As the world of neurodegenerative disease drug development continues to be roiled by controversies, one company has taken a different, noninvasive approach to treating Alzheimer’s disease.
In a yearlong phase 2 study, Sinaptica Therapeutics’ personalized, precision transcranial magnetic brain stimulation slowed the progression of cognitive decline in patients with mild to moderate Alzheimer’s by 44% compared to the sham control group. Cognitive function was measured using Clinical Dementia Rating Scale Sum of Boxes scores.
Patients receiving treatment also showed no significant declines in their ability to perform daily life activities at the end of the trial, as measured by the Alzheimer's Disease Cooperative Study–Activities of Daily Living scale.
The results were shared in an Oct. 31 release and in a presentation by scientific co-founder Giacomo Koch, M.D., Ph.D., at the Clinical Trials on Alzheimer’s Disease conference in Madrid. The researchers said they plan to publish their findings in a peer-reviewed journal soon.
“We see the consistency of the effect, whether it's cognition, function or behavior. We see consistency in electrophysiology measures. We see consistency in imaging measures,” Sinaptica CEO Ken Mariash told Fierce Biotech in a joint interview with Koch and Emiliano Santarnecchi, Ph.D., the company’s other scientific co-founder. “All of this gives us a lot of confidence that what we're seeing is a very strong signal, at least as good, if not potentially better than some of the drugs that are out there.”
In principle, the treatment is similar to how astronauts exercise while in space in order to fight the weakening of their muscles and bones that comes from being in low gravity. Alzheimer’s progression isn’t stopped by TMS, but it is significantly slowed.
“I think it’s important for us in the field to explore multiple different potential therapeutic pathways, in part because Alzheimer’s disease is multi-faceted and a single strategy is probably not going to be enough,” Winston Chiong, M.D., Ph.D., a neurologist and ethicist at the University of California, San Francisco who wasn’t involved with the study, told Fierce in an email. For example, some Alzheimer’s patients are unable to take new antibody treatments like Kisunla and Leqembi that target the pathological protein amyloid beta, Chiong said, and need other options.
In addition to slowing cognitive decline, Koch added that the team was pleasantly surprised to see the treatment also reduced behavioral disturbances caused by the disease such as anxiety, eating disorders and sleep disorders.
“This broad series of behavioral disorders can become very important for the quality of life,” Koch said.
The company hopes to initiate a phase 3 trial next year, Mariash said. Sinaptica is already in talks with regulators about the trial’s design, he added, which will feature fewer patients than required for a drug trial because the technique used to stimulate the brain is already known to be safe—side effects are mild and typically include scalp discomfort, tingling and headaches.
Thirty-two patients completed the phase 2 trial, which involved two weeks of daily 20-minute brain stimulation sessions (excluding weekends) followed by one session a week for the rest of the year.
Sinaptica’s personal neuromodulation treatment targets the precuneus, the central hub of the brain’s default mode network, or DMN, which is heavily involved in memory. Before treatment began, Sinaptica pulsed each patient’s brain with magnetic stimulation in nine places to gather data on what the connections making up their DMN look like. The treatment is then targeted at the area that most activated the network in each patient.
“It's important to personalize the location, because even if we're off by a centimeter, we could miss the network entirely,” said Mariash.
In an earlier, 24-week phase 2 trial, transcranial magnetic stimulation was also shown to slow cognitive decline and, in a follow-up, the treatment was found to have protected the gray matter in patients’ precunei from degrading.
TMS has been approved for depression since 2008, and using the tools to perform it doesn’t require extensive special training—around a day or two, Mariash said. This makes Sinaptica hopeful that its Alzheimer’s treatment can readily be rolled out to hospitals, infusion centers and, potentially, nursing homes that focus on memory care.
Koch and Santarnecchi were both trained in Italy’s tight-knit electrophysiology and neuromodulation community but didn’t meet face-to-face until a conference in 2015. They quickly realized that their respective work on brain stimulation could be combined to address Alzheimer’s, Santarnecchi said. They co-founded Sinaptica in 2021.
“At that conference, we kind of had a eureka moment,” Santarnecchi said. Years later, “when we saw the results of the phase 2, partially it was a confirmation of all our hypotheses tested over 10 years.”