Renal Denervation: Stepping Back To Move Forward

With the announcement that Medtronic is going back to the clinical drawing board after the pivotal SYMPLICITY HTN-3 trial of its renal denervation device failed to meet its primary efficacy endpoint, the industry is taking a cautious but still optimistic stance on the highly touted potential treatment for resistant hypertension.

Hypertension is the single largest contributor to death worldwide, increasing the risk of heart attack and stroke for more than 77 million Americans and about one billion adults worldwide. Approximately 10% of those diagnosed have severe resistant hypertension – defined as a systolic blood pressure of 140 mm Hg or higher despite adherence to at least three maximally tolerated doses of antihypertensive medications. With a lack of effective treatment options, the promise of a device-based therapy for resistant hypertension entered the picture about five years ago, on the heels of the successful use of catheter-delivered radiofrequency (RF) ablation for the treatment of complex ventricular arrhythmias, certain cancers, and other disorders. Early data from trials in which renal denervation (RDN) therapy was used to disrupt the renal nerves that regulate blood pressure demonstrated reductions of approximately 30 mm Hg at three-year follow-up. This is a tremendous result considering that each 2 mm Hg reduction in systolic blood pressure confers a 10% cardiovascular mortality reduction, according to studies. With these dramatic results, an exuberant industry flocked to the high-potential RDN space.

Catheter-based RDN is in clinical use in more than 80 countries, including parts of Europe, South America, Australia, and Canada. Most of the clinical experience to date has been with the Symplicity RF-based RDN system, invented by Ardian Inc. and acquired by Medtronic PLC for $800 million in 2011. Medtronic carefully designed the SYMPLICITY HTN-3 trial, a large-scale, blinded, randomized, controlled study of its Symplicity device, to overcome some of the methodological shortcomings of initial nonrandomized and randomized trials. These studies included small sample sizes, had limited assessment of ambulatory blood pressure, and lacked blinding and a sham procedure as a control, making broad application of the findings unreliable.

However, the much-hyped RDN industry now finds itself in a state of uncertainty and flux, following Medtronic's surprise announcement in January that in the Phase III trial its Symplicity device failed to meet its primary endpoint of significantly lowering blood pressure in patients with drug-resistant hypertension on maximum medical therapy. In the 535-patient study conducted at 87 US centers, office systolic blood pressure dropped by 14.13 mm Hg in the denervation group and by 11.74 mm Hg in the sham-control group (renal angiogram only) at six months (p < 0.001 for both from baseline), yielding a between-group difference of only 2.39 mm Hg (p = 0.26 with a superiority margin of 5 mm Hg), according to researchers. Detailed results were presented in March in Washington, DC, as a late-breaking clinical trial session at ACC.14, the American College of Cardiology’s (ACC’s) Scientific Session, with simultaneous online publication in the New England Journal of Medicine (NEJM).

Although RDN did not have an advantage for blood pressure reduction over the sham procedure, Medtronic was quick to point out that it was shown to be safe. The primary safety endpoint – a composite of all-cause death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at one month or renal artery stenosis of more than 70% at six months – occurred at similar rates in the denervation and control groups (1.4% versus 0.6%, p = 0.67). (Also see (Also see "Renal Denervation Story Not Over Yet Despite SYMPLICITY HTN-3 Disappointment" - Medtech Insight, 2 Apr, 2014.).)

Further supporting its safety claim as well as efficacy in a real-world setting, Medtronic also presented data at ACC.14 of six-month follow-up of the first 913 of 1,000 total patients enrolled in the Global SYMPLICITY Registry. Results showed that RDN with Medtronic's system resulted in significant reductions in both office and 24-hour ambulatory blood pressure compared with baseline. Overall office systolic blood pressure reduction was 11.9 mm Hg (n = 751), and 24-hour ambulatory systolic blood pressure reduction was 7.9 mm Hg (n = 404). For patients with office blood pressure ≥160 mm Hg and ambulatory blood pressure ≥135 mm Hg at baseline receiving three or more antihypertensive medication classes, a blood pressure reduction of 20.2 mm Hg was reported at six months (n = 244). The registry will seek to enroll more than 5,000 patients at a minimum of 200 centers with planned follow-up to five years, and will also gather data for other co-morbid diseases often associated with hypertension and elevated sympathetic drive, such as type 2 diabetes, heart failure, and chronic kidney disease.

