Carogra (carotegrast methyl) / Kissei, Eisai - LARVOL DELTA

Real-world effectiveness and safety of carotegrast methyl in patients with ulcerative colitis: a multicenter retrospective cohort study. (PubMed, Intest Res) - "Carotegrast methyl demonstrated good efficacy and safety, potentially benefiting patients with low baseline disease activity. This drug may be a useful treatment option to consider before systemic corticosteroid therapy for ulcerative colitis."

Journal • Real-world evidence • Retrospective data • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Efficacy and safety of carotegrast methyl in active ulcerative colitis: a real-world prospective cohort study. (PubMed, Intest Res) - "Carotegrast methyl effectively induces both clinical and endoscopic remission in patients with active UC and has a favorable safety profile. Re-administration is safe and effective for patients experiencing relapse."

Journal • Real-world evidence • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Inflammatory Bowel Disease • Liver Failure • Ulcerative Colitis

NOVEL ORAL INHIBITOR OF Α4Β1 AND Α4Β7 INTEGRINS ABROGATES EXPERIMENTAL COLITIS (DDW 2025) - "While systemic α4 blockade was particularly effective (natalizumab), its use has been limited due to risk of progressive multifocal leukoencephalopathy (PML)...WU-106 has an IC 50 of 0.5 nM in the soluble VCAM assay for inhibition of VLA4, more than 200 times greater potency compared to AJM300 (118.3 nM), and an IC 50 of 5 nM in the α4β7 SPRA assay. WU-106 shows promise as an oral therapeutic agent targeting both α4β7 and α4β1 integrins in colitis models. WU-106 appears particularly effective in gut-specific contexts, with significantly enhanced potency and minimal systemic exposure after oral dosing, warranting further investigation for clinical application."

CNS Disorders • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Rare Diseases • Ulcerative Colitis

CAR in UC: Carotegrast Methyl in Ulcerative Colitis (clinicaltrials.gov) - P4 | N=50 | Completed | Sponsor: Takayuki Yamamoto

New P4 trial • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Relationship between Total Corticosteroid Dose Prior to Advanced Therapy Induction and Primary Non-Response (ECCO-IBD 2025) - "CS treatment efficacy decreases with repeated use, affecting therapeutic outcomes of GMA and carotegrast...Conclusion As previously reported, elderly-onset UC requires careful management due to potentially poor treatment response. The total CS dose appears to significantly impact primary non-response, suggesting that early transition to Advanced Therapy may be crucial for optimal patient outcomes."

Metastases • Crohn's disease • Inflammatory Bowel Disease • Ulcerative Colitis

Real-World Effectiveness and Safety of Carotegrast Methyl in Japanese Patients with Moderately Active Ulcerative Colitis. (PubMed, Inflamm Intest Dis) - "No adverse drug reactions, including progressive multifocal leukoencephalopathy, were reported during the study period. This single-center, retrospective, observational study of 14 Japanese patients with UC showed that CGM was safe and effective as a remission induction treatment for moderately active UC with an inadequate response to 5-aminosalicylates in real-world settings."

Journal • Real-world • Real-world effectiveness • Real-world evidence • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Pain • Rare Diseases • Ulcerative Colitis

Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins (PubMed, Korean J Gastroenterol) - "Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG)."

Journal • Review • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Ulcerative Colitis • TNFA

CLINICAL SIGNIFICANCE OF EOSINOPHILS IN CORTICOSTEROID THERAPY FOR ACTIVE ULCERATIVE COLITIS (DDW 2024) - "Currently new immunomodulatory therapies are being developed for the treatment of UC in particular carotegrast methyl a drug showing promise in the treatment of patients with moderate UC refractory to 5-aminosalicylic acid (5-ASA)... Both eosinophil ratios and total count numbers in the blood may be potential biomarkers for steroid responsiveness prior to administration. Histologically changes in eosinophilic infiltration may serve as response indicators for the administration of steroid therapy."

Clinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

The Era of Small Molecules: Good Things Come in Small Packages (IMKASID 2024) - "Following tofacitinib, filgotinib and upadacitinib were also introduced as JAK inhibitors for the treatment of ulcerative colitis...Ozanimod was the first S1PR modulator approved for the treatment o f ulcerative colitis in the United States and Europe, followed by the approval of etrasimod in Europe for the same indication...In Jap an, the oral α4 inhibitor carotegrast methyl is also available for the treatment of ulcerative colitis...They also lack antigenicity, offering the possibility of drug holidays. On the other hand, the development of biomarkers to predict the effectiveness of the numerous molecular targeted therapies, including biologics, for individu al patients is urgently needed."

