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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 rats after oral dosing. The significance of differences in effect sizes (analyzed as % of vehicle) produced by the doses within each timepoint was tested. a-c: 3 μmol/kg (squares), 10 μmol/kg (circles), and 30 μmol/kg (triangles). Mean values ± SD are shown, n = 5. a NB-360 exposure in blood and brain. b Aβ40 in forebrain, *p < 0.05 3 vs 10 μmol/kg, $ p < 0.05 3 vs 30 μmol/kg, # p < 0.01 3 vs 30 μmol/kg c: Aβ40 in CSF, ***p < 0.001 3 vs 10 μmol/kg, $ p < 0.05, $$ p < 0.01, $$$ p < 0.001 3 vs 30 μmol/kg, # p < 0.05 and ### p < 0.001 10 vs 30 μmol/kg, d: Dose-response in brain based on 4 h data
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Fig2: Pharmacokinetics and pharmacodynamics of NB-360 in rats after oral dosing. The significance of differences in effect sizes (analyzed as % of vehicle) produced by the doses within each timepoint was tested. a-c: 3 μmol/kg (squares), 10 μmol/kg (circles), and 30 μmol/kg (triangles). Mean values ± SD are shown, n = 5. a NB-360 exposure in blood and brain. b Aβ40 in forebrain, *p < 0.05 3 vs 10 μmol/kg, $ p < 0.05 3 vs 30 μmol/kg, # p < 0.01 3 vs 30 μmol/kg c: Aβ40 in CSF, ***p < 0.001 3 vs 10 μmol/kg, $ p < 0.05, $$ p < 0.01, $$$ p < 0.001 3 vs 30 μmol/kg, # p < 0.05 and ### p < 0.001 10 vs 30 μmol/kg, d: Dose-response in brain based on 4 h data

Mentions: NB-360 was orally dosed to rats at 3, 10, and 30 μmol/kg, and compound concentrations were measured at different time points over 24 h in blood and in forebrain (Fig. 2a). NB-360 was rapidly absorbed with a Tmax around 1 h, and showed a parallel decline in blood and brain over time. Aβ40 was determined in the brain homogenate and in CSF (Fig. 2b and 2c), and a dose- and time-dependent reduction was observed in both tissues. Maximum activity was between 4 and 8 h, and Aβ40 concentrations returned to baseline after 24 h. Significant (>50 %) Aβ40 lowering was observed even at the lowest dose of 3 μmol/kg, and the effect saturated at higher doses. At the 30 μmol/kg dose, 90.9 % inhibition was reached at 4 h, corresponding to 0.06 pmol Aβ40/mg brain tissues. Although we did not perform a formal determination of the quantification limit of Aβ40 in rat brain, previous experience indicated that this was the practical limit of quantification under our extraction and analysis conditions. Since NB-360 showed such a profound inhibition even at the 3 μmol/kg p.o. dose, in a second study we extended the dose range to 0.3 and 1 μmol/kg and calculated an efficacious dose (ED50) of 1.6 ± 0.25 μmol/kg for inhibition of forebrain Aβ40 in the rat at 4 h (Fig. 2d). Overall, NB-360 was highly potent in the rat, and compound exposure correlated well to effect.Fig. 2


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 rats after oral dosing. The significance of differences in effect sizes (analyzed as % of vehicle) produced by the doses within each timepoint was tested. a-c: 3 μmol/kg (squares), 10 μmol/kg (circles), and 30 μmol/kg (triangles). Mean values ± SD are shown, n = 5. a NB-360 exposure in blood and brain. b Aβ40 in forebrain, *p < 0.05 3 vs 10 μmol/kg, $ p < 0.05 3 vs 30 μmol/kg, # p < 0.01 3 vs 30 μmol/kg c: Aβ40 in CSF, ***p < 0.001 3 vs 10 μmol/kg, $ p < 0.05, $$ p < 0.01, $$$ p < 0.001 3 vs 30 μmol/kg, # p < 0.05 and ### p < 0.001 10 vs 30 μmol/kg, d: Dose-response in brain based on 4 h data
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Pharmacokinetics and pharmacodynamics of NB-360 in rats after oral dosing. The significance of differences in effect sizes (analyzed as % of vehicle) produced by the doses within each timepoint was tested. a-c: 3 μmol/kg (squares), 10 μmol/kg (circles), and 30 μmol/kg (triangles). Mean values ± SD are shown, n = 5. a NB-360 exposure in blood and brain. b Aβ40 in forebrain, *p < 0.05 3 vs 10 μmol/kg, $ p < 0.05 3 vs 30 μmol/kg, # p < 0.01 3 vs 30 μmol/kg c: Aβ40 in CSF, ***p < 0.001 3 vs 10 μmol/kg, $ p < 0.05, $$ p < 0.01, $$$ p < 0.001 3 vs 30 μmol/kg, # p < 0.05 and ### p < 0.001 10 vs 30 μmol/kg, d: Dose-response in brain based on 4 h data
Mentions: NB-360 was orally dosed to rats at 3, 10, and 30 μmol/kg, and compound concentrations were measured at different time points over 24 h in blood and in forebrain (Fig. 2a). NB-360 was rapidly absorbed with a Tmax around 1 h, and showed a parallel decline in blood and brain over time. Aβ40 was determined in the brain homogenate and in CSF (Fig. 2b and 2c), and a dose- and time-dependent reduction was observed in both tissues. Maximum activity was between 4 and 8 h, and Aβ40 concentrations returned to baseline after 24 h. Significant (>50 %) Aβ40 lowering was observed even at the lowest dose of 3 μmol/kg, and the effect saturated at higher doses. At the 30 μmol/kg dose, 90.9 % inhibition was reached at 4 h, corresponding to 0.06 pmol Aβ40/mg brain tissues. Although we did not perform a formal determination of the quantification limit of Aβ40 in rat brain, previous experience indicated that this was the practical limit of quantification under our extraction and analysis conditions. Since NB-360 showed such a profound inhibition even at the 3 μmol/kg p.o. dose, in a second study we extended the dose range to 0.3 and 1 μmol/kg and calculated an efficacious dose (ED50) of 1.6 ± 0.25 μmol/kg for inhibition of forebrain Aβ40 in the rat at 4 h (Fig. 2d). Overall, NB-360 was highly potent in the rat, and compound exposure correlated well to effect.Fig. 2

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