Failure of a pivotal US trial would put a lot of companies off pursuing FDA clearance. Not Nexstim. The Finnish group’s electric field-based stroke therapy, called NBT, missed the primary endpoint of the phase III Niche trial last month owing to a high response rate in the sham group, but the company will press on anyway with a de novo 510(k) application.
Remarkably, Nexstim believes that the trial missed because the sham control was nothing of the sort. “The hypothesis is that [the sham treatment] was active, as the patients have been responding in the same way, with the same very high response rate as the active NBT coil,” chief executive Janne Huhtala tells EP Vantage. If Nexstim can prove that this is the case, US clearance is not out of the question.
Nexstim’s Navigated Brain Therapy (NBT) system uses transcranial magnetic stimulation produced by a magnetic coil to generate an electric field in the part of the brain directly opposite the stroke site. The idea is that this field attenuates neural function, forcing the stroke-damaged nerves to pick up the slack, thereby recovering function (Interview – Nexstim aims to electrify post-acute stroke, May 6, 2015).
Niche enrolled 200 patients who had had had an ischaemic or haemorrhagic stroke on one side of the brain, resulting in upper extremity paresis, 3-12 months prior to the study. The treatment group underwent NBT-guided transcranial magnetic stimulation whereas the sham group underwent a different type of stimulation without using the NBT system.
The second interim analysis of Niche found that there was no significant difference in the treatment and sham groups in the primary endpoint of change in upper extremity Fugl-Meyer score, a measure of motor function (Nexstim’s value wiped out at a stroke, February 29, 2016). The news slashed the company’s shares, and although these are today up 80% on both the Stockholm and Helsinki exchanges, they are still far beneath their value before the Niche miss emerged.
Nexstim now says the similarly high response rates – over two thirds of patients in both groups saw an improvement of five points or more in Fugl-Meyer score, which Mr Huhtala says is clinically meaningful – suggests that the supposedly sham treatment worked.
The sham group used a different kind of coil to induce electric fields to the active group. The coil could not simply be switched off as it produces sensations – the patients can feel it – so it must be at least slightly active to permit blinding.
Mr Huhtala says it appears that the control group received some stimulation, although of a different kind and via a different stimulation method to the active NBT treatment. The trial appears to have shown that it is the magnetic stimulation that works on the patients – not specifically the NBT system.
Approval and reimbursement
The unexpected sham treatment data have led Nexstim to file a patent application on this novel stimulation method. But the next thing for Nexstim is to get past the FDA. To get a normal 510(k) clearance a company must show its device works similarly to an approved device, but in the case of de novo applications there is nothing similar enough to serve as a predicate. In this case the device must succeed on its own merits.
“Safety is the primary criterion, and the current data shows that it is very safe,” Mr Huhtala says. As for efficacy, the lack of control group means that the FDA will listen to clinicians’ opinions, he says, and “they have not seen this kind of response in this patient population, which would support our idea with the FDA.”
If Nexstim gets its de novo clearance it will still have to continue trials, this time with an eye to reimbursement. Even before the Niche failure it had plans in this direction, with postmarketing studies designed to prove to the CMS that the technology is worth covering. In the meantime, Mr Huhtala says that once Nexstim gets its approval, patients can pay out of pocket for the treatment or use private insurance.
Nexstim has not priced the technology for the US market. But it is approved in Europe as a diagnostic – a far smaller market than the therapeutic indication it is seeking – and for that purpose the system costs between €200,000 and €300,000. A disposable device to allow correct alignment of the system must also be used, and this costs around €400-1,200.
The system is likely to be cheaper in the stroke treatment setting, but with 18 treatment sessions necessary it will still be costly.
Nexstim must publish detailed clinical data from Niche with a full explanation of what exactly occurred in the sham group. It must obtain clearance for NBT, and after that reimbursement. It had better get cracking.