Il-1beta Signal Inhibition in acute alcoholic hepatitis: a multicentre, randomised, double-blind, placebo-controlled phase 2 trial of canakinumab therapy (ISAIAH)

Vergis, Nikhil; Patel, Vishal C.; Bogdanowicz, Karolina; Czyzewska-Khan, Justyna; Keshinro, Rosemary; Fiorentino, Francesca; Day, Emily; Middleton, Paul; Cross, Mary; Babalis, Daphne; Foster, Neil R.; Quaglia, Alberto; Lloyd, Jill; Goldin, Robert D.; Rosenberg, William; Parker, Richard; Richardson, Paul G.; Masson, Steven; Whitehouse, Gavin; Sieberhagen, Cyril; Patch, David; Dhanda, Ashwin; Lord, Emma; Forrest, Ewan; Naoumov, Nikolai V.; Thursz, Mark

doi:10.1016/s0168-8278(22)00480-9

Cited by 11 publications

(6 citation statements)

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“…96 In a recent multicenter placebo controlled clinical trial on 57 patients with biopsy proven AH (mDF ≥ 32 and MELD ≤ 27), canakinumab ( N = 28) improved liver histology (58.3 vs. 41.7%, p = 0.025), but failed to improve 28-day patient survival (93% in each group). 97 There were no drug-related safety concerns in this study.…”

Section: Management Of Liver Diseasementioning

confidence: 80%

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Therapeutic Pipeline in Alcohol-Associated Liver Disease

2022

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Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria. Over the last decade, several therapeutic targets have evolved of promise with ongoing clinical trials in patients with cirrhosis and alcoholic hepatitis. Even with availability of effective medical therapies for alcohol-associated liver disease, long-term outcome depends on abstinence from alcohol use in any spectrum of alcohol-associated liver disease. However, alcohol use disorder treatment remains underutilized due to several barriers even in patients with advanced disease. There is an urgent unmet need to implement and promote integrated multidisciplinary care model with hepatologists and addiction experts to provide comprehensive management for these patients. In this review, we will discuss newer therapies targeting liver disease and therapies targeting alcohol use disorder in patients with alcohol-associated liver disease.

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Section: Management Of Liver Diseasementioning

confidence: 80%

“…32 and MELD 27), canakinumab (N ¼ 28) improved liver histology (58.3 vs. 41.7%, p ¼ 0.025), but failed to improve 28-day patient survival (93% in each group). 97 There were no drug-related safety concerns in this study.…”

Section: Drugs Targeting Hepatic Inflammationmentioning

confidence: 80%

Therapeutic Pipeline in Alcohol-Associated Liver Disease

2022

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“…36 Twenty-nine patients were enrolled to canakinumab group and 28 to placebo group. 37 The primary endpoint was histologic improvement at 28 days compared to baseline, which was not significantly different between the two groups (58.3% in canakinumab vs 41.7% in placebo, P = 0.248). The rate of infection as a serious adverse event was not significantly different between the two groups (1% in canakinumab vs 17% in placebo, P = 0.380).…”

Section: ) Hepatic Inflammationmentioning

confidence: 89%

“…Canakinumab, which is a monoclonal antibody specifically targeting IL‐1β, has been used in a multicenter, double‐blind, randomized, placebo‐controlled trial in patients with alcoholic hepatitis (DF ≥ 32, but MELD ≤ 27) as an inhibitor of IL‐1 signal 36 . Twenty‐nine patients were enrolled to canakinumab group and 28 to placebo group 37 . The primary endpoint was histologic improvement at 28 days compared to baseline, which was not significantly different between the two groups (58.3% in canakinumab vs 41.7% in placebo, P = 0.248).…”

Section: Current Treatment Optionsmentioning

confidence: 99%

Current and future treatment for alcoholic‐related liver diseases

Yoon

Kim

2023

J of Gastro and Hepatol

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The socioeconomic burden of alcohol-related liver disease has been increasing worldwide. Its prevalence is underestimated, and patients with alcohol-related liver disease are rarely diagnosed in the earlier phase of the disease spectrum. Alcoholic hepatitis is a distinct syndrome with life-threatening signs of systemic inflammation. In severe alcoholic hepatitis, prednisolone is indicated as the first-line treatment even with the possibility of various complications. Early liver transplantation can be another option for highly selected patients with a null response to prednisolone. Most importantly, abstinence is the mainstay of long-term care, but relapse is frequent among patients. Recent findings on the pathogenesis of alcoholic hepatitis have enabled us to discover new therapeutic targets. Preventing hepatic inflammation, reducing oxidative stress, improving gut dysbiosis, and enhancing liver regeneration are the main targets of emerging therapies. Herein, we review the pathogenesis, current treatment, and barriers to successful clinical trials of alcoholic hepatitis. Additionally, clinical trials for alcoholic hepatitis, either ongoing or recently completed, will be briefly introduced.

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“…However, there is no generally accepted pathophysiological concept, and it seems likely that the mechanisms leading to ACLF are highly individual, depending on the underlying liver disease, on the ACLF trigger but also on the type of organ system involvement ( 5 - 8 ). The fact that several attempts to establish ACLF disease modifying therapies such as granulocyte-colony stimulating factor (G-CSF) ( 9 ), the unselective interleukin-1 (IL-1) inhibitor Anakinra ( 10 ), or selective IL-1beta inhibitor canakinumab ( 11 ) failed in clinical studies clearly emphasizes that the complexity of the underlying pathomechanisms of this disease is still not well understood.…”

mentioning

confidence: 99%