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

Matsuoka, Katsuyoshi; Watanabe, Mamoru; Ohmori, Toshihide; Nakajima, Koji; Ishida, Tetsuya; Ishiguro, Yoh; Kanke, Kazunari; Kobayashi, Kiyonori; Hirai, Fumihito; Watanabe, Kenji; Mizusawa, Hidehiro; Kishida, Shuji; Miura, Yoshiharu; Ohta, Akira; Kajioka, Toshifumi; Hibi, Toshifumi; Group, AJM300 Study

doi:10.2139/ssrn.3978554

Cited by 17 publications

(25 citation statements)

References 27 publications

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“…Fifty manuscripts reporting on the results of 53 studies (4096 participants) met the inclusion criteria and were included in the review (Figure S1). 9,11,18–65 Several manuscripts report on the results of more than one study. Sandborn et al 9 report on the results of two phase III RCTs.…”

Section: Resultsmentioning

confidence: 99%

“…Five studies assessed the efficacy of small molecules. Two studies 59 compared RDP58 with placebo, one study 44 compared AJM300 with placebo, and two studies (ELEVATE UC 12 and ELEVATE UC 52) 51 compared etrasimod with placebo. None of the included studies assessed biologic therapy for the treatment of UP.…”

Section: Resultsmentioning

confidence: 99%

“…Matsuoka et al 44 assessed the efficacy and safety of AJM300 in patients with UC or UP. No statistically significant difference between AJM300 and placebo in the proportion of UP patients who achieved a clinical response was found (RR 1.40, 95% CI 0.5–3.94).…”

Section: Resultsmentioning

confidence: 99%

“…41 However, the sample size was small (n = 21), and further RCTs or real-world evidence are needed to confirm this observation. Five additional studies 44,51,59 assessed the efficacy and safety of advanced small molecules in UP. Two studies 59 found no difference in clinical remission rates between RDP58 and placebo in patients with UP.…”

Section: Discussionmentioning

confidence: 99%

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Systematic review with meta‐analysis: Medical therapies for treatment of ulcerative proctitis

Aruljothy,

Singh,

Narula

et al. 2023

Aliment Pharmacol Ther

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SummaryBackgroundUlcerative proctitis (UP) is a common highly symptomatic form of ulcerative colitis that can be difficult to treat.AimTo assess the efficacy of medical treatments for UP.MethodsWe searched MEDLINE, EMBASE, and CENTRAL on 23 November 2022 for randomised controlled trials (RCTs) of medical therapy for adults with UP. Primary outcomes included induction and maintenance of clinical remission. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for each outcome.ResultsWe included 53 RCTs (n = 4096) including 46 induction studies (n = 3731) and seven maintenance studies (n = 365). First‐line therapies included topical 5‐aminosalicylic acid (5‐ASA), conventional corticosteroids, budesonide, and oral 5‐ASA. Therapy for refractory UP included topical tacrolimus and small molecules. Topical 5‐ASA was superior to placebo for induction (RR 2.72, 95% CI 1.94–3.82) and maintenance of remission (RR 2.09, 95% CI 1.26–3.46). Topical corticosteroids were superior to placebo for induction of remission (RR 2.83, 95% CI 1.62–4.92). Topical budesonide was superior to placebo for induction of remission (RR 2.34, 95% CI 1.44–3.81). Combination therapy with topical 5‐ASA and topical corticosteroids was superior to topical monotherapy with either agent. Topical tacrolimus was superior to placebo. Etrasimod was superior to placebo for induction (RR 4.71, 95% CI 1.2–18.49) and maintenance of remission (RR 2.08, 95% CI 1.31–3.32).ConclusionsTopical 5‐ASA and corticosteroids are effective for active UP. Topical 5‐ASA may be effective for maintenance of remission. Tacrolimus may be effective for induction of remission. Etrasimod may be effective for induction and for maintenance of remission. Trials should include UP to expand the evidence base for this under‐represented population.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Systematic review with meta‐analysis: Medical therapies for treatment of ulcerative proctitis

Aruljothy,

Singh,

Narula

et al. 2023

Aliment Pharmacol Ther

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“…The concept of interfering with immune cell trafficking to treat IBD has cued a whole family of therapeutics, of which the anti‐α4β7 integrin antibody vedolizumab and the sphingosine‐1‐phosphate receptor (S1PR) agonist ozanimod have entered clinical routine care 33 . While further compounds, such as the S1PR agonist etrasimod 34 or the α4 integrin antagonist AJM300, 35 have successfully passed phase III trial programs, other candidates failed during clinical development 17 …”

Section: Discussionmentioning

confidence: 99%

Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing

Sommer

Heidbreder

Kreiß

et al. 2023

Clinical & Translational Med

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Background Closing mucosal defects to reach mucosal healing is an important goal of therapy in inflammatory bowel disease (IBD). Among other cells, monocyte‐derived macrophages are centrally involved in such intestinal wound healing. We had previously demonstrated that the anti‐α4β7 integrin antibody vedolizumab blocks the recruitment of non‐classical monocytes as biased progenitors of wound healing macrophages to the gut and delays wound healing. However, although important for the interpretation of disappointing results in recent phase III trials in IBD, the effects of the anti‐β7 antibody etrolizumab on wound healing are unclear so far. Methods We analyzed the expression of etrolizumab targets on human and mouse monocyte subsets by flow cytometry and assessed their function in adhesion and homing assays. We explored wound‐associated monocyte recruitment dynamics with multiphoton microscopy and compared the effects of etrolizumab and vedolizumab surrogate (‐s) antibodies on experimental wound healing and wound‐associated macrophage abundance. Finally, we investigated wound healing macrophage signatures in the large intestinal transcriptome of patients with Crohn's disease treated with etrolizumab. Results Human and mouse non‐classical monocytes expressed more αEβ7 integrin than classical monocytes and were a target of etrolizumab‐s, which blocked non‐classical monocyte adhesion to MAdCAM‐1 and E‐Cadherin as well as gut homing in vivo. Intestinal wound healing was delayed on treatment with etrolizumab‐s along with a reduction of peri‐lesional wound healing macrophages. Wound healing macrophage signatures in the colon of patients with Crohn's disease were substantially down‐regulated on treatment with etrolizumab, but not with placebo. Conclusions Combined blockade of αEβ7 and α4β7 with etrolizumab seems to exceed the effect of anti‐α4β7 treatment on intestinal wound healing, which might help to inform further investigations to understand the recent observations in the etrolizumab phase III trial program.

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Emerging drugs for the treatment of inflammatory bowel disease

Wong

Cross

2022

Expert Opinion on Emerging Drugs

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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

Cited by 17 publications

References 27 publications

Systematic review with meta‐analysis: Medical therapies for treatment of ulcerative proctitis

Systematic review with meta‐analysis: Medical therapies for treatment of ulcerative proctitis

Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing

Emerging drugs for the treatment of inflammatory bowel disease

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