Since renal denervation abruptly and unexpectedly started showing signs of working two years ago, several companies have redoubled their efforts in the space in the hope of finding a treatment for uncontrolled hypertension. Ablative Solutions is one such, and its therapeutic approach is unusual.
“Instead of using energy we use alcohol as our way to mediate the renal denervation procedure,” says Kate Rumrill, the newly-appointed chief executive of Ablative. The group has just kicked off a potentially pivotal study of its Peregrine kit, and earlier this year took a $77m VC haul to fund it – but Medtronic is the leading light in this area, and competing with the behemoth will not be easy.
Renal denervation involves inserting a catheter into the renal arteries to introduce, in most cases, electrodes that emit radiofrequency or ultrasound energy though the vessel wall. This is intended to deaden the sympathetic nerves that surround the arteries, lowering blood pressure.
The Peregrine device uses a different means to ablate the nervous function.
“It has three microtubes that position the tip of the catheter centrally within the artery and then we advance needles through the arterial wall into the adventitial space. And then that’s where we inject the alcohol,” Ms Rumrill says.
She says that alcohol has been used to decrease nerve function in peripheral pain indications, but that Ablative is the only company applying the technique to renal denervation.
The FDA granted clearance for the Peregrine catheter in 2014, but not specifically for renal denervation – the indications was given as “infusion of diagnostic and therapeutic agents into the perivascular area of the peripheral vasculature”.
The company is not selling the Peregrine catheter. Instead it is focused on getting approval for the Peregrine kit – the combination of the catheter and the alcohol it delivers. And management is well aware that it will book hardly any sales in renal denervation without hard clinical evidence that the system works.
To this end the company is pursuing a major pivotal trial. Last month it began the US study, Target BP I, in 1,550 patients whose blood pressure is uncontrolled despite taking between two and five antihypertensive drugs – it is crucial to show a benefit over drug therapy since this reflects read-world practice.
This is a huge trial to run for a relatively young company, at more than three times the size of Medtronic’s pivotal trial. Fortunately Ablative can afford it, having scored a $77m funding round in January (Medtech VC and the billion-dollar era, July 10, 2019).
Half the enrolees will be treated with the Peregrine kit, while the other half will undergo a sham procedure in which the catheter is inserted but no alcohol is injected into the nerve. The company will consider the trial a success if the active arm shows a statistically significantly greater reduction in blood pressure over sham. The study is due to report in early 2021.
At least two other groups are aiming at the same goal. The Paradise system, developed by Recor Medical, the company bought by Otsuka a year ago, has a 225-patient study which will read out at roughly the same time as Target BP I.
There is no disguising the real threat, however. The US phase III trial of Medtronic’s Symplicity Spyral device will read out towards the end of next year, and if that is a success the product could go on sale in the US towards the beginning of 2021.
|Selected US pivotal renal denervation trials|
|Company||Device||Mechanism||Trial name||N||Endpoint||Data possible|
|Medtronic||Symplicity Spyral||Radiofrequency||Spyral HTN||433||Change in 24-hour ASBP at 3mth||Q3 2020|
|Paradise||Ultrasound||Radiance-II||225||Change in average daytime ASBP at 2mth||Q1 2021|
|Ablative Solutions||Peregrine kit||Neurolytic agent||Target BP I||1,550||Change in 24-hour ASBP at 3mth||Q1 2021|
|Note: ASBP = ambulatory systolic blood pressure. Source: clinicaltrials.gov.|
The question of how this and other renal denervation devices will sell will largely be determined by the magnitude of the blood pressure reduction they allow. In previous sham-controlled trials, Medtronic’s device reduced blood pressure by 7.4mmHg and Otsuka/Recor’s by 6.3mmHg (Renal denervation goes from Symplicity to complexity, May 23, 2018).
Ablative has not yet reported any sham-controlled data. In uncontrolled trials its technology showed a change of 11mmHg in mean systolic 24-hour ambulatory blood pressure at six-month follow-up – more than the 9.0mmHg Medtronic’s device managed, according to interim data from the Spyral HTN On Med trial, in a similar setting.
Even if, when all three pivotal trials report, the Peregrine kit can match the other techs’ reductions in blood pressure, its success will not be assured. There is a great deal of discussion and precious little agreement among cardiologists over whether a 6 or 7mmHg reduction is enough to justify use of the technique, in terms of both trauma to the patient and cost to the healthcare system.
“Time will tell what the ultimate decision is in the marketplace,” Ms Rumrill says. “Everyone in this space has ongoing clinical trials and I’m really rooting for them. But how it all shakes out is still to be determined.”