Cardiovascular • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Herpes Zoster • Inflammatory Bowel Disease • Macular Edema • Ophthalmology • Ulcerative Colitis • Varicella Zoster • TYK2

Effects of rifampicin on the pharmacokinetics and safety of carotegrast methyl in healthy subjects: A randomized 2 × 2 crossover study. (PubMed, Br J Clin Pharmacol) - "Coadministration of carotegrast methyl with rifampicin significantly increased the exposure of carotegrast compared with carotegrast methyl administration alone. In this single dose study, the incidence of AEs of carotegrast methyl with rifampicin increased compared with carotegrast methyl alone, but the incidence of adverse drug reactions did not increase with combination administration."

Journal • PK/PD data

Evaluation of the potential drug-drug interactions of carotegrast methyl with midazolam, prednisolone, or atorvastatin in healthy adults. (PubMed, Br J Clin Pharmacol) - "Carotegrast methyl was classified as a moderate CYP3A4 inhibitor in humans. Carotegrast methyl might enhance the action of drugs that are metabolized by CYP3A4."

Journal

BIOMARKER OF CORTICOSTEROID THERAPY FOR MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS (UEGW 2023) - "Currently, new immunomodulatory therapies are being developed for the treatment of UC, like carotegrast methyl, a drug showing promise in the treatment of patients with moderate UC refractory to 5-aminosalicylic acid (5-ASA)...The proportion of patients treated with azathioprine was significantly higher in the SNR group (40%) than in the SR group (39%)... Both eosinophil ratios in the blood and rectal mucosa, and neutrophil-lymphocyte ratios in the blood may be potential biomarkers for steroid responsiveness prior to administration."

Biomarker • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

DUAL THERAPY WITH CAROTEGRAST (AJM300: ORAL Α4 INTEGRIN ANTAGONIST) AND BIOLOGICS FOR REFRACTORY ULCERATIVE COLITIS (UEGW 2023) - "Six patients (3 males, median age 27 years) who underwent dual therapy with carotegrast and another biologic (4 cases of ustekinumab and 2 cases of infliximab) for treatment refractory ulcerative colitis at the Advanced Clinical Center for Inflammatory Bowel Diseases, Tokyo Medical and Dental University after May 2022 were included, Patient background, short-term efficacy, and safety profile were investigated. Dual therapy with carotegerast and another biologic may be effective and safe in ulcerative colitis patients with biologics failure."

Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Arthritis • Inflammatory Bowel Disease • Pain • Rheumatoid Arthritis • Rheumatology • Ulcerative Colitis

A Study to Evaluate the Safety and Efficacy of AJM300 in Participants With Active Ulcerative Colitis (clinicaltrials.gov) - P3 | N=198 | Completed | Sponsor: EA Pharma Co., Ltd. | Active, not recruiting ➔ Completed | Trial completion date: Oct 2023 ➔ Mar 2023

Trial completion • Trial completion date • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Inflammatory bowel disease (IBD)-specific immune cell recruitment and response can be modulated with anti-TNF-α therapies in the human Colon Intestine-Chip (P853) (IMMUNOLOGY 2023) - "Clinically relevant IBD drugs, including anti-TNF-α antibodies (Humira and Cimzia), as well as dexamethasone and AJM300 were administered through the vascular channel during PBMC administration. The human Colon Intestine-Chip can both model complex immune cell-driven IBD and validate effects of clinically relevant IBD drugs. This system could provide predictive validity for pre-clinical development of new IBD drugs."

Immune cell • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • CD4 • CD8 • CRP

Pharmacological and Clinical data of oral alpha 4 integrin antagonist, Carotegrast methyl, CAROGRA (PubMed, Nihon Yakurigaku Zasshi) - "Carotegrast methyl can be a treatment option that meets that unmet medical need and has the potential to greatly contribute to the treatment of ulcerative colitis based on the thorough practice of proper use. This article mainly introduces the pharmacological properties and clinical trial results of carotegrast methyl."

Clinical data • Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • ITGA4

Targeting integrin pathways: mechanisms and advances in therapy. (PubMed, Signal Transduct Target Ther) - "To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research."