Despite Medtronic's significant setback, which casts a shadow over the emerging RDN industry, company management has stated that based on the recommendation of independent advisors the company is not dropping its RDN program, but instead is planning to go back to the drawing board to pursue a new Investigational Device Exemption (IDE) trial in the US. Important questions remain: does the trial signal the failure of this space, or is it just a normal hiccup in a young market, based primarily on the single-point RF technology employed in the trial and the high learning curve associated with the procedure? Other concerns voiced by the clinical community include a potential placebo effect in the sham arm, no confirmation of drug adherence through blood testing, relatively short follow-up, patient selection, and the lack of a direct measurement of denervation. On the positive side, the procedure still has the support of the European Society of Hypertension, which issued a supportive statement regarding Medtronic's study results and RDN therapy in early April.

Medtronic's situation does present a challenge and an opportunity to those companies that remain in the game – including venture-backed start-ups developing ultrasound-based denervation technologies – to provide rigorous clinical data addressing the many critical questions that the SYMPLICITY HTN-3 trial has brought to light. These answers will be needed to not only support the use of alternative RDN systems, but also to determine the future of the market. Beyond this, future reimbursement for the procedure is a big question mark, as well.

The Aftermath To Date

Medtronic is now in full damage-control mode, investigating what happened in its trial and how RDN fits into the care paradigm for hypertension. A panel of independent physician and researcher advisors will be making recommendations about the future of the company's global hypertension clinical trial program, including physician and patient access to the Symplicity technology in the 88 countries where it is currently approved. The company has suspended enrollment in its three current regulatory approval trials: SYMPLICITY HTN-4 in the US, HTN-Japan, and HTN-India. But it is continuing to ensure access to the technology at the discretion of the physicians in markets where it is approved. Medtronic will also continue its Global SYMPLICITY post-market surveillance registry and RDN studies evaluating other non-hypertension indications, including the use of its technology in chronic heart failure and renal impairment.

Meanwhile, several other market-leading medtech companies that have made major investments in this area – including St. Jude Medical Inc., Boston Scientific Corp., Cordis Corp./Johnson & Johnson, and Medtronic Minimally Invasive Therapies – have examined their strategies regarding continued clinical and product development in this space. (See Exhibit 1.) In December, prior to Medtronic's announcements, St. Jude announced it was halting its EnligHTN-IV study, a Phase III study of its CE mark-approved EnligHTN Multi-Electrode Renal Denervation System, in 590 patients with resistant hypertension. At the time, the company cited concerns that Medtronic's Symplicity device would beat it to the US market, and as a result it would have problems enrolling patients to a sham procedure. St. Jude is not calling it quits, however; according to company CEO Daniel Starks at the JP Morgan Healthcare Conference this January, based on favorable early clinical results the firm plans to continue developing its EnligHTN system.

Exhibit 1

Renal Denervation – Who's Still In?

Company	Product	Technology	Clinical/Regulatory Status
Ablative Solutions Inc.	Peregrine System	Perivascular renal denervation device that delivers a targeted chemical (ethanol) treatment to the outer layer of the renal arteries	Early clinical evaluations
Boston Scientific Corp.	Vessix Renal Denervation System	RF balloon-expandable multipoint renal denervation platform	CE mark-approved 2012
Cordis Corp./Johnson & Johnson	RENLANE Renal Denervation System	Helical-shaped ablation catheter with five irrigated RF electrodes at the tip	CE mark-approved February 2014
Kona Medical Inc.	Surround Sound Renal Denervation System	Utilizes ultrasound imaging to guide the external delivery of focused ultrasound energy to specific target tissue, while automatically tracking movement and enabling continuous therapy delivery	Clinical studies outside the US; CE mark expected in 2015
Medtronic Inc.	Symplicity Renal Denervation System	Catheter with standard dispersive electrode delivers low-level RF energy through the wall of the renal artery	CE mark-approved in 2010; pivotal SYMPLICITY HTN-3 trial in the US did not achieve its primary endpoint; company will work with FDA to design a new trial
ReCor Medical Inc.	Paradise Ultrasound Denervation System	Cylindrical transducer that emits ultrasound energy circumferentially, allowing for a more efficient denervation procedure; fluid-filled, low-pressure balloon cools the endothelium during energy delivery thereby minimizing damage to non-target tissues	CE mark-approved in 2012
St. Jude Medical Inc.	EnligHTN Renal Denervation System	RF multi-electrode renal denervation system	CE mark-approved in 2012; US EnligHTN IV study cancelled in December 2013

