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Phase 2a study to evaluate the safety and tolerability and anti-viral of 4 doses of a novel, controlled-release interferon-alfa 2b (Locteron) given every 2 weeks for 12 weeks in treatment-naive patients with chronic hepatitis C (genotype 1)
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Reported by Jules Levin
ASSLD, Nov 2-6, 2007, Boston, MA
S. Zeuzem6; I. Dzyublyk1; T. Yegorova2; L. Moroz3; O. Popovych3; I. Zaytsev4; V. Miroshnichenko4; E. Herrmann5; E. J. van Hoogdalem7; J. E. Humphries8
1. P.L. Shupyk National Medical Academy of Postgraduate Education, Kiev, Ukraine.
2. Kiev City Hospital, Kiev, Ukraine.
3. M.I. Pyrogov Vinnitsa National Medical University, Vinnitsa, Ukraine.
4. M. Gorky Donetsk State Medical University, Donetsk, Ukraine.
5. Saarland University, Homburg/Saar, Germany.
6. Saarland University Hospital, Homburg/Saar, Germany.
7. OctoPlus, N.V., Leiden, Netherlands.
8. Biolex Therapeutics, Pittsboro, NC, USA.
Background: Controlled-release recombinant interferon-alfa 2b (Locteron) is a novel approach to delivery of interferon (IFN) given every 2 weeks with improved tolerability combined with a high level of hepatitis C virus (HCV)RNA reduction.
Methods: A phase 2a, open-label, dose-ranging study was conducted in treatment-naïve patients with genotype 1 chronic HCV infection to evaluate the safety, tolerability and anti-viral effect of Locteron. 32 patients were randomized to receive subcutaneous injections of Locteron 14 days apart over 12 weeks in 4 dose cohorts (8 per cohort) of 160, 320, 480 and 640 μg, with the 640 μg group starting after safety evaluation of the other cohorts. All subjects received weight-based ribavirin. HCV RNA reduction modeling was performed.
Results:
The mean HCV RNA reduction at week 4 for the 160, 320, 480 and 640 μg groups were 1.1, 3.1, 2.9 and 3.1 logs, respectively. Percent of HCV negative subjects at week 4 were 0, 25, 38 and 25, respectively.
Average viral reduction after 12 weeks for the 3 lower doses of Locteron (160, 320 and 480 μg) was 1.8, 4.5 and 4.2 logs, respectively. 63% of subjects at the 2 middle doses (320 & 480 μg) were HCV negative (LLOQ < 28 IU/mL) at 12 weeks.
Early viral response (EVR: 12-week ≥ 2-log drop in HCV RNA) was achieved in 88% and 100% of subjects in the 320 and 480 μg Locteron dose cohorts, respectively.
Modeling of HCV kinetics demonstrated dose-dependent biphasic kinetics reflected by mean and maximum efficiency in blocking viral production from day 1 to day 28 of treatment. Mean and maximum efficiency were 41%±23% and 54%±27%, respectively, in the 160 μg cohort, 58%±19% and 71%±21% in the 320 μg cohort, 72%±20% and 84%±11% in the 480 μg cohort, and 73%±24% and 80%±22% in the 640 μg cohort.
The median T1/2 of free HCV RNA was 2 hours and the median T1/2 of infected cells was 2.8 days.
Clinical adverse events were almost exclusively mild in intensity with only 1 severe adverse event in the 3 lower dose cohorts. The most common adverse events were arthralgia (50%), weakness (50%), myalgia (38%) and headache (33%), with chills, nausea and diarrhea each reported in fewer than 5% of subjects. Fever (Temp ≥ 38.0°C) occurred in only 1 subject in these first 3 cohorts. Full data on all 4 cohorts for all 12 weeks will be available by the AASLD meeting.
Conclusions: In this study, Locteron, a controlled-release formulation of unmodified IFN-alfa 2b, administered every 2 weeks to treatment-naïve patients with chronic hepatitis C (genotype 1) demonstrated strong anti-viral activity combined with an improved safety and tolerability profile compared to currently marketed IFNs and those in development.
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