Synapses are specialized points of contact between brain cells (neurons) where fast electrical communication takes place. The smallest units of brain function, synapses literally represent “cognitive real estate.” The number of synapses in the brain is highly correlated with memory ability and cognitive performance. The loss of synapses in the brain is therefore analogous to end organ damage in other organ systems.
In the brains of Alzheimer’s patients, the binding of toxic Aβ oligomers to their receptors on synapses interferes with the delicate protein machinery responsible for normal memory function. In response, the neuron resorbs the impaired synapse structure. If a large enough number of synapses are lost, the neuron dies.
Elayta is designed to protect synapses from the neurotoxic cascade triggered by Aβ oligomers. Elayta is currently enrolling patients with mild-to-moderate Alzheimer’s disease in a comprehensive Phase 2 clinical program.
Summary of Preclinical and Clinical Results
In preclinical studies, Elayta displaced Aβ oligomers from synaptic receptor sites, cleared oligomers from the brain into the cerebrospinal fluid (CSF), and restored synapse number and cognitive performance in aged transgenic mouse models of Alzheimer’s disease.
In Phase 1 clinical studies, Elayta was deemed to be safe and well tolerated with single doses up to 1120 mg and with multiple doses up to 840 mg in healthy young volunteers and 560 mg in healthy elderly volunteers.
In a double-blind, placebo-controlled Phase 1b/2 study in 19 mild-to-moderate (MMSE 18-26) Alzheimer’s disease patients, Elayta was safe and well tolerated across all doses with no severe adverse events reported. CSF concentrations of neurogranin and synaptotagmin-1, synaptic proteins that are important for normal synaptic function and plasticity, were measured at baseline and after 28 days of Elayta treatment as an exploratory outcome. At 28 days, placebo-treated patients’ CSF neurogranin and synaptotagmin concentrations increased 11% and 24% compared to baseline, while concentrations in Elayta-treated patients decreased by 18% and 19%, respectively. The reductions of these proteins were consistent with a positive effect on synapses in Alzheimer’s patients and with Elayta’s synaptoprotective mechanism of action.
Ongoing Clinical Studies
Cognition is currently conducting three clinical trials focused on increasing patient exposures for efficacy and safety assessments and on establishing the PK/PD relationship between the dose of Elayta and the change in biomarkers of Alzheimer’s disease progression. These studies are:
- SNAP (AβO Displacement from Synapses on Neurons in Alzheimer’s Patients) (COG0104)
The SNAP study is a multi-center, Phase 1b double‐blind, placebo‐controlled, parallel‐group trial in 18 adults with mild-to-moderate Alzheimer’s disease randomized to receive either a single dose of Elayta or placebo in a 2:1 (Elayta:placebo) ratio. The primary outcome of SNAP will be the evaluation of target engagement by measuring the displacement of Aβ oligomers into CSF. Secondary measurements will include the effect of Elayta on certain plasma and CSF proteins and other biomarkers. This study will also evaluate the safety and tolerability of Elayta as well as pharmacokinetics.
SNAP is funded by a $2.4 million grant from the National Institute on Aging of the NIH under award number RF1AG057780.
More information may be found at www.clinicaltrials.gov under trial identifier NCT03522129.
- SPARC (Synaptic Protection for Alzheimer’s Recovery of Cognition) (COG0105)
The SPARC study is a double-blind, placebo-controlled, 26-week trial designed to measure changes in synaptic number and function in approximately 21 Alzheimer’s disease patients randomized to receive 100 mg or 300 mg doses of Elayta or placebo. The primary outcome is the safety and tolerability of Elayta. Secondary outcomes include assessment of cognition, changes in biomarkers and evaluation of the effects of Elayta on the density of synapses in the brain.
SPARC is the first therapeutic study to use the novel imaging agent UCB-J to measure the number of synapses in the brain of Alzheimer’s disease patients over time compared to their baseline measurements.
SPARC is funded by a $4.2 million grant from the National Institute on Aging of the NIH under award number RF1AG057553.
More information may be found at www.clinicaltrials.gov under trial identifier NCT03493282.
- SHINE (Synaptic Health and Improvement of Neurological Function with Elayta) (COG0201)
The SHINE study is a randomized, double-blind, placebo-controlled, parallel-group Phase 2 safety and efficacy trial designed to enroll up to 160 adults with mild-to-moderate Alzheimer’s disease (MMSE 18-26) who will receive Elayta in oral doses of 100 or 300 mg per day or placebo for six months. The primary outcome of the SHINE study is the safety and tolerability of Elayta.
SHINE is funded by a $16.6 million grant from the National Institute on Aging of the NIH under award number R01AG058660.
More information may be found at www.clinicaltrials.gov under trial identifier NCT03507790.