Kenji Suzuki1, Junji Yokoyama2, Yusuke Kawauchi2, Yutaka Honda2, Hiroki Sato2, Yutaka Aoyagi2, Shuji Terai2, Kazuichi Okazaki3, Yasuo Suzuki4, Yukinori Sameshima5, Tsuneo Fukushima6, Kazuyuki Sugahara7, Raja Atreya8, Markus F Neurath8, Kenichi Watanabe9, Hiroyuki Yoneyama10, Hitoshi Asakura2. 1. Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan kjsuzuki@med.niigata-u.ac.jp. 2. Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan. 3. Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Osaka, Japan. 4. Internal Medicine, Toho University, Sakura Medical Center, Sakura, Chiba, Japan. 5. Sameshima Hospital, Kagoshima, Kagoshima, Japan. 6. Matsushima Hospital, Yokohama city, Kanagawa, Japan. 7. Laboratory of Proteoglycan Signaling and Therapeutics, Hokkaido University, Sapporo, Hokkaido, and Department of Pathobiochemistry, Meijo University, Nagoya, Aichi, Japan. 8. Department of Medicine a, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 9. Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Science, Niigata, Niigata, Japan. 10. Stelic Institute & Co., Inc., Minato, Tokyo, Japan.
Abstract
BACKGROUND AND AIMS: Carbohydrate sulphotransferase 15 [CHST15] is a specific enzyme biosynthesizing chondroitin sulphate E that binds various pathogenic mediators and is known to create local fibrotic lesions. We evaluated the safety of STNM01, a synthetic double-stranded RNA oligonucleotide directed against CHST15, in Crohn's disease [CD] patients whose mucosal lesions were refractory to conventional therapy. METHODS: This was a randomized, double-blind, placebo-controlled, concentration-escalation study of STNM01 by a single-dose endoscopic submucosal injection in 18 CD patients. Cohorts of increasing concentration of STNM01 were enrolled sequentially as 2.5nM [n = 3], 25nM [n = 3], and 250nM [n = 3] were applied. A cohort of placebo [n = 3] was included in each concentration. Safety was monitored for 30 days. Pharmacokinetics was monitored for 24h. The changes from baseline in the segmental Simple Endoscopic Score for CD [SES-CD] as well as the histological fibrosis score were evaluated. RESULTS:STNM01 was well tolerated and showed no drug-related adverse effects in any cohort of treated patients. There were no detectable plasma concentrations of STNM01 at all measured time points in all treatment groups. Seven of nine subjects who received STNM01 showed reduction in segmental SES-CD at Day 30, when compared with those who received placebo. Histological analyses of biopsy specimens revealed that STNM01 reduced the extent of fibrosis. CONCLUSION: Local application of STNM01 is safe and well tolerated in CD patients with active mucosal lesions.
RCT Entities:
BACKGROUND AND AIMS: Carbohydrate sulphotransferase 15 [CHST15] is a specific enzyme biosynthesizing chondroitin sulphate E that binds various pathogenic mediators and is known to create local fibrotic lesions. We evaluated the safety of STNM01, a synthetic double-stranded RNA oligonucleotide directed against CHST15, in Crohn's disease [CD] patients whose mucosal lesions were refractory to conventional therapy. METHODS: This was a randomized, double-blind, placebo-controlled, concentration-escalation study of STNM01 by a single-dose endoscopic submucosal injection in 18 CDpatients. Cohorts of increasing concentration of STNM01 were enrolled sequentially as 2.5nM [n = 3], 25nM [n = 3], and 250nM [n = 3] were applied. A cohort of placebo [n = 3] was included in each concentration. Safety was monitored for 30 days. Pharmacokinetics was monitored for 24h. The changes from baseline in the segmental Simple Endoscopic Score for CD [SES-CD] as well as the histological fibrosis score were evaluated. RESULTS:STNM01 was well tolerated and showed no drug-related adverse effects in any cohort of treated patients. There were no detectable plasma concentrations of STNM01 at all measured time points in all treatment groups. Seven of nine subjects who received STNM01 showed reduction in segmental SES-CD at Day 30, when compared with those who received placebo. Histological analyses of biopsy specimens revealed that STNM01 reduced the extent of fibrosis. CONCLUSION: Local application of STNM01 is safe and well tolerated in CDpatients with active mucosal lesions.
Authors: Patrizio Scarozza; Heike Schmitt; Giovanni Monteleone; Markus F Neurath; Raja Atreya Journal: Front Pharmacol Date: 2019-04-24 Impact factor: 5.810
Authors: Yang Sun; Fengjun Xiao; Huiyan Sun; Lin Zhang; Weida Chen; Li Du; Chengfeng Sun; Weiyuan Zhang; Qinqin Xu; Chengli Miao; Lisheng Wang Journal: Ann Transl Med Date: 2022-03