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

NCT04248426 | Completed Phase 1

• 1 other identifier: ANTT101
• Study Type: interventional
• Target: 88
• Locations: 3 countries
• Sites: 3

Brief 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.

Conditions

Hepatitis B, Chronic

Outcome Measures

Primary Outcomes (5)

• The percentage of subjects who experienced at least 1 treatment-emergent adverse event (TEAE)

  Through study completion, an average of 1 year

• The percentage of subjects who experienced at least one treatment emergent serious AE (SAE).

  Through study completion, an average of 1 year

• Percentage of subjects who experienced a treatment-emergent dose limiting toxicity (DLT)

  Through study completion, an average of 1 year

• Percentage of subjects who experienced at least one treatment emergent Grade 1, 2, 3, 4 or 5 laboratory abnormality

  Through study completion, an average of 1 year

• Percentage of subjects who discontinued study drug due to a TEAE

  Through study completion, an average of 1 year

Secondary Outcomes (42)

• Peak plasma concentration (Cmax) of ATI-2173 and clevudine in Single Dose Healthy Volunteers

  Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

• Food effect on Peak plasma concentration (Cmax) of ATI-2173 and clevudine in Single Dose Healthy Volunteers

  Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

• Peak plasma concentration (Cmax) of ATI-2173 and clevudine in Multiple Dose Healthy Volunteers

  Day 1 & Day 14: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Day 14 only: post-dose at 48, 72, 144, 216, and 312 hours

• Peak plasma concentration (Cmax) of ATI-2173 and clevudine in Multiple Dose HBV Infected Patients

  Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

• Time of maximum observed plasma concentration (Tmax) of ATI-2173 and clevudine in Single Dose Healthy Volunteers

  Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

Study Arms (2)

ATI-2173

EXPERIMENTAL

Drug: ATI-2173

ATI-2173 Placebo

PLACEBO COMPARATOR

Drug: ATI-2173 Placebo

Interventions

ATI-2173 DRUG

ATI-2173 is a liver-targeted phosphoramidate prodrug of clevudine designed to enhance anti-HBV activity while decreasing systemic exposure to clevudine. It will be dosed as a capsule by mouth.

ATI-2173

ATI-2173 Placebo DRUG

ATI-2173 Placebo is used as an inactive comparator to ATI-2173. It will be dosed as a capsule by mouth.

ATI-2173 Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All subjects:
• Provision of signed and dated informed consent form (ICF)
• Stated willingness to comply with all study procedures and availability for the duration of the study
• If female, meets 1 of the following criteria:
• Is of childbearing potential and agrees to use an accepted contraceptive method. Acceptable method of contraception include:
• Abstinence from heterosexual intercourse from at least 28 days prior to the first study drug administration through to at least 30 days after the last dose of the study drug or until completion of the study, whichever is longer
• Male partner vasectomized at least 6 months prior to the first study drug administration
• Use a systemic contraceptive or an intrauterine device (with or without hormones), from at least 28 days prior to the first study drug administration through to at least 30 days after the last dose of the study drug or until completion of the study, whichever is longer, with a male condom or a diaphragm/cervical cap plus spermicide, from the first study drug administration through to at least 30 days after the last dose of the study drug or until completion of the study, whichever is longer Or
• Male partner has had a vasectomy less than 6 months prior to dosing, and agrees to use an additional acceptable contraceptive method from the first study drug administration through to at least 30 days after the last dose of the study drug or until completion of the study, whichever is longer Or
• Is of non-childbearing potential, defined as surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a postmenopausal state (i.e. at least 1 year without menses without an alternative medical condition prior to the first study drug administration and follicle-stimulating hormone levels ≥ 40 mIU/mL at screening)
• If male, meets 1 of the following criteria:
• Is able to procreate and agrees to use 1 of the accepted contraceptive regimens and not to donate sperm from the first study drug administration to at least 90 days after the last drug administration. An acceptable method of contraception includes 1 of the following:
• Abstinence from heterosexual intercourse
• Male condom with spermicide or male condom with a vaginal spermicide (gel, foam, or suppository) or
• Is unable to procreate; defined as surgically sterile (i.e. has undergone a vasectomy at least 180 days prior to the first study drug administration)

You may not qualify if:

• All subjects:
• Female who is lactating at screening
• Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration
• History of significant hypersensitivity to clevudine or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs
• History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease
• Presence of clinically significant muscle disorders, myopathies or other forms of liver disease
• Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment
• Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration
• Any history of tuberculosis
• Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration
• Active illicit drug use including, but not limited to, cocaine, heroin and methamphetamine (the use of cannabinoid is acceptable)
• Donation of 50 mL or more of blood in the 28 days prior to the first study drug administration
• Donation of 500 mL or more of blood in the 56 days prior to the first study drug administration
• Healthy subjects (Phase 1a):
• Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (\> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)

Sponsors & Collaborators

• Antios Therapeutics, Inc: lead

Study Sites (3)

Altasciences

Montreal, Quebec, H3P 3P1, Canada

Location

Republican Clinical Hospital "Timofei Mosneaga" Arensia EM Unit

Chisinau, Republic of Moldova, Moldova

Location

Medical Center of Limited Liability Company "Harmoniya krasy" Department of Clinical Trials

Kyiv, Ukraine

Location

Related Publications (17)

• 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.

  PMID: 11124844 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.

  PMID: 15239097 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.

  PMID: 16628625 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.

  PMID: 18363895 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.

  PMID: 17464992 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.

  PMID: 17647293 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.

  PMID: 19665816 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.

  PMID: 19615776 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.

  PMID: 19333909 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.

  PMID: 21444706 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.

  PMID: 28427875 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.

  PMID: 28762522 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.

  PMID: 29405329 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

  BACKGROUND

• 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.

  PMID: 36201354 DERIVED

MeSH Terms

Conditions

Hepatitis B, Chronic

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Douglas Mayers, MD

  Antios Therapeutics, Inc

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 22, 2020
• First Posted: January 30, 2020
• Study Start: February 5, 2020
• Primary Completion: May 18, 2021
• Study Completion: May 18, 2021
• Last Updated: August 19, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

UA (1); CA (1); MO (1)