Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2)
Company: Cognition Therapeutics Inc.
CT1812 is a small-molecule ligand for the sigma2 receptor, also known as the progesterone receptor membrane component 1. The rationale behind this therapeutic approach is that ligands for the sigma2/PGRMC1 receptor will compete with oligomeric Aβ binding to this receptor and thus interfere with Aβ-induced synaptic toxicity. CT1812 grew out of screening programs at Cognition Therapeutics. Company scientists have reported that compounds in this series not only block binding of a range of different Aβ species to this receptor but also displace it when applied after Aβ has bound (see Dec 2014 conference news).
The structure of CT1812 has not been disclosed, but similar compounds in the series have been reported to enter the brain, occupy up to 80 percent of sigma2/PGRMC1 receptors, and restore behavioral deficits in APP transgenic mice (Izzo et al., 2014).
From September 2015 to May 2016, Cognition Therapeutics ran a Phase 1 trial in 114 healthy volunteers aged 18 to 75 in Melbourne, Australia. A first phase of single-ascending-dose administration was followed by a second phase of multiple ascending doses given once daily for two weeks. The dose range in this trial spanned 10 mg to 650 mg; if this would not generate data to set a maximum tolerated dose, doses up to 1,350 mg were to be tried. Outcome measures included safety, tolerability, plasma pharmacokinetics, and CSF CT1812 concentration. At the July 2016 AAIC conference, company scientists reported that single doses up to 1,120 mg were given, as were multiple doses of up to 560 mg. The drug was reported to be well tolerated, with suitable pharmacokinetics as well as sufficient brain penetrance and target exposure (see AAIC abstract for details).
In September, Cognition Therapeutics started a Phase 1/2 trial, at sites across Australia, of 16 participants with mild to moderate Alzheimer's disease supported by a recent MRI. It compares a four-week course of 280 mg or 560 mg of CT 1812 to placebo for various safety and tolerability parameters.
For details, see clinicaltrials.gov.
- Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One. 2014;9(11):e111898. Epub 2014 Nov 12 PubMed.
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