GAITHERSBURG, Md. — Members of an FDA advisory committee didn’t take a formal vote on the neuroAD Therapy System for treating Alzheimer’s disease at their meeting Thursday, but there appeared to be a consensus that its sponsor’s trial data failed to demonstrate a clinically meaningful benefit in patients with mild to moderate symptoms.
That’s not to say that Neuronix’s neuroAD — which combines transcranial magnetic stimulation (TMS) with cognitive training — didn’t offer hope.
Many members of the Neurological Devices Panel saw potential in the data Neuronix presented and encouraged the company to consider developing a new study, looking perhaps at a group of Alzheimer’s patients with milder dementia or using a different trial design.
“I think we all think there’s probably a signal here,” said panel member David Knopman of the Mayo Clinic in Rochester, Minnesota. But the data Neuronix presented is “hypothesis-generating to do a study better,” he continued. “I don’t see that what we have before us is something that could be approved.”
At the meeting, Neuronix presented the results of a multicenter pivotal trial of 106 mild-to-moderate Alzheimer’s patients. The trial had a primary effectiveness endpoint of change in Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) from baseline to week 7. Neuronix failed to meet that endpoint: at 7 weeks, sham performed better than the device by 1.45 points. However, at 12 weeks — approximately 6 weeks after the final treatment in the study — ADAS-Cog scores reversed direction and the treatment group outperformed sham by 0.42 points. But that’s on a 70-point scale.
Neuronix suggested it was possible TMS had a delayed effect, but many panel members voiced concerns that, even at 12 weeks, the change in ADAS-Cog was not enough. Most panelists said clinically meaningful changes in ADAS-Cog should be at least 2 points, if not 3 or more.
In its presentation, Neuronix pointed to a subset of patients with baseline ADAS-Cog scores ≤30 who demonstrated greater improvement and showed several small studies in other countries with similar findings. However, many panel members felt the post-hoc data and supplemental studies should not be considered. “If you cherry-pick, you are going to get a biased estimate of how good the effect is,” said panelist Michael Proschan, PhD, of the National Institute of Allergy and Infectious Disease in Bethesda, Maryland. “I don’t see that they have distinguished the results from chance.”
The discouraging dearth of Alzheimer’s treatments — amplified by the decision of Biogen and Eisai to stop trials of the anti-amyloid agent aducanumab the same day — was echoed by nearly every speaker at the meeting. But that did not mean the FDA should offer therapies that lack a clear benefit, panelists emphasized.
“On the basis of the evidence we saw today, I wouldn’t want this being marketed to my own grandmother who had dementia as something my uncle would have had to bring her to every day, five days a week,” said panel member Felipe Jain, MD, of Massachusetts General Hospital in Boston. “But I feel there is a signal, and I’m hopeful it will continue to undergo further development.”
“The problem is that the data are null on the primary outcome, and two of three secondary outcomes,” added panelist Paul Rosenberg, MD, of Johns Hopkins Medicine in Baltimore. “Like many people around this table, I’m deeply moved by my patients’ frustration at treatment, but I don’t think we’ll do them a service by approving if there’s a lot of uncertainty with this one.”
The neuroAD system was a de novo premarket submission, available for novel devices that don’t pose high risk to patients. Other TMS devices that were first of a kind — for major depressive disorder and obsessive compulsive disorder — were cleared through the same de novo pathway. While the FDA will consider input from the panel before it makes its final decision, the agency is not obliged to follow recommendations from its advisory committees.