Delving into the Latest Updates on ME-3738 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

IL-6RA

Mechanism

IL-6R agonists(Interleukin-6 receptor alpha subunit agonists)

Therapeutic Areas

Infectious DiseasesDigestive System Disorders

Active Indication-

Inactive Indication

Hepatitis C, Chronic

Originator Organization

Meiji Seika Pharma Co., Ltd.

Active Organization-

Inactive Organization

Meiji Seika Pharma Co., Ltd.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC31H52O3

InChIKeyPKYIOGUKISFMKN-NUKYOBHGSA-N

CAS Registry186415-82-7

Soyasapogenol, an aglycon of soyasaponin, ameliorates liver injury induced by concanavalin A in mice. A derivative of soyasapogenol, 22β-methoxyolean-12-ene-3β, 24(4β)-diol (ME3738), was reported to induce the gene expression of interferon (IFN)-β in hepatitis C virus replicon cells. The effect of ME3738 on hepatocellular carcinoma (HCC) cell lines was investigated in the present study. A total of 11 HCC cell lines were cultured in medium containing 0-10 µM ME3738, and after 24, 48, or 72 h of culture, morphological observation and MTT cell growth assays were performed. Furthermore, the effects of ME3738 with or without PEG-IFN-α-2b on cell lines were investigated. Induction of apoptosis was examined on cells treated with 1 µM of ME3738 using an Annexin V assay. The effect of ME3738 (0.63 and 2.5 µM) on cell cycle progression was analyzed on two cell lines. The mice with subcutaneous tumors were divided into four groups: i) Control; ii) ME3738 alone; iii) PEG-IFN-α-2b alone and iv) ME3738+PEG-IFN-α-2b (combination). ME3738 was mixed with food (1.5 mg/g) and was taken orally for 15 days. PEG-IFN-α-2b (1,920 IU/mouse) was subcutaneously injected twice a week for two consecutive weeks. On day 15, the mice were sacrificed and the tumors were resected. A dose-dependent anti-proliferative effect was observed to various degrees in all the HCC cell lines in vitro. This inhibitory effect reached its maximal level 24 h after the treatment and the 50% inhibitory dose was between 0.8 and 2.4 µM. The combination treatment did not show a synergistic effect. Induction of apoptosis was not observed. Cell cycle arrest at S-phase was observed in two of the examined cell lines. On day 15, the tumor volume of mice receiving ME3738, PEG-IFN-α-2b, and ME3738+PEG-IFN-α-2b was 69, 30, and 33%, respectively, of the control tumor volume. ME3738 induced antiproliferative effects on the HCC cells in vitro and in vivo. The data suggested potential clinical application of ME3738.

01 Apr 2014·Hepatology ResearchQ3 · MEDICINE

Clinical efficacy of combination therapy with ME3738 and pegylated interferon‐alpha‐2a in patients with hepatitis C virus genotype 1

Q3 · MEDICINE

Article

Author: Okita, Kiwamu ; Imawari, Michio ; Saibara, Toshiji ; Onishi, Saburo ; Sata, Michio ; Chayama, Kazuaki ; Kaneko, Shuichi ; Enomoto, Nobuyuki

AimME3738, a derivative of soyasapogenol B, enhances the anti‐hepatitis C virus (HCV) effect of interferon in an in vitro replication system and an in vivo mouse model of HCV infection. ME3738 plus pegylated interferon (PEG IFN)‐α‐2a treatment for 12 weeks decreased HCV RNA levels in enrolled late virus responder (LVR) patients with relapsed HCV. Half of the patients reached undetectable HCV RNA level. The present clinical study of ME3738 was conducted in naïve chronic hepatitis C patients to investigate the sustained virological response (SVR) and safety of 48‐week treatment with ME3738 plus PEG IFN‐α‐2a.MethodsSubjects (n = 135) with genotype 1b chronic hepatitis C with high viral loads were divided into three groups (ME3738 50 mg b.i.d., 200 mg b.i.d. or 800 mg b.i.d.). ME3738 was administrated p.o. and PEG IFN‐α‐2a (180 μg/week) s.c. for 48 weeks, and SVR was assessed at 24 weeks of treatment‐free follow up.ResultsThe viral disappearance rates at 12 and 48 weeks were 23.0% and 48.9%, respectively. SVR was seen in 5.9% of subjects. ME3738 did not worsen the adverse reactions generally seen with PEG IFN‐α‐2a treatment, and any adverse reactions specific to ME3738 were not observed.ConclusionME3738 plus PEG IFN‐α‐2a treatment to naïve chronic hepatitis C patients showed an antiviral effect and a good safety profile up to 48 weeks. However, HCV RNA was again detected in many subjects after treatment termination. Even though ME3738 is not enough to suppress HCV reproduction in this treatment. ME3738 was concurrently used with PEG IFN‐α‐2a treatment; however, a clear additional effect on SVR was not confirmed.

01 Jul 2011·Journal of HepatologyQ1 · MEDICINE

ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo

Q1 · MEDICINE

Article

Author: Shoichi Takahashi ; Kazuaki Chayama ; Nobuhiko Hiraga ; C. Nelson Hayes ; Shoichi Murakami ; Hiromi Abe ; Kenji Asai ; Masataka Tsuge ; Hidenori Ochi ; Michio Imamura ; Tomokazu Kawaoka ; Nobuyuki Yamashita ; Takashi Matsuhira ; Chise Tateno ; Katsutoshi Yoshizato ; Toshiro Maekawa ; Fukiko Mitsui

BACKGROUND & AIMSME3738 (22β-methoxyolean-12-ene-3β, 24-diol), a derivative of soyasapogenol B, attenuates liver disease in several animal models of acute and chronic liver injury. ME3738 is thought to inhibit replication of hepatitis C virus (HCV) by enhancing interferon (IFN)-β production, as determined using the HCV full-length binary expression system. We examined the effect of ME3738 combined with IFN-α on HCV replication using the genotype 1b subgenomic replicon system and an in vivo mouse HCV model.METHODSHCV replicon cells (ORN/3-5B/KE cells and Con1 cells) were incubated with ME3738 and/or IFN-α, and then intracellular IFN-stimulated genes (ISGs) and HCV RNA replication were analyzed by reverse-transcription-real time polymerase chain reaction and luciferase reporter assay. HCV-infected human hepatocyte chimeric mice were also treated with ME3738 and/or IFN-α for 4 weeks. Mouse serum HCV RNA titer, HCV core antigen, and ISGs expression in the liver were measured.RESULTSME3738 induced gene expression of oligoadenylate synthetase 1 and inhibited HCV replication in both HCV replicon cells. The drug enhanced the effect of IFN to significantly increase ISG expression levels, inhibit HCV replication in replicon cells, and reduce mouse serum HCV RNA and core antigen levels in mouse livers. The combination treatment was not hepatotoxic as evident histologically and did not reduce human serum albumin in mice.CONCLUSIONSME3738 inhibited HCV replication, enhancing the effect of IFN-α to increase ISG expression both in vitro and in vivo, suggesting that the combination of ME3738 and IFN might be useful therapeutically for patients with chronic hepatitis C.

100 Deals associated with ME-3738

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