Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial

The Lancet

Volumn 389, Issue 10070, 2017, Pages 709-717

  van der Ree, Meike H ^a   de Vree, J Marleen ^b   Stelma, Femke ^a   Willemse, Sophie ^a   van der Valk, Marc ^a   Rietdijk, Svend ^a,c   Molenkamp, Richard ^a   Schinkel, Janke ^a   van Nuenen, Ad C ^a   Beuers, Ulrich ^a   Hadi, Salah ^d   Harbers, Marten ^d   van der Veer, Eva ^e   Liu, Kai ^f   Grundy, John ^f   Patick, Amy K ^f   Pavlicek, Adam ^f   Blem, Jacqueline ^f   Huang, Michael ^f   Grint, Paul ^f   Neben, Steven ^f   Gibson, Neil W ^f   Kootstra, Neeltje A ^a   Reesink, Hendrik W ^a   more..

^a ACADEMIC MEDICAL CENTER   (Netherlands)

^b UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^c ONZE LIEVE VROUWE GASTHUIS   (Netherlands)

^d PRA HEALTH SCIENCES   (United States)

^e DDL DIAGNOSTIC LABORATORY   (Netherlands)

^f REGULUS THERAPEUTICS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ALKALINE PHOSPHATASE; ALPHA INTERFERON; ANTIVIRUS AGENT; ASPARTATE AMINOTRANSFERASE; BILIRUBIN; C REACTIVE PROTEIN; GAMMA GLUTAMYLTRANSFERASE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MICRORNA 122; PEGINTERFERON; PLACEBO; PROTEINASE INHIBITOR; RG 101; RIBAVIRIN; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; VIRUS RNA; MICRORNA; N ACETYLGALACTOSAMINE; OLIGONUCLEOTIDE;

5' UNTRANSLATED REGION; ABDOMINAL PAIN; ADULT; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALKALINE PHOSPHATASE BLOOD LEVEL; ANTIVIRAL THERAPY; AREA UNDER THE CURVE; ARTHRALGIA; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BACKACHE; BILIRUBIN BLOOD LEVEL; CHOLESTEROL BLOOD LEVEL; CHRONIC HEPATITIS C; COHORT ANALYSIS; CONTROLLED STUDY; DIARRHEA; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG BINDING SITE; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG SAFETY; DRUG TOLERABILITY; EMOTIONAL DISORDER; EMOTIONAL STRESS; FATIGUE; FECES COLOR; FEMALE; FLATULENCE; FOLLOW UP; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; HEADACHE; HEPATITIS C VIRUS GENOTYPE 1; HEPATITIS C VIRUS GENOTYPE 3; HEPATITIS C VIRUS GENOTYPE 4; HUMAN; HYPERHIDROSIS; IMMUNOTHERAPY; INJECTION SITE IRRITATION; INJECTION SITE REACTION; INSOMNIA; INTRAHEPATIC CHOLESTASIS; MALE; MAXIMUM PLASMA CONCENTRATION; MIDDLE AGED; MULTICENTER STUDY; MUSCLE SPASM; MYALGIA; NAUSEA; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REBOUND; RHINOPHARYNGITIS; RNA BINDING; SIDE EFFECT; SINGLE DRUG DOSE; SKIN IRRITATION; TIME TO MAXIMUM PLASMA CONCENTRATION; TRIACYLGLYCEROL BLOOD LEVEL; VIRUS GENOME; VIRUS LOAD; XEROSTOMIA; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; DRUG EFFECTS; SUBCUTANEOUS DRUG ADMINISTRATION;

ACETYLGALACTOSAMINE; COHORT STUDIES; DOUBLE-BLIND METHOD; FEMALE; HEPATITIS C, CHRONIC; HUMANS; INJECTIONS, SUBCUTANEOUS; MALE; MICRORNAS; MIDDLE AGED; OLIGONUCLEOTIDES; VIRAL LOAD;

EID: 85009502126     PISSN: 01406736     EISSN: 1474547X     Source Type: Journal    
DOI: 10.1016/S0140-6736(16)31715-9     Document Type: Article

References (33)

