Tesamorelin for the Potential Treatment of NASH
Non-alcoholic fatty liver disease (NAFLD) is a term that defines a continuum of different liver diseases. The early stage starts with non-alcoholic fatty liver (NAFL), which may progress to chronic liver inflammation (non-alcoholic steatohepatitis [NASH]), fibrosis, cirrhosis and hepatocellular carcinoma (HCC)12, 1, 2. NAFLD is the most common chronic liver condition. It is estimated that approximately 20 to 25% of adults in many countries (United States, France, Germany, Italy, Spain, United Kingdom and Canada) have NAFLD3, 4. The prevalence of NASH is between 2.5 to 5% in those countries. Most people with NAFLD simply have fatty liver. NAFLD pathogenesis includes many contributing factors like lipogenesis and lipotoxicity, inflammation, insulin resistance and oxidative stress2.
NAFL begins with an increase of free fatty acid that can stimulate inflammation and ballooning leading to NASH1, 2. The injury caused to the liver fat is reversible until it leads to cirrhosis and HCC1.
Unlike administration of exogenous growth hormone (GH), tesamorelin (a growth hormone releasing hormone [GHRH] analog) induces endogenous pulsatile secretion of GH by the pituitary gland5. Endogenous GH induces lipolysis and decreases liver steatosis. In addition, increased concentration of GH caused by tesamorelin doesn’t induce the same adverse events as exogenous GH since the pulsatile secretion is preserved6, 7.
Stimulation of endogenous GH production maintains pulsatile secretion and preserves negative feedback loop which improves its safety profile.
GH dysfunction is closely linked to adipose tissue dysfunction. GH deficiency is associated with a significant increase of lipid uptake and synthesis, leading to liver steatosis8. Clinical studies have demonstrated a significant correlation between liver fat increase, lobular inflammation and hepatocyte ballooning and endogenous GH secretion decrease9-11. Increased GH concentration is associated with3, 10, 12, 13:
- a decrease of liver steatosis within the hepatocytes that will lead to a decrease of cell damage
- a reduction of the oxidative stress that will be associated with a decrease of inflammation
- a diminution of liver fibrosis
In a Phase 2 clinical study in people with HIV (PWH) with NAFLD, tesamorelin significantly decreased liver steatosis by 37%9, 14. A high percentage of subjects (60%) were able to achieve 30% decrease of liver fat reduction after 1 year of treatment compared to placebo subjects (16%, internal data). Tesamorelin also demonstrated an impact on liver fibrosis by significantly reducing fibrosis progression compared to placebo group14. In addition, the results of the study demonstrated critical changes associated with tesamorelin treatment relative to placebo in key liver gene sets, including reduction in hepatic fat oxidation, and reduction in key inflammatory and fibrotic pathways13.
- Anstee, Q.M., et al., From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol, 2019.
- Lim, S., M.R. Taskinen, and J. Boren, Crosstalk between nonalcoholic fatty liver disease and cardiometabolic syndrome. Obes Rev, 2018.
- Estes, C., et al., Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol, 2018. 69(4): p. 896-904.
- Swain, M.G., et al., Burden of nonalcoholic fatty liver disease in Canada, 2019-2030: a modelling study. CMAJ Open, 2020. 8(2): p. E429-E436.
- Stanley, T.L., et al., Effects of a growth hormone-releasing hormone analog on endogenous GH pulsatility and insulin sensitivity in healthy men. J Clin Endocrinol Metab, 2011. 96(1): p. 150-158.
- Serono, E., Serostim® Product Monograph. 2007.
- Casanueva, F.F., Physiology of growth hormone secretion and action. Endocrinol. Metab Clin. North Am, 1992. 21(3): p. 483-517.
- Liu, Z., et al., Growth Hormone Control of Hepatic Lipid Metabolism. Diabetes, 2016. 65(12): p. 3598-3609.
- Stanley, T.L., et al., Effect of Tesamorelin on Visceral Fat and Liver Fat in HIV-Infected Patients With Abdominal Fat Accumulation: A Randomized Clinical Trial. Jama, 2014. 312(4): p. 380-389.
- Xu, L., et al., Association between serum growth hormone levels and nonalcoholic fatty liver disease: a cross-sectional study. PLoS One, 2012. 7(8): p. e44136.
- Dichtel, L.E., et al., The Association Between IGF-1 Levels and the Histologic Severity of Nonalcoholic Fatty Liver Disease. Clin Transl Gastroenterol, 2017. 8(1): p. e217.
- Takahashi, Y., The Role of Growth Hormone and Insulin-Like Growth Factor-I in the Liver. Int J Mol Sci, 2017. 18(7).
- Fourman, L.T., et al., Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD. JCI Insight, 2020. 5(16).
- Stanley, T.L., et al., Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. The Lancet HIV, 2019.
1 Definition & Facts of NAFLD & NASH. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts. Published November 1, 2016. Accessed August 7, 2020.
2 Nonalcoholic fatty liver disease. https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/symptoms-causes/syc-20354567. Published August 22, 2019. Accessed August 7, 2020.
3 Connolly JJ et al. J Clin Transl Hepatol. 2018 Sep 28;6(3):264-275. 5. Liu Z et al. Diabetes. 2016 Dec;65(12):3598-3609.5. 6. Sanz S et al. Gut. 2005; 54:134-141. 7. Stefano JT et al. World J Gastroenterol. 2006 Jun 28; 12(24):3821–3828. 8. Ditchel LE et al. Clin Transl Gastroentrol. 2017; 8:e217