A phase Ib multiple ascending dose study of the safety, tolerability, and central
nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease.
Author(s): Nygaard HB(1), Wagner AF(2), Bowen GS(2), Good SP(2), MacAvoy MG(2), Strittmatter
KA(3), Kaufman AC(3), Rosenberg BJ(4), Sekine-Konno T(5), Varma P(6), Chen K(7),
Koleske AJ(8), Reiman EM(7), Strittmatter SM(9), van Dyck CH(10).
Affiliation(s): Author information:
(1)Alzheimer's Disease Research Unit, Yale University School of Medicine, New
Haven, Connecticut USA ; Department of Neurology, Yale University School of
Medicine, New Haven, Connecticut USA ; Program in Cellular Neuroscience,
Neurodegeneration and Repair (CNNR), Yale University School of Medicine, New
Haven, Connecticut USA ; Current address: University of British Columbia,
Division of Neurology, Djavad Mowafaghian Centre for Brain Health, Vancouver,
Canada. (2)Alzheimer's Disease Research Unit, Yale University School of Medicine,
New Haven, Connecticut USA ; Department of Psychiatry, Yale University School of
Medicine, New Haven, Connecticut USA. (3)Program in Cellular Neuroscience,
Neurodegeneration and Repair (CNNR), Yale University School of Medicine, New
Haven, Connecticut USA. (4)Department of Molecular Biophysics and Biochemistry,
Yale University School of Medicine, New Haven, Connecticut USA. (5)Department of
Neurology, Yale University School of Medicine, New Haven, Connecticut USA.
(6)Department of Diagnostic Radiology, Yale University School of Medicine, New
Haven, Connecticut USA. (7)Banner Alzheimer's Institute, Phoenix, Arizona USA.
(8)Program in Cellular Neuroscience, Neurodegeneration and Repair (CNNR), Yale
University School of Medicine, New Haven, Connecticut USA ; Department of
Molecular Biophysics and Biochemistry, Yale University School of Medicine, New
Haven, Connecticut USA. (9)Department of Neurology, Yale University School of
Medicine, New Haven, Connecticut USA ; Program in Cellular Neuroscience,
Neurodegeneration and Repair (CNNR), Yale University School of Medicine, New
Haven, Connecticut USA. (10)Alzheimer's Disease Research Unit, Yale University
School of Medicine, New Haven, Connecticut USA ; Department of Neurology, Yale
University School of Medicine, New Haven, Connecticut USA ; Department of
Psychiatry, Yale University School of Medicine, New Haven, Connecticut USA.
Publication date & source: 2015, Alzheimers Res Ther. , 7(1):35
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.
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