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

Abstract

Umibecestat, an orally active β-secretase inhibitor, reduces the production of amyloid beta-peptide that accumulates in the brain of patients with Alzheimer's disease. The echocardiogram effects of umibecestat, on QTcF (Fridericia-corrected QT), on PR and QRS and heart rate (HR), were estimated by concentration-effect modeling. Three phase I/II studies with durations up to 3 months, with 372 healthy subjects over a wide age range, including both sexes and 2 ethnicities, were pooled, providing a large data set with good statistical power. No clinically relevant effect on QTcF, PR interval, QRS duration, or HR were observed up to supratherapeutic doses. The upper bound of 90% confidence intervals of the ∆QTcF was below the 10 ms threshold of regulatory concern for all concentrations measured. Prespecified sensitivity analysis confirmed the results in both sexes, in those over and below 60 years, and in Japanese subjects. All conclusions were endorsed by the US Food and Drug Administration (FDA). Alzheimer's disease (AD) is one of the most prevalent and debilitating neurodegenerative disorders, and there is a high unmet medical need for effective prevention or treatment. According to the Global Burden of Disease Study 2016, a total of 43.8 million individuals were living with dementia globally. 1 Although the approved pharmacological agents (donepezil, galantamine, rivastigmine, and memantine) treat the symptoms of AD, no disease-modifying treatment for presymptomatic or prodromal AD is currently available. 2 AD is associated with the accumulation of amyloid beta (Aβ)-peptide plaques and tau proteins, which are the hallmarks of the multifactorial nature of late-onset AD. 3,4 These plaques consist of aggregated fibrils of Aβ peptides that are derived via enzymatic processing of the amyloid precursor protein (APP). 5 A substantial body of genetic, histopathological, and biomarker evidence supports a potential causal role for Aβ in AD. 6-9 Thus, prevention of Aβ formation by inhibiting the protease responsible for the critical first step in

Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer’s Disease

“…However, the manual patch clamp assay showed, in contrast, an IC 50 > 10 μM. No QTc prolongation was detected in animal safety studies nor in human phase I and IIa studies of compound 15 . We attribute the favorable cardiosafety profile of 15 to the low free plasma exposure at active doses.…”

“…No QTc prolongation was detected in animal safety studies nor in human phase I and IIa studies of compound 15. 36 We attribute the favorable cardiosafety profile of 15 to the low free plasma exposure at active doses. This compound, which offered the best overall profile, in terms of BACE1/BACE2 selectivity, pharmacodynamic, and pharmacokinetic properties, was further profiled for transition to clinical studies in humans.…”

Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer’s disease

“…However, APP cleavage via β and γ-secretase results in a sAPPβ fragment and Aβ peptide, the primary component of amyloid plaques in AD [26,27]. Several human clinical trials for AD have focused on inhibition of β and γ-secretase to decrease Aβ production [28][29][30][31][32][33][34]. Although these trials showed a decrease in plasma and CSF Aβ levels, they have failed when it comes to establishing safety and efficacy.…”

“…Although these trials showed a decrease in plasma and CSF Aβ levels, they have failed when it comes to establishing safety and efficacy. These trials have been discontinued based on increased incidence of skin cancer and worsening cognitive scores [29][30][31][32][33][34].…”

“…These trials either target clearance of Aβ and tau or focus on immunotherapy involving active or passive immunization. Several of them have failed in Phase 2/3 clinical trials due to lack of efficacy or toxicity issues [29][30][31][32][33][34][174][175][176][177]. The development of a human choroid plexus organoid [178] may accelerate the drug discovery process since it is involved in the production of CSF which regulates movement of nutrients/drugs into the brain [179].…”