Data to be presented at the EASL Digital International Liver Congress™ 2021
Two poster presentations and supporting slides are available at https://www.antiostherapeutics.com/scientific-approach/publications-presentations/
MENDHAM, NJ, June 23, 2021 — Antios Therapeutics, Inc. (“Antios”) today announced pharmacokinetic (PK), safety and efficacy data from a Phase 1b clinical trial of ATI-2173, the Company’s Active Site Polymerase Inhibitor Nucleotide (ASPIN), in chronic HBV-infected adult patients. The compelling results of the trial demonstrated low systemic levels of ATI-2173 consistent with preclinical evidence of selective liver targeting previously demonstrated in rat and monkey models. ATI-2173 was generally well tolerated and led to off-treatment sustained viral suppression in chronic HBV patients as monotherapy. The data will be presented as two posters at the European Association of Liver Diseases (EASL) Digital International Liver Congress™ 2021 being held virtually from June 23-26.
“Current treatments for chronic HBV infections generally must be life-long because cessation of therapy usually results in re-emergence of the virus,” said Douglas Mayers, M.D., Chief Medical Officer of Antios. “ATI-2173 is an investigational prodrug of clevudine, which historically demonstrated potent and sustained reductions in HBV viral load, but high plasma levels of clevudine were associated with a rare adverse reaction of reversible myopathy. Our hypothesis is that a compound with a similar mechanism of action in the liver, but minimal plasma exposure would potentially replicate clevudine’s antiviral activity without off-target systemic toxicity, and therefore could be positioned, if successful, as the backbone of a once-daily curative regimen for HBV infection.
“In this study, ATI-2173 was generally well-tolerated and successfully targeted the liver with greatly reduced systemic exposure of clevudine compared with historical clevudine data. ATI-2173 also demonstrated sustained off-treatment antiviral responses as a monotherapy. The results of this study strongly support our hypothesis. We are now evaluating 25 mg and 50 mg once-daily doses in combination with tenofovir for 3 months in a Phase 2a clinical trial in adult patients with either chronic HBV infection or chronic HBV/hepatitis D virus co-infection.”
Details of the presentations are below. Both posters can be found on the Antios website at https://www.antiostherapeutics.com/scientific-approach/publications-presentations/.
Title: Pharmacokinetics of ATI-2173, a novel active site polymerase inhibitor nucleoside, in a Phase 1b clinical trial
Authors: Katherine Squires et al.
Presenter: Katherine Squires, Ph.D.
Track: Viral hepatitis B/D: therapy
Abstract Number: 1240
Title: Phase 1 Results for ATI-2173, a novel active site polymerase inhibitor nucleotide, in HBV-infected subjects
Authors: Douglas Mayers et al.
Presenter: Douglas Mayers, M.D.
Track: Viral hepatitis B/D: therapy
Abstract Number: 1251
The Phase 1b clinical trial enrolled 24 chronic HBV patients (positive for HBV surface antigen (HBsAg)) who were randomized to receive either 10 mg (n=6), 25 mg (n=5), or 50 mg (n=6) of ATI-2173 or placebo (n=7) once-daily for 28 days. Safety analyses included monitoring for adverse events (AEs) and measuring several clinical laboratory parameters. PK analyses included a comparison of ATI-2173 and its metabolites (M1 and clevudine) with historically published PK parameters of clevudine. Antiviral activity was evaluated via several measures including HBV DNA, HBsAg, HBV pregenomic RNA (pgRNA) and HBV core-related antigen (HBcrAg) and were recorded periodically during the treatment period and for up to 24 weeks following cessation of treatment.
28-day treatment with ATI-2173 resulted in potent and sustained antiviral activity.
- HBV DNA showed a 2.7 log10 copies/ml reduction for all three doses compared to placebo which showed no change in HBV DNA levels. This is comparable with the 2.5 to 3 log10 reduction reported previously following one month of treatment with clevudine.
- At the end of the treatment period, 71% of treated patients – three of six subjects (10 mg arm), four of five subjects (25 mg arm) and five of six subjects (50 mg arm) – had HBV DNA levels below the limit of detection.
- Sustained viral response (SVR) post treatment was 100% (nine of nine subjects in the 25 and 50 mg groups) after four weeks off treatment and 44% (four of nine subjects) after 12 weeks off treatment. One patient maintained an SVR through 24 weeks off treatment.
- HBsAg levels did not change during the 28-day treatment period for any dose or placebo, which was expected due to the short treatment period.
- HBV pgRNA showed a mean decrease of 0.9 log10 copies/ml with both 25 mg and 50 mg doses of ATI-2173 whereas placebo showed a mean increase of 0.6 log10 copies/ml.
- HBcrAg showed a mean 0.2 log10 copies/ml decrease following treatment with ATI-2173 whereas placebo showed a 0.4 log10 copies/ml increase.
- ALT levels were normalized with all doses of ATI-2173 whereas ALT levels remained elevated in placebo patients.
ATI-2173 is designed to be highly targeted to the liver and was found to be generally well-tolerated across all treatment groups.
- ATI-2173 was rapidly absorbed following single doses with maximum plasma concentration measured at 0.5 hours post dose then declined rapidly to undetectable levels by eight hours post dose. Plasma clevudine remains detectible through 24 hours post-dose.
- Mean plasma ATI-2173 concentrations were dose proportional with no evidence of plasma accumulation following 28 days of dosing, whereas plasma clevudine concentrations showed higher total exposure on day 28.
- Standard PK measures show that oral ATI-2173 resulted in low plasma clevudine exposures compared to historical clevudine data (see table below), while retaining potent antiviral activity.
|Drug||Cmax, ng/mL||Cmin, ng/mL||AUC24, ng·h/mL|
|Historical clevudine 30 mg, mean5||203||56||2010|
|ATI-2173 10 mg, mean (% historical value)a||6 (3)||0||92 (5)|
|ATI-2173 25 mg, mean (% historical value)a||17 (8)||9 (15)||257 (13)|
|ATI-2173 50 mg, mean (% historical value)a||42 (20)||22 (40)||691 (34)|
AUC24, 24-hour area under the plasma concentration-time curve; Cmax, maximum concentration; Cmin, minimum concentration; PK, pharmacokinetic. aPercent historical value was calculated by dividing the mean plasma clevudine PK parameter following 28 days of ATI-2173 administration by the mean plasma clevudine PK parameter reported following administration of clevudine 30 mg for 12 weeks.5
- No ATI-2173 dose-related treatment-emergent AEs were reported with headache being the most common AE reported in both ATI-2173 and placebo groups.
- There were no reported Serious Adverse Events (SAEs) or AEs leading to study drug discontinuation.
ATI-2173 is a novel, orally administered, liver-targeted Active Site Polymerase Inhibitor Nucleotide (ASPIN) molecule designed to deliver the 5’-monophosphate of clevudine to the liver. This L-nucleoside’s active 5’-triphosphate has unique antiviral properties as a non-competitive, non-chain terminating HBV polymerase inhibitor that distorts the active site of HBV polymerase resulting in potent HBV antiviral activity and extended off-treatment suppression of HBV DNA. ATI-2173 targets the liver, delivering high levels of the unique 5’- triphosphate while limiting systemic exposure to the parent L-nucleoside. ATI-2173 has the potential to become an integral part of a curative combination regimen for chronic hepatitis B.
About Antios Therapeutics Inc.
Antios Therapeutics is a clinical-stage biopharmaceutical company focused on the development of innovative therapies to treat and cure viral diseases. Antios is currently developing ATI-2173, aiming to provide chronic hepatitis B infected patients with a curative combination regimen.
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