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ALBUFERON: New HCV Drug Dosed Every Every 2-4 Weeks by subcutaneous injection
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"SAFETY, PHARMACOKINETICS AND PHARMACODYNAMIC RESULTS OF HIGHER DOSES OF ALBUFERON IN A PHASE 1/2 SINGLE AND DOUBLE DOSE-ESCALATION STUDY IN TREATMENT EXPERIENCED SUBJECTS WITH CHRONIC HEPATITIS C"
Reported by Jules Levin
Researchers presented results from an early study of this new potential therapy for HCV. Here is their report presented in a poster at the 39th Annual EASL Conference (April 14-18, 2004, Berlin Germany).
Authors;
V. Balan^{1}, M. Sulkowski ^{2}, D. Nelson ^{3}, G. Everson ^{4}, R. Dickson ^{5}, L. Lambiase ^{6}, A. Post ^{7}, R. Redfield ^{8}, R. Wiesner ^{9}, J. Recta ^{10}, B. Osborn ^{10}, L. Novello ^{10}, W. Freimuth ^{10}, M. Subramanian ^{10}; ^{1}Mayo Clinic, Phoenix AZ, USA; ^{2}Johns Hopkins University, Baltimore MD, USA; ^{3}University of Florida, Gainesville FL, USA; ^{4}University of Colorado, Denver CO, USA; ^{5}Mayo Clinic, Jacksonville FL, USA; ^{6}University of Florida At Jacksonville, Jacksonville FL, USA; ^{7}University Hospitals of Cleveland, Cleveland OH, USA; ^{8}University of Maryland, Baltimore MD, USA; ^{9}Mayo Clinic, Rochester MN, USA; ^{10}Human Genome Sciences, Inc., Rockville MD, USA
ABSTRACT
Albuferon is a novel recombinant protein consisting of IFN alfa genetically fused to human serum albumin. The phase 1/2, dose escalation study is conducted in HCV subjects who had previously failed IFN alfa containing regimens.
Subjects were enrolled sequentially to receive 1 or 2 subcutaneous injections of Albuferon up to 80 mcg. Further dose escalation included single injection cohorts up to 600 mcg. Double injection dose cohorts up to 600 mcg (400 mcg, 500 mcg and 600 mcg) on Day 1 and 14 will also be evaluated.
81 subjects are currently enrolled. 97% were infected with HCV genotype 1, with a mean prior therapy duration of 68 weeks.
Albuferon was well tolerated. Adverse events were transient, most were mild to moderate, and did not show dose related increases. No subjects developed anti-Albuferon antibodies.
Cmax following single injection doses was dose-proportional. Preliminary analyses suggest a median terminal half-life of 143 hours at the two highest single injection cohorts (500 and 600 mcg). The magnitude and duration of viral reduction in the 2 cohorts combined were statistically significant (P-value <0.02) at Day 1 through Day 21.
Antiviral response (>0.5 log reduction) was observed in 62.5% (25/40) of subjects in the single injection cohorts (120-600 mcg). cDNA array analysis demonstrated a molecular profile consistent with drug response.
Authors concluded: Albuferon was safe and well tolerated. Dosing every 2-4 weeks is supported by the pharmacokinetics. Anti-viral response was observed in the higher single dose cohorts.
STUDY DETAILS
Patients received one or two injections at varying doses of the drug. Single injection doses ranged from 7-80 µg up to 900 µg and followed for 28 days. Patients who received two injections were followed for 42 days and received varying similar doses. There are 92 patients enrolled; mean BMI: 30.2; mean viral load: 6.2 x 106 copies/ml; 94% genotype 1; total duration of prior therapies: mean 68 weeks, range 12-296 weeks.
PHARMACOKINETICS SUMMARY
Drug isdetectable for up to 4 weeks following asingle injection of Albuferon.And apparently beyond 42 days following doses at day 1 and day 14.
Most subjects showed an increased Cmax following the second 400 µg dose of Albuferon.
The mean Cmax was about 20% higher following the second dose. Variability was high and the changes were not statistically significant.
Dosing at 2-4 week intervals is supported by the pharmacokinetic behavior of the drug.
