Contributions
Abstract: EP1607
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Although current disease-modifying drugs for Multiple sclerosis (MS) significantly improved prognosis of the patients, there are several problems to be solved including limited efficacy, risk of severe infectious diseases, injection related side effects etc. Orally available more effective and safer drugs are awaited. Diminished regulatory component of the immune system are reported in MS. We previously reported that oral administration of a sphingosine-truncated analog of α-galactosylceramide, OCH, selectively induced IL-4 production from iNKT cells, thereby preventing the development of experimental autoimmune encephalomyelitis (EAE) (Nature 2001). To develop OCH as a therapeutic agent for MS, we have completed a first-in-human phase 1 study of OCH in 15 healthy subjects (HS) and 9 patients with relapsing remitting MS. To assess the effect of OCH in vivo, flow cytometer and DNA microarray analyses were conducted for peripheral blood samples obtained before and after oral OCH treatment. First of all, we have confirmed tolerability of OCH in both HS and MS patients. Pharmacokinetics/pharmacodynamics study revealed that absorption of OCH from gut is better in human than primates and rodents. We have observed several immune-related changes in the blood of the HS and MS: (i) a significant increase of Treg [CD45RA-Foxp3+ effector/activated regulatory T cells] at 6 h, (ii) upregulation of immunoregulatory genes (MAFB and IL4I1) at 6 and 24 h, (iii) downregulation of immune-activating genes (NR4A2, FOS, and FOSB) at 6 and 24 h, and (iv) downregulation of GZMB and killer cell immunoglobulin-like receptors. The results are promising and we are now in preparation for a phase 2 study.
Disclosure: W Sato received speaker honoraria from Takeda Pharmaceutical Co., Ltd. D Noto reports no disclosures. M. Araki received honoraria from Chugai Pharmaceutical Co., Ltd.; Novartis Pharmaceuticals; Biogen Japan; Bayer Holding Ltd; Takeda Pharmaceuti-cal Co., Ltd. T. Okamoto received funding for a clinical trial from Takeda Pharmaceutical Co., Ltd. Y. Lin received speaker honoraria from Asahi Kuraray Medical, Ltd. T. R Saga, Y Hirakawa, H Yamaguchi report no disclosures. T Yamamura served on the scientific advisory board for Biogen Japan, Chugai Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd and received travel funding and/or speaker honoraria from Mitsubishi Tanabe Pharma, Novartis, Nihon, Santen, Abbott Japan/Eisai, Biogen Japan, Dainippon Sumitomo, Bayer Holding, and Astellas Pharma Inc., and Takeda Pharmaceutical Co., Ltd., and received research support from Ono, Chugai, Teva, Mitsubishi Tanabe Pharma, Asahi Kuraray Medical, and the Ministry of Health, Labor, and Welfare of Japan.
Abstract: EP1607
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Although current disease-modifying drugs for Multiple sclerosis (MS) significantly improved prognosis of the patients, there are several problems to be solved including limited efficacy, risk of severe infectious diseases, injection related side effects etc. Orally available more effective and safer drugs are awaited. Diminished regulatory component of the immune system are reported in MS. We previously reported that oral administration of a sphingosine-truncated analog of α-galactosylceramide, OCH, selectively induced IL-4 production from iNKT cells, thereby preventing the development of experimental autoimmune encephalomyelitis (EAE) (Nature 2001). To develop OCH as a therapeutic agent for MS, we have completed a first-in-human phase 1 study of OCH in 15 healthy subjects (HS) and 9 patients with relapsing remitting MS. To assess the effect of OCH in vivo, flow cytometer and DNA microarray analyses were conducted for peripheral blood samples obtained before and after oral OCH treatment. First of all, we have confirmed tolerability of OCH in both HS and MS patients. Pharmacokinetics/pharmacodynamics study revealed that absorption of OCH from gut is better in human than primates and rodents. We have observed several immune-related changes in the blood of the HS and MS: (i) a significant increase of Treg [CD45RA-Foxp3+ effector/activated regulatory T cells] at 6 h, (ii) upregulation of immunoregulatory genes (MAFB and IL4I1) at 6 and 24 h, (iii) downregulation of immune-activating genes (NR4A2, FOS, and FOSB) at 6 and 24 h, and (iv) downregulation of GZMB and killer cell immunoglobulin-like receptors. The results are promising and we are now in preparation for a phase 2 study.
Disclosure: W Sato received speaker honoraria from Takeda Pharmaceutical Co., Ltd. D Noto reports no disclosures. M. Araki received honoraria from Chugai Pharmaceutical Co., Ltd.; Novartis Pharmaceuticals; Biogen Japan; Bayer Holding Ltd; Takeda Pharmaceuti-cal Co., Ltd. T. Okamoto received funding for a clinical trial from Takeda Pharmaceutical Co., Ltd. Y. Lin received speaker honoraria from Asahi Kuraray Medical, Ltd. T. R Saga, Y Hirakawa, H Yamaguchi report no disclosures. T Yamamura served on the scientific advisory board for Biogen Japan, Chugai Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd and received travel funding and/or speaker honoraria from Mitsubishi Tanabe Pharma, Novartis, Nihon, Santen, Abbott Japan/Eisai, Biogen Japan, Dainippon Sumitomo, Bayer Holding, and Astellas Pharma Inc., and Takeda Pharmaceutical Co., Ltd., and received research support from Ono, Chugai, Teva, Mitsubishi Tanabe Pharma, Asahi Kuraray Medical, and the Ministry of Health, Labor, and Welfare of Japan.