1. 1 Lindenbach, BD, Rice, CM, Unravelling hepatitis C virus replication from genome to function. Nature 436 (2005), 933–938.
2. 2 Hajarizadeh, B, Grebely, J, Dore, GJ, Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol 10 (2013), 553–562.
3. 3 European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2015. J Hepatol 63 (2015), 199–236.
4. 4 van der Meer, A, Veldt, BJ, Feld, JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 308 (2012), 2584–2593.
5. 5 Morgan, RL, Baack, B, Smith, BD, Yartel, A, Pitasi, M, Falck-Ytter, Y, Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 158 (2013), 329–337.
6. 6 Kohli, A, Kattakuzhy, S, Sidharthan, S, et al. Four-week direct-acting antiviral regimens in noncirrhotic patients with hepatitis C virus genotype 1 infection: an open-label, nonrandomized trial. Ann Intern Med 163 (2015), 899–907.
7. 7 Kohli, A, Osinusi, A, Sims, Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet 385 (2015), 1107–1113.
8. 8 Flisiak, R, Jaroszewicz, J, Flisiak, I, Łapiński, T, Update on alisporivir in treatment of viral hepatitis C. Expert Opin Investig Drugs 21 (2012), 375–382.
9. 9 Janssen, HLA, Reesink, HW, Lawitz, EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med 368 (2013), 1685–1694.
10. 10 Li, Y-P, Gottwein, JM, Scheel, TK, Jensen, TB, Bukh, J, MicroRNA-122 antagonism against hepatitis C virus genotypes 1-6 and reduced efficacy by host RNA insertion or mutations in the HCV 5′ UTR. Proc Natl Acad Sci USA 108 (2011), 4991–4996.
11. 11 Pawlotsky, J-M, What are the pros and cons of the use of host-targeted agents against hepatitis C?. Antiviral Res 105 (2014), 22–25.
12. 12 Esau, C, Davis, S, Murray, SF, et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3 (2006), 87–98.
13. 13 Krützfeldt, J, Rajewsky, N, Braich, R, et al. Silencing of microRNAs in vivo with “antagomirs”. Nature 438 (2005), 685–689.
14. 14 Elmén, J, Lindow, M, Schütz, S, et al. LNA-mediated microRNA silencing in non-human primates. Nature 452 (2008), 896–899.
15. 15 Bai, S, Nasser, MW, Wang, B, et al. MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib. J Biol Chem 284 (2009), 32015–32027.
16. 16 Zeng, C, Wang, R, Li, D, et al. A novel GSK-3 beta-C/EBP alpha-miR-122-insulin-like growth factor 1 receptor regulatory circuitry in human hepatocellular carcinoma. Hepatology 52 (2010), 1702–1712.
17. 17 Nassirpour, R, Mehta, PP, Yin, M-J, miR-122 regulates tumorigenesis in hepatocellular carcinoma by targeting AKT3. PLoS One, 8, 2013, e79655.
18. 18 Xu, J, Zhu, X, Wu, L, et al. MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/β-catenin pathway. Liver Int 32 (2012), 752–760.
19. 19 Jopling, CL, Yi, M, Lancaster, AM, Lemon, SM, Sarnow, P, Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309 (2005), 1577–1581.
20. 20 Lanford, RE, Hildebrandt-Eriksen, ES, Petri, A, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327 (2010), 198–201.
21. 21 Sedano, CD, Sarnow, P, Hepatitis C virus subverts liver-specific miR-122 to protect the viral genome from exoribonuclease Xrn2. Cell Host Microbe 16 (2014), 257–264.
22. 22 Li, Y, Masaki, T, Yamane, D, McGivern, DR, Lemon, SM, Competing and noncompeting activities of miR-122 and the 5′ exonuclease Xrn1 in regulation of hepatitis C virus replication. Proc Natl Acad Sci USA 110 (2013), 1881–1886.
23. 23 Machlin, ES, Sarnow, P, Sagan, SM, Masking the 5′ terminal nucleotides of the hepatitis C virus genome by an unconventional microRNA-target RNA complex. Proc Natl Acad Sci USA 108 (2011), 3193–3198.
24. 24 Masaki, T, Arend, KC, Li, Y, et al. miR-122 stimulates hepatitis C virus RNA synthesis by altering the balance of viral rnas engaged in replication versus translation. Cell Host Microbe 17 (2015), 217–228.
25. 25 Prakash, TP, Graham, MJ, Yu, J, et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res 42 (2014), 8796–8807.
26. 26 Tsai, W-C, Hsu, S-D, Hsu, C-S, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 122 (2012), 2884–2897.
27. 27 Hsu, S, Wang, B, Kota, J, et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest 122 (2012), 2871–2883.
28. 28 Coulouarn, C, Factor, VM, Andersen, JB, Durkin, ME, Thorgeirsson, SS, Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene 28 (2009), 3526–3536.
29. 29 van der Ree, MH, van der Meer, AJ, de Bruijne, J, et al. Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients. Antiviral Res 111 (2014), 53–59.
30. 30 Neben, S, Liu, K, Berman, C, et al. P0907: pharmacokinetics, pharmacodynamics, and toxicity profile of RG-101, a novel GalNAc-conjugated hepatocyte-targeting inhibitor of microrna-122, in rodents and cynomolgus monkeys. J Hepatol 62 (2015), S684–S685.
31. 31 Liu, F, Shimakami, T, Murai, K, et al. Efficient suppression of hepatitis C virus replication by combination treatment with miR-122 antagonism and direct-acting antivirals in cell culture systems. Sci Rep, 6, 2016, 30939.
32. 32 Ottosen, S, Parsley, TB, Yang, L, et al. In vitro antiviral activity and preclinical and clinical resistance profile of miravirsen, a novel anti-hepatitis C virus therapeutic targeting the human factor miR-122. Antimicrob Agents Chemother 59 (2015), 599–608.
33. 33 Sepp-Lorenzino, L, Sprague, AG, Mayo, T, et al. Parallel 4: hepatitis B: novel treatments and treatment targets: 36—GalNAc-siRNA conjugate ALN-HBV targets a highly conserved, pan-genotypic X-orf viral site and mediates profound and durable HBsAg silencing in vitro and in vivo. Hepatology 62 (2015), 222A–225A.