How CT1812 works
CT1812 is a small-molecule that binds to a protein called the sigma-2 receptor, also known as the progesterone receptor membrane component 1 (sigma-2/PGRMC1). This receptor is found on the surface of many cells, including brain cells, and is thought to mediate the attachment of beta-amyloid to nerve cells. Beta-amyloid is the protein that accumulates in the brains of Alzheimer’s patients and causes nerve cells to die, contributing to such symptoms of the disease as memory loss.
It is thought that the binding of CT1812 to the sigma-2/PGRMC1 receptor will prevent beta-amyloid from binding to it and interfere with its toxicity. CT1812 has been shown, in several Alzheimer’s animal disease models, to protect against memory loss.
In addition, similar compounds to CT1812 have been shown to displace beta-amyloid that has already bound to the sigma-2/PGRMC1 receptor, not just blocking beta-amyloid from binding to it in the first place. Company scientists report that these compounds were able to reach the brain and restore behavioral deficits in mouse models of Alzheimer’s.
CT1812 in clinical trials
A Phase 1 clinical trial (NCT02570997) assessed ascending doses of CT1812 in 80 healthy volunteers, ages 18 to 50, in Melbourne, Australia, between September 2015 and May 2016. Outcome measures included safety, tolerability, plasma pharmacokinetics (the study of the movement of a medication within the body), and CT1812 concentrations in the cerebrospinal fluid (the fluid that bathes the brain and the spinal cord). In July 2016, company scientists reported that the medication was well-tolerated, showed suitable pharmacokinetics, and penetrated the brain very well.
A Phase 1/2 clinical trial (NCT02907567) then enrolled 19 individuals in Australia with mild-to-moderate Alzheimer’s disease, who were randomized to receive either a placebo or one of three doses of CT1812 (90 mg, 280 mg, or 560 mg) for 28 days. Safety and pharmacokinetics were the primary objectives of the study, with changes in protein biomarkers and cognitive outcomes as exploratory objectives.
Trial results were given in an oral presentation at the 10th clinical trials on Alzheimer’s disease (CTAD) meeting in Boston by Dr. Lon Schneider, a professor at the USC Keck School of Medicine, and in a poster presentation by a company executive.
They showed that CT1812 was well-tolerated at all doses, and adverse events reported in 16 of the 19 patients were mild or moderate (headache,
fatigue, lethargy, nausea, etc.). Pharmacokinetics were similar to those seen in previous studies.
Levels of proteins that are typically present in Alzheimer’s patients were analyzed in the cerebrospinal fluid of participants. In the group treated with CT1812, significantly lower levels of a protein called neurogranin, which is high in Alzheimer’s disease patients and a marker of synaptic damage. Synaptic damage refers to damage to the signaling ability of neurons, or nerve cells, which can lead to Alzheimer’s.
Lower levels of ther Alzheimer’s-related proteins were also seen in patients treated with CT1812, including synaptotagmin-1, another marker of synaptic damage.
Cognitive outcomes after 28 days of treatment, however, were similar between the CT1812 and placebo-treated groups.
The trial is still ongoing but no longer recruiting. It is expected to be finish in June 2018.
CT1812 was granted fast track by the U.S. Food and Drug Administration (FDA) in October 2017. Fast track designation is intended to facilitate the development and expedite the FDA review of new compounds intended to treat serious or life-threatening conditions, and that address an unmet medical need.
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