Study details and key findings

TMS is a noninvasive therapy that uses magnetic fields to stimulate the brain, which then causes neurons to fire electrical signals that travel through the brain. Repeated stimulation is believed to help neurons preserve existing connections, while also encouraging them to form new ones.

In 2008, FDA approved TMS to treat depression. Since then, the agency has also approved the therapy to treat migraines, obsessive-compulsive disorder, and to help people quit smoking. Over the last decade, several trials have tested TMS on subjects with Alzheimer's and have found some signs of efficacy.

In a new Phase 2 trial, Sinaptica tested TMS on 32 patients at the Santa Lucia Foundation, a neurological rehabilitation hospital in Rome. The trial initially included 31 patients from a six-month study who decided to continue treatment, along with 17 newly randomized patients. After excluding those who did not complete the full protocol, there were 18 patients who received TMS, and 14 patients in the sham group.

Unlike past TMS trials, Sinaptica personalized the treatment to each patient by calibrating the intensity of magnetic pulses and the exact spot they hit in the brain. The researchers combined TMS with an electroencephalogram to help them determine that they were triggering the right ripples of neural activity.

The trial was divided into two periods: first, a two-week induction phase where participants went through 10 sessions to calibrate their treatment, and then weekly maintenance therapy for the remainder of the trial. Each session was around 20 minutes.

Overall, the researchers found that participants who received TMS experienced a 44% slowing in the rate of their disease progression after one year compared to those who received the sham treatment. In addition, 37% of patients who received TMS had no signs of disease progression during the trial period compared to 17% of the sham group.

The researchers used the Clinical Dementia Rating sum of boxes (CDR-SB), which measures six cognitive domains and rates them on a scale of zero to 18, to compare the TMS and the sham groups. Higher scores on the CDR-SB indicate more severe dementia. After a year of treatment, the TMS group had a 1.3-point increase to their CDR-SB score compared to a 2.4-point increase in the sham group.

In addition to slowing cognitive decline, the researchers also noted that the treatment helped reduce behavioral disturbances associated with Alzheimer's, such as anxiety, eating disorders, and sleep disorders.

Commentary

The study's findings were originally shared in an Oct. 31 release and in a presentation at the Clinical Trials on Alzheimer's Disease conference in Madrid. The researchers are planning to publish their findings in a peer-reviewed journal soon.

According to Sinaptica CEO Ken Mariash, the company was excited by the findings, and said that if the therapy is approved, it could someday be used in combination with Alzheimer's drugs like Leqembi or Kisunla.

"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," Mariash said. "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."

However, outside experts have said that more research is needed to confirm the trial's findings since they were based on a small group of patients.

"These results are interesting; they justify a bigger study," said David Knopman, a neurologist and Alzheimer's expert at Mayo Clinic. "I'm encouraged and pleased that there are so many people interested in … approaches to things that are outside of the amyloid-lowering world."

Currently, Sinaptica is planning a 280-person pivotal study and expects to begin treatment by the end of 2025. This trial will include around 20 sites, with most of them in the United States. Other site locations will be in Italy and potentially other European countries.

In this larger trial, researchers plan to evaluate whether there are biomarkers that can predict patients' responses to treatment. The researchers are planning to use brain imaging data, neural inflammation levels, and amyloid and tau measurements to guide their analysis. (Wosen, STAT+ [subscription required], 10/31; Incorvaia, Fierce Biotech, 10/31)

As occurrence of neurodegenerative disease in the U.S. has increased, advances in medicine have expanded the outlook for diagnosing, treating, and curing these diseases. Download the report to explore  four key drivers that are changing the treatment prospect and delivery of care for patients with neurodegenerative diseases.