ASP1126, a Novel Sphingosine-1-Phosphate–Selective Agonist With a Favorable Safety Profile, Prolongs Allograft Survival in Rats and Nonhuman Primates in Combination With Tacrolimus With a Broad Safety Margin for Bradycardia

• Published in: Transplantation proceedings Vol. 51; no. 6; pp. 2081 - 2098
• Main Authors: Okimoto, Akira, Yamamoto, Rie, Hirose, Jun, Shimatani, Kenichiro, Koshika, Tadatsura, Maeda, Masashi, Hattori, Kazuyuki, Morokata, Tatsuaki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2019
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2019.05.012

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of 5 G protein–coupled receptors (S1P1 to S1P5). Among these, S1P1 is a major regulator of lymphocyte trafficking. Fingolimod, whose active metabolite, fingolimod phosphate, acts as a nonselective S1P-receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating lymphocyte trafficking via downregulation of S1P1 expression on lymphocytes. Here, we describe the pharmacologic profile of a novel S1P1 agonist, ASP1126. ASP1126 preferentially activated S1P1 compared to S1P3 in rat and human guanosine-5'-(γ-thio)-triphosphate (GTPγS) assays. Oral single administration of ASP1126 decreased the number of peripheral lymphocytes and repeated dosing showed a cumulative effect on lymphopenia in both rats and monkeys. ASP1126 prolonged allograft survival in a rat heterotopic heart transplantation model in combination with a subtherapeutic dose of tacrolimus that was independent of drug-drug interactions. In addition, in nonhuman primate (NHP) renal transplantation, pretreatment with ASP1126 reduced not only the number of naive T cells and central memory T cells but also effector memory T cells in the peripheral blood, all of which could contribute to acute graft rejection and prolonged allograft survival in combination with tacrolimus. Further, we confirmed that ASP1126 has a broad ranging safety margin with respect to its effect on lung weight in rats and bradycardia in NHPs, which were the adverse events found in clinical studies of fingolimod. ASP1126 with improved safety profile has the potential to be an adjunct therapy in combination with tacrolimus in clinical transplantation. •ASP1126 preferentially activates sphingosine-1-phosphate compared to sphingosine-1-phosphate receptor 3 in a human guanosine-5'-(γ-thio)-triphosphate(GTPγS)-binding assay.•ASP1126 and tacrolimus synergistically prolong allograft survival in rats and monkeys.•ASP1126 has a broad safety margin with respect to its effect on lung weight in rats.•There is an absence of bradycardia at 100 times the dose that induces graft survival in monkeys.•ASP1126 with tacrolimus reduces peripheral effector memory T cells in monkeys.