Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial

Abstract

Background: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed.

Aim: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease.

Methods: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis.

Results: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-β3 and IL-10 pathways with treatment.

Conclusion: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-β3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials.

Trial registration: ClinicalTrials.gov NCT01707472.

Keywords: hepatic venous pressure gradient; lysyl oxidases; magnetic resonance elastography; transforming growth factor beta-3.

Conflict of interest statement

Dr. Meissner receives grant support from Gilead Sciences, Inc. Drs. Kanwar, Myers and Subramanian are employed by and own stock in Gilead Sciences Inc. Dr. Goodman reports grant support from Gilead Sciences, Inc., Tobira, Intercept, Galectin, Conatus, and Alexion. All other co-authors report no conflicts of interest.

© 2016 This article is a U.S. Government work and is in the public domain in the USA.

Figures

Figure 1

No significant change was seen in portal pressure gradient (HVPG) (A), fibrosis (B), MRE (C), liver inflammation (D) or AST/platelet ratio index (APRI) (E) after 22 weeks of treatment with simtuzumab. Median values are indicated with red lines. Abbreviations: PRE (pre-treatment) and EOT (end-of-treatment, week 22).

Figure 2

Predicted upstream activation of TGF-β3 (A) and IL-10 (B) pathways. Shown are ratios of end of treatment (EOT, week 20) over pre-treatment (PRE) gene expression, with red representing increased post-treatment gene expression, blue representing decreased gene expression, and ratio indicated in each field. TGF-β3 and IL-10 pathways had an Ingenuity Pathway Analysis (IPA) activation Z-scores 2.4 and 2.2, respectively.

Figure 3

A significant increase was seen in serum TGF-β3 (C), but not TGF-β1 (A) or TGF-β2 (B), during simtuzumab therapy (n=18). Displayed p-values are by paired t-test. Abbreviations: PRE (pre-treatment) and EOT (end-of-treatment, week 20).