Medtech Insight

Boston Scientific is also still in the running, but is taking a cautious stance. At the JP Morgan conference, company CEO Mike Mahoney indicated that the firm's hypertension programs were officially on pause while it reviews what happened to rival Medtronic. At the Transcatheter Cardiovascular Therapeutics (TCT) conference last October, in an interim analysis of 139 patients enrolled in the REDUCE-HTN post-market study it was reported that 85% of patients treated with the company's Vessix system experienced a clinically meaningful decrease in blood pressure (24.6 mm Hg reduction in systolic blood pressure [p < 0.0001]) at six months. Vessix is the only RDN system to utilize low-power, bipolar RF energy, providing a more localized and precise approach, according to the company. The system is currently available in Europe, the Middle East, Australia, New Zealand, and select Asian markets. Cordis/Johnson & Johnson is also still in play; in late February it announced CE mark approval for its femoral RENLANE system, which uses a helical-shaped, irrigated, multi-electrode ablation catheter combined with a multi-channel RF system.

Covidien, on the other hand, is bowing out. Two weeks following Medtronic's announcement, the company stated that it will exit its OneShot Renal Denervation program, including cancelling its planned RAPID II randomized study. The company cited that its decision was part of a regular review of strategic programs and is in response to slower-than-expected development of the RDN market. The OneShot system, CE mark-approved in 2012, is an over-the-wire, balloon-based, irrigated RF catheter technology. Management has also stated that its decision is not connected to Medtronic's setback, and it believes that the long-term hypertension market remains attractive and will continue to explore other opportunities in this area.

Ultrasound The Key To Success?

If technology and technique end up being a critical factor in the failure of Medtronic's SYMPLICITY HTN-3 trial, then ensuring a more complete denervation, in a more targeted way, with easier-to-use, more reliable technologies will be an important step forward in this market. One alternative to RF that two start-up companies in this space, ReCor Medical Inc. and Kona Medical Inc., are betting on is ultrasound.

Palo Alto, CA- and Amsterdam, The Netherlands-based ReCor Medical is committed to the success of RDN as a treatment for hypertension via an ultrasound-based approach. The company offers the only CE-marked RDN system, the Paradise system, which uses a cylindrical ultrasound electrode within a balloon to ablate the renal nerves in a 360-degree circumferential pattern around the renal arteries, in two, 10-second procedures per artery. Ultrasound energy is used to generate heat in the tissue outside the renal arteries containing the renal nerves, while water is cycled continuously through the low-pressure balloon to cool the arterial endothelium. The 360-degree heating profile of the system is automatically tailored for each artery size, by varying how much water is cycled through the balloon and how much electrical energy is fed into the ultrasound transducer.

The latest generation of the company's Paradise system, which was CE-marked and commercially launched in Europe this January, allows for the potential of faster procedures, more thorough denervation, and improved vessel safety, says ReCor Medical president and CEO, and more than 20-year industry veteran, Andrew Weiss, in an interview with Medtech Insight. Also in January, the company announced the first use of its CE-marked 5 French (5F) Radiance catheter line, which is rapid-exchange compatible, and was successfully introduced via the radial artery, as opposed to the femoral artery.

RF-based systems from most of ReCor's competitors, in contrast, generally provide a point of heating and ablation inside the vessel wall, which then works to heat and injure the adjacent renal nerves outside the vessel, according to Weiss. And if the renal nerve, by chance, is not adjacent to the point of RF energy delivery, then no denervation would take place. RF energy for RDN is not designed for use in a circumferential pattern, as there would be a risk of renal artery stenosis due to vessel swelling following thermal injury, he continues. Thus, its ability to create a more complete denervation is limited. In addition, a number of the RF systems require larger arterial access, 8F or 9F, and extensive physician training is required to ensure good treatment location and electrode-vessel contact, says Weiss.

In light of Medtronic's SYMPLICITY HTN-3 results, after reviewing ReCor's own clinical study results, and conferring with its medical and scientific advisors, ReCor is confident that its product is well-differentiated from the RF-based approaches, has a significant ability to downregulate the sympathetic nervous system, and has strong signals of benefit for patients with hypertension, says Weiss. "We applaud Medtronic and the HTN-3 investigators for conducting a high-quality, randomized trial of RDN in truly resistant hypertensive patients," says Weiss. "However, we agree with many physicians who have expressed concern about a number of elements of the trial design, including population heterogeneity, drug response in both the treatment and sham groups, and the reliability of the technology itself," he says. Weiss does acknowledge that Medtronic's results will make acceptance of this therapy more challenging for everyone.

