A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease

Abstract

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.

Figures

Figure 1

AZD0530 in human cerebrospinal fluid at different doses. (A) Each point represents fasting trough cerebrospinal fluid (CSF) AZD0530 level from a different human subject for the left three columns. The mouse trough CSF values are derived from brain levels at the 5 mg/kg per day dose that rescued memory deficits [43]. **P < 0.001, one-way analysis of variance with Tukey post-hoc comparisons. (B) Relationship between CSF and plasma AZD0530 levels. Each point is from a different individual, and different dose groups are illustrated with different colors. There is a tight correlation of plasma and CSF level as indicated (R2 = 0.97, Pearson correlation coefficient). Bars represent mean ± standard error of the mean. n.s, Not significant.

Figure 2

AZD0530 peripheral target engagement. Four-week treatment with 100 mg and 125 mg AZD0530 reduces serum cross-linked C-telopeptide of type 1 collagen (sCTX), a marker of osteoclast activity. Compared to placebo, mean difference in the change in sCTX from baseline for 50 mg was 51% (95% confidence interval, −22.0 to 124.3), for 100 mg 85% (95% confidence interval, 8.2 to −161.6), and for 125 mg 83% (95% confidence interval, 6.2 to 159.6). **P < 0.05, analysis of variance with Dunnet’s multiple comparisons test. n.s., Not significant.

Figure 3

Plasma from AZD0530-treated subjects does not inhibit Abl signaling to Stat5. (A) The level of pStat5 and total Stat5 in K-562 cells incubated with the indicated concentrations of AZD0530 or STI-571 is shown. (B) The pStat5 level from experiments in (A) was measured by microdensitometry and a half maximal inhibitory concentration (IC50) determined for each compound. (C) The plasma inhibitory activity for Abl was detected by pStat5 level in K-562 cells incubated with plasma from subjects treated with the indicated doses of AZD0530. (D) The plasma Abl inhibitory activity determined by pStat5 level was measured in all subjects, and is plotted as mean ± standard error of the mean. No significant difference between groups was observed (n.s.).