Norursodeoxycholic Acid Improves Cholestasis in Primary Sclerosing Cholangitis: Results of a Phase II Dose Finding Study

Trauner, Michael; Fickert, Peter; Hirschfield, G.M.; Reiter, Florian P.; Altorjay, I; Marschall, H.-U.; Färkkilä, Martti; Schramm, C; Spengler, Ulrich; Chapman, Richard; Bergquist, Annika; Schrumpf, E.; Nevens, Frederik; Halilbasic, Emina; Greinwald, Roland; Proels, Markus; Manns, MP

doi:10.1016/s0168-8278(16)00171-9

Cited by 10 publications

(12 citation statements)

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“…Recently, there is a resurgence of interest from the pharmaceutical industry for this orphan disease, and a handful of phase 2 trials are currently underway and two have presented results. 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%

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%

Design and Endpoints for Clinical Trials in Primary Sclerosing Cholangitis

et al. 2018

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“…Primary efficacy endpoint was the mean relative change (%) in s-ALP levels between the baseline visit and the end-of-treatment visit in the intention to treat population. NorUDCA resulted in a profound and dose-dependent reduction of serum ALP and other liver enzymes after 12 weeks of treatment [22] . NorUDCA was effective in both patients -previously treated UDCA (independent whether they were responding or not to UDCA therapy) and UDCAnaïve patients [23] .…”

Section: Norudca In Pscmentioning

confidence: 95%

“…Based on these promising preclinical mechanisms and the excellent safety in phase I studies, norUDCA has recently been tested in patients with PSC and the key results have been reported as oral presentations at meetings in the abstract form [22,23]. The full publication is currently under preparation.…”

Section: Norudca In Pscmentioning

confidence: 99%

Nor-Ursodeoxycholic Acid as a Novel Therapeutic Approach for Cholestatic and Metabolic Liver Diseases

Halilbasic

Steinacher²,

Trauner³

2017

Dig Dis

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Norursodeoxycholic acid (norUDCA) is a side-chain-shortened derivative of ursodeoxycholic acid with relative resistance to amidation, which enables its cholehepatic shunting. Based on its specific pharmacologic properties, norUDCA is a promising drug for a range of cholestatic liver and bile duct disorders. Recently, norUDCA has been successfully tested clinically in patients with primary sclerosing cholangitis (PSC) as first application in patients. Moreover, hepatic enrichment of norUDCA facilitates direct therapeutic effects on both parenchymal and non-parenchymal liver cells, thereby counteracting cholestasis, steatosis, hepatic inflammation and fibrosis, inhibiting hepatocellular proliferation, and promoting autophagy. This may open its therapeutic use to other non-cholestatic and metabolic liver diseases. This review article is a summary of a lecture given at the XXIV International Bile Acid Meeting (Falk Symposium 203) on “Bile Acids in Health and Disease” held in Düsseldorf, on June 17-18, 2016 and summarizes the recent progress of norUDCA as novel therapeutic approach in cholestatic and metabolic liver disorders with a specific focus on PSC.

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“…This leads to significantly greater choleresis than with UDCA [32]. In addition, nor -UDCA causes choleresis of more hydrophobic bile, with a significant increase in biliary glutathioine and bicarbonate secretion in mouse models [34]. Unlike UDCA, nor UDCA can also increase the expression of basolateral efflux pumps (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Unlike UDCA, nor UDCA can also increase the expression of basolateral efflux pumps (i.e. Mrp4 and Mrp3) and upregulate phase I and II detoxification enzymes (Sult2a1, Ugt1a1, Cyp2b10 and Cyp3a11), the latter leading to a significant decrease in serum bile acids [34]. …”

Section: Introductionmentioning

confidence: 99%

Emerging pharmacologic therapies for primary sclerosing cholangitis

Cheung

Lazaridis

LaRusso

et al. 2017

Current Opinion in Gastroenterology

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Purpose of review The only currently approved treatment for primary sclerosing cholangitis (PSC) is liver transplantation, with a median time to transplant of 12–18 years after diagnosis. There are a number of emerging drugs that have the potential to meet this critically unmet need that will be summarized and discussed herein. Recent findings Although the cause of PSC is unknown, there are a number of novel therapeutics under development. These drugs target presumed pathogenic mechanisms largely extrapolated from ex-vivo and in-vivo preclinical models, as well as translational observations. Summary Future therapeutic strategies for PSC may include a multitude of complex pathogenic mechanisms encompassing pathways of immunomodulation, the microbiome and inflammation-related fibrosis.

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Norursodeoxycholic Acid Improves Cholestasis in Primary Sclerosing Cholangitis: Results of a Phase II Dose Finding Study

Cited by 10 publications

References 0 publications

Design and Endpoints for Clinical Trials in Primary Sclerosing Cholangitis

Design and Endpoints for Clinical Trials in Primary Sclerosing Cholangitis

Nor-Ursodeoxycholic Acid as a Novel Therapeutic Approach for Cholestatic and Metabolic Liver Diseases

Emerging pharmacologic therapies for primary sclerosing cholangitis

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