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

Neumann U, Rueeger H, Machauer R, Veenstra SJ, Lueoend RM, Tintelnot-Blomley M, Laue G, Beltz K, Vogg B, Schmid P, Frieauff W, Shimshek DR, Staufenbiel M, Jacobson LH - Mol Neurodegener (2015)

Bottom Line: Current symptomatic treatments delay, but do not halt, disease progression.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.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. ulf.neumann@novartis.com.

ABSTRACT

Background: Alzheimer'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.

Results: Treatment 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.

Conclusions: In 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.

No MeSH data available.


Related in: MedlinePlus

Pharmacokinetics and pharmacodynamics of NB-360 in Beagle dogs. a Exposure of NB-360 in blood and CSF of cannulated dogs (mean ± SD, n = 4) after 0.5 mg/kg p.o. dosing, b concentrations of CSF Aβ40 for the individual dogs, late CSF samples were missing for dogs 1 and 2, c CSF Aβ40 in vehicle and treatment group, expressed as percent of the mean of the -24 h and the -1 h predose values (mean ± SD), d plasma Aβ40 in vehicle and treatment groups
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Fig3: Pharmacokinetics and pharmacodynamics of NB-360 in Beagle dogs. a Exposure of NB-360 in blood and CSF of cannulated dogs (mean ± SD, n = 4) after 0.5 mg/kg p.o. dosing, b concentrations of CSF Aβ40 for the individual dogs, late CSF samples were missing for dogs 1 and 2, c CSF Aβ40 in vehicle and treatment group, expressed as percent of the mean of the -24 h and the -1 h predose values (mean ± SD), d plasma Aβ40 in vehicle and treatment groups

Mentions: We selected dogs to evaluate the NB-360 pharmacology in a non-rodent animal model because they are commonly used for toxicological investigations, and are discussed as models for human AD [15]. Furthermore dog and human Aβ show sequence identity. Our pharmacokinetic studies in dogs (Table 3) showed good oral bioavailability and much longer half-life, compared to rodents. Based on pharmacokinetic data, we selected a dose of 0.5 mg/kg (1.1 μmol/kg) p.o. for a pharmacokinetic/pharmacodynamic study of NB-360 in young Beagle dogs, carrying an implanted ventricular port for repeated CSF sampling. Blood and CSF were sampled before treatment (at -24 and at -1 h) and at various time points after oral dosing, up to 168 h. The pharmacokinetic profiles of NB-360 in blood and in CSF were very similar (Fig. 3a). The peak concentration of 0.7 μM was reached in blood quickly after dosing. At the 168 h time point, NB-360 concentrations were 0.023 ± 0.031 μM in blood, and below detection limit in CSF. The average CSF/blood ratio was 0.023 ± 0.014 (mean ± SD, calculated from n = 20 CSF/blood data pairs). Without radiolabeled NB-360 being available, we were unable to accurately determine the plasma protein binding in dog plasma, Therefore, a precise calculation of the CSF/free blood ratio could not be done.Fig. 3


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

Neumann U, Rueeger H, Machauer R, Veenstra SJ, Lueoend RM, Tintelnot-Blomley M, Laue G, Beltz K, Vogg B, Schmid P, Frieauff W, Shimshek DR, Staufenbiel M, Jacobson LH - Mol Neurodegener (2015)

Pharmacokinetics and pharmacodynamics of NB-360 in Beagle dogs. a Exposure of NB-360 in blood and CSF of cannulated dogs (mean ± SD, n = 4) after 0.5 mg/kg p.o. dosing, b concentrations of CSF Aβ40 for the individual dogs, late CSF samples were missing for dogs 1 and 2, c CSF Aβ40 in vehicle and treatment group, expressed as percent of the mean of the -24 h and the -1 h predose values (mean ± SD), d plasma Aβ40 in vehicle and treatment groups
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559881&req=5

Fig3: Pharmacokinetics and pharmacodynamics of NB-360 in Beagle dogs. a Exposure of NB-360 in blood and CSF of cannulated dogs (mean ± SD, n = 4) after 0.5 mg/kg p.o. dosing, b concentrations of CSF Aβ40 for the individual dogs, late CSF samples were missing for dogs 1 and 2, c CSF Aβ40 in vehicle and treatment group, expressed as percent of the mean of the -24 h and the -1 h predose values (mean ± SD), d plasma Aβ40 in vehicle and treatment groups
Mentions: We selected dogs to evaluate the NB-360 pharmacology in a non-rodent animal model because they are commonly used for toxicological investigations, and are discussed as models for human AD [15]. Furthermore dog and human Aβ show sequence identity. Our pharmacokinetic studies in dogs (Table 3) showed good oral bioavailability and much longer half-life, compared to rodents. Based on pharmacokinetic data, we selected a dose of 0.5 mg/kg (1.1 μmol/kg) p.o. for a pharmacokinetic/pharmacodynamic study of NB-360 in young Beagle dogs, carrying an implanted ventricular port for repeated CSF sampling. Blood and CSF were sampled before treatment (at -24 and at -1 h) and at various time points after oral dosing, up to 168 h. The pharmacokinetic profiles of NB-360 in blood and in CSF were very similar (Fig. 3a). The peak concentration of 0.7 μM was reached in blood quickly after dosing. At the 168 h time point, NB-360 concentrations were 0.023 ± 0.031 μM in blood, and below detection limit in CSF. The average CSF/blood ratio was 0.023 ± 0.014 (mean ± SD, calculated from n = 20 CSF/blood data pairs). Without radiolabeled NB-360 being available, we were unable to accurately determine the plasma protein binding in dog plasma, Therefore, a precise calculation of the CSF/free blood ratio could not be done.Fig. 3

Bottom Line: Current symptomatic treatments delay, but do not halt, disease progression.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.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. ulf.neumann@novartis.com.

ABSTRACT

Background: Alzheimer'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.

Results: Treatment 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.

Conclusions: In 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.

No MeSH data available.


Related in: MedlinePlus