A Phase I/II study evaluating escalating doses of recombinant human albumin-interferon-alpha fusion protein in chronic hepatitis C patients who have failed previous interferon-alpha-based therapy.
Albumin-interferon-alpha (IFN-alpha) is a novel 85.7-kDa recombinant protein consisting of IFN-alpha that is genetically fused to human serum albumin. In this Phase I/II, multicentre, open-label study, we evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics of albumin-IFN-alpha in IFN-alpha-experienced patients with chronic hepatitis C. Albumin-IFN-alpha was administered in 22 escalating doses (7-900 microg) in a single injection or in two injections 14 days apart. In the 119 patients studied, there were no discontinuations because of adverse events, and albumin-IFN-alpha had a favourable safety profile at doses up to 900 microg. The most common adverse events were headache (56%), fatigue (52%), injection site erythema (38%), arthralgias (32%) and pyrexia (27%). Reduced clearance resulted in a mean elimination half-life of 159 h, which supports dosing at 2- to 4-week intervals. Induction of the IFN-specific gene OAS1 was maintained for > or = 28 days following a single injection of albumin-IFN-alpha at doses of > or = 40 microg. Dose-dependent antiviral activity was observed in this IFN-alpha-experienced study population. Antiviral activity of > or = 1.0-log reductions in HCV RNA was observed in 47% (37/78) of patients in the 120- to 900-microg cohorts and in 59% (16/27) in the 400- to 900-microg double-injection cohorts. These results support further clinical studies of albumin-IFN-alpha for the treatment of patients with chronic hepatitis C.
Balan
Vijayan
V
Mayo Clinic, Phoenix, AZ, USA. Balan.Vijayan@mayo.edu
Nelson
David R
DR
Sulkowski
Mark S
MS
Everson
Gregory T
GT
Lambiase
Louis R
LR
Wiesner
Rusell H
RH
Dickson
Rolland C
RC
Post
Anthony B
AB
Redfield
Robert R
RR
Davis
Gary L
GL
Neumann
Avidan U
AU
Osborn
Blaire L
BL
Freimuth
William W
WW
Subramanian
G Mani
GM
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012709:Serum Albumin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000075462:Serum Albumin, Human; D016896:Treatment Outcome
D000998:Antiviral Agents; D016898:Interferon-alpha; D012709:Serum Albumin; C473631:albuferon; D000075462:Serum Albumin, Human