A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice

Abstract

BackgroundAlzheimer’s disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans.ResultsTreatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared.ConclusionsIn a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer’s disease.

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

“…NB-360 inhibits the enzymatic activity of BACE, which is required for the generation of Aβ peptides from APP (12). Indeed, quantification of Aβ revealed a substantial reduction of the Aβ plaque burden ( (9,13).…”

“…The BACE inhibitor NB-360 was used in this study. A detailed description of the compound's in vitro and in vivo efficacy, pharmacokinetics, and brain penetration in various animal models has been described previously (9). Oral treatment with NB-360 was provided by incorporating the drug into food pellets (0.25 g/kg; Provimi Kliba, Kaiseraugst, Switzerland).…”

“…To clarify the causal relationship between Aβ and pathophysiology in vivo, we made use of a novel compound that reduces Aβ by inhibiting the β-secretase BACE, the rate-limiting enzyme for Aβ production (9). This approach allowed us to determine how the inhibition of Aβ production affects neural circuit and memory impairments in APP23xPS45 transgenic mice overexpressing mutant human amyloid precursor protein (APP) and presenilin 1 (PS1).…”

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

“…These effects were attributed to the ability of NB‐360 to reduce the formation of Aβ oligomers. When researchers reintroduced soluble Aβ oligomers to these mice, the positive implication of NB‐360 was reverted and the mice showed again the typical symptoms of AD . Therefore, these in vivo studies revealed evidence on the implication of BACE1 inhibitors as a valid approach to tackle AD and that Aβ oligomers are having a downstream effect on AD progression …”

“…Moreover, many in vivo studies confirmed that β‐secretase play a vital role in AD progression and the use of BACE1 inhibitors improved the neurological function and surpassed the neurological defects imposed in mice of AD model . For example, in a recent study utilizing NB‐360 as BACE1 inhibitor in mice with familial Alzheimer disease, the administration of this agent resulted in the enhancement of neuronal activity and the improvement of memory . These effects were attributed to the ability of NB‐360 to reduce the formation of Aβ oligomers.…”