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Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780.

Toyn JH, Thompson LA, Lentz KA, Meredith JE, Burton CR, Sankaranararyanan S, Guss V, Hall T, Iben LG, Krause CM, Krause R, Lin XA, Pierdomenico M, Polson C, Robertson AS, Denton RR, Grace JE, Morrison J, Raybon J, Zhuo X, Snow K, Padmanabha R, Agler M, Esposito K, Harden D, Prack M, Varma S, Wong V, Zhu Y, Zvyaga T, Gerritz S, Marcin LR, Higgins MA, Shi J, Wei C, Cantone JL, Drexler DM, Macor JE, Olson RE, Ahlijanian MK, Albright CF - Int J Alzheimers Dis (2014)

Bottom Line: Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 lowering.Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued.Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aβ1-42 without Notch-related side effects.

View Article: PubMed Central - PubMed

Affiliation: Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.

ABSTRACT
Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-β peptide (Aβ), particularly the 42-amino acid Aβ1-42, in the brain. Aβ1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aβ production. BMS-869780 is a potent GSM that decreased Aβ1-42 and Aβ1-40 and increased Aβ1-37 and Aβ1-38, without inhibiting overall levels of Aβ peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aβ1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aβ1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aβ1-42 without Notch-related side effects.

No MeSH data available.


Related in: MedlinePlus

Pharmacokinetics (PK) of BMS-869780 across species for prediction of human PK. Rats, dogs, and cynomolgus monkeys were dosed with BMS-869780 intravenously (IV ▲) at 1 mg/kg or oral nanosuspension (PO ●) at 5 mg/kg. Plasma concentrations of BMS-869780 were determined for up to 24 hours after the dose. (a) Rat. (b) Dog. (c) Cynomolgus monkey. The derived PK parameters are summarized in Table 4.
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fig9: Pharmacokinetics (PK) of BMS-869780 across species for prediction of human PK. Rats, dogs, and cynomolgus monkeys were dosed with BMS-869780 intravenously (IV ▲) at 1 mg/kg or oral nanosuspension (PO ●) at 5 mg/kg. Plasma concentrations of BMS-869780 were determined for up to 24 hours after the dose. (a) Rat. (b) Dog. (c) Cynomolgus monkey. The derived PK parameters are summarized in Table 4.

Mentions: To make a prediction of human PK for BMS-869780, the PK profiles for solution IV and nanoparticle suspension PO dosing of BMS-869780 were determined in rat, dog, and cynomolgus monkey (Figure 9; Table 4). Plasma exposure was readily detectable for 24 hours after dosing, and the average bioavailability of the nanoparticle suspension for the three species was 28%. Allometric scaling of the observed animal PK parameters was used to predict human PK parameters (Table 4) [70, 71]. From the predicted human PK, in combination with the PK/PD parameters from rat, a 10 mg/kg once daily dose (700 mg total) was predicted to achieve a steady-state AUC = 17.8 μM·h, Cmax⁡ = 1.27 μM, and corresponding brain Aβ1-42 ABEC = 25% (Table 3).


Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780.

Toyn JH, Thompson LA, Lentz KA, Meredith JE, Burton CR, Sankaranararyanan S, Guss V, Hall T, Iben LG, Krause CM, Krause R, Lin XA, Pierdomenico M, Polson C, Robertson AS, Denton RR, Grace JE, Morrison J, Raybon J, Zhuo X, Snow K, Padmanabha R, Agler M, Esposito K, Harden D, Prack M, Varma S, Wong V, Zhu Y, Zvyaga T, Gerritz S, Marcin LR, Higgins MA, Shi J, Wei C, Cantone JL, Drexler DM, Macor JE, Olson RE, Ahlijanian MK, Albright CF - Int J Alzheimers Dis (2014)

Pharmacokinetics (PK) of BMS-869780 across species for prediction of human PK. Rats, dogs, and cynomolgus monkeys were dosed with BMS-869780 intravenously (IV ▲) at 1 mg/kg or oral nanosuspension (PO ●) at 5 mg/kg. Plasma concentrations of BMS-869780 were determined for up to 24 hours after the dose. (a) Rat. (b) Dog. (c) Cynomolgus monkey. The derived PK parameters are summarized in Table 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4109680&req=5

fig9: Pharmacokinetics (PK) of BMS-869780 across species for prediction of human PK. Rats, dogs, and cynomolgus monkeys were dosed with BMS-869780 intravenously (IV ▲) at 1 mg/kg or oral nanosuspension (PO ●) at 5 mg/kg. Plasma concentrations of BMS-869780 were determined for up to 24 hours after the dose. (a) Rat. (b) Dog. (c) Cynomolgus monkey. The derived PK parameters are summarized in Table 4.
Mentions: To make a prediction of human PK for BMS-869780, the PK profiles for solution IV and nanoparticle suspension PO dosing of BMS-869780 were determined in rat, dog, and cynomolgus monkey (Figure 9; Table 4). Plasma exposure was readily detectable for 24 hours after dosing, and the average bioavailability of the nanoparticle suspension for the three species was 28%. Allometric scaling of the observed animal PK parameters was used to predict human PK parameters (Table 4) [70, 71]. From the predicted human PK, in combination with the PK/PD parameters from rat, a 10 mg/kg once daily dose (700 mg total) was predicted to achieve a steady-state AUC = 17.8 μM·h, Cmax⁡ = 1.27 μM, and corresponding brain Aβ1-42 ABEC = 25% (Table 3).

Bottom Line: Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 lowering.Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued.Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aβ1-42 without Notch-related side effects.

View Article: PubMed Central - PubMed

Affiliation: Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.

ABSTRACT
Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-β peptide (Aβ), particularly the 42-amino acid Aβ1-42, in the brain. Aβ1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aβ production. BMS-869780 is a potent GSM that decreased Aβ1-42 and Aβ1-40 and increased Aβ1-37 and Aβ1-38, without inhibiting overall levels of Aβ peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aβ1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aβ1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aβ1-42 without Notch-related side effects.

No MeSH data available.


Related in: MedlinePlus