Specific and selective induction of miR-124 in immune cells by the quinoline ABX464: a transformative therapy for inflammatory diseases

Tazi, Jamal; Begon-Pescia, Christina; Campos, Noëlie; Apolit, C.; Garcel, Aude; Scherrer, Didier

doi:10.1016/j.drudis.2020.12.019

Cited by 40 publications

(30 citation statements)

References 55 publications

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“…ABX464, as a novel drug candidate for human immunodeficiency virus (HIV), has shown strong antiviral properties (227). Recent studies have discovered that ABX464 can upregulate the expression of miR-124, thus inhibiting the inflammatory response for IBD treatment (228,229). A phase 2 study in moderate to severe UC patients treated with oral administration of ABX464 or placebo was conducted (230).…”

Section: Othersmentioning

confidence: 99%

Treatment of Inflammatory Bowel Disease: A Comprehensive Review

2021

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Inflammatory bowel disease (IBD), as a global disease, has attracted much research interest. Constant research has led to a better understanding of the disease condition and further promoted its management. We here reviewed the conventional and the novel drugs and therapies, as well as the potential ones, which have shown promise in preclinical studies and are likely to be effective future therapies. The conventional treatments aim at controlling symptoms through pharmacotherapy, including aminosalicylates, corticosteroids, immunomodulators, and biologics, with other general measures and/or surgical resection if necessary. However, a considerable fraction of patients do not respond to available treatments or lose response, which calls for new therapeutic strategies. Diverse therapeutic options are emerging, involving small molecules, apheresis therapy, improved intestinal microecology, cell therapy, and exosome therapy. In addition, patient education partly upgrades the efficacy of IBD treatment. Recent advances in the management of IBD have led to a paradigm shift in the treatment goals, from targeting symptom-free daily life to shooting for mucosal healing. In this review, the latest progress in IBD treatment is summarized to understand the advantages, pitfalls, and research prospects of different drugs and therapies and to provide a basis for the clinical decision and further research of IBD.

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Section: Othersmentioning

confidence: 99%

Treatment of Inflammatory Bowel Disease: A Comprehensive Review

2021

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“…Indeed, miR-124 target genes that control the production of a number of inflammatory mediators (eg, TNF-α, IL-6, IL-17) implicated in the intense inflammatory reaction that drives RA 5–9. An upregulated biogenesis of miR-124 has been consistently reported with ABX464, across non-clinical and clinical studies in different indications,15 still a definitive correlation with clinical response remains to be established. Interestingly though, no significant difference in miR-124 upregulation was seen between the two ABX464 doses, indicating the absence of a dose-dependent effect, which reminds the absence of dose-related efficacy of the drug reported in clinics in patients with UC 14…”

Section: Discussionmentioning

confidence: 99%

“…ABX464 has demonstrated durable efficacy in treating patients suffering from UC, a chronic inflammatory disorder of the colonic mucosa 14. The efficacy and safety profiles of this compound are likely related to its unique mechanism of action 15. Recently, non-clinical in vivo data provided evidence that ABX464 (40 mg/Kg, per os) strongly reduced the incidence of collagen-induced arthritis in DBA-1 male mice 10.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study

et al. 2022

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ObjectiveThis phase 2a randomised, double blind, placebo controlled, parallel group study evaluated the safety and efficacy of a first-in-class drug candidate ABX464 (obefazimod, 50 mg and 100 mg per day), which upregulates the biogenesis of the mRNA inhibitor micro-RNA (miR)-124, in combination with methotrexate (MTX) in 60 patients (1:1:1 ratio) with moderate-to-severe active rheumatoid arthritis (RA) who have inadequate response to MTX or/and to an anti-tumour necrosis factor alpha (TNFα) therapy.MethodsThe primary end point was the safety of ABX464; efficacy endpoints included the proportion of patients achieving American College of Rheumatology (ACR)20/50/70 responses, disease activity scores (DAS) 28, simplified disease activity score, clinical disease activity score), European League Against Rheumatism response, DAS28 low disease activity or remission.ResultsABX464 50 mg was safe and well tolerated. Two serious adverse events were reported (one on placebo group and one on ABX464 100 mg). Eleven patients were withdrawn for AEs (9 patients on 100 mg, 1 on 50 mg and 1 on placebo). Drug discontinuation was mainly due to gastrointestinal disorders. No cases of opportunistic infection, no malignancies and no death were reported. Compared with placebo, ABX464 50 mg showed significantly higher proportions of patients achieving ACR20 and ACR50 responses at week 12. DAS28-C reactive protein (CRP) and DAS28-erythrocyte sedimentation rate decreased significantly and rates of categorical DAS28-CRP response or CDAI remission increased significantly on ABX464 at week 12. A significant upregulation of miR-124 was observed in blood for every patient dosed with ABX464.ConclusionABX464 50 mg was safe, well tolerated and showed a promising efficacy. Mild-to-moderate gastrointestinal AEs led to a high drop-out rate of patients on ABX464 100 mg, which may not be a relevant dose to use. These findings warrant exploration of ABX464 at 50 mg per day or less for treating patients with RA.Trial registration namePhase IIa randomised, double blind, placebo controlled, parallel group, multiple dose study on ABX464 in combination with MTX, in patients with moderate to severe active RA who have inadequate response to MTX or/and to an anti- TNFα therapy or intolerance to anti-TNFα therapy.EUDRACT number: 2018-004677-27Trial registration numberNCT03813199.

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“…Finally, Abivax (Paris, France) is producing and testing ABX464, a REV (HIV protein) inhibitor, in different diseases. It has been shown that ABX464 can not only inhibit viral replication but can upregulate the anti-inflammatory response through upregulating miR-124 [126,127]. Currently, seven phase 1 and 2 clinical trials using ABX464 have closed, demonstrating encouraging results, and six-phase 2 and 3 remain open.…”

Section: Other Diseasementioning

confidence: 99%

microRNAs as Novel Therapeutics in Cancer

Romano

Acunzo

Nana‐Sinkam

2021

Cancers

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In the last 20 years, the functional roles for miRNAs in gene regulation have been well established. MiRNAs act as regulators in virtually all biological pathways and thus have been implicated in numerous diseases, including cancer. They are particularly relevant in regulating the basic hallmarks of cancer, including apoptosis, proliferation, migration, and invasion. Despite the substantial progress made in identifying the molecular mechanisms driving the deregulation of miRNAs in cancer, the clinical translation of these important molecules to therapy remains in its infancy. The paucity of vehicles available for the safe and efficient delivery of miRNAs and ongoing concerns for toxicity remain major obstacles to clinical application. Novel formulations and the development of new vectors have significantly improved the stability of oligonucleotides, increasing the effectiveness of therapy. Furthermore, the use of specific moieties for delivery in target tissues or cells has increased the specificity of treatment. The use of new technologies has allowed small but important steps toward more specific therapeutic delivery in tumor tissues and cells. Although a long road remains, the path ahead holds great potential. Currently, a few miRNA drugs are under investigation in human clinical trials with promising results ahead.

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Specific and selective induction of miR-124 in immune cells by the quinoline ABX464: a transformative therapy for inflammatory diseases

Cited by 40 publications

References 55 publications

Treatment of Inflammatory Bowel Disease: A Comprehensive Review

Treatment of Inflammatory Bowel Disease: A Comprehensive Review

Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study

microRNAs as Novel Therapeutics in Cancer

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