Clinical trial met all key endpoints, demonstrating ‘statistically significant’ benefits across cognitive, functional and behavioral domains.
A new paper published in Alzheimer’s Research & Therapy this week highlights the compelling results of a Phase 2 clinical trial evaluating an investigational neuromodulation system for the treatment of Alzheimer’s. In the 52-week trial, a system developed by neurotech company Sinaptica Therapeutics was used to treat in patients with mild-to-moderate Alzheimer’s disease, demonstrating statistically significant benefits across cognitive, functional, and behavioral domains, and meeting all primary and key secondary endpoints.
The SinaptiStim system is a personalized, non-invasive neuromodulation approach designed to alter the course of Alzheimer’s by targeting the brain’s Default Mode Network (DMN). It combines repetitive transcranial magnetic stimulation (rTMS) with real-time electroencephalography (EEG) and advanced imaging to deliver tailored neuromodulation therapy.
By focusing on the precuneus, a critical hub within the DMN, the system is designed to restore communication across a brain network that becomes increasingly dysregulated as Alzheimer’s progresses. The therapy’s closed-loop architecture allows for precise calibration based on each patient’s unique brain activity patterns.
Phase 2 trial results
According to the paper, patients receiving SinaptiStim treatment in the 12-month, randomized, double-blind, sham-controlled study, experienced a 44% reduction in disease progression as measured by the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB). The mean change in CDR-SB scores was significantly lower in the active treatment group compared with the sham group, indicating a slower decline in cognitive function.
Secondary outcomes also favored the treatment, with statistically significant improvements observed in measures such as the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11), the Mini-Mental State Examination (MMSE), the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) and the Neuropsychiatric Inventory (NPI).
The treatment group retained nearly all of their ability to perform daily activities over the course of a year, while the control group experienced marked deterioration. Neurophysiological analysis showed that rTMS enhanced functional connectivity within the DMN, and this connectivity increase correlated with clinical improvements. Importantly, the procedure was safe and well tolerated, with no serious side effects and only minimal adverse events reported.
Beyond clinical endpoints, the therapy’s physiological impact was corroborated by imaging and electrophysiological data. Functional MRI indicated strengthened connectivity across the DMN, while EEG analysis showed preservation of TMS-evoked potentials (TEPs) and increased gamma band activity – both indicators of healthier brain function. Structural MRI scans suggested a slowing of gray matter atrophy in treated patients compared with those receiving placebo.
“These peer reviewed results not only highlight the treatment’s durability in all disease domains over one year, but the data also points to the importance of confirming broad network engagement of the DMN by measuring distal evoked potentials via neuronavigated TMS-EEG technology,” said Sinaptica CEO Ken Mariash. “This highly personalized approach ensures the neuromodulation pulses can reach distal targets in the DMN so as to induce widespread neuroplasticity throughout the DMN – and furthermore to personalize the dose for every patient to stay within safe-yet-effective bounds.”
Plans for Phase 3 in 2025
Sinaptica’s approach is grounded in the concept that Alzheimer’s disease may be as much a disorder of brain network dysregulation as it is of biochemical pathology. The company’s scientific strategy reflects growing interest in the electrical underpinnings of neurodegenerative disease, aiming to reestablish synchronization within disrupted networks. The Default Mode Network, which supports episodic memory and introspection, becomes fragmented and hypoactive in Alzheimer’s, and its dysfunction is closely associated with disease progression. By restoring excitability and connectivity across this network, Sinaptica’s therapy seeks to preserve cognitive function and slow decline.
The system operates by importing a patient’s MRI into specialized neuronavigation software to map the DMN in three dimensions. This allows the stimulation coil to be positioned with high precision over the precuneus. During calibration, single TMS pulses are administered while EEG captures the propagation of neural activity through the DMN. These recordings are processed by a machine learning engine that generates a personalized treatment protocol based on spatiotemporal patterns unique to the patient. Weekly stimulation sessions are then conducted, with session durations decreasing from 25 to as little as six minutes using the newer generation of the system.
Sinaptica is now moving toward a 300-patient pivotal Phase 3 trial, slated to begin this year. This upcoming study will expand on current findings by incorporating additional biomarkers, including measures of beta amyloid, phosphorylated tau, neuroinflammation and synaptic function. The trial will also use real-time TMS-EEG and MRI-guided neuronavigation to enable continual re-calibration of treatment parameters throughout the study period, offering a dynamic and adaptive therapeutic strategy.
“This publication reaffirms our confidence in the potential for our non-invasive precision neuromodulation therapy, nDMN, to slow the impairment of cognitive functions, preserve activities of daily living, and reduce behavioral disturbances in Alzheimer’s patients,” said Sinaptica’s scientific co-founder, Dr Giacomo Koch. “We continue to build on our positive clinical evidence including with a just-initiated Phase 2 study in Early Alzheimer’s patients, as well as ongoing preparations to launch a pivotal trial in Mild-to-Moderate patients.”
