INTRODUCTION: Despite significant progress, a disease-modifying therapy for 
Alzheimer's disease (AD) has not yet been developed. Recent findings implicate 
soluble oligomeric amyloid beta as the most relevant protein conformation in AD 
pathogenesis. We recently described a signaling cascade whereby oligomeric 
amyloid beta binds to cellular prion protein on the neuronal cell surface, 
activating intracellular Fyn kinase to mediate synaptotoxicity. Fyn kinase has 
been implicated in AD pathophysiology both in in vitro models and in human 
subjects, and is a promising new therapeutic target for AD. Herein, we present a 
Phase Ib trial of the repurposed investigational drug AZD0530, a Src family 
kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients 
with mild-to-moderate AD.
METHODS: The study was a 4-week Phase Ib multiple ascending dose, randomized, 
double-blind, placebo-controlled trial of AZD0530 in AD patients with 
Mini-Mental State Examination (MMSE) scores ranging from 16 to 26. A total of 24 
subjects were recruited in three sequential groups, with each randomized to 
receive oral AZD0530 at doses of 50 mg, 100 mg, 125 mg, or placebo daily for 
4 weeks. The drug:placebo ratio was 3:1. Primary endpoints were safety, 
tolerability, and cerebrospinal fluid (CSF) penetration of AZD0530. Secondary 
endpoints included changes in clinical efficacy measures (Alzheimer's Disease 
Assessment Scale - cognitive subscale, MMSE, Alzheimer's Disease Cooperative 
Study - Activities of Daily Living Inventory, Neuropsychiatric Inventory, and 
Clinical Dementia Rating Scale - Sum of Boxes) and regional cerebral glucose 
metabolism measured by fluorodeoxyglucose positron emission tomography.
RESULTS: AZD0530 was generally safe and well tolerated across doses. One subject 
receiving 125 mg of AZD0530 was discontinued from the study due to the 
development of congestive heart failure and atypical pneumonia, which were 
considered possibly related to the study drug. Plasma/CSF ratio of AZD0530 was 
0.4. The 100 mg and 125 mg doses achieved CSF drug levels corresponding to brain 
levels that rescued memory deficits in transgenic mouse models. One-month 
treatment with AZD0530 had no significant effect on clinical efficacy measures 
or regional cerebral glucose metabolism.
CONCLUSIONS: AZD0530 is reasonably safe and well tolerated in patients with 
mild-to-moderate AD, achieving substantial central nervous system penetration 
with oral dosing at 100-125 mg. Targeting Fyn kinase may be a promising 
therapeutic approach in AD, and a larger Phase IIa clinical trial of AZD0530 for 
the treatment of patients with AD has recently launched.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT01864655. Registered 12 June 2014.