ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: a phase 2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension

Vermeire, Séverine; Sands, Bruce E.; Tilg, Herbert; Tulassay, Zsolt; Kempiński, Radosław; Danese, Silvio; Bunganič, Ivan; Nitcheu, Josianne; Santo, Julien; Scherrer, Didier; Biguenet, Sophie; Ehrlich, Hartmut J.; Steens, Jean Marc; Gineste, Paul; Sandborn, William J.

doi:10.1016/s2468-1253(22)00233-3

Cited by 34 publications

(23 citation statements)

References 15 publications

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“…The major challenges to miRNA-based therapy include developing efficient and targeted delivery systems, dosage concerns, degradation caused by nucleases, and off-target effects ( 98 , 99 ). ABX464, which upregulates miR-124, was approved for clinical trials to treat ulcerative colitis and rheumatoid arthritis ( 100 – 102 ). RG-012, an effective inhibitor of miR-21, is undergoing Phase 2 HERA trials for Alport syndrome; and MRG-201, the agonist to miR-29b, is in Phase 1 clinical trial for scleroderma ( 103 , 104 ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-183/96/182 cluster in immunity and autoimmunity

Wang

Dai²,

Ahmed³

2023

Front. Immunol.

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MicroRNAs (miRNAs) are crucial post-transcriptional regulators of gene expression in ubiquitous biological processes, including immune-related pathways. This review focuses on the miR-183/96/182 cluster (miR-183C), which contains three miRNAs, miR-183, -96, and -182, having almost identical seed sequences with minor differences. The similarity among seed sequences allows these three miRNAs to act cooperatively. In addition, their minor differences permit them to target distinct genes and regulate unique pathways. The expression of miR-183C was initially identified in sensory organs. Subsequently, abnormal expression of miR-183C miRNAs in various cancers and autoimmune diseases has been reported, implying their potential role in human diseases. The regulatory effects of miR-183C miRNAs on the differentiation and function of both innate and adaptive immune cells have now been documented. In this review, we have discussed the complex role of miR-183C in the immune cells in both normal and autoimmune backgrounds. We highlighted the dysregulation of miR-183C miRNAs in several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ocular autoimmune disorders, and discussed the potential for utilizing miR-183C as biomarkers and therapeutic targets of specific autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-183/96/182 cluster in immunity and autoimmunity

Wang

Dai²,

Ahmed³

2023

Front. Immunol.

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“…The serum samples from patients who received ABX464 (25, 50, or 100 mg) or placebo were collected during 5 visits (day 1, weeks 1, 4, 8, and 16) of a phase 2b trial ( 10 ). Nine biomarkers (IL1b, IL4, IL6, IL10, IL23, IFNγ, CCL2, TNF-α, and IL17a) were measured using the 8-plex assay on the ELLA Platform (Biotechne) and the MSD IL23 V-plex assay (MSD).…”

Section: Methodsmentioning

confidence: 99%

“…ABX464 (obefazimod), a quinoline that induces the anti-inflammatory micro-RNA (miR)-124, has been proposed for the treatment of UC. ABX464 has demonstrated durable efficacy in patients with UC who were all intolerant and/or refractory to at least 1 approved treatment (steroids and biologic drugs) ( 9 , 10 ). Clinical findings showed that once-daily treatment with ABX464 (25, 50, or 100 mg) led to a significant reduction in the modified Mayo score at week 8.…”

Section: Introductionmentioning

confidence: 99%

“…Clinical findings showed that once-daily treatment with ABX464 (25, 50, or 100 mg) led to a significant reduction in the modified Mayo score at week 8. Significant improvements were seen in key secondary endpoints, including endoscopic improvements, clinical remission, clinical responses, and reductions in fecal calprotectin and rectal tissue inflammation compared with placebo ( 10 ). In addition to its efficacy, ABX464 may have a safety advantage over other nonconventional drugs, as in the phase 2b trial described above, ABX464-associated adverse events were mild, transient, dose-dependent, and similar to those in the placebo group at the lowest dose of 25 mg.…”

