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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $3,156,733

## Abstract

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.

## Key facts

- **NIH application ID:** 10111792
- **Project number:** 1R01AG070353-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** DOUGLAS R GALASKO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $3,156,733
- **Award type:** 1
- **Project period:** 2021-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111792

## Citation

> US National Institutes of Health, RePORTER application 10111792, A Single Ascending Dose / Multiple Ascending Dose Phase I study of the GSM 776890 in healthy normal subjects (1R01AG070353-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10111792. Licensed CC0.

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