Journal • Review

Appraisal of ICH E14/S7B Q&As adopted in February 2022 using thorough QT/QTc study data for α4-integrin antagonist carotegrast methyl in Japanese healthy subjects. (PubMed, J Pharmacol Sci) - "In concentration-response analysis, moxifloxacin attained the estimated mean values for ΔQTcF and ΔΔQTcF of 11.4 ms (8.5, 14.4) and 16.7 ms (14.0, 19.4) at the mean C, whereas carotegrast methyl provided those of -4.6 ms (-7.3, -1.9) and 0.7 ms (-1.4, 2.8), respectively. Thus, lack of placebo control did not influence the interpretation of TQT study with either of the analysis in line with updated E14/S7B Q&As."

Journal • Cerebral Hemorrhage

Carotegrast Methyl: First Approval. (PubMed, Drugs) - "In March 2022, carotegrast methyl received its first approval in Japan for the treatment of moderate ulcerative colitis in patients who had inadequate response to 5-aminosalicylic acid. This article summarizes the milestones in the development of carotegrast methyl leading to this first approval for the treatment of moderate ulcerative colitis."

Journal • Review • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • VCAM1

Takeda Pharmaceutical launches angioedema prevention drug [Google translation] (Medi-consumer News) - "Japan's Takeda Pharmaceutical announced on the 30th (local time) that it has released Takhzyro (pictured), an acute seizure inhibitor for hereditary angioedema (HAE)....On the same day, Kisei Pharmaceutical announced that it had launched CAROGRA, a treatment for ulcerative colitis."

Launch Japan • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Results of domestic phase III clinical trial (AJM300 / CT3) of ulcerative colitis treatment “Carogra Tablets 120mg“ published in “The Lancet Gastroenterology & Hepatology“ [Google translation] (Kissei Press Release) - P3 | N=198 | NCT03531892 | Sponsor: EA Pharma Co., Ltd. | "EA Pharma Co., Ltd...and Kissei Pharmaceutical Co., Ltd...is a therapeutic agent for ulcerative colitis 'Carotegra ® Tablets 120 mg'...The results of the domestic phase III clinical trial (AJM300 / CT3) were published in 'The Lancet Gastroenterology & Hepatology', a related magazine of The Lancet, one of the world's medical journals....After oral administration of Carogra® tablets or placebo three times daily for 8 weeks and examining the efficacy and safety of Carogra® tablets, improvement at 8 weeks of administration using the primary endpoint, Mayo Score. In terms of rate, the superiority of the Carogra® tablet group to the placebo group was shown. In addition, statistically significant improvements were also observed in multiple secondary endpoints such as mucosal remission rates..."

P3 data • Crohn's disease • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Obtained domestic manufacturing and marketing approval for ulcerative colitis treatment “Carogra Tablets 120 mg“ Approved for the first time in the world as an orally administrable α4 integrin inhibitor [Google translation] (Kissei Press Release) - "EA Pharma Co., Ltd...and Kissei Pharmaceutical Co., Ltd...announced that EA Pharma in Japan on March 28, 'Carogra Tablets ® 120 mg' (generic name: Carotegrastomethyl, development number: AJM300, hereinafter 'Carogra') for the treatment of ulcerative colitis. We are pleased to inform you that we have obtained manufacturing and marketing approval for '® Tablets')."

Japanese regulatory • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

AJM300 (carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. (PubMed, Lancet Gastroenterol Hepatol) - P3 | "AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis."

Journal • P3 data • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammatory Bowel Disease • Ulcerative Colitis

A Study to Evaluate the Safety and Efficacy of AJM300 in Participants With Active Ulcerative Colitis (clinicaltrials.gov) - P3 | N=198 | Active, not recruiting | Sponsor: EA Pharma Co., Ltd. | Trial completion date: Mar 2023 ➔ Oct 2023

Trial completion date • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Change of Marketing Scheme for "RECTABUL 2mg Rectal Foam 14 Doses" and AJM300 (Nonproprietary Name: Carotegrast Methyl), Both for Treatment of Ulcerative Colitis - Agreement Concluded (Kissei Press Release) - "EA Pharma Co., Ltd...and Kissei Pharmaceutical Co., Ltd...announced that the two companies signed an agreement to change the marketing scheme for their anti-ulcerative colitis products 'RECTABUL®2mg Rectal Foam 14 Doses' and AJM300 (nonproprietary name: carotegrast methyl), the latter is under marketing approval examination."

Licensing / partnership • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis