Evaluating Potential QT Effects of JNJ‐54861911, a BACE Inhibitor in Single‐ and Multiple‐Ascending Dose Studies, and a Thorough QT Trial With Additional Retrospective Confirmation, Using Concentration‐QTc Analysis

Abstract

Nonclinical assays with JNJ-54861911, a β-secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4-way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ-54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high-precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first-in-human single-ascending dose (SAD) and multiple-ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo-corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9-18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure-response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ-54861911 peak plasma concentrations (C ) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; C , 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ-54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects

“…As BACE1 inhibition typically requires a basic amine for interaction with the catalytic aspartic acids at the active site of the BACE1 enzyme [40], BACE inhibitors in general are potential hERG ligands [36]. Most BACE1 inhibitors, as reported, inhibited hERG in in vitro studies [15,17,36], and displayed a dosedependent effect on QT prolongation in early clinical studies [15,17,18]. However, these QT effects were small and not clinically significant at up to the highest clinically relevant (supratherapeutic) doses.…”

“…While it is 75% homologous to BACE (BACE1), studies indicate that BACE2 does not play an active role in A␤ peptide production in the brain [13] and BACE2 inhibition can thus be considered off-target for the treatment of AD. Despite this, and although a number of BACE inhibitors have progressed to late-stage clinical trials, including AZD3293, MK-8931, JNJ-54861911, CNP520, and E2609 [14][15][16][17][18], progress in designing a BACE inhibitor that has good selectivity for BACE1 over BACE2 has been limited. Indeed, aside from CNP520, which has shown some selectivity for BACE1 [16], current BACE inhibitors appear to inhibit BACE1 and BACE2 to a similar degree [19].…”

A Pooled Analysis of Three Randomized Phase I/IIa Clinical Trials Confirms Absence of a Clinically Relevant Effect on the QTc Interval by Umibecestat

“…24 Atabecestat inhibited the hERG current in HEK293 starting at a 0.2 μM and prolonged the action potential in guinea pig papillary muscle preparations from 1 μM; it also induced QTc prolongation and increased HR in dogs. 25 For umibecestat, the hERG IC 50 was 3.2 μM, estimating a safety margin of 114-fold over the anticipated free C max of 0.028 μM at multiple 50 mg daily doses in the Generation Program. 11 Assessment of the inhibition of hERG by umibecestat demonstrated an IC 50 of 3.2 μM, that was estimated to provide a 114-fold safety margin based on the anticipated therapeutic C max of the free plasma concentration of 0.028 μM (estimated free C max at multiple doses of 50 mg daily, the highest dose investigated in the Generation Program).…”

Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target?

“…Elenbecestat (E2609) is a small molecule β-secretase inhibitor with two phase III clinical trials (NCT02956486 and NCT03036280) currently ongoing for efficacy and safety evaluation in early AD treatment, and one phase II trial (NCT02322021) for MCI and mild to moderate AD. Atabecestat (JNJ-54861911) is a β-secretase inhibitor proven to reduce CSF-Aβ concentrations in a dose-dependent manner in both healthy elderlies and early stage AD patients [138,139,140]. Two phase II/III clinical trials of this drug are still ongoing (NCT01760005 and NCT02569398).…”