Therapeutics

AZD3293

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Overview

Name: AZD3293
Synonyms: BACE1 inhibitor
Therapy Type: Small Molecule
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: AstraZeneca

Background

AZD3293 is an inhibitor of BACE1, the β-secretase sheddase that cleaves the APP protein to release APP's C99 fragment. This fragment then becomes a substrate for subsequent γ-secretase cleavage and Aβ peptide generation. The rationale is that inhibiting BACE1 will reduce amyloid-related toxicity in Alzheimer's disease. AZD3293 is one of several BACE1 inhibitors currently in development. Preclinical data have not been formally published. AZD3293 is administered in tablet form.

Findings

In December 2012, AstraZeneca started a Phase 1 study that evaluated the safety and pharmacological effects of single doses of oral AZD3293 in 72 healthy volunteers. Doses ranged from 1–1,000 mg. In 2013 and 2014, six additional phase 1 studies in the U.S. and Japan further evaluated safety, tolerability, metabolism and potential drug interactions of single and multiple ascending doses of a tablet and an oral formulation in both elderly volunteers and Alzheimer patients. Effects on biomarkers in plasma and CSF were also measured. Results are not yet published in peer-reviewed journals, but the company has reported at scientific conferences that the inhibitor strongly reduced CSF Ab levels (see March 2014 story /news/research-news/bace-inhibitor-heads-phase-23-trials.)

In September 2014, AstraZeneca and Eli Lilly announced that they would jointly develop AZD3293, with AstraZeneca handling manufacturing and Eli Lilly clinical trials (see company press release http://www.astrazeneca.com/Media/Press-releases/Article/astrazeneca-and-lilly-announce-alliance).

The clinical development of this compound will largely skip over phase 2, running no medium-size phase 2 trials but instead a large phase2/3 trial in a targeted 1,551 patients. Beginning in October 2014 and set to run for 5 years, a new trial called AMARANTH will compare AZD3293 to placebo given for 2 years. This multi-center trial will enroll people who meet NIA-AA criteria for MCI due to AD or mild AD. They or their partner must report worsening in the past 6 months and their MMSE must be above 21 at screening. To ascertain that they have brain amyloid accumulation, participants will undergo either an amyloid PET scan or a lumbar puncture and continue in respective substudies monitoring those markers for treatment response. The trial will compare 2 doses given once daily as a table to placebo, and measure success by change from baseline on the clinical dementia rating sum of boxes (CDR-SOB). The ADAS-cog and ADCS-ADL are secondary outcome measures, along with other clinical markers as well as change in CSF markers, functional and amyloid PET, and MRI. For all clinical trials of AZD3293, see http://clinicaltrials.gov/ct2/show/NCT02245737?term=AZD3293&rank=8 .

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