A Single Ascending Dose / Multiple Ascending Dose Phase I study of the GSM 776890 in healthy normal subjects

Scientific Abstract AD is currently a huge health problem that imposes a severe social and economic burden; in the absence of an effective disease modifying treatment it is projected to become a dominant source of health care expenditures over the next several decades. Unfortunately, existing treatments are palliative providing only

temporary symptomatic benefit. Through an NIH Blueprint Neurotherapeutics (BPN) Network and U01 award we have discovered and developed a highly potent γ -secretase modulator (GSM), 776890 (also referred to as compound 2). Unlike semagacestat and other γ -secretase inhibitors (GSIs), GSMs do not inhibit gamma-secretase activity (e.g. Notch proteolysis) but rather allosterically enhance APP processing

by reducing the net production of Aβ42 and to a lesser extent Aβ40 while concomitantly augmenting the production of Aβ38 and Aβ37. Compound 2 (776890), demonstrates excellent potency in vitro (IC50 = 4.0 nM), as well as in vivo (~55% lowering of brain and CSF Aβ42 levels and ~ 85% plasma Aβ42 levels in rats

and mice at doses of 5 or 10 mg/kg p.o, respectively). In addition to showing robust dose-dependent in vivo efficacy in two different rodent species, 7-day dose-range finding toxicology studies in both rats and non- human primates (NHPs) has been completed and a no observed-adverse-effect-level (NOAEL) of >50

mg/kg was established in rats, resulting in a therapeutic index (safety margin) of >20. In addition, following 3-months of repeated daily (qd) oral dosing of compound 2 (25 mg/kg) showed no evidence of toxicity based on full body necropsy. Compound 2 is currently undergoing investigational new drug (IND)-enabling,

good laboratory practice (GLP) 28-day safety and toxicity testing in rats and NHPs through the NIH BPN Network. Here we propose a single ascending dose (SAD) safety and tolerability study, to detail the pharmacokinetics (PK) following ascending doses (12.5, 50, 100, 200, 400 and 600 mg) and assess peripheral target engagement utilizing specific plasma biomarker MSD V-plex ELISA assays. In addition, we

will perform a 14-day multiple ascending dose (MAD) safety and tolerability study, detailing the PK following multiple ascending doses (50 mg, 100 mg and 200 mg) and establishing engagement of mechanism via studies with plasma and CSF samples using a novel and innovative IP-MS analysis from 48 subjects

treated with or placebo both at baseline and after ascending doses of treatment. Our collaborator in Sweden (Dr Kaj Blennow, MD, PhD) has developed a highly innovative immunoprecipitation - mass spectrometry (IP-MS) method using a QExactive instrument that enables accurate and rapid monitoring of all of the major

Aβ isoforms in human CSF. Plasma concentrations of Aβ38, Aβ40, and Aβ42 will be measured using specific plasma biomarker MSD V-plex ELISA assays.