Background:

NGP555 is a γ-secretase modulator.

NGP555 potently lowers Aβ42 in cell cultures (9 nM) while increasing shorter forms of Aβ[1].

NGP555 significantly lowers Aβ42 in the cerebrospinal fluid (CSF) at time points from 8 to10 hours post dose, panel B shows that reduction of Aβ cerebrospinal fluid (CSF) levels is significant at 3.75 mg/kg of NGP555 and above, and panel C shows an increase in Aβ38 levels at 15 mg/kg of NGP555 and above. When combining the reduction of Aβ42 with an increase in Aβ38, NGP555 is effective at raising CSF Aβ38/42 ratio at 1.87 mg/kg and above (panel D). NGP555-treated Tg mice show a significant protection from decline in performance with >65% less decline (P<0.005) when comparing the differential of Tg to non-Tg vehicle-treated mice. NGP555 also shows good oral bioavailability and is brain-penetrant with a brain:plasma ratio of