ReCor's Paradise system, based on technology acquired from the former ProRhythm Inc. in 2009, has been used in about 150 patients, many in the company's hypertension clinical studies. The company recently completed enrollment in its REALISE study in two French centers, evaluating its technology in highly managed, yet resistant, hypertensive patients. Results are due later this year. The company has two ongoing hypertension trials; RETREAT, a German 20-patient investigation designed to assess the effect of ReCor's system on patients who previously failed to respond to RF-based RDN, and ACHIEVE, a 100-patient, multicenter study to demonstrate safety and effect of Paradise in patients with uncontrolled hypertension. These trials will continue enrollment through the end of the year. ReCor will be presenting data from its various studies at the EuroPCR meeting in Paris this May.

In terms of future plans, ReCor is planning efforts in both hypertension and in new areas such as heart failure, kidney disease, and diabetes, including efforts in Europe, the US and Asia. One specific direction of interest is in earlier-stage hypertension patients, to prevent progression to five or more drugs at maximum dose, as was seen in many of the patients in HTN-3. Evidence for this is supported by Medtronic's randomized HTN-2 study, and in the under-65 patient group in HTN-3, both of which demonstrated successful blood pressure reductions.

The company has raised approximately $30 million in funding to date, from US and European investors including Sofinnova Partners, and Jacques Seguin, MD, PhD, who was the founder and chairman of CoreValve Inc. (now Medtronic CoreValve LLC). ReCor is planning future funding to support its commercial growth and to extend clinical studies both in and beyond hypertension.

ReCor Medical remains convinced that RDN has the potential to become a key component of hypertension therapy, and management believes that the Paradise system provides the safe, reliable, and complete denervation needed to become the category leader in this field, according to Weiss. "Our biggest risk today is that based on one trial of one device in one population, the medical, technical, and investment communities shy away from a promising therapy,” he says.

Bellevue, WA- and Menlo Park, CA-based Kona Medical, founded in 2010, is taking a unique, noninvasive approach to RDN for severe hypertension with its Surround Sound Renal Denervation System. The system utilizes ultrasound imaging to guide the external delivery of focused ultrasound energy to create an ablative field around the vessel. This then ablates the nerves without impacting the artery, while automatically tracking patient movement and enabling continuous therapy delivery. Kona’s fully integrated, portable, stand-alone system can be used with minimal anesthesia in virtually any exam room in a hospital, office or clinic, and does not require a catheterization lab, invasive instruments, or radiation. And, it has the potential to greatly reduce cost, lower risk, and improve access to treatment. "Our approach opens the door to a wider range of patients, those who cannot tolerate an invasive procedure in particular," says Michael Gertner, MD, a general surgeon, inventor, and Kona Medical's founder and CEO.

At the October TCT meeting, Kona announced three-month results from its WAVE II study and complete six-month results for its WAVE I first-in-man study. Data presented from WAVE II demonstrated that resistant hypertension patients treated with the Surround Sound system experienced a 19.4 mm Hg drop in systolic blood pressure and 6.5 mm Hg drop in diastolic blood pressure at three months (n = 17). In WAVE I, patients experienced blood pressure reductions of 22/9 mm Hg at three months and 29/12 mm Hg at six months (n = 24). For the combined studies, which took place in Australia, Canada, and the Czech Republic, 73% of patients experienced a clinically significant drop in systolic blood pressure of 10 mm Hg or more at three months and 81% at six months, with no device-related serious adverse events in either study. Both of these studies included the use of a catheter inside the renal artery to assist with targeting and tracking, even though all the therapeutic energy is delivered from outside the patient. Also, WAVE II utilized a dosing pattern that reduces therapy delivery time from 13 minutes per patient side to less than three minutes when compared with WAVE I. Kona has also initiated the sham-controlled WAVE III study, which is evaluating the use of noninvasive ultrasound imaging to guide externally delivered therapeutic ultrasound energy, without the use of a targeting catheter. The company is currently completing the commercial design of its system and expects to have CE mark approval next year. About 70 patients have received the treatment to date outside the US. It is also in discussions with the FDA regarding a pivotal trial planned for 2015.

Kona is well funded, with about $65 million raised to date. Last October, it brought in $10 million from a single investor, Morningside Group, with the goal of expanding Kona's technology into China. In 2012, the company raised $40 million in two rounds of a Series C venture financing, led by two undisclosed large-cap strategic investors, along with existing investors Essex Woodlands Health Ventures (where Gertner is an adjunct venture partner), Morgenthaler Ventures, Western Technology Investments, Domain Associates, and BioStar Ventures. Kona recognizes that there is more skepticism now about this space, but it is pleased that Medtronic is continuing with renal denervation, says Gertner. The company is optimistic as its noninvasive treatment has good initial data and a supportive syndicate of investors, he continues.