A Phase 1 Double-Blinded Study for Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of ATI-2173 in Healthy Subjects and Subjects With Chronic Hepatitis B Virus Infection

Summary

This is a double-blinded, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics, and antiviral activity in both healthy volunteers and volunteers with chronic hepatitis B virus infection. Healthy volunteers will be administered either a single oral dose or multiple oral doses of ATI-2173 and assessed for safety and tolerability including blood tests to show how the body metabolizes and eliminates the investigational drug. Volunteers with a diagnosis of chronic hepatitis B virus infection will be administered multiple oral doses of ATI-2173 and assessed for safety and tolerability including blood tests to show how the body metabolizes and eliminates the investigational drug as well as how the drug effects the virus infection.

Timeline

Start

2020-02-05

Primary completion

2021-05-18

Completion

2021-05-18

Publications

• Background Peek SF, Cote PJ, Jacob JR, Toshkov IA, Hornbuckle WE, Baldwin BH, Wells FV, Chu CK, Gerin JL, Tennant BC, Korba BE. Antiviral activity of clevudine [L-FMAU, (1-(2-fluoro-5-methyl-beta, L-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax). Hepatology. 2001 Jan;33(1):254-66. doi: 10.1053/jhep.2001.20899.
• Background Marcellin P, Mommeja-Marin H, Sacks SL, Lau GK, Sereni D, Bronowicki JP, Conway B, Trepo C, Blum MR, Yoo BC, Mondou E, Sorbel J, Snow A, Rousseau F, Lee HS. A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B. Hepatology. 2004 Jul;40(1):140-8. doi: 10.1002/hep.20257.
• Background Lee HS, Chung YH, Lee K, Byun KS, Paik SW, Han JY, Yoo K, Yoo HW, Lee JH, Yoo BC. A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology. 2006 May;43(5):982-8. doi: 10.1002/hep.21166.
• Background Lim SG, Leung N, Hann HW, Lau GK, Trepo C, Mommeja-Marin H, Moxham C, Sorbel J, Snow A, Blum MR, Rousseau F, Marcellin P. Clinical trial: a phase II, randomized study evaluating the safety, pharmacokinetics and anti-viral activity of clevudine for 12 weeks in patients with chronic hepatitis B. Aliment Pharmacol Ther. 2008 Jun;27(12):1282-92. doi: 10.1111/j.1365-2036.2008.03686.x. Epub 2008 Mar 22.
• Background Yoo BC, Kim JH, Chung YH, Lee KS, Paik SW, Ryu SH, Han BH, Han JY, Byun KS, Cho M, Lee HJ, Kim TH, Cho SH, Park JW, Um SH, Hwang SG, Kim YS, Lee YJ, Chon CY, Kim BI, Lee YS, Yang JM, Kim HC, Hwang JS, Choi SK, Kweon YO, Jeong SH, Lee MS, Choi JY, Kim DG, Kim YS, Lee HY, Yoo K, Yoo HW, Lee HS. Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology. 2007 May;45(5):1172-8. doi: 10.1002/hep.21629.
• Background Yoo BC, Kim JH, Kim TH, Koh KC, Um SH, Kim YS, Lee KS, Han BH, Chon CY, Han JY, Ryu SH, Kim HC, Byun KS, Hwang SG, Kim BI, Cho M, Yoo K, Lee HJ, Hwang JS, Kim YS, Lee YS, Choi SK, Lee YJ, Yang JM, Park JW, Lee MS, Kim DG, Chung YH, Cho SH, Choi JY, Kweon YO, Lee HY, Jeong SH, Yoo HW, Lee HS. Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression. Hepatology. 2007 Oct;46(4):1041-8. doi: 10.1002/hep.21800.
• Background Fleischer RD, Lok AS. Myopathy and neuropathy associated with nucleos(t)ide analog therapy for hepatitis B. J Hepatol. 2009 Oct;51(4):787-91. doi: 10.1016/j.jhep.2009.06.011. Epub 2009 Jul 1.
• Background Kim BK, Oh J, Kwon SY, Choe WH, Ko SY, Rhee KH, Seo TH, Lim SD, Lee CH. Clevudine myopathy in patients with chronic hepatitis B. J Hepatol. 2009 Oct;51(4):829-34. doi: 10.1016/j.jhep.2009.04.019. Epub 2009 May 28.
• Background Seok JI, Lee DK, Lee CH, Park MS, Kim SY, Kim HS, Jo HY, Lee CH, Kim DS. Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA. Hepatology. 2009 Jun;49(6):2080-6. doi: 10.1002/hep.22959.
• Background Wang L, Sun R, Eriksson S. The kinetic effects on thymidine kinase 2 by enzyme-bound dTTP may explain the mitochondrial side effects of antiviral thymidine analogs. Antimicrob Agents Chemother. 2011 Jun;55(6):2552-8. doi: 10.1128/AAC.00109-11. Epub 2011 Mar 28.
• Background European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18.
• Background PEGASYS® (peginterferon alfa-2a) Injection, for Subcutaneous Use. Initial U.S. Approval: 2002 Prescribing Information. https://www.gene.com/patients/medicines/pegasys
• Background Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: From discovery to regulatory approval. Hepatology. 2017 Oct;66(4):1296-1313. doi: 10.1002/hep.29323. Epub 2017 Aug 1.
• Background Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. No abstract available.
• Background VIREAD® (tenofovir disoproxil fumarate), Initial U.S. Approval 2001 Prescribing Information. https://www.gilead.com/science-and-medicine/- /media/files/pdfs/medicines/hiv/viread/viread_pi.pdf?la=en
• Background BARACLUDE® (entecavir), Initial U.S. Approval 2005 Prescribing Information. https://packageinserts.bms.com/pi/pi_baraclude.pdf
• Squires KE, Ogilvie L, Jucov A, Anastasiy I, Ghicavii N, Huguet J, Melara R, Constantineau M, De La Rosa A, Mayers DL. A randomized phase 1b trial of the active site polymerase inhibitor nucleotide ATI-2173 in patients with chronic hepatitis B virus infection. J Viral Hepat. 2023 Jan;30(1):19-28. doi: 10.1111/jvh.13753. Epub 2022 Oct 22.

Drugs

Indications