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Albuferon: new HCV drug in early study
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V Balan, Mayo Clinic, Phoenix, AZ, and colleagues andHuman Genome Sciences, Inc., Rockville, MD presented this phase I/II study reporting on pharmcokinetics, safety, and antiviral activity.
Albuferon(tm) is a novel, 85.7 kD protein consisting of recombinant interferon alfa (IFNa) genetically fused to recombinant human serum albumin. The resulting single polypeptide combines in one molecule the antiviral properties of interferon- a with the long serum half-life of albumin. The objectives of this phase 1/2, open-label, dose escalation study were to evaluate the pharmacokinetics, safety, tolerability, immunogenicity, and pharmacodynamics of Albuferon in subjects with hepatitis C virus (HCV) who had previously failed IFNa containing regimens.
Subjects were initially enrolled in 4 sequential dose groups (10-12 subjects per each group at 7 µg, 20 µg, 40 µg, and 80 µg). Within each dose group a minimum of 5 and a maximum of 6 subjects per cohort were enrolled sequentially to receive 1 or 2 subcutaneous (SC) doses of Albuferon administered 14 days apart.
Dose escalation beyond 80 µg included single injections of 120 µg, 180 µg, 240 µg, 320 µg and 400 µg. Plasma Albuferon concentrations and antibody to Albuferon were measured by ELISA. HCV RNA was measured using the Amplicor HCV monitor kit (Roche). 2' 5' oligoadenylate synthetase (OAS1) mRNA levels in whole blood was measured by a research-based Taqman PCR assay.
Of the 63 subjects currently enrolled, 96% were infected with HCV genotype 1 with a mean baseline viral burden of 2 million copies/mL. 78% of subjects enrolled in these cohorts had previously failed pegylated IFNa containing regimens.
Albuferon pharmacokinetics showed linear increases in AUC0-8 and Cmax with mean terminal half-lives of 139-158 hours with doses of 80 µg and higher. Tmax occurred between days 4 and 5. There is an approximately 40% increase in AUC after the second injection in the double injection cohort at 80 µg. Albuferon was well tolerated and there were no discontinuations.
No subjects developed detectable anti-Albuferon antibodies. Adverse events were transient and most were mild to moderate. The most common adverse events were injection site erythema (39%), headache (30%), fatigue (26%), mylagia (21%) and arthralgia (19%). The mean reductions in the nadir neutrophil counts in the higher single dose cohorts ranged from 40-60%. There was induction of OAS1 mRNA expression in all cohorts, with approximately 9-fold increase in median values at day 7.
In the single dose cohorts (=80 µg), 52% of subjects showed a maximal 0.55 log or greater reduction in HCV viral load during the first two weeks. Also, 20% or greater reductions in ALT levels were observed in 36% of subjects in these single dose cohorts.
In the ongoing phase 1/2 study, Albuferon demonstrated a favorable safety and immunogenicity profile. The pharmacokinetic profile supports dosing every 2-4 wks given its reduced clearance and extended half-life of up to 158 hours. All cohorts showed evidence of biological activity, as demonstrated by OAS1 induction, with anti-viral activity evident in the higher single dose cohorts.
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