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

 -  2017 
<br/><br/> 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. 
<br/><br/><br/>English 
<br/><br/><label>ISSN: </label>1387-2877 
<br/><br/><label>Standard No.: </label>10.3233/JAD-160701 [doi] JAD160701 [pii] 
<br/><br/><label>Subjects--Topical Terms: </label><br/>*Alzheimer Disease/dt [Drug Therapy]<br/>*Antipsychotic Agents/pk [Pharmacokinetics]<br/>*Antipsychotic Agents/tu [Therapeutic Use]<br/>*Imidazoles/pk [Pharmacokinetics]<br/>*Imidazoles/tu [Therapeutic Use]<br/>*Spiro Compounds/pk [Pharmacokinetics]<br/>*Spiro Compounds/tu [Therapeutic Use]<br/>Adolescent<br/>Adult<br/>Age Factors<br/>Aged<br/>Aged, 80 and over<br/>Amyloid beta-Peptides/bl [Blood]<br/>Amyloid beta-Peptides/cf [Cerebrospinal Fluid]<br/>Cross-Over Studies<br/>Dose-Response Relationship, Drug<br/>Double-Blind Method<br/>Drug Administration Schedule<br/>Female<br/>Follow-Up Studies<br/>Food<br/>Healthy Volunteers<br/>Humans<br/>Male<br/>Middle Aged<br/>Neurologic Examination<br/>Peptide Fragments/bl [Blood]<br/>Peptide Fragments/cf [Cerebrospinal Fluid]<br/>Time Factors<br/>Young Adult
<br/><br/><label>Subjects--Geographic Terms: </label><br/>MedStar Harbor Hospital
<br/><br/><label>Index Terms--Function: </label><br/>Clinical Trial, Phase I<br/>Journal Article<br/>Randomized Controlled Trial