Conţinutul numărului revistei |
Articolul precedent |
Articolul urmator |
230 0 |
SM ISO690:2012 SQUIRES, Katherine E., OGILVIE, Lauren, JUCOV, Alina, ANASTASIY, Igor, GHICAVÎI, Nelea, HUGUET, Jade, MELARA, Rebeca, CONSTANTINEAU , Martin, DE LA ROSA, Abel, MAYERS, Douglas. A randomized phase 1b trial of the active site polymerase inhibitor nucleotide ATI-2173 in patients with chronic hepatitis B virus infection. In: Journal of Viral Hepatitis, 2023, nr. 1(30), pp. 19-28. ISSN 1352-0504. DOI: https://doi.org/10.1111/jvh.13753 |
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Journal of Viral Hepatitis | ||||||
Numărul 1(30) / 2023 / ISSN 1352-0504 /ISSNe 1365-2893 | ||||||
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DOI:https://doi.org/10.1111/jvh.13753 | ||||||
Pag. 19-28 | ||||||
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Rezumat | ||||||
ATI-2173 is an active site polymerase inhibitor nucleotide in development as part of a potentially curative regimen for chronic hepatitis B virus (HBV) infection. This study evaluated the safety, tolerability, pharmacokinetics (PK) and antiviral activity of ATI-2173. This was a phase 1b, randomized, double-blind, placebo-controlled trial in treatment-naive adults with chronic HBV infection conducted in the Republic of Moldova and Ukraine (ClinicalTrials.gov: NCT04248426). Patients positive for hepatitis B surface antigen were randomized 6:2 to receive once-daily oral doses of ATI-2173 10, 25, or 50 mg (n = 6 per dose) or placebo (n = 7) for 28 days, with off-treatment monitoring for 24 weeks. Endpoints included PK parameters of ATI-2173 and its metabolite clevudine, maximum reduction from baseline in HBV DNA, and safety and tolerability. Treatment-emergent adverse events occurred in eight patients (47%) receiving ATI-2173 and five (71%) receiving placebo; headache was the most common (n = 4). ATI-2173 PK was generally dose proportional. Systemic clevudine exposure with ATI-2173 dosing was substantially reduced compared with historical values observed with clevudine administration. On Day 28, mean changes from baseline in HBV DNA were −2.72 to −2.78 log10 IU/ml with ATI-2173 and +0.17 log10 IU/ml with placebo. Off-treatment sustained viral suppression and decreases in covalently closed circular DNA biomarkers were observed in most patients; one maintained undetectable HBV DNA at 24 weeks off treatment. In this 28-day monotherapy study, ATI-2173 demonstrated safety and antiviral activity, with sustained off-treatment effects and substantially reduced systemic clevudine exposure. These results support evaluation of ATI-2173 with tenofovir disoproxil fumarate in phase 2 studies. |
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Cuvinte-cheie active site polymerase inhibitor nucleotide, cccDNA, clevudine, hepatitis B virus, nucleoside analogue |
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