HAIMOVITCH MEDICAL

TECHNOLOGY CONSULTANTS

 
 

By Larry Haimovitch

Medical Device Daily Contributing Writer

March 13, 2013

SAN FRANCISCO — The acquisition of privately-owned, venture capital-backed Ardian (Mountain View, California) in January 2011 by Medtronic (MDT; Minneapolis) for $800 million in cash upfront, plus commercial milestones equal to the annual revenue growth through the end of Medtronic’s fiscal year 2015 sent shockwaves through the cardiology and medical device communities.

Not only was the purchase price a staggering sum for a company without any revenue or solid pivotal trial data but also the whole concept of treating resistant hypertension (RH) with a catheter-based procedure had been viewed with considerable skepticism. However, In the past two plus years, much has changed in the landscape of renal denervation (RDN) for RH and there were numerous sessions at this year’s American College of Cardiology (ACC; Bethesda, Maryland) focused on this exciting new market opportunity

Since that mind-boggling MDT deal, the interest in the RDN has gushed in the medical device and venture capital communities. Numerous new companies pursuing RDN dot the med-tech landscape and it seems that there is a new start-up funded every month. Indeed, in a detailed research report dated March 7, 2013, medical device analyst Joanne Wuensch of BMO Capital Markets (New York) estimated that there are approximately 60 organizations worldwide that are pursuing the RDN market.

Clearly, there is no doubt that hypertension in general and RH is a huge clinical problem. The global prevalence of hypertension approximates one billion people, or one in three adults. Numerous studies have attempted to accurately size the RH market, with estimates ranging from 9% to under 2%. Using a mid-point range of 4% to 6% yields an RH pool that conservatively can be estimated at 40 to 60 million persons.

The topic of the size of the RDN market opportunity was addressed here by Chandan Devireddy, MD, from Emory Healthcare (Atlanta) in a talk titled “Prevalence and Characteristics of Patients Eligible for Catheter Based Renal Arterial Denervation in an Academic Cardiology Clinic.” Devireddy and his colleagues at Emory did a study of nearly 1800 outpatients that appeared at their clinic over a six-month period to determine which would be eligible for RDN based on the strict Medtronic HTN-2 trial inclusion and exclusion criteria.

Their conclusion was that “patients meeting criteria for RDN based on published studies represent an exceedingly small proportion of the total hypertensive population.” Specifically, they believe that less than 1% of the hypertensive patients in their clinic, if being screened today, would qualify for RDN.

Devireddy concluded his talk saying “that further studies are necessary to determine if blood pressure reduction after RDN can be generalized to a broader range of hypertensive patients than has been included in previous trials.”

Medtronic is the most visible renal denervation player and is clearly in the lead with its SYMPLICITY system. The company has already enrolled more than 250 patients in the HTN-1 and HTN-2 studies, 530 patients are being enrolled in the pivotal domestic HTN-3 study, and 5,000 patients are being enrolled in the Global SYMPLICITY Registry.  It recently submitted an IDE for a new pivotal trial called HTN-4. When the FDA gives the go-ahead for the HTN-4 trial, MDT will have two randomized pivotal clinical trials in the U.S., whereas none of its competitors have any pivotal trial underway anywhere in the world.

Medtronic also recently announced that the FDA and the Centers for Medicare & Medicaid Services (CMS) have accepted SYMPLICITY in their parallel review program, which will allow CMS to begin consideration for national coverage determination while the FDA completes its review of safety and efficacy.

Two papers at this meeting attest to the clinical benefits of MDT’s technology. Professor Henry Krum, MD, from Monash University (Melbourne, Australia) presented two-year data from the HTN-2 on 66 patients. This international, prospective, randomized 1:1 controlled trial at 24 months showed that patients sustained a significant drop in blood pressure of -31/-11 mm Hg from baseline. In addition, 26 subjects in the control group who crossed-over and received RDN following assessment of the six-month primary endpoint had an average blood pressure reduction of -35/-13 mm Hg. Further, Krum reported that the safety data was excellent.

