Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ‐54861911, a potent oral BACE inhibitor

Timmers, Maarten; Broeck, Bianca Van; Ramael, Steven; Slemmon, J. Randall; Waepenaert, Katja De; Russu, Alberto; Bogert, Jennifer; Stieltjes, Hans; Shaw, Leslie M.; Engelborghs, Sebastiaan; Moechars, Dieder; Mercken, Marc; Liu, Enchi; Sinha, Vikash; Kemp, John A.; Nueten, Luc Van; Tritsmans, Luc; Streffer, Johannes

doi:10.1016/j.trci.2016.08.001

Cited by 55 publications

(59 citation statements)

References 29 publications

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“…Subsequent intramembrane proteolysis catalyzed by the c-secretase complex releases amyloid-b peptides of 38-43 amino acids, which form the pathogenic oligomeric and fibrillary Ab species (Haass, 2004;Masters & Selkoe, 2012). Inhibition of BACE-1 by low-molecular-weight compounds has emerged as a new concept for treatment of AD (Vassar et al, 2014;Eketjall et al, 2016;Kennedy et al, 2016;Timmers et al, 2016Timmers et al, , 2017Yan et al, 2016;Cebers et al, 2017) by preventing the generation and deposition of Ab rather than just treating the dementia symptoms. However, limited selectivity for BACE-1 over cathepsin D (CatD), the off-target inhibition of which is a principal driver of ocular toxicity, and liver enzyme elevation have led to the termination of some early BACE-1 inhibitors in clinical trials (May et al, 2011(May et al, , 2015Zuhl et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

The BACE ‐1 inhibitor CNP 520 for prevention trials in Alzheimer's disease

et al. 2018

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The beta‐site amyloid precursor protein cleaving enzyme‐1 (BACE‐1) initiates the generation of amyloid‐β (Aβ), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti‐Aβ therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE‐1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aβ in rats and dogs, and Aβ plaque deposition in APP‐transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose‐dependent Aβ reduction in the cerebrospinal fluid. Thus, long‐term, pivotal studies with CNP520 have been initiated in the Generation Program.

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Section: Introductionmentioning

confidence: 99%

The BACE ‐1 inhibitor CNP 520 for prevention trials in Alzheimer's disease

et al. 2018

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“…Seven days of dosing with the supratherapeutic dose, 150 mg, resulted in a mean JNJ-54861911 plasma C max of 1380 ng/mL, which is substantially above maximal therapeutic levels (C max at 50 mg equals 364 ng/mL). 5 Expectedly, ER analysis of these data demonstrated a positive and statistically significant slope of 0.0133 milliseconds per ng/mL. However, in the expected therapeutic dose range (up to 25 mg of JNJ-54861911), the extent of QT prolongation is expected to be consistently smaller than 5 milliseconds, that is, a mean of -0.4 milliseconds (90%CI, -0.8 to 0.1 milliseconds) at a 25mg dose (geometric mean C max , 71 ng/mL, based on population PK modeling).…”

Section: Discussionmentioning

confidence: 99%

“…Both studies have been described in detail elsewhere. 5 Both studies were double-blind, randomized, and placebocontrolled. All subjects were required to have a normal baseline ECG with QTc interval <430 milliseconds for men and <450 milliseconds for women in the SAD study, and <450 milliseconds for men and <470 milliseconds for women in the MAD study.…”

Section: Sad and Mad Studiesmentioning

confidence: 99%

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

Timmers

Sinha

Darpö

et al. 2018

The Journal of Clinical Pharma

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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.

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“…Human studies have shown similar results concerning the reduction of Aβ levels in response to treatment with BACE-1 inhibitor atabecestat. Results of a placebo-controlled phase I study in patients with early AD showed an up to 95% reduction of toxic Aβ levels in the CSF upon treatment with atabecestat [58]. With these promising results of reduced Aβ levels, severe ascription to the Aβ hypothesis would logically conclude parallel reductions in cognitive impairment.…”

Section: Nftmentioning

confidence: 99%

“…Drug candidates developed in this scheme include inhibitors of BACE-1 and γ-secretase. Evidence as to the pharmacologic engagement of BACE-1 inhibitors is often inferred from a reduction in Aβ concentrations subsequent to treatment with such an inhibitor, as determined by amyloid positron-emission tomography (amyloid PET) or immunoassay analysis [57,58]. A 2017 study conducted by Villarreal et al, using a murine model of advanced age, showed reduction of plasma Aβ 1-40 by 98% and Aβ 1-42 by 90% upon treatment with BACE-1 inhibitor verubecestat.…”

Section: Nftmentioning

confidence: 99%

Clinical Trials in Alzheimer’s Disease: A Hurdle in the Path of Remedy

Oxford

Stewart

Rohn

2020

International Journal of Alzheimer's Disease

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Human clinical trials seek to ameliorate the disease states and symptomatic progression of illnesses that, as of yet, are largely untreatable according to clinical standards. Ideally, clinical trials test “disease-modifying drugs,” i.e., therapeutic agents that specifically modify pathological features or molecular bases of the disease and would presumably have a large impact on disease progression. In the case of Alzheimer’s disease (AD), however, this approach appears to have stalled progress in the successful development of clinically useful therapies. For the last 25 years, clinical trials involving AD have centered on beta-amyloid (Aβ) and the Aβ hypothesis of AD progression and pathology. According to this hypothesis, the progression of AD begins following an accumulation of Aβ peptide, leading to eventual synapse loss and neuronal cell death: the true overriding pathological feature of AD. Clinical trials arising from the Aβ hypothesis target causal steps in the pathway in order to reduce the formation of Aβ or enhance clearance, and though agents have been successful in this aim, they remain unsuccessful in rescuing cognitive function or slowing cognitive decline. As such, further use of resources in the development of treatment options for AD that target Aβ, its precursors, or its products should be reevaluated. The purpose of this review was to give an overview of how human clinical trials are conducted in the USA and to assess the results of recent failed trials involving AD, the majority of which were based on the Aβ hypothesis. Based on these current findings, it is suggested that lowering Aβ is an unproven strategy, and it may be time to refocus on other targets for the treatment of this disease including pathological forms of tau.

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Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ‐54861911, a potent oral BACE inhibitor

Cited by 55 publications

References 29 publications

The BACE ‐1 inhibitor CNP 520 for prevention trials in Alzheimer's disease

The BACE ‐1 inhibitor CNP 520 for prevention trials in Alzheimer's disease

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

Clinical Trials in Alzheimer’s Disease: A Hurdle in the Path of Remedy

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