Subramanian, G. Mani

Albumin-interferon-α (alb-IFN) is a novel recombinant protein derived from IFN-α2b genetically fused to human albumin. The resulting single polypeptide combines in one molecule the antiviral properties of IFN-α with the long serum half-life of albumin. IFN-mediated biological responses stem from the engagement of IFN-α with its target receptor and subsequent modulation of IFN-specific gene (ISG) expression. To evaluate the pharmacodynamics of alb-IFN during the Phase I/II study conducted in patients with chronic hepatitis C (CHC) who had previously failed IFN-α-containing regimens, ISG induction was evaluated in peripheral blood and compared with antiviral response. Whole blood was obtained at day 0, day 7 and day 28 from 21 patients enrolled in the higher dose (500–900 μg) alb-IFN cohort, who received two injections on day 0 and day 14. Taqman real-time PCR was used to assess candidate ISG expression. There was sustained induction on day 7 and day 28 of the ISG's OAS1, IRF-7, IFI44 and IFI27. Although all patients showed a molecular response to alb-IFN, individual variability in pretreatment gene expression levels and fold of modulation during treatment was observed. At day 28, induction of OAS1, IFI44 and IRF7 showed pairwise correlation in individual patients ( P<0.05). Moreover, the induction of expression at day 28, and pretreatment levels of OAS1 and IFI44 correlated with hepatitis C virus RNA reduction at day 28 ( P<0.05). In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the response associated with an IFN-α.

Albumin-interferon-α (IFN-α) is a novel 85.7–kDa recombinant protein consisting of IFN-α 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-α in IFN-α-experienced patients with chronic hepatitis C. Albumin-IFN-α was administered in 22 escalating doses (7–900 μg) 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-α had a favourable safety profile at doses up to 900 μg. 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 159h, which supports dosing at 2- to 4-week intervals. Induction of the IFN-specific gene OAS1 was maintained for ≥28 days following a single injection of albumin-IFN-α at doses of ≥40 μg. Dose-dependent antiviral activity was observed in this IFN-α-experienced study population. Antiviral activity of ≥1.0–log reductions in HCV RNA was observed in 47% (37/78) of patients in the 120- to 900-μg cohorts and in 59% (16/27) in the 400- to 900-μg double-injection cohorts. These results support further clinical studies of albumin-IFN-α for the treatment of patients with chronic hepatitis C.

SummaryBackgroundMatrix metalloproteinase‐9 is a proteolytic enzyme whose expression is increased in ulcerative colitis.AimTo evaluate the safety and efficacy of GS‐5745, a fully humanised anti‐matrix metalloproteinase‐9 monoclonal antibody, in moderately‐to‐severely active ulcerative colitis.MethodsWe randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS‐5745 or placebo. Multiple‐dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS‐5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS‐5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS‐5745. Exploratory analyses in the multiple‐dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS‐5745 were explored using histological and molecular approaches.ResultsTwenty‐three of the 42 patients (55%) receiving multiple doses of GS‐5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS‐5745 showed target‐mediated drug disposition, approximately dose‐proportional increases in maximum plasma concentration and more than dose‐proportional increases in the area under the plasma drug concentration‐time curve. Clinical response occurred in 18/42 patients (43%) receiving GS‐5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS‐5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS‐5745 had reductions in matrix metalloproteinase‐9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation.ConclusionThis phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS‐5745 in the treatment of ulcerative colitis.