title: AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease.
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.
authors: AstraZeneca, Neuroscience, Waltham, MA, USA.
authors: Gvido
authors: G
authors: Cebers
authors: AstraZeneca, Neuroscience, Waltham, MA, USA.
authors: Robert C
authors: RC
authors: Alexander
authors: AstraZeneca, Neuroscience, Waltham, MA, USA.
authors: Samantha Budd
authors: SB
authors: Haeberlein
authors: PAREXEL, Early Phase Clinical Unit, Glendale, CA, USA.
authors: David
authors: D
authors: Han
authors: PAREXEL, Clinical Pharmacology Research Unit, Harbor Hospital, Baltimore, MD, USA.
authors: Ronald
authors: R
authors: Goldwater
authors: PAREXEL, Early Phase Clinical Unit, Glendale, CA, USA.
authors: Larry
authors: L
authors: Ereshefsky
authors: AstraZeneca, Neuroscience, Waltham, MA, USA.
authors: Tina
authors: T
authors: Olsson
authors: AstraZeneca, Neuroscience, Waltham, MA, USA.
authors: Naidong
authors: N
authors: Ye
authors: AstraZeneca, Neuroscience, Waltham, MA, USA.
authors: Laura
authors: L
authors: Rosen
authors: AstraZeneca, Protein Biomarkers, Personalised Healthcare and Biomarkers, Alderley Park, UK.
authors: Muir
authors: M
authors: Russell
authors: AstraZeneca, Protein Biomarkers, Personalised Healthcare and Biomarkers, Alderley Park, UK.
authors: Justine
authors: J
authors: Maltby
authors: AstraZeneca Integrated Cardio Metabolic Centre, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, Karolinska Institutet, Solna, Sweden.
authors: Susanna
authors: S
authors: Eketjäll
authors: AstraZeneca, Neuroscience, Waltham, MA, USA.
authors: Alan R
authors: AR
authors: Kugler
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005502:Food; D064368:Healthy Volunteers; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009460:Neurologic Examination; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid; D013141:Spiro Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013997:Time Factors; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D007093:Imidazoles; D010446:Peptide Fragments; D013141:Spiro Compounds; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C000608388:lanabecestat
keywords: AZD3293; Amyloid-beta peptides; BACE1 protein-human; Phase I 
  clinical trials; cerebrospinal fluid 
  proteins; early onset Alzheimer’s disease; pharmacodynamics; pharmacokinetics