When Medtronic’s pivotal US trial of its renal denervation system Symplicity failed in January 2014 the technique was all but written off. However, over the last year or so a handful of companies have quietly picked their technologies back up with the intention of proving that the hypertension therapy can work after all.
One such is ReCor Medical, one of the smaller groups to have been pursuing renal denervation. ReCor is about to kick off a major trial of its Paradise system, and believes that with a more rigorous approach it can score a clinical hit and in the process re-establish the validity of the technique. “This is really the rebirth of the field,” chief executive Andrew Weiss tells EP Vantage.
To say that hopes were high for renal denervation in the early days of 2014 is an understatement. The procedure, in which a radiofrequency catheter is used to attenuate the nerves surrounding the renal arteries from within the arteries themselves, had been linked with extraordinary blood pressure-lowering effects in previously untreatable patients. In the week before Medtronic’s Symplicity HTN-3 trial crashed, analysts at JP Morgan said they had “high conviction in an early 2015 US approval” and Jefferies analysts predicted a market worth nearly $3bn by 2020.
“Some of the early studies showed enormous promise but they weren’t done with sufficient rigour,” says Mr Weiss. It was accepted at the time that the HTN-3 study was more strict than the earlier trials that had allowed no fewer than nine renal denervation devices to gain European CE mark approval (Failure of Medtronic’s Symplicity trial exacerbates concerns over renal denervation, January 9, 2014). According to Mr Weiss, though, it was still not good enough.
“The study was in our view both poorly designed and poorly executed. People were overly confident of the treatment effect of renal denervation,” he says. He adds that HTN-3 did not conclusively prove denervation worthless, being instead inconclusive. “The Medtronic trial didn’t prove that renal denervation worked or didn’t work – it didn’t even prove safety because of the uneven application of the technology.”
The feasibility trial ReCor is about to begin, Radiance-HTN, will correct what the company believes are the main flaws of Medtronic’s HTN-3 trial: enrolling patients with different types of hypertension – some essential, some diabetic, some caused by obesity – failing to control drug therapy and to apply denervation consistently, and “perhaps most importantly”, using an unreliable endpoint.
This was change in blood pressure over the sham treatment group as measured in the doctor’s office. This is associated with the so-called “white-coat effect” where patient get excited or stressed when they go to the doctor, making the readings taken there inaccurate.
Radiance’s endpoint is the drop in ambulatory blood pressure two months after denervation. Patients wear a cuff for 24 hours that tests their blood pressure every 30 minutes and an average reading is taken. In combination with testing the device in patients with a single form of high blood pressure – essential hypertension – and controlling drug therapy and nerve ablation more strictly the trial ought to give a clear picture of Paradise’s effect.
Mr Weiss says that a rigorous academic study conducted last year by Michel Azizi of the Georges Pompidou Hospital in Paris – who is a co-investigator of Radiance – showed an appreciable drop in ambulatory blood pressure. “[Dr Azizi] proved with statistical significance that renal denervation provided a very large 6mmHg drop in blood pressure than drugs alone,” says Mr Weiss. “This in our view is the only scientifically sound study of renal denervation to date.”
This is, to be sure, a smaller drop in blood pressure than was anticipated back in the days of 2013 – then, figures like 15mmHg were bandied around. But achieving a significant fall in drug-resistant patients’ blood pressure in an FDA-agreed, company-sponsored trial would stand ReCor in good stead for a second, pivotal study.
ReCor is not alone in trying again. Medtronic is conducting similar studies specifically designed to address the confounding factors in the Symplicity HTN-3 trial. It has also redesigned its technology – the new device is called Spyral.
St Jude is trialling a redesign of its EnligHTN product. And Boston Scientific is conducting a simpler study of its technology, which it acquired through the takeout of Vessix Vascular three months before sector-wide disaster struck (Boston Scientific gatecrashes renal denervation market with Vessix buy, November 9, 2012).
Data from Radiance and some of the other industry-backed trials will start to emerge in 2017. But ReCor is much smaller than Medtronic and Boston and so it is taking a greater gamble.
Despite its CE mark, Paradise is no longer bringing in any European revenue. “We essentially stopped all marketing last year,” Mr Weiss says – following Symplicity’s failure the customer base for all renal denervation devices vanished overnight. “No marketing of the technology is worthwhile until we see the results from the Radiance study.”
So, while Radiance will not be sufficient to get FDA approval for Paradise – it is powered for efficacy but not safety – it will boost uptake in Europe, where the safety of the system has already been accepted.
The private company completed a $15m series D round last April, with an additional tranche this January – a $2m milestone from its series D lead, the Japanese medtech Otsuka. But that will not be enough to see it through to the end of Radiance.
“We will need substantially more funds,” says Mr Weiss. “We’re in discussions with a number of other players to raise another $20-30m, sufficient funds to complete the trial.” He says he is “cautiously optimistic” that the company will be able to raise the cash sometime in the next two or three months, though he says that this is “an extraordinarily difficult time” to seek investment.
“We just have to ensure that ReCor has the funds and that we conduct the trials well,” says Mr Weiss, almost sounding insouciant. Investors might wonder why Medtronic and its fellows did not do that in the first place.
|Selected ongoing trials of renal denervation devices|
|Company||Product||Trial name||Design||Completion date||Trial ID|
|ReCor||Paradise||Radiance-HTN||292 patients, randomised, sham control, with and without drug therapy||August 2017||NCT02649426|
|Medtronic||Symplicity Spyral||Spyral HTN-On Med||100 patients on three standard antihypertensive medications||October 2016||NCT02439775|
|Medtronic||Symplicity Spyral||Spyral HTN-Off Med||120 patients, without drug therapy||February 2017||NCT02439749|
|Boston Scientific||Vessix Reduce||Reduce HTN:Reinforce||100 patients, randomised, sham-control, with or without drug therapy||November 2016||NCT02392351|