Ceralifimod

Ceralifimod (ONO-4641) is selective, high potent agonist for sphingosine 1-phosphate receptors 1 and 5, with EC₅₀s of 27.3, 334 pM for human S1P receptor 1 and 5, respectively. IC50 & Target: EC50: 27.3 pM (hS1P₁), 334 pM (hS1P₅)^[1]. In Vitro: Ceralifimod (ONO-4641) has an agonistic action for S1P₁ and S1P₅, and there is no difference between human and rat in the agonistic action of Ceralifimod (ONO-4641) for S1P₁. Ceralifimod (ONO-4641) also induces S1P₁ down-regulation in a concentration-dependent manner and by approximately 90% at concentration of 25 nM^[1]. In Vivo: The clinical scores of the Ceralifimod (ONO-4641) 0.03 and 0.1 mg/kg groups remain lower than that in the control group. The maximum clinical scores decrease dose-dependently in the Ceralifimod (ONO-4641) groups and those in the Ceralifimod (ONO-4641) 0.03 and 0.1 mg/kg groups are significantly lower than that in the control group. Specifically, paralysis is inhibited completely in seven of eight animals in the Ceralifimod (ONO-4641) 0.1 mg/kg group.
In normal NOD mice, the number of peripheral blood lymphocytes is decreased by approximately 20, 60 and 80% at 24 h after a single oral dose of 0.01, 0.03 and 0.1 mg/kg of Ceralifimod (ONO-4641), respectively. In the control group of the NOD mouse model of relapsing-remitting EAE, the relapse rate is 90.0%, and two of the nine animals die. The cumulative clinical score in the control group is 65.4±18.50. In contrast, none of animals in the Ceralifimod (ONO-4641) 0.1 mg/kg group have a relapse; that is, Ceralifimod completely prevents relapse at a dose of 0.1 mg/kg. In the Ceralifimod (ONO-4641) groups, two of the nine animals in the 0.01 mg/kg die^[1].