Sinaptica’s Novel Approach to Alzheimer’s Leverages Electrical Brain Stimulation
Using precision neuromodulation therapy to electrically stimulate the brain, Sinaptica Therapeutics is able to slow the progression of Alzheimer’s, with impressive Phase 2 results.
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Origin Story
Giacomo Koch, MD, PhD, and Emiliano Santarnecchi, PhD, have been working together for over a decade on issues related to Alzheimer’s and neuromodulation. At the Santa Lucia Foundation in Rome, Dr. Koch, a practicing neurologist and neuroscientist, works with Alzheimer’s patients as well as conducting research in his lab, while on the other side of the Atlantic, Dr. Santarnecchi – who directs the Precision Neuroscience lab at Harvard-MGH – uses neuroimaging and electrophysiology to develop diagnostic and therapeutic solutions for Alzheimer’s patients.
Their collaboration led to a groundbreaking study in which they proved that personalized noninvasive neuromodulation therapy for Alzheimer’s patients slowed the progression of the disease by 82% at six months. Sinaptica Therapeutics – the business entity now responsible for developing the therapy – claims they have unprecedented clinical trial efficacy.
“Our therapy works better than any drug that I’ve seen in 20 years,” says Ken Mariash, CEO, who previously worked as head of strategy at Boston Scientific’s $1B Neuromodulation Division.
The Problem
Alzheimer’s disease directly or indirectly touches millions of people, including those on Sinaptica’s core team. “I got to see the first-hand effects of Alzheimer’s on my grandmother,” says Mariash. He was also struck by its effect on his extended family. “I saw it swallow up my family in a way that I could have never imagined,” he says.
Rich Macary, Sinaptica’s president, was working in the biotech space on rare diseases when a family member developed Alzheimer’s disease, which put him on a search for novel solutions, leading him to Drs Koch and Santarnecchi and eventually a new area of focus in his career.
Although Macary’s relative ended up in assisted living, he’s hopeful others will have a different story. He points to the Phase 2 study by Sinaptica’s scientific co-founders that showed how neuromodulation therapy allowed Alzheimer’s patients to maintain activities of daily living (ADLs) over six months, whereas the sham cohort had diminished ADLs. “In the study, we saw full preservation of function, the thing we as caregivers and family members care about most, which can enable the patient to remain living independently,” says Macary. “I would do anything to have kept my loved one out of assisted living,” he adds.
Although the impact of Alzheimer’s disease is widely understood by the general public, treatment options have been lacking for decades, until two recent drug approvals that come with some efficacy and safety challenges. Sinaptica is forging a new path with a non-drug approach and a new disease target, separate from ‘the usual suspects:’ amyloid, an aggregate of misfolded proteins that form in the spaces between nerve cells; and tau, a protein that when abnormally formed causes the internal structure of neurons in the brain to fall apart. The scientific community has “spent decades and billions of dollars targeting amyloid,” says Mariash, which Sinaptica believes is more of a covariant – just one aspect of the pathology of the disease. “We’re going beyond amyloid,” he says.
The Solution
Sinaptica Therapeutics posits that Alzheimer’s might be as much of an electrophysiological disease as a biochemical disease. “The brain is electric and operates as multiple overlapping networks. The Alzheimer’s brain shows dysregulation of the complex signaling in those networks, which is related to synaptic dysfunction. Excitation/inhibition imbalances and dysregulated oscillatory patterns (e.g. epileptiform activity) are well-known in AD. This suggests that neuromodulation can restore balance to the network and induc eneuroplasticity – strengthening synapses – thereby restoring network connectivity.”
The therapy process begins with a patient receiving an MRI and then a calibration session to personalize the therapy. Drs Santarnecchi and Koch’s research took a big leap forward in 2015 when they realized they could personalize the therapy to hit the right network in the brain that is implicated in Alzheimer’s. “The brain works as a combination of networks,” says Dr. Santarnecchi. “We go after the default mode network (DMN), one specific network known to impact Alzheimer’s disease,” he adds. This network is the biggest cortical network in the brain, across which memories are integrated. Yet, each brain works differently, so Sinaptica’s therapy begins by mapping out a custom blueprint of the brain so that the therapy can be targeted to the correct region for each patient.
Mariash likens the calibration process to active sonar: TMS (transcranial magnetic stimulation) pulses, and EEG (electroencephalography) ‘listens.’ “It’s better to understand a complex system by sending a perturbation to the system and see how the system responds,” says Dr. Santarnecchi. “When you send a magnetic pulse and listen to the brain you get very specific information,” he adds. With this information, it’s possible to create personalized weekly therapy that sends magnetic pulses to the targeted region of the brain.
During their therapy, patients spend 20 minutes sitting back in a reclining chair, with the neuromodulation system just behind their head. The therapy uses repetitive magnetic stimulation to generate electrical activity in the DMN in the brain via the precuneus. During the foundational Phase 2 study, the results of which were published in Brain in 2022, patients who underwent this therapy once a week for six months showed over 80% slowing of disease progression relative to sham on the Clinical Dementia Rating Scale (CDR-SB, primary endpoint), Alzheimer’s Diseases Assessment-Cognitive (ADAS-COG), Mini-Mental State Examination (MMSE), and Activities of Daily Living (ADCS-ADL, referenced earlier). The study conclusions show confidence in the potential of using precision neuromodulation to slow the progression of cognitive and functional decline in Alzheimer’s.
Mariash draws a parallel to working out: “When you stimulate your muscle tissue by lifting a heavy object, you strengthen muscles.” By stimulating key parts of the brain involved in memory, neuromodulation strengthens those networks, new connections are made, and the progression of the disease lessens. It’s not a cure for Alzheimer’s, but rather a slowing of its momentum that can provide precious time and independence. “This disease is a freight train. We're working to slow it down,” says Macary.
Where They Are in the Process
Sinaptica holds a unique position as a startup company buoyed by compelling data from a Phase 2 clinical trial and patented technology with FDA Breakthrough designation. They’re currently in the process of raising additional funds and replicating the Phase 2 data in a Phase 3 clinical trial that will follow patients for one year and include participants in about 20 sites throughout the US and EU. They are working with other Alzheimer’s experts to get broad input and interest in the design of the clinical trial and they are in frequent contact with the FDA through the TAP program, which gives extra level of access to the FDA for breakthrough devices.
Part of their work also involves convincing the wider medical community that advances in treatment for Alzheimer’s can include neuromodulation as well as drugs. “In Alzheimer's, neuromodulation is just beginning to be acknowledged, and there is some skepticism” says Mariash. “But our therapy has its foundations in a $7B industry that's affecting all kinds of areas of medicine, from Parkinson's, to pain, to epilepsy, to rheumatoid arthritis, to depression…. Neuromodulation is a well-established space.” Sinaptica is on a path to introduce this non-pharmacological intervention for Alzheimer’s disease to the market.
Our Take
Sinaptica Therapeutics presents groundbreaking data for slowing the progression of Alzheimer’s disease. Their therapy sidesteps the usual targets, instead using a personalized solution that focuses on the unique electrical makeup of a patient’s brain. It’s an original and effective approach that holds promise for extending the cognitive functions of people with Alzheimer’s. We’re excited to partner with them and seek creative solutions for tackling this disease.
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Published: Jun 20, 2024