Tuesday, May 12, 2015

Drugs in Clinical Pipeline: AZD3293

AZD3293 [4-Methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''-amine] is an oral, potent and selective small molecule inhibitor of BACE that has been shown in Phase I studies to significantly and dose-dependently reduce levels of amyloid beta (Aβ) in the cerebrospinal fluid (CSF) of Alzheimer’s patients and healthy volunteers.

Amyloid beta (Aβ) deposition in the brain is thought to be one of the causes of Alzheimer's disease. It is expected that developing a new treatment for Alzheimer's disease which reduces amyloid beta will not only improve symptoms, but also help slow down the progression of the disease. AZD3293 may reduce the overall amount of amyloid beta by inhibiting Beta-site amyloid precursor protein cleaving enzyme (BACE). BACE1 is the first step in the processing of APP to Aβ peptides, and its inhibition is an attractive target for therapeutic intervention to stop the production of Aβ.

This novel compound was discovered at AstraZeneca which have taken it up to Phase II trials. In September 2014, AstraZeneca and Eli Lilly and Company (Lilly) announced an agreement to jointly develop and commercialise AZD3293 as a potential treatment for Alzheimer’s disease.

Common Name: AZD3293
Synonyms:  AZD3293; AZD 3293; AZD-3293; LY3314814; LY 3314814; LY-3314814
IUPAC Name: 4-Methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''-amine
CAS Number: 1628076-74-3
Mechanism of Action: BACE1 Inhibitor; Beta-site amyloid precursor protein (APP) cleaving enzyme 1 Inhibitor
Indication: Alzheimer's disease; Treatment of Dementia
Development Stage: Phase II
Company: AstraZeneca/Eli Lilly

The potency of AZD3293 in cellular models on secretion of Aβ40 has been studied in SHSY5Y/APP cells (human neuronal cells over expressing human APPwt), N2A cells (mouse neuronal cells), primary mouse neurons and primary guinea pig neurons, using ELISA technology. Mice treated with AZD3293 as a single administration, or repeated administrations twice daily during 7 days, demonstrated a statistically significant dose- and time-dependent reduction of the levels of Aβ40, Aβ42 and sAPPβ in plasma and brain. Guinea pigs treated with AZD3293 as a single administration demonstrated a statistically significant dose- and time-dependent reduction of the levels of Aβ40, Aβ42 and sAPPβ in plasma, CSF and brain. In vitro potency in mouse and guinea pig primary cortical neuronal cells was strongly correlated to potency in mouse mouse and guinea pig in vivo potency [1].

To check the hypothesis that whether AZD3293 causes a dose dependent decrease of sAPPβ, and increase of sAPPα, clinical data for soluble fragments alpha (sAPPα) and beta (sAPPβ) were collected during a Multiple Ascending Dose study in elderly Healthy Volunteers, with the BACE inhibitor AZD3293. It was expected that a dose dependent decrease of sAPPβ, and increase of sAPPα would result from BACE1 inhibition in this study. CSF and plasma in healthy volunteers were sampled pre-treatment and during 24h continuous CSF sampling after 14 days of 15 and 50 mg dosing. Plasma and CSF sAPP α and β data were compared to corresponding AZD3293 concentration data to assess PK/PD correlations. The results were on the expected lines, where a dose-dependent sustained decrease in CSF of sAPPβ, and broadly dose-dependent increase of sAPPα, were observed. While sAPPα levels generally increased, data were variable with no apparent dose dependency. Within the linear range of the sAPPβ assay, a direct correlation between AZD3293 concentration (Cmax) and sAPPβ inhibition was observed on a similar timeline to effects seen for Aβ40/42. The observations are consistent with the hypothesized mechanism of action of AZD3293 and indicate that sustained inhibition of BACE1 leads to reduced sAPPβ levels and increased flux through the non-pathogenic α-secretase-mediated pathway [2].

1. Haeberlein, S. B.; et. al. AZD3293, a potent and selective orally active, brain-permeable BACE1 inhibitor. Alzheimer's and Dementia 2013, 9(4), P813.
2. Hoglund, K.; et. al. Monitoring the soluble amyloid precursor protein alpha (sappa) and beta (sappb) fragments in plasma and csf from healthy individuals treated with bace inhibitor azd3293 in a multiple ascending dose study: pharmacokinetic and pharmacodynamic correlate. Alzheimer's and Dementia 2014, 10(4), P447.