A Phase 2 clinical trial has demonstrated that personalized neuromodulation treatment significantly slowed the progression of Alzheimer's disease in patients with mild-to-moderate symptoms. The 52-week study, conducted by Sinaptica Therapeutics, Inc., revealed that non-invasive, personalized neuromodulation of the Default Mode Network (DMN) met all key endpoints with statistical significance and showed no serious side effects. The results, presented at the Clinical Trials on Alzheimer's Disease (CTAD) conference, highlight the potential of this novel approach to address the cognitive, functional, and behavioral aspects of Alzheimer's.
Key Findings from the Phase 2 Study
The Phase 2 study was a monocentric, randomized, double-blind, sham-controlled trial involving 48 patients. The treatment involved personalized neuronavigated repetitive transcranial magnetic stimulation (rTMS) targeting the DMN, a critical brain network affected by Alzheimer's. Personalization of the rTMS treatment was achieved using single-pulse TMS combined with electroencephalography (TMS-EEG) and patient MRI data. The treatment consisted of a 2-week course of 20-minute sessions, five times per week, followed by a 50-week maintenance phase with weekly stimulation.
The primary outcome measure was the change from baseline to week 52 in the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB). Secondary outcomes included changes in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale 11 (ADAS-Cog11), Alzheimer's Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL), Neuropsychiatric Inventory (NPI), and Mini-Mental State Examination (MMSE).
The study demonstrated a significant effect on the primary outcome measure, CDR-SB. The estimated mean change in CDR-SB after 52 weeks was 1.36 for the rTMS-EEG group (95% CI [0.68, 2.04]) and 2.45 for the sham group (95% CI [1.85, 3.05]), resulting in a statistically significant separation of 1.09 points. This represents a 44% slowing of Alzheimer’s progression over the 12-month study duration.
Impact on Activities of Daily Living and Behavior
Notably, on the key functional secondary outcome measure, Activities of Daily Living (ADCS-ADL), patients receiving the neuromodulation treatment remained nearly unchanged after one year. This suggests that the treatment may help preserve the ability of patients to perform everyday tasks. Furthermore, TMS-EEG data indicated that rTMS increased functional connectivity within the DMN, and this increase correlated with changes in clinical scores as measured by CDR-SB.
Additional analysis of the Phase 2 data revealed that 37% of rTMS patients, compared to 17% of sham patients, showed no disease progression, defined as a CDR-SB score change from baseline of less than or equal to 0. The iADRS and GST endpoints demonstrated significant differences between treatment groups at 52 weeks, showing approximately 66% and 51% slowing, respectively. The study also indicated that disease progression was delayed by 10.4 months as measured by ADCS-ADL during the 12-month period.
Expert Commentary
Giacomo Koch, MD, PhD, Sinaptica scientific co-founder, highlighted the potential of the personalized rTMS-EEG approach to enhance neuroplasticity, remodel brain connectivity, and enhance gamma oscillatory activity in the DMN. Jeffrey Cummings, MD, ScD, from the University of Nevada, Las Vegas (UNLV), noted the consistency of efficacy signals across endpoints and the lack of serious side effects, suggesting that this precision medicine neuromodulation approach represents a promising new direction for treatment research in Alzheimer’s.
Future Directions
Sinaptica Therapeutics is preparing to initiate a Phase 3 study in 2025 to further evaluate the efficacy and safety of the SinaptiStim® System. This system delivers weekly 20-minute sessions of customized neurostimulation targeting the precuneus section of the brain, the central hub of the DMN. The upcoming trial will also assess the effects of the SinaptiStim® System on biomarkers measuring beta amyloid, phosphorylated tau, neural inflammation, and synaptic transmission.
