Lanabecestat
Preclinical pharmacology
Lanabecestat is a brain-permeable inhibitor of human BACE1 (nonselective for BACE1 vs BACE2, 0.6nM and 0.9nM in binding assays respectively) that has been shown to reduce levels of Aβ1-40 and Aβ1-42 in the brain, cerebrospinal fluid (CSF), and plasma in several animal models, as well as in human CSF and plasma.
Safety and tolerability
Lanabecestat has been evaluated in Phase 1 and Phase 2/3 studies as part of its development program as a potential treatment for early Alzheimer’s Disease. Lanabecestat was generally well tolerated. In the Phase 2/3 program, treatment-emergent psychiatric adverse events were numerically greater in lanabecestat treatment groups compared with placebo and were consistent with dose dependence. Lanabecestat exposure was also associated with hair color changes and weight loss. No other pattern of potentially clinically significant vital signs, laboratory values, or ECG parameters was observed in the Phase 2/3 program.
Clinical pharmacology
The PK of lanabecestat was determined following single doses over a range from 1 to 750 mg, and at steady-state from 15- 150 mg. Plasma Aβ1-40 and Aβ1-42 levels were rapidly reduced by >70% after a single dose of lanabecestat of 5-750 mg. In Phase 2/3 studies (AMARANTH and DAYBREAK-ALZ), lanabecestat treatment produced substantial dose-related reductions in CSF Aβ1-40 concentration (58.0% and 73.3% for 20 mg and 50 mg, respectively) and Aβ1-42 concentration (51.3% and 65.5% for 20 mg and 50 mg, respectively).
The annualized LS mean change from baseline of florbetapir PET scan using SUVr was significantly greater with lanabecestat (20 mg and 50 mg) compared with placebo. In AMARANTH, the LS mean (SE) centiloid change from baseline of florbetapir PET scan using SUVr was significantly greater with lanabecestat (20 mg and 50 mg) over 2 years compared with placebo (−13.7 [2.6] and −17.7 [2.7] centiloids, respectively).
Suitable for and exclusions
Lanabecestat is suitable for both preclinical and clinical research.
Mechanism of Action
Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor (human)
Original Therapeutic Area
Neuroscience
CNS Penetrant
Yes
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Wessels AM., et al. (2020).
Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials. JAMA Neurol. 77(2):199–209. doi:10.1001/jamaneurol.2019.3988.
2. Cebers G., et al. (2017).
AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease. J Alzheimers Dis.;55(3):1039-1053. doi: 10.3233/JAD-160701. PMID: 27767991.
