Alzheimer’s disease serves as bookends to Brent Vaughan’s career so far. Twenty years ago, he worked for a Bay Area biotech whose pipeline included small molecules in development for the neurodegenerative disorder. At that time, the most recently approved Alzheimer’s drug was Forest Laboratories’ memantine—everything else had failed, he said.

Vaughan’s career took him to other companies working in other indications, and upon his return to Alzheimer’s, he found nothing had changed. When Vaughan joined Cognito Therapeutics as its CEO in 2020, memantine still stood as the most recently approved Alzheimer’s therapy amid a long list of drug failures. In the years since, the FDA has approved two new Alzheimer’s drugs, antibodies from Biogen and Eisai designed to clear amyloid protein from the brain. Vaughan is now trying to make a medical device the next Alzheimer’s therapeutic approval.

“Everyone has been focused on this target space of looking at the pathological proteins, pathological folding of amyloid and tau,” Vaughan said. “The only reason we care about the pathological proteins is because they change electrical activity. Electricity is the fundamental current of the brain.”

Cognito’s wearable device uses light and sound to modulate the electricity in the brain as a way of improving neuron connectivity and reducing levels of pathological proteins. The Cambridge, Massachusetts-based startup is moving forward with a Phase 3 study designed to produce the data that could support an FDA submission. It has raised $73 million to finance the clinical research.

The science behind Cognito’s device originated with the research of Li-Huei Tsai and Ed Boyden, both neuroscience professors at MIT. The scientists were studying the mechanisms of Alzheimer’s progression in mice when they noticed a change in electrical activity in the brain, Vaughan said. Specifically, they noticed the mice were losing activity in a low gamma frequency known to be key in building synaptic activity. The scientists addressed this problem with optogenetics, which is the use of light to control the activity of neurons. The MIT scientists’ approach led to reductions in amyloid protein. Results were published in the journal Nature in 2016, the same year that Cognito was founded.

The Cognito device is a headset that administers to patients oscillating light and sounds. Light and audio each activate different parts of the brain, Vaughan explained. But before patients use the device, they start with an electroencephalogram to establish a baseline of activity. This test also assesses whether their brains respond to gamma frequency light and sound stimulation. Non-responders are ineligible for the device.

Patients are instructed to wear the headset for an hour a day. Results from a 76-patient, sham-controlled Phase 2 study were presented last August at the Alzheimer’s Association International Conference. They showed that daily use of the device led to a reduction in the loss of white matter in the brain measured at six months. But results were observed sooner than that. After eight weeks of treatment, brain differences were observable on fMRI scans, Vaughan said. Alzheimer’s leads to a loss of brain volume. At 12 weeks, the brain volume was greater in patients in the treatment arm compared to the control group. No treatment-related adverse effects were reported in the clinical trial.

In addition to the increase in synaptic connectivity, the Phase 2 results also showed an increase in activity of microglia, immune cells in the brain that get rid of pathogens. Some biotech companies, such as GSK-partnered Alector, are developing neurodegenerative disorder therapies intended to enhance microglial activity.

“We use electrical activity as our active ingredient versus an antibody or a small molecule,” Vaughan said.

Cognito now aims to see show that the Phase 2 results can hold up in a larger group. The Phase 3 study is designed to enroll 500 patients. Though the trial will be conducted at 55 sites across the country, study volunteers can participate from home after receiving the device in the mail. The trial has two main goals: measuring at 12 months the change in score according to a scale used to assess how Alzheimer’s patients perform activities of daily living, and measuring changes according to a combined assessment of daily activities and cognitive impairment, also at 12 months. The study was designed with an eye on what will be needed to commercialize the product if approved. Payers care about measuring function because the loss of function is what leads to higher costs in caring for Alzheimer’s patients, Vaughan said.

Cognito’s approach to Alzheimer’s could become part of a future combination treatment with a drug therapy, Vaughan said. Noting that Eisai’s Leqembi led to a 27% reduction in clinical decline in its Phase 3 study, he said it’s possible Cognito’s device could serve a complementary role in slowing decline even further. Combinations are not part of Cognito’s current trial clinical program. But in addition to the Phase 3 study, Cognito also plans to launch a parallel study enrolling patients with mild cognitive impairment. This research has the potential to bring the device to patients in earlier stages of decline. By targeting electrical dysregulation in the brain rather than a particular protein, such as amyloid or tau, a patient would not need to wait until the detection of a pathological protein before beginning treatment, Vaughan said.

The Series B financing was led by FoundersX Ventures. The round also added new investors Alzheimer’s Drug Discovery Foundation, Starbloom Capital, IAG Capital, and WS Investment Company. Since inception, Cognito says it has raised $93 million total.

Photo by Cognito Therapeutics