Efficacy and safety of simtuzumab for the treatment of primary sclerosing cholangitis: results of a phase 2b, dose-ranging, randomized, placebo-controlled trial

Muir, A.; Goodman, Z.; Levy, C.E.; Janssen, H.; Montano-Loza, A.J.; Bowlus, Christopher L.; Ding, Dayou; Jia, Chunhua; Mccolgan, B.; Myers, Rob; Subramanian, Megha; McHutchison, J.; Manns, Michael P.; Chapman, R W; Afdhal, Nezam H.; Eksteen, Bertus

doi:10.1016/s0168-8278(17)30408-7

Cited by 13 publications

(13 citation statements)

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“…Norursodeoxycholic acid, a side‐chain–shortened C23 homologue of UDCA, showed a dose‐dependent improvement of cholestasis in a 12‐week, phase 2 multicenter study . Simtuzumab, a humanized IgG4 monoclonal antibody against lysl oxidase like‐2, failed to show a significant reduction compared to controls in mean hepatic collagen content in a 96‐week phase 2b trial …”

Section: Scope Of the Problemmentioning

confidence: 99%

“…(31) Simtuzumab, a humanized IgG4 monoclonal antibody against lysl oxidase like-2, failed to show a significant reduction compared to controls in mean hepatic collagen content in a 96-week phase 2b trial. (32) Endpoints that have been used in past clinical trials include serum biochemistries, primarily ALP and bilirubin, histopathology, and clinical outcomes, for example, the occurrence of events such as death, LT, complications of cirrhosis, and CCA. There have been four randomized controlled clinical trials in PSC that used clinical events as primary outcome parameters with a follow-up ranging from 2 to 5 years.…”

Section: Previous Clinical Trials In Pscmentioning

confidence: 99%

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Design and Endpoints for Clinical Trials in Primary Sclerosing Cholangitis

et al. 2018

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Primary sclerosing cholangitis (PSC) is a rare and chronic liver disease for which there is no effective therapy. Interest has grown in developing treatments for this condition, with several agents proposed as potential therapies. However, there is a lack of clarity about how to measure clinical benefit in trials involving patients with this complex and rare disease. This article reviews regulatory information, the available literature on natural history, as well as potential candidate clinical and surrogate endpoints for PSC. (Hepatology 2018; 00:000-000).

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Section: Scope Of the Problemmentioning

confidence: 99%

Section: Previous Clinical Trials In Pscmentioning

confidence: 99%

Design and Endpoints for Clinical Trials in Primary Sclerosing Cholangitis

et al. 2018

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“…Hepatic biochemical tests in PSC typically indicate cholestasis, with the most common biochemical abnormality being elevated ALP. Baseline ALP values from published clinical trials ranged from 1.5‐10× ULN, with a mean ranging between 2‐4× ULN . However, ALP may be normal or during an episode of cholangitis can be ≥10x ULN .…”

Section: Hepatic Eligibility Criteria For Patients With Pscmentioning

confidence: 99%

“…Levels ranging from <1.5× ULN to <3× ULN are required for eligibility into most clinical trials, in the absence of Child Pugh B or C or liver decompensation . As such, most baseline total bilirubin levels in published clinical trials of treatment for PSC have been normal or slightly abnormal …”

Section: Hepatic Eligibility Criteria For Patients With Pscmentioning

confidence: 99%

Consensus guidelines: best practices for detection, assessment and management of suspected acute drug‐induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease

Palmer

Regev

Lindor

et al. 2019

Aliment Pharmacol Ther

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Summary Background Improved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug‐induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients. Aims To outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases – Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). Methods This is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in‐depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI‐related issues occurring during clinical trials for cholestatic liver diseases. Results Recommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules. Conclusions This paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.

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“…Along with these interesting preclinical data we also suggest for future clinical trials in PSC or PBC combining immunomodulatory drugs with bile acid pool‐reducing agents or choleretic substances, or, if disease stage is more advanced, with anti‐fibrotic strategies (Figure ). Particularly, since several of the drugs have already been safely used for different diseases (eg vedolizumab) or passed phase II trials safely, but did not meet primary endpoints as single compound (eg simtuzumab), combinatory efforts appear to be plausible from a clinical perspective.…”

Section: Why Do We Need Multimodal Combination Therapy?mentioning

confidence: 99%