AZD0530 was generally safe and well tolerated across doses. One subject receiving 125

Related literature Cited by Google blog search Other articles by authors   on Google Scholar Nygaard HB Wagner AF Bowen GS Good SP MacAvoy MG Strittmatter KA Kaufman AC Rosenberg BJ Sekine-Konno T Varma P Chen K Koleske AJ Reiman EM Strittmatter SM van Dyck CH   on PubMed Nygaard HB Wagner delfi sportas AF Bowen GS Good SP MacAvoy MG Strittmatter KA Kaufman AC Rosenberg BJ Sekine-Konno T Varma P Chen K Koleske AJ Reiman EM Strittmatter SM van Dyck CH Related articles/pages on Google on Google Scholar on PubMed Tools Download references Download XML Order reprints Post a comment   Download to ... Papers Mendeley Download to ... Papers Mendeley Share this article
Haakon B Nygaard 1 2 3 8 , Allison F Wagner 1 4 , Garrett S Bowen 1 4 , Susan P Good 1 4 , Martha delfi sportas G MacAvoy 1 4 , Kurt A Strittmatter 3 , Adam C Kaufman 3 , Brian J Rosenberg 5 , Tomoko Sekine-Konno 2 , Pradeep Varma 6 , Kewei Chen 7 , Anthony J Koleske 3 5 , Eric M Reiman 7 , Stephen M Strittmatter 2 3 * and Christopher H van Dyck 1 2 4 *
Alzheimer's Research delfi sportas & Therapy 2015, 7 :35  delfi sportas doi:10.1186/s13195-015-0119-0
This is an Open Access article delfi sportas distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly delfi sportas credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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 delfi sportas drug AZD0530, a Src family delfi sportas kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients with mild-to-moderate AD. Methods delfi sportas
The study was a 4-week delfi sportas 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, delfi sportas with each randomized to receive oral AZD0530 at doses of 50 mg, 100 mg, delfi sportas 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 delfi sportas subscale, MMSE, Alzheimer s Disease Cooperative Study Activities delfi sportas 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 delfi sportas
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 delfi sportas heart failure and atypical pneumonia, which were considered possibly related to the study drug. Plasma/CSF delfi sportas 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. delfi sportas Conclusions
AZD0530 is reasonably safe and well tolerated in patients with mild-to-moderate AD, achieving substantial central delfi sportas 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
Despite considerable ongoing efforts to halt or reverse delfi sportas the symptoms of Alzheimer s disease (AD), a disease-modifying intervention for this devastating illness has not yet emerged. The major approach to AD therapeutic development has been to target amyloid-beta (Aβ), by either limiting delfi sportas its cleavage from the amyloid precursor protein, or facilitating its clearance by active or passive immunization [ 1 ]. An alternative approach to AD treatment is to target the downstream effects of pathologic Aβ signaling, without altering protein levels. This may be a particularly attractive approach as some forms of Aβ could have important physiologic roles [ 2 ], [ 3 ]. More recently, preclinical