In another study of 54 patients, Professor Roland Schneider from the Universitat Hamburg (Germany) addressed the question “How effective is RDN in less severe patients?” After six months post RDN catheter ablation blood pressure declined moderately -13/-7 mm Hg. The investigators concluded that “RDN does decrease blood pressure substantially in patients with moderate resistant hypertension” but cautioned that this will need to be confirmed in a larger study. Medtronic’s HTN-4 trial will address this cohort of patients.

A partial listing of some of the many players in the RDN field is provided in the following table.

 



      









Covidien (Dublin, Ireland), Boston Scientific (BSC; Natick, Massachusetts), and Medtronic all entered the RDN market via acquisitions. Covidien joined the RDN race in May 2012, purchasing Maya Medical (Campbell, California) for $60 million cash upfront. It will pay up to an additional $170 million if Maya meets certain regulatory and sales milestones. BSC acquired Vessix Vascular (Laguna Hills, California) in late 2012 with an upfront cash payment of $125 million, plus an additional $300 million for clinical and revenue-based performance milestones. Maya Medical’s OneShot RF system received the CE Mark in February 2012 and BSC/Vessix received theirs in May 2012.

St. Jude Medical (St. Paul, Minnesota), is a well-established RDN player, with its EnligHTN system that features a multi-electrode ablation technology along with a unique, non-occlusive basket design. It recently announced that it plans to evaluate whether renal denervation and medication can provide health benefits to patients beyond lowering blood pressure in a new landmark study dubbed the EnligHTNment trial. According to St. Jude, this is the first large-scale study that will examine the long-term effects of renal denervation in patients who have uncontrolled hypertension to see if this technique also reduces the risk of major cardiovascular events such as heart attack, stroke and death.

The EnligHTNment trial will be an international, multi-center, randomized, controlled study examining the safety and effectiveness of renal denervation with the EnligHTN renal denervation system in reducing risk of major cardiovascular events.

Horst Sievert, MD, interventional cardiologist from CardioVascular Center Frankfurt CVC (Frankfurt, Germany) provided an overview of the newer companies in a talk titled “Emerging RF Devices for Renal Sympathetic Denervation.” He first discussed the product attributes and presented European data for the St. Jude Medical (St. Paul, Minnesota) EnligHTN, the Cordis/Johnson & Johnson (New Brunswick, New Jersey) Thermocool irrigated catheter, the Medtronic “second generation” muliti-electrode device, which are all RF based. Then he provided an update on the two devices that use RF and a balloon to deliver the energy. This included the Covidien OneShot and the BSC/Vessix V2 system.

All five of these products have CE Mark and have at least some human data but none of them has initiated a trial in the U.S.

Todd Brinton. MD, interventional cardiologist at the Stanford University Medical Center (Stanford, California) in a talk titled “Ultrasound Technologies for Sympathetic Renal Denervation” noted that there are some significant advantages of ultrasound. It appears to be very safe, demonstrating “optimal vascular safety”, has shown solid efficacy in limited human trials and last, but most importantly, ultrasound energy for RDN can be delivered non-invasively.

“Ultrasound for renal denervation may represent a paradigm shift in device therapy for the treatment of refractory hypertension,” he said.

Brinton provided information on the Kona Medical (Bellevue, Washington) Surround System. Holland I think MDD ran a story on them recently?  Date please?  He indicated that results from its WAVE 1 clinical study have been excellent so far. Two other trials, aptly called WAVE 2 and WAVE 3, are in process. The former just began enrolling while the latter will begin later this year. Both trials will occur outside the U.S. at multiple centers.

An interesting and potentially new RDN technology was shown at a poster session. CyberHeart (Sunnyvale, California), which has developed proprietary software for cardiac ablation using stereotactic radiosurgery technology, recently completed animal trials using their system for RDN. Like ultrasound, the energy can be delivered non-invasively.

The authors of this poster stated that “radiosurgical ablation with its inherent preplanning capability, motion compensation and precision potentially offers an attractive therapeutic option . . . “

 

American College of Cardiology 2013

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