Title: Is Rapid Reversal of Liver Fibrosis Possible?

Author: Peter G. Traber

Introduction

Treatment of liver fibrosis is a major focus of drug development with multiple companies examining a variety of targets. All etiologies of chronic liver disease are associated with progressive fibrosis, including the top causes of non-alcoholic steatohepatitis (NASH), chronic viral hepatitis B and C (HBV and HCV), and alcoholic steatohepatitis (ASH). There is an increased risk of all-cause and liver-related mortality with increasing liver fibrosis stage [Dulai, et al. Hepatology 2017;65:1557-1565].

Since the development of significant liver fibrosis develops over years and decades, most experts in liver disease recommend that treatments directed at liver fibrosis should be given for at least a year to see an effect, and likely longer to have a clinically meaningful effect. However, there is tantalizing, albeit preliminary, evidence that improvement in liver fibrosis may be amenable to shorter treatment regimens.

Mixed versus fibrosis-specific mechanisms

Many drugs may affect the underlying pathophysiology of the liver disease and thereby reduce, and potentially reverse fibrosis. For example, eradication of HCV often results in gradual reduction of fibrosis, but this occurs over the course of 5-10 years or more. Multiple drugs targeting NASH affect multiple pathways in NASH, such as insulin resistance, lipid synthetic and metabolic pathways, and inflammation. While some have a direct effect on fibrogenesis as well, much of the effect may be secondary changes in the processes of fibrogenesis and/or fibrolysis.

There are fewer drugs that affect strictly fibrogenesis and/or fibrolysis. One such drug was simtuzumab (GILD) which inhibited LOXL2 which cross links collagen fibrils, but this failed in multiple phase 2 clinical trials [Harrison, et al. Gastroenterology 2018;155:1140–115]. While there are other drugs that have been classified as primarily anti-fibrotics, most have not been clearly shown to have this primary effect. There are promising drug targeting approaches that may be primarily anti-fibrotic in liver disease, such as integrin inhibitors and others. One of interesting target in this regard is HSP47 (heat shock protein 47) which is an ER-resident molecular chaperone that is essential for proper folding of collagen.

Targeting faster resolution of liver fibrosis

Inhibition of HSP47 has the potential to both inhibit fibrogenesis and increase fibrolysis, the key to achieving faster resolution of liver fibrosis. Bristol Myers Squibb in-licensed BMS-986263 from Nitto Denko which is a stellate cell-targeted, lipid nanoparticle encapsulated HSP47 siRNA that reduces liver HSP47 in a dose dependent fashion and has robust effects in animal models.

BMS reported preliminary results of an open label exploratory, dose escalation phase 2 study at the AASLD meetings in 2017 in which BMS-986263 was administered intravenously once or twice weekly for five weeks in patients with F-3 and F-4 fibrosis from both NASH and HCV [Lawitz, et al. AASLD; abstract 1433]. While this was a small study of only 23 patients, there were some promising results with improvement in fibrosis stage in some patients with both F-3 and F-4 fibrosis. Additionally, in the patients where the drug reduced HSP47, this reduction was correlated with fibrosis improvement as assessed by quantitative morphometry. Based on these results, BMS-986263 is being evaluated in a phase 2 study in HCV patients who have advanced fibrosis and have had eradication of the HCV virus.

What does this mean for potential treatments for liver fibrosis?

Admittedly, the clinical results with BMS-986263 are preliminary in a small number of patients, cautioning against excessive extrapolation particularly considering the well-documented sampling error associated with liver biopsy. However, an approach that may reduce liver fibrosis over several months opens the therapeutic area to multiple approaches. First, a rapidly acting antifibrotic might be acceptable in clinical practice with intravenous administration as for BMS-986263. Such drugs could be used in an induction phase to reduce fibrosis and then a maintenance phase of treatment. Additionally, a drug that rapidly resolves fibrosis could be combined with other agents that act over a longer period of time with different mechanisms of action.

As one views the landscape of liver fibrosis therapeutics, drugs that affect both fibrinogenesis and fibrolysis may act to reduce fibrosis in a shorter time than traditionally viewed. This possibility adds exciting new options to the therapeutic space. As a disclaimer, there are other drugs in development that may have faster effects on liver fibrosis, such as Selonsertib (GILD) which reports out two phase 3 clinical trials in first half of 2019 in patients with NASH cirrhosis and advanced bridging fibrosis, but this note was meant to highlight one novel mechanism and the concept of rapid reversal of liver fibrosis.

More information

For information on my consulting work and background please visit here: /consultants/peter-g-traber/

Additional blog posts by Peter G. Traber


Disclosure: From March 2011 through June 2018 the author was CEO and CMO of Galectin Therapeutics (NASDAQ: GALT), a company with a NASH development asset.

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