Section: Introductionmentioning

confidence: 99%

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ABX464 (obefazimod) up-regulates miR-124 to reduce pro-inflammatory markers in inflammatory bowel diseases

Apolit

Campos

Vautrin

et al. 2022

Clin Transl Gastroenterol

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Advanced therapies have transformed the treatment of inflammatory bowel disease; however, many patients fail to respond, highlighting the need for therapies tailored to the underlying cell and molecular disease drivers. The first-in-class oral molecule ABX464 (obefazimod), which selectively upregulates miR-124, has demonstrated its ability to be a well-tolerated treatment with rapid and sustained efficacy in patients with ulcerative colitis (UC). Here, we provide evidence that ABX464 affects the immune system in vitro , in the murine model of inflammatory bowel disease, and in patients with UC. In vitro , ABX464 treatment upregulated miR-124 and led to decreases in proinflammatory cytokines including interleukin (IL) 17 and IL6, and in the chemokine CCL2. Consistently, miR-124 expression was upregulated in the rectal biopsies and blood samples of patients with UC, and a parallel reduction in Th17 cells and IL17a levels was observed in serum samples. In a mouse model of induced intestinal inflammation with dextran sulfate sodium, ABX464 reversed the increases in multiple proinflammatory cytokines in the colon and the upregulation of IL17a secretion in the mesenteric lymph nodes. By upregulating miR-124, ABX464 acts as “a physiological brake” of inflammation, which may explain the efficacy of ABX464 with a favorable tolerability and safety profile in patients with UC.

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“…Several pharmaceutical and biotech companies are working in the development of miRNA-based therapeutics, mainly miRNA mimics and antogomiRs. There are clinical trials focused on cancer, for example, targeting miR-155 in T-cell lymphoma (130); liver disease, as targeting miR-122 (Miravisen) in HCV infected hepatocytes (131,132); or structural gastrointestinal diseases, for instance miRNA-124 as a target in inflammatory bowel disease (133). As the application of this biomarkers or intervention targets is increasing and miRNAs have proven to play an important role in vascular dysfunction, atherosclerotic disease should be a contemplated in future clinical trials given the high associated morbidity and mortality.…”

Section: Mir-amentioning

confidence: 99%

The role of miRNAs in the diagnosis of stable atherosclerosis of different arterial territories: A critical review

Teixeira

Ferreira²,

Pereira-da-Silva³

et al. 2022

Front. Cardiovasc. Med.

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Atherosclerotic disease is a major cause of morbidity and mortality worldwide. Atherosclerosis may be present in different arterial territories and as a single- or multi-territorial disease. The different phenotypes of atherosclerosis are attributable only in part to acquired cardiovascular risk factors and genetic Mendelian inheritance. miRNAs, which regulate the gene expression at the post-transcriptional level, may also contribute to such heterogeneity. Numerous miRNAs participate in the pathophysiology of atherosclerosis by modulating endothelial function, smooth vascular cell function, vascular inflammation, and cholesterol homeostasis in the vessel, among other biological processes. Moreover, miRNAs are present in peripheral blood with high stability and have the potential to be used as non-invasive biomarkers for the diagnosis of atherosclerosis. However, the circulating miRNA profile may vary according to the involved arterial territory, considering that atherosclerosis expression, including the associated molecular phenotype, varies according to the affected arterial territory. In this review, we discuss the specific circulating miRNA profiles associated with atherosclerosis of different arterial territories, the common circulating miRNA profile of stable atherosclerosis irrespective of the involved arterial territory, and the circulating miRNA signature of multi-territorial atherosclerosis. miRNAs may consist of a simple non-invasive method for discriminating atherosclerosis of different arterial sites. The limitations of miRNA profiling for such clinical application are also discussed.

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ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: a phase 2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension

Cited by 34 publications

References 15 publications

MicroRNA-183/96/182 cluster in immunity and autoimmunity

MicroRNA-183/96/182 cluster in immunity and autoimmunity

ABX464 (obefazimod) up-regulates miR-124 to reduce pro-inflammatory markers in inflammatory bowel diseases

The role of miRNAs in the diagnosis of stable atherosclerosis of different arterial territories: A critical review

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