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

Eric G. Meissner, Mary McLaughlin, Lindsay Matthews, Ahmed M. Gharib, Bradford J. Wood, Elliot Levy, Ralph Sinkus, Kimmo Virtaneva, Dan Sturdevant, Craig Martens, Stephen F. Porcella, Zachary D. Goodman, Bittoo Kanwar, Robert P. Myers, Mani Subramanian, Colleen Hadigan, Henry Masur, David E. Kleiner, Theo Heller, Shyam KottililJoseph A. Kovacs, Caryn G. Morse

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1783-1792
Number of pages10
JournalLiver International
Volume36
Issue number12
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

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Hepacivirus
Liver Cirrhosis
HIV
Safety
Liver
Fibrosis
Venous Pressure
Biopsy
Interleukin-10
Liver Diseases
Protein-Lysine 6-Oxidase
End Stage Liver Disease
Virus Diseases
Coinfection
Up-Regulation
Monoclonal Antibodies
Clinical Trials
Wounds and Injuries
Enzymes
Serum

Keywords

  • hepatic venous pressure gradient
  • lysyl oxidases
  • magnetic resonance elastography
  • transforming growth factor beta-3

ASJC Scopus subject areas

  • Hepatology

Cite this

Meissner, E. G., McLaughlin, M., Matthews, L., Gharib, A. M., Wood, B. J., Levy, E., ... Morse, C. G. (2016). Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. Liver International, 36(12), 1783-1792. https://doi.org/10.1111/liv.13177

Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults : results of a 6-month open-label safety trial. / Meissner, Eric G.; McLaughlin, Mary; Matthews, Lindsay; Gharib, Ahmed M.; Wood, Bradford J.; Levy, Elliot; Sinkus, Ralph; Virtaneva, Kimmo; Sturdevant, Dan; Martens, Craig; Porcella, Stephen F.; Goodman, Zachary D.; Kanwar, Bittoo; Myers, Robert P.; Subramanian, Mani; Hadigan, Colleen; Masur, Henry; Kleiner, David E.; Heller, Theo; Kottilil, Shyam; Kovacs, Joseph A.; Morse, Caryn G.

In: Liver International, Vol. 36, No. 12, 01.12.2016, p. 1783-1792.

Research output: Contribution to journalArticle

Meissner, EG, McLaughlin, M, Matthews, L, Gharib, AM, Wood, BJ, Levy, E, Sinkus, R, Virtaneva, K, Sturdevant, D, Martens, C, Porcella, SF, Goodman, ZD, Kanwar, B, Myers, RP, Subramanian, M, Hadigan, C, Masur, H, Kleiner, DE, Heller, T, Kottilil, S, Kovacs, JA & Morse, CG 2016, 'Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial', Liver International, vol. 36, no. 12, pp. 1783-1792. https://doi.org/10.1111/liv.13177
Meissner, Eric G. ; McLaughlin, Mary ; Matthews, Lindsay ; Gharib, Ahmed M. ; Wood, Bradford J. ; Levy, Elliot ; Sinkus, Ralph ; Virtaneva, Kimmo ; Sturdevant, Dan ; Martens, Craig ; Porcella, Stephen F. ; Goodman, Zachary D. ; Kanwar, Bittoo ; Myers, Robert P. ; Subramanian, Mani ; Hadigan, Colleen ; Masur, Henry ; Kleiner, David E. ; Heller, Theo ; Kottilil, Shyam ; Kovacs, Joseph A. ; Morse, Caryn G. / Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults : results of a 6-month open-label safety trial. In: Liver International. 2016 ; Vol. 36, No. 12. pp. 1783-1792.
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AU - McLaughlin, Mary

AU - Matthews, Lindsay

AU - Gharib, Ahmed M.

AU - Wood, Bradford J.

AU - Levy, Elliot

AU - Sinkus, Ralph

AU - Virtaneva, Kimmo

AU - Sturdevant, Dan

AU - Martens, Craig

AU - Porcella, Stephen F.

AU - Goodman, Zachary D.

AU - Kanwar, Bittoo

AU - Myers, Robert P.

AU - Subramanian, Mani

AU - Hadigan, Colleen

AU - Masur, Henry

AU - Kleiner, David E.

AU - Heller, Theo

AU - Kottilil, Shyam

AU - Kovacs, Joseph A.

AU - Morse, Caryn G.

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N2 - 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.

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