AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease

• Published in: Journal of Alzheimer's disease Vol. 55; no. 3; p. 1039
• Main Authors: Cebers, Gvido, Alexander, Robert C, Haeberlein, Samantha Budd, Han, David, Goldwater, Ronald, Ereshefsky, Larry, Olsson, Tina, Ye, Naidong, Rosen, Laura, Russell, Muir, Maltby, Justine, Eketjäll, Susanna, Kugler, Alan R
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2017
• Subjects: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease - drug therapy; Amyloid beta-Peptides - blood; Amyloid beta-Peptides - cerebrospinal fluid; Antipsychotic Agents - pharmacokinetics; Antipsychotic Agents - therapeutic use; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Food; Healthy Volunteers; Humans; Imidazoles - pharmacokinetics; Imidazoles - therapeutic use; Male; Middle Aged; Neurologic Examination; Peptide Fragments - blood; Peptide Fragments - cerebrospinal fluid; Spiro Compounds - pharmacokinetics; Spiro Compounds - therapeutic use; Time Factors; Young Adult; Phase I clinical trials; early onset Alzheimer’s disease; pharmacodynamics; pharmacokinetics; AZD3293; BACE1 protein-human; Amyloid-beta peptides; cerebrospinal fluid proteins
• DOI: 10.3233/JAD-160701

AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.