Name:	BMS-708163
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Oral, small molecule
Mechanisms:	γ-secretase inhibitor
Development Status:	investigational in U.S.
FDA Phase:	Phase II/IIa/IIb
Role in Alzheimer's Disease:	BMS-708163 is a potent and selective γ-secretase inhibitor (GSI). Phase I clinical trial studies showed that in humans, it decreased CSF Aβ40 and Aβ42 approximately 30 percent following daily dose of 100 mg after 28 days and by 60 percent at daily dose of 150 mg. While it has an IC50 for APP cleavage of 0.3 nM, significantly more potent than GSI-953, another selective GSI (15 nM), BMS-708163, is 190-fold more selective for APP than Notch, having an IC50 of 58 nM for Notch (Albright et al., 2008). (See also ARF related news story.)
Side Effects:	The 190-fold selectivity of BMS-708163 on targets APP vs. Notch suggests that the profile of adverse effects might be significantly fewer than those seen previously with LY450139, affecting gastrointestinal, skin, and immune cell functions. In support of this idea, BMS-708163 demonstrated none of the typical adverse effects in animals treated with 10-fold higher dose than that required to reduce Aβ. Preliminary results from single and multi-dose studies in healthy young subjects show that BMS-708163 is safe and well tolerated with acceptable pharmacokinetics (orally available with a multi-phasic profile, Tmax = 1-2 h, linear pharmacokinetics up to 200 mg, and a terminal half-life of approximately 40 h). Single dose of BMS-708163 decreased CSF Aβ more than 25 percent at exposures similar to those that were safe and tolerable following multiple dosing (Albright et al., 2008).
Companies:	Bristol-Myers Squibb
Notes:	A Phase II multicenter, double-blind, placebo-controlled safety and tolerability study of BMS-708163 in patients with mild to moderate Alzheimer disease is currently ongoing participants. Mild to moderate AD and a Phase II multicenter, double-blind, placebo-controlled safety and tolerability study in Prodromal AD is currently recruiting patients Prodromal AD. This entry posted on Dec 21, 2009.

References

Albright C, Dockens R, Olson R, Jere M, Slemmon R, Lentz K, Wang J, Denton R, Pilcher G, Zacaek R, Macor J, Wong O, Gu H, Berman R, Tong G. (2008) BMS-708163, a potent and selective γ-secretase inhibitor, decreases CSF Aβ at safe and tolerable doses in animals and humans. International Conference on Alzheimer's Disease, July 26-31, Chicago, Illinois. (Abstract HT-01-05)