Lanabecestat
Preclinical pharmacology
Lanabecestat is a brain-permeable inhibitor of human BACE1 (nonselective for BACE1 vs BACE2, (0.6nM and 0.9nM in vitro radioligand 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 both mouse and guinea pig, as well as in human CSF and plasma. The potency of lanabecestat in cellular models on secretion of Aβ40 has been studied in SHSY5Y/APP cells, N2A cells, primary mouse neurons, and primary guinea pig neurons, using ELISA. Lanabecestat exhibits consistent high picomolar potency across multiple in vitro assay formats.
Safety and tolerability
Lanabecestat was evaluated in GLP oral, repeat-dose, general toxicity studies of up to 6- months dosing duration in Wistar Han rats (40-250mg/kg) and up to 9- months dosing duration in beagle dogs (1-20mg/kg). Hypopigmentation of skin and fur was observed in the 3-month and 9-month dog toxicology studies with lanabecestat with no apparent dose relationship to severity and is thought to be associated with BACE2 inhibition. Clinically, lanabecestat exposure was associated with hair color changes in the Phase 2/3 program.The potential for reproductive toxicity with lanabecestat has been assessed in GLP studies of fertility (in rats) and embryofetal development (in rats and rabbits) and no reproductive toxicity liability was identified. The abuse potential of lanabecestat was also assessed in drug abuse liability studies in rats and no abuse potential was identified.
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.
