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

by Goldwater, Ronald.
Citation: Journal of Alzheimer's Disease. 55(3):1039-1053, 2017.Journal: Journal of Alzheimer's disease : JAD.Published: 2017ISSN: 1387-2877.Full author list: Cebers G; Alexander RC; Haeberlein SB; Han D; Goldwater R; Ereshefsky L; Olsson T; Ye N; Rosen L; Russell M; Maltby J; Eketjall S; Kugler AR.UI/PMID: 27767991.Subject(s): Adolescent | Adult | Age Factors | Aged | Aged, 80 and over | *Alzheimer Disease/dt [Drug Therapy] | Amyloid beta-Peptides/bl [Blood] | Amyloid beta-Peptides/cf [Cerebrospinal Fluid] | *Antipsychotic Agents/pk [Pharmacokinetics] | *Antipsychotic Agents/tu [Therapeutic Use] | Cross-Over Studies | Dose-Response Relationship, Drug | Double-Blind Method | Drug Administration Schedule | Female | Follow-Up Studies | Food | Healthy Volunteers | Humans | *Imidazoles/pk [Pharmacokinetics] | *Imidazoles/tu [Therapeutic Use] | Male | Middle Aged | Neurologic Examination | Peptide Fragments/bl [Blood] | Peptide Fragments/cf [Cerebrospinal Fluid] | *Spiro Compounds/pk [Pharmacokinetics] | *Spiro Compounds/tu [Therapeutic Use] | Time Factors | Young AdultInstitution(s): MedStar Harbor HospitalActivity type: Journal Article.Medline article type(s): Clinical Trial, Phase I | Journal Article | Randomized Controlled TrialDigital Object Identifier: http://dx.doi.org/10.3233/JAD-160701 (Click here) Abbreviated citation: J Alzheimers Dis. 55(3):1039-1053, 2017.Abstract: AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (beta-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 Abeta40 and Abeta42 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) Abeta peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Abeta with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.

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