Ozanimod

Ozanimod (RPC-1063) is a potent, selective agonist of S1P1 and S1P5 receptor with EC50 of 0.41 nM and 11 nM respectively; less potent for S1P2, S1P3 and S1P4 (EC50> 10 uM); induces S1P1 receptor internalization and induced a reversible reduction in circulating B and CCR7(+) T lymphocytes in vivo; shows high oral bioavailability and volume of distribution, and a circulatory half-life.Multiple Sclerosis Phase 3 Clinical(In Vitro):Ozanimod (RPC-1063) has potency and intrinsic activity of S1P receptor modulators for S1P5 across species with [35S]-GTPgS binding, and the EC50 values of 1.03 nM, 1.29 nM, 0.90 nM, 1.02 nM and 0.61 nM for Human S1P1, Cynomolgus monkey S1P1, Mouse S1P1, Rat S1P1 and Canine S1P1, respectively; and the EC50 values of 8.6 nM, 15.9 nM, 957.5 nM, 2032.7 nM and 1662.0 nM for Human S1P5, Cynomolgus monkey S1P5, Mouse S1P5, Rat S1P5 and Canine S1P5, respectively.Ozanimod restores the potency with EC50 from 958 nM for mS1P5 to 6.7 nM for mS1P5_A120T to closely mirror the EC50 for hS1P5 of 8.6 nM by mutating the alanine in the mouse sequence.Ozanimod has binding affinity with Ki values of 2.0 nM, 59.9 nM and 5.6 nM for hS1P5, mS1P5 and mS1P5 _A120T, respectively.Ozanimod has saturation binding of [3H]-ozanimod to hS1P5, and mS1P5_A120T with KD values of 6.56 nM, 7.35 nM, respectively and also has saturation binding for [3H]-A971432 to S1P5D value of 8.75 nM.(In Vivo):Ozanimod (RPC-1063) (oral gavage; 0.05, 0.2, or 1 mg/kg; once daily; for 14 consecutive days) exposures sufficient to engage S1P1, but not S1P5, resulted in reduced circulating lymphocytes, disease scores, and body weight loss; reduced inflammation, demyelination, and apoptotic cell counts in the spinal cord; and reduced circulating levels of the neuronal degeneration marker, neurofilament light.Ozanimod (oral gavage; 5 mg/kg; once-daily) prevented axonal degradation and myelin loss during toxin challenge but did not facilitate enhanced remyelination after intoxication.Ozanimod (oral, 1 or 5 mg/kg, for 7 days) has good pharmacokinetics in mice.