How Personalized Repetitive Transcranial Magnetic Stimulation May Transform Alzheimer Treatment

Ken Mariash

The Alzheimer disease (AD) treatment pipeline is ever evolving, with numerous different modalities and targets currently being explored. In recent years, the field has had major breakthroughs with the development and commercialization of monoclonal antibodies targeting amyloid plaques; however, several in the field believe that these therapeutics will not solve the complete puzzle of AD. One emerging method of counteracting the cognitive dysfunction seen in AD has been through repetitive transcranial magnetic stimulation (rTMS).

Through increasing research the precuneus (PC) has been identified as the ideal rTMS target for stimulation to slow down cognitive and functional decline in AD. The PC is a key node of the Default Mode Network (DMN) and it is the earliest region to be affected by amyloid deposition as well as by gray matter loss, and functional connectivity disconnection between regions and organizations within networks. Sinaptica’s SinaptiStim System, a neuromodulation device targeting PC, recently demonstrated efficacy and safety in a phase 2 study (NCT05454540) of patients with mild-to-moderate AD, meeting its primary end point of change in Clinical Dementia Rating-Sum of Boxes.

The study, a 52-week double-blind, sham-controlled trial, included a 2-week intensive course where rTMS (or sham) was applied over the PC daily, followed by a 50-week maintenance phase in which the same stimulation was applied once weekly. Following the data announcement, NeurologyLive® reached out to Ken Mariash, chief executive officer at Sinaptica, to give greater insights on the significance of the findings. In the conversation, he detailed the promising phase 2 data, including the system’s effect on cognitive decline and activities of daily living, as well as the safety and patient acceptance of the therapy. Furthermore, he spoke briefly on the plans to launch a phase 3 trial in 2025 under the FDA’s Breakthrough Device pathway.

How does the SinaptiStim System operate? Why do we believe it can be therapeutically beneficial for Alzheimer disease?

Ken Mariash: Sinaptica is developing a new, non-drug way to treat Alzheimer’s disease using personalized precision network neuromodulation of the Default Mode Network or nDMN, the primary functional brain network impacted by Alzheimer’s disease.

The Phase 2 study detailed in the Alzheimer’s Research and Therapy publication was a monocentric, randomized, double-blind, sham-controlled, 52-week trial to determine the safety and efficacy of treatment with personalized neuronavigated rTMS targeting the Default Mode Network,

Personalization of the rTMS treatment is established using single-pulse TMS concurrently in combination with electroencephalography (TMS-EEG) based on the recording, processing, and proprietary analysis of transcranial evoked potentials (TEPs) and patient MRI data.

Then the personalized therapy prescription is delivered in 20-minute sessions once per week, with the patient comfortably reclining in a chair for the painless treatment.

What were the greatest and most notable takeaways from the phase 2 data? From a clinical perspective

Overview

The study showed that personalized, precision neuromodulation treatment significantly slowed Alzheimer’s progression in a 12-month Phase 2 study, meeting and showing statistical significance in all gold-standard Alzheimer's endpoints, including 87% slowing of Activities of Daily Living – meaning minimal loss of independence – after a year.

Results

The study showed that personalized neuromodulation of the Default Mode Network had a significant effect on the primary outcome measure, Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB). The estimated mean change in CDR-SB after 52 weeks was 1.36 for rTMS-EEG group (95% confidence interval (CI) [0.68, 2.04]) and 2.45 for sham group (95%CI [1.85, 3.05]), resulting in a statistically significant and clinically meaningful separation of 1.09points, representing a44%slowing of Alzheimer’s progression over the 12-month study duration.

There were also statistically significant effects for the secondary outcomes ADAS-Cog₁₁, MMSE, ADCS-ADL and NPI scores.

• On key functional secondary outcome measure, Activities of Daily Living (ADCS-ADL), patients receiving treatment were nearly unchanged after one year.
• TMS-EEG showed that rTMS increased functional connectivity within the Default Mode Network, and such increase correlated with the changes in clinical scores as measured by the CDR-SB.

What are some of the challenges and considerations when designing a study testing a neuromodulation approach for AD?

Training. While TMS has been used in over 100,000 cases in depression since 2008, it is typically prescribed by psychiatrists, not by neurologists. Therefore, one challenge is familiarizing neurologists and their staff with the TMS device. Neurologists understand the principles involved, given their familiarity with EEG—they perform nerve conduction tests on a routine basis, so for them the theory of electrically inducing neuroplasticity is not difficult to grasp. For the staff and technicians administering the therapy it takes about three days it to train and does not take much specialized skill.

Patient acceptance. While neuromodulation may be familiar to many of us who work in medicine, for a long time it was less familiar to patients. This has changed over the last 10 to 20 years as neuromodulation therapies like spinal cord stimulation (for back pain), deep brain stimulation (for Parkinson’s and Tremor), sacral nerve stimulation (for overactive bladder), and phrenic nerve stimulation (for OSA) have made it into the mainstream. We find that many patients intuitively grasp the concept that “when you stimulate neurons, they strengthen.”Then it’s mainly the task of answering their questions about the procedure. Most patients are excited to be part of a study that involves a non-invasive therapy with so few side effects, given the alternatives can involve much more serious and sometimes deadly side effects. One unique appeal of our therapy is that we have a highly targeted, very personalized approach--unlike drugs that are systemic, we target just the brain network most affected by Alzheimer’s, and the dose is calibrated to the individual. Most patients understand that each individuals’ brain responds differently to stimulation, so the appeal is our therapy accounts for these individual differences.

What did the safety of the therapy show?

The data from the 52-week study showed strong separation from placebo and statistical significance in mild-to-moderate patients, with no serious side-effects. The procedure was safe and well tolerated with very few minor adverse events reported.

Has Sinaptica had discussions on what the next steps are to advance this treatment?

Taken together with the previous positive 6-month study data, along with published imaging data that showed the treatment decreased brain atrophy and increased connectivity in the Default Mode Network, this 12-month clinical data suggests nDMN therapy is durable and potentially disease-modifying, having an impact on all three Alzheimer’s domains: cognition, function, and behavior. These positive results lay a strong foundation as we move forward with plans to initiate a Phase 3 study in 2025.

Sinaptica is part of the TAP program and so has had regular frequent consultations with FDA under Breakthrough Device Designation as we design our pivotal study.