Novel pharmacologic treatment approaches targeting fibrogenesis

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As the aetiology of primary sclerosing Cholangitis (PSC) remains unknown, no causal drug therapy currently exists. To this day, the only effective therapeutic option is liver transplantation. One of the major clinical challenges in PSC is the progression to liver fibrosis. Therefore, novel pharmacologic treatment approaches targeting fibrogenesis are urgently needed. In a recent issue of Hepatology, Muir et al. published the results of a dose-ranging, randomized, double-blind, placebo-controlled Phase 2b Trial on the effect of Simtuzumab in PSC (DOI: 10.1002/hep.30237). Simtuzumab is a humanized monoclonal antibody targeting Lysyl oxidase-like protein 2 (LOXL2) that is considered to mediate profibrotic effects by collagen crosslinking. Even though Simtuzumab showed no significant benefit in reducing fibrosis or preventing clinical complications such as ascending cholangitis, ascites or hepatic encephalopathy in PSC patients, the study provides interesting insights into the natural history of disease and highlights challenges in future study designs.

The Lysyl oxidase-like protein 2 (LOXL2) promotes stabilization of the extracellular matrix, chemotaxis and cell growth. Induction of LOXL2 expression was demonstrated in fibrotic liver diseases and elevated serum and hepatic expression levels correlated with fibrosis stage in PSC. Therefore, Simtuzumab, a monoclonal humanized antibody directed against LOXL2, was tested for its antifibrotic effects in PSC.

The study „Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results with Insights on the Natural History of Disease“ (DOI: 10.1002/hep.30237) was published in August 2018 in Hepatology by Muir et al.1 In this trial, 234 patients with compensated liver disease caused by PSC were randomly assigned 1:1:1 to receive weekly subcutaneous injections of Simtuzumab 125mg, 75mg or placebo over 96 weeks. In addition to regular blood tests MRCP and liver biopsies were performed at week 0, 48 and 96. The primary endpoint of the study was the mean change from baseline in hepatic collagen content, assessed via morphometry on liver biopsy specimens between baseline and week 96. Secondary endpoints included changes in Ishak fibrosis stage on liver biopsy and the frequency of PSC-related clinical events (ascending cholangitis, ascites, hepatic encephalopathy, cholangiocarcinoma etc.). At the beginning of the trial, 40% of patients had bridging fibrosis and 11% had cirrhosis. 194 of the 234 randomized patients completed study treatment.

At week 96 hepatic collagen content had not improved with Simtuzumab in comparison to the placebo group. Changes in hepatic collagen content did not significantly differ according to baseline UDCA use, IgG4 status (≤140 mg/dl vs >140 mg/dl) or presence or absence of UC. Moreover, Simtuzumab did not significantly improve the Ishak fibrosis stage nor could it prevent progression to cirrhosis among non-cirrhotic patients at baseline. Similarly, no significant difference with regard to the frequency of PSC-related clinical events was shown between the groups.

Although the primary endpoint was not achieved for Simtuzumab, the study by Muir et al. provides important clinical information concerning the natural progression of PSC: 20% (n=47) of 234 patients developed PSC-related clinical events over the 2-year-period. Ascending cholangitis was the most common complication (13% of 234 patients, n=31). On top of that, predictors of progression to cirrhosis or predictors of clinical events such as ascending cholangitis, ascites or hepatic encephalopathy could be confirmed by the study: 34% of patients with ALP levels > 324 U/l developed PSC-related complications, thereby confirming serum ALP levels as an important clinical stratifier for PSC. Moreover, an advanced histological stage of fibrosis resulted in a two-fold risk of complications compared to moderate or no fibrosis. Non-invasive markers of fibrosis (liver stiffness measured by Transient Elastography and Enhanced Liver Fibrosis Test) mapped these findings: Patients with a liver stiffness >8,7 kPa measured by Transient Elastography had a 6-fold risk of clinical PSC-related events, thereby confirming previous studies.2,3

Despite all of this, the fact that Simtuzumab could neither meet the primary nor the secondary endpoints leads to several conclusions. As the authors already mention, there could be multiple reasons the ineffectiveness of Simtuzumab in PSC. With regards to former failures of Simtuzumab, demonstrated in trials of patients with NASH and advanced fibrosis, it is likely that Simtuzumab is not appropriate for an antifibrotic single-drug concept or it may not access the areas of liver tissue relevant for fibrogenesis.4,5 Further research should therefore focus on stage-adapted and multi-drug anti-fibrotic regimens. The study also demonstrates that proof of concept studies in patients could help to guide future trial designs in PSC. By doing this, invasive and costly large trials could be optimized to provide the largest benefit for patients, caregivers and industry alike.

Alena Laschtowitz
I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Contact: a.laschtowitz@uke.de

References

  1. Muir AJ, Levy C, Janssen HLA, et al., Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease. Hepatology, 2018.
  2. Corpechot C, Gaouar F, El Naggar A, et al., Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis. Gastroenterology, 2014.
  3. Ehlken H, Wroblewski R, Corpechot C, et al., Validation of Transient Elastography and Comparison with Spleen Length Measurement for Staging of Fibrosis and Clinical Prognosis in Primary Sclerosing Cholangitis. PLoS One, 2016.
  4. Harrison SA, Abdelmalek MF, Caldwell S, et al., Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology, 2018.
  5. Meissner EG, McLaughlin M, Matthews L, et al., Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. Liver Int, 2016.