OP34 AJM300, an Oral Antagonist of α4-Integrin, as induction therapy for patients with Moderately Active Ulcerative Colitis: A Phase 3, randomized, double-blind, placebo-controlled induction study
Watanabe, M.(1);Matsuoka, K.(2); Ohmori, T.(3);Nakajima, K.(4);Ishida, T.(5);Ishiguro , Y.(6);Kanke, K.(7);Kobayashi, K.(8);Hirai, F.(9);Watanabe, K.(10);Hibi, T.(11)
(1)Tokyo Medical and Dental University, Advanced Research Institute, Tokyo, Japan;(2)Toho University Sakura Medical Center, Department of Gastroenterology and Hematology, Chiba, Japan;(3)Ohmori Toshihide gastro-intestinal Clinic, Gastroenterology, Saitama, Japan;(4)Matsushima Clinic Yokohama Japan, Department of gastrointestinal division, Kanagawa, Japan;(5)Ishida Clinic of IBD and Gastroenterology, IBD and Gastroenterology, Oita, Japan;(6)National Hospital Organization Hirosaki National Hospital, Department of Gastroenterology and Hematology, Aomori, Japan;(7)Kanke Gastrointestinal Clinic, Gastrointestinal division, Tochigi, Japan;(8)Kitasato University School of Medicine, Research and Development Center for New Medical Frontiers, Kanagawa, Japan;(9)Fukuoka University Hospital, Department of Gastroenterology and Medicine, Fukuoka, Japan;(10)Hyogo College Of Medicine College Hospital, Department of Intestinal Inflammation Research, Hyogo, Japan;(11)Kitasato University Kitasato Institute Hospital, Center for Advanced IBD Research and Treatment, Tokyo, Japan
AJM300 (INN; carotegrast methyl), an orally active small molecule antagonist of the α4 subunit of α4β1/α4β7 integrins, demonstrated the efficacy and safety in patients with moderately active ulcerative colitis (UC) in a phase 2 study. The phase 3 study (NCT 03531892) of AJM300 as induction therapy was conducted in patients with moderately active UC.
Eligible patients were moderately active Japanese UC, defined as total Mayo Clinic scores (MCS) of 6-10, endoscopic subscores (ES) ≥2, and rectal bleeding subscores (RBS) ≥1, who had inadequate response or intolerance to oral 5-ASA. Followed by a 2-week single-blind placebo (PBO) run-in phase, patients were randomized 1:1 to receive AJM300 960 mg or PBO 3 times daily for 8 weeks. Responders or remitters were allowed to receive AJM300 960 mg again at the subsequent relapse (open-label). The primary endpoint was clinical response at week 8, defined as reduction of the MCS of ≥3-pts and ≥30%, reduction in RBS of ≥1-pt or RBS of ≤1, and ES ≤1.
The randomized 203 patients had moderately active endoscopic evidence at baseline with median UC duration of 6.1 years and MCS of 7.8. For the primary endpoint, 45.1% (46/102) and 20.8% (21/101) of patients in the AJM300 and PBO groups, respectively, achieved clinical response at week 8 (OR=3.30 [95% CI, 1.73-6.29]; p=0.0003). Symptomatic remission, endoscopic improvement and endoscopic remission were also statistically significant for AJM300 vs PBO (Table). In case of episodic AJM300 treatment, AJM300 exhibited similar response to initial treatment. Overall, the incidence of AEs and serious AEs were similar between AJM300 and PBO. There were no deaths or cases of progressive multifocal leukoencephalopathy.
AJM300 induced clinical response as well as endoscopic remission with good tolerability. AJM300 may become a novel therapeutic option for patients who had inadequate response or intolerance to oral 5-ASA.
Table. Efficacy results at Week 8
|Endpoint||PBO, n (%) (n=101)||AJM300, n (%) (n=102)||Percent difference (95% CI)||P value|
|Clinical response||21 (20.8)||46 (45.1)||24.3 (11.4,36.1)||0.0003|
|Clinical remission||14 (13.9)||23 (22.5)||8.7 (-2.0,19.2)||0.1089|
|Symptomatic remission||22 (21.8)||42 (41.2)||19.4 (6.6,31.3)||0.0029|
|Endoscopic improvement||27 (26.7)||56 (54.9)||28.2 (14.7,40.2)||<0.0001|
|Endoscopic remission||3 (3.0)||14 (13.7)||10.8 (3.1,19.0)||0.0057|
Clinical response=a reduction of the MCS of ≥3-pts and ≥30%, reduction in RBS of ≥1-pt or RBS of ≤1, and ES ≤1; Clinical remission=MCS≤2 and no subscores >1; Symptomatic remission=total of RBS and stool frequency subscores ≤1; Endoscopic improvement=ES ≤1; Endoscopic remission=ES =0.
CI, confidence interval; ES, endoscopic subscores; MCS, Mayo Clinic Score; PBO, placebo; RBS, rectal bleeding subscores.