RDN sales for MDT in CY2021-2026 of $9M, $61M, $115M, $195M, and $334M, respectively.”

Medtronic isn’t the only company looking to treat hypertension with RDN. Last year, Recor Medical Inc. reported six-month “on-medication” results from its RADIANCE-HTN SOLO trial, showing patients treated with the Recor Paradise ultrasound denervation system were prescribed fewer antihypertensive drugs and had larger blood pressure drops than those treated with a sham procedure. Moreover, patients in the Paradise group sustained lower blood pressures at six months, with no adverse effects. The study was published in the March 29, 2019, issue of Circulation. The company is currently conducting a pivotal study, RADIANCE-II, to build on the RADIANCE-HTN SOLO results and assess patients with moderate hypertension.

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