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Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimers disease : randomized, double-blind, placebo-controlled study
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| Background β-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimers disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. Methods In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 68/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 140 [Aβ140] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated. Results In both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aβ140 levels from baseline at day 28 in both the 10-mg (6768%) and 50-mg (8790%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were − 69.37 (− 72.25; − 61.50) and − 92.74 (− 100.08; − 85.39), and for Japanese with preclinical AD, they were − 62.48 (− 78.32; − 46.64) and − 80.81 (− 96.13; − 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 6070% and 90% Aβ140 reductions, respectively. The trend of the reduction was similar across the Aβ137, Aβ138, and Aβ142 fragments in both atabecestat dose groups, consistent with Aβ140. CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period. Conclusions JNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aβ140 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults. |
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English
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Alzheimer's research & therapy | |
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2018
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1758-9193
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10(2018), 18 p.
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85
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000443965600002
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30134967
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E-only publicatie
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