Single SC injection PK
AUC (ng/mL)*hr:
120 mg (n=5): 1815±600
180 mg (n=6): 3040±1111
240 mg (n=5): 5718±2304
320 mg (n=6): 4752±142
400 mg (n=6): 4125±897
500 mg (n=6): 6939±1935
600 mg (n=6): 6908±2008
SAFETY AND TOLERABILITY SUMMARY
Albuferon was well tolerated and there were no discontinuations due to adverse events.
Adverse events were transient and mild to moderate in severity.
Common adverse events included headache (47%), injection site erythema (35%), fatigue (34%), arthralgia (25%), pyrexia (25%), nausea (22%), and myalgia (20%).
One serious adverse event: transient hallucinations which lasted 2 days and resolved spontaneously.
Summary of Hematologic Abnormalities
Absolute neutrophil count(ANC) reductions:
--occurred over the first week and did not show a dose response
--12/51 (24%) had grade 3 ANC reductions (ANC<1000) in the 120-600 µg cohorts and 2of those 12 had grade 1-3 neutropenia at baseline
--none required medical intervention or necessitated withholding the second dose
Platelet count reductions:
--occurred over the first week and did not show a dose response
--no grade changes occurred
No significant reductions in hemoglobin levels were observed.
IMMUNOGENECITY
There have been no anti-Albuferon antibodies detected in subjects treated with Albuferon.
PHARMACODYNAMICS & VIRAL LOAD RESPONSE
Summary
51 subjects were treated with Albuferon 120-600 µg SI and 400-500 DI.
28 of 51 subjects (55%) showed antiviral response (>0.5 log reduction on 2 or more consecutive time points).
22 of 28 subjects (79%) showed >=0.9 log reductions in HCV viral load.
19 of 22 responding subjects were genotype 1.
Higher Albuferon doses (320-600 µg) provided more consistent reductions in HCV viral load in subjects with BMI >25.
16 subjects received 120-240 µg of whom 44% (n=7) were responders (>0.5 log reduction at 2 consecutive time points). The maximum viral load drop was median 1.52 log (range 0.99-2.12). 5 subjects had BMI<25 and 80% were responders: meximum viral loaddrop was median 1.79 log (range 1.52-2.12). 6 subjects had BMI>25 but <30 and 33% (n=2) were responders (>0.5 log). Maximum viral load drop median 1.10 log (range 0.99-1.20). 5 subjects had BMI>30 and 20% were responders (n=1). Maximum viral load drop was 1.24.
24 subjects received 320-600 µg and 58% were responders (>0.5 log). Maximum viral load drop was median 1.34 log (range 0.57-3.55). 7 patients had BMI<25 and 57% were responders. Maximum viral load drop was median 1.24 (range 0.57-3.55). 7 subjects had BMI>25 but <30 and 57% were responders. Maximum viral load drop was median 1.79 log (range 0.84-1.01). 10 subjects had BMI >30 and 60% were responders. Maximum viral load drop was median 1.08 log (range 0.68-2.67).
cDNA Array Analysis Shows Induction of Interferon Responsive Genes (IRG) by both Pegylated Interferons and Albuferon at Day 7
A data set of Day 7/Day 0 ratop profiles included 25 study subjects: 5 treated with PegIntron+RBV (IFN-naïve subjects), 6 treated with Pegasys+RBV (IFN-naïve subjects), 6 treated with Pegasys+RBV )IFN-experienced subjects), and 8 treated with Albuferon (IFN-experienced subjects).
51 genes showed 2-fold or greater change on Day 7, compared with Day 0, in at least 12 of the 25 subjects.
Gene expression profiles were comparable across the 4 treatment groups.
AUTHOR CONCLUSION
Albuferon has a favorable safety and tolerability profile.
The PK profile supports dosing every 2-4 weeks given its reduced clearance and median half-life of 142 hours.
Antiviral response (>0.5 log reduction at 2 or more consecutive time points) was observed in 55% (28/51) of treatment experienced subjects in the 120-600 µg SI and 400-500 µg DI cohorts. 22 of those 28 (79%) showed a >=0.9 log reduction.
Albuferon shows evidence of biological activity (OAS1 mRNA induction