Data presented at CTAD showed strong separation from placebo and statistical significance in mild-to-moderate patients on key global, cognitive, and behavioral measures including CDR-SB, ADAS- Cog11 and NPI.
On key functional measure, Activities of Daily Living (ADCS-ADL), Alzheimer's disease patients receiving treatment were nearly unchanged after one year
Personalized Neuromodulation (rTMS-EEG) targeting the Default Mode Network slowed Alzheimer's in all 3 clinically measured domains: cognition, function, and behavior, with no serious side-effects.
Sinaptica Therapeutics, Inc., a clinical-stage company leading the development of a new class of personalized neuromodulation therapeutics to treat Alzheimer's and other primary neurodegenerative diseases, today announced results of a 52-week Phase 2 study in Mild-to -Moderate Alzheimer's disease patients showing that non-invasive personalized neuromodulation of the Default Mode Network (DMN), a key network in the brain involved in memory, "nDMN", met all key endpoints with statistical significance, with no serious side-effects.
The data were presented in an oral presentation at the Clinical Trials on Alzheimer's Disease (CTAD) conference being held October 29-November 1, 2024, in Madrid in a presentation titled "Results of a 52-Week Phase II Trial of Repetitive TMS of the Default Mode Network in Mild to Moderate Alzheimer's Disease." Additional positive data presented in a late-breaker poster by Pentara and colleagues titled "Additional Analysis of a 52-Week Phase II Trial of Neuromodulation of the Default Mode Network to Optimize Design of a Phase 3 Trial to Demonstrate Clinical Meaningfulness."
"We're excited that our non-invasive precision neuromodulation therapy continues to demonstrate promise in slowing Alzheimer's, after 52 weeks of treatment using rTMS-EEG based personalization to target the DMN via the Precuneus in mild-to-moderate Alzheimer's patients," said Giacomo Koch, MD, PhD, Sinaptica scientific co-founder, Neurologist, Professor of Physiology, University of Ferrara, and Director, Non-Invasive Brain Stimulation Laboratory, Santa Lucia Foundation. "These latest results provide new additional evidence at 12 months, building on our prior positive six-month Phase 2 study, supporting the potential for nDMN to slow the impairment of cognitive functions, preserve activities of daily living, and reduce behavioral disturbances in Alzheimer's patients, with no significant side-effects. These data confirm the potential of personalized rTMS-EEG approach on multiple clinical aspects of Alzheimer's disease by enhancing neuroplasticity, remodeling brain connectivity, and enhancing gamma oscillatory activity in the DMN."
The Phase 2 study was a monocentric, randomized, double-blind, sham-controlled, 52-week trial to determine the safety and efficacy of treatment with personalized neuronavigated repetitive transcranial magnetic stimulation (rTMS) targeting the Default Mode Network, the primary functional brain network impacted by Alzheimer's disease.
- Personalization of the rTMS treatment was 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.
- The trial included an initial 2-week course of 20-minute sessions of neuronavigated nDMN rTMS, five times per week (M-F), with the patient comfortably reclining in a chair for the painless treatment. This was followed by a 50-week maintenance phase in which the same stimulation was applied once weekly.
- The trial included 48 patients, of which 32 completed the 52-week study (16 patients were unable to complete the study due to COVID pandemic-related impacts). 31 patients accepted to extend treatment duration up to 52 weeks after being included in a 24-week trial (NCT03778151) with the same experimental design, and 17 were recruited de novo.
- The primary outcome measure for the study was the change from baseline to week 52 of the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB).
- Secondary outcomes included score changes in:
- 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)
- Mini Mental State Examination (MMSE)
- Frontal Assessment Battery (FAB) was included as a negative control
- Changes in cortical activity and connectivity were monitored by TMS-EEG
- Secondary outcomes included score changes in:
- The study was conducted at Santa Lucia Foundation in Rome with support from the Italian Ministry of Health and the BrightFocus Foundation.
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 1.09 points, representing a 44% 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.
- The procedure was safe and well tolerated with very few minor adverse events reported.
- Based on additional analysis of the Phase 2 data presented in a poster session by Pentara and colleagues, an independent clinical data analysis consulting firm:
- 37% of rTMS patients vs 17% of sham patients demonstrated no progression of disease 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.
- During the 12-month period of the study, disease progression was delayed by 10.4 months as measured by ADCS-ADL.
"We're encouraged by these positive results showing the potential for personalized neuromodulation as a treatment modality for Alzheimer's," said Howard Fillit, MD, Co-Founder and Chief Science Officer of the Alzheimer's Drug Discovery Foundation, who chaired the CTAD conference presentation session. "At the ADDF, we recognize that this challenging disease requires a multi-faceted approach. Sinaptica's study aligns with our efforts to advance the development of novel therapeutics that may ultimately be considered a component of a combination therapy and precision medicine strategy aimed at slowing the progression of or stopping the onset of Alzheimer's altogether."
"I'm encouraged by consistency of the efficacy signals across endpoints in this 1-year monocentric placebo-controlled study," said Jeffrey Cummings, MD, ScD, Joy Chambers-Grundy Professor of Brain Science at the School of Integrated Health Sciences at University of Nevada, Las Vegas (UNLV). "Given its lack of serious side-effects, this Precision Medicine neuromodulation approach represents a promising new direction for treatment research in the field of Alzheimer's."
"We are pleased to support this important Phase 2, 1-year clinical study," said Diane Bovenkamp, PhD, Vice President of Scientific Affairs at BrightFocus Foundation. "We pride ourselves on supporting bold, innovative approaches, and are thrilled to see such a successful outcome from a noninvasive therapy, providing a new avenue of hope for patients with this new class of electromagnetic therapeutics."
The results presented today follow the recent publication of a controlled imaging sub-study, which revealed statistically significant differences in grey matter volume, micro-cortical morphology, and functional connectivity associated with rTMS intervention, as measured by MRI and fMRI-all of which support the clinical effects seen in the present study (Mencarelli et al 2024 https://doi.org/10.1186/s13195-024-01501-z).
"Taken together with the previous positive 6-month study data, and the published imaging data, 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-something not seen in any other studies," said Ken Mariash, Sinaptica CEO. "The additional positive impact now seen on behavior (NPI) was especially encouraging, indicating the potential to alleviate patient apathy in particular, which can be such a burden to caregivers. In total, these positive results lay a strong foundation as we move forward with plans to initiate a Phase 3 study in 2025."
About the Phase 2 Study
This was a monocentric, sham-controlled, randomized, and double-blind Phase 2 trial of rTMS in patients with mild-to-moderate Alzheimer's disease. Forty-eight individuals were included in this 52-week study. The therapy was personalized using single-pulse TMS concurrently with EEG based on the proprietary analysis of transcranial evoked potentials (TEPs) and each patient's MRI data. Treatment was delivered daily for 10 sessions during the induction phase followed by weekly 20-minute sessions for the next 50 weeks. The primary endpoint was global performance measured by the CDR-SB and secondary endpoints were a cognitive measure (ADAS-Cog11), a functional measure (ADCS-ADL), a behavioral measure (NPI), a negative control measure (FAB), and a neurophysiologic marker (TMS-EEG). The present study (NCT 05454540) included 31 patients from the previous 6-month randomized study (NCT 3778151), who extended therapy to 12 months, remaining blinded in their arms. Subsequently, another 17 new patients were randomized and received the identical protocol for the entire 12 months. 16 patients were lost to follow-up, mainly due to COVID. In total 32 patients ultimately completed the 12-month protocol.
About the SinaptiStim® System
The SinaptiStim® System is an investigational new approach to treating Alzheimer's disease using non-invasive personalized precision neuromodulation. Calibrated to each individual's brain, the therapy is delivered weekly in 20-minute sessions in a recliner, with safe, painless, customized neurostimulation technology targeting prescribed areas of the precuneus section of the brain. The precuneus is the central hub of the Default Mode Network (DMN), an important brain network associated with episodic memory and introspection. There has been a tremendous amount of recent research identifying the DMN as playing a central role in AD pathology and progression. It is thought that stimulating the DMN increases neuroplasticity and stabilizes the brain's electrical network, helping to preserve existing connectivity and build new memory pathways and connections.
The technology was granted Breakthrough Device Designation by the FDA in 2022 and the company is preparing for a pivotal randomized controlled clinical trial in 2025 In the upcoming trial the treatment will be calibrated quarterly using TMS and EEG concurrently in combination with MRI-guided neuronavigation, which enables the SinaptiStim System to achieve customized precise repeatable targeting and dosage for each patient, tracking progress and adjusting over time to achieve the best possible individualized outcomes with its nDMN therapy. The pivotal trial will also be designed to determine the effects of SinaptiStim® System on several biomarkers measuring beta amyloid, phosphorylated tau, neural inflammation, and synaptic transmission.
About Sinaptica Therapeutics
Sinaptica Therapeutics is a clinical-stage neuromodulation therapeutics company leading the development of a new class of novel personalized therapeutics to revolutionize the treatment of Alzheimer's and other primary neurodegenerative diseases. The company utilizes a patented non-invasive approach to treating Alzheimer's via precision neurostimulation of a key brain network involved in memory, the Default Mode Network. Sinaptica's scientific co-founders pioneered research on this novel approach which a growing body of evidence indicates can slow disease progression. Sinaptica's mission is to bring a safe, effective, and non-invasive neuromodulation therapy to Alzheimer's patients that can help to significantly slow the progression of cognitive, functional, and behavioral decline. Learn more at sinapticatx.com and follow us on LinkedIn and X @SinapticaTX.
The SinaptiStim® System is for investigational use only. It has not been approved by the U.S. Food and Drug Administration and is not available for commercial sale in any geography.
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Contacts:
Kathryn Morris, BrightPoint
kathryn@brightpointny.com
914-204-6412
