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

Article type: Research Article

Authors: Cebers, Gvido^{a; 1} | Alexander, Robert C.^{a; 2} | Haeberlein, Samantha Budd^{a; 3} | Han, David^b | Goldwater, Ronald^c | Ereshefsky, Larry^b | Olsson, Tina^{a; 3} | Ye, Naidong^{a; 4} | Rosen, Laura^{a; 5} | Russell, Muir^d | Maltby, Justine^d | Eketjäll, Susanna^{e; *} | Kugler, Alan R.^{a; 6}

Affiliations: [a] AstraZeneca, Neuroscience, Waltham, MA, USA | [b] PAREXEL, Early Phase Clinical Unit, Glendale, CA, USA | [c] PAREXEL, Clinical Pharmacology Research Unit, Harbor Hospital, Baltimore, MD, USA | [d] AstraZeneca, Protein Biomarkers, Personalised Healthcare and Biomarkers, Alderley Park, UK | [e] AstraZeneca Integrated Cardio Metabolic Centre, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, Karolinska Institutet, Solna, Sweden

Correspondence: [*] Correspondence to: Susanna Eketjäll, PhD, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Novum, Blickargången 6, SE-141 57 Huddinge, Sweden. Tel.: +46 553 22977; Fax: +46 8 31 11 01; E-mail: [email protected].

Note: [] Current Addresses: 1Independent Consultant, Cambridge, MA, USA.

Note: [] 2Pfizer Inc., Cambridge, MA, USA.

Note: [] 3Biogen Idec, Inc., Cambridge, MA, USA.

Note: [] 4Millendo Therapeutics, Inc., Ann Arbor, MI, USA.

Note: [] 5Flex Pharma, Inc., Boston, MA, USA.

Note: [] 6Coastal Pharma Group, Concord, MA, USA.

Abstract: 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.

Keywords: Amyloid-beta peptides, AZD3293, BACE1 protein-human, cerebrospinal fluid proteins, early onset Alzheimer’s disease, pharmacodynamics, pharmacokinetics, Phase I clinical trials

DOI: 10.3233/JAD-160701

Journal: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1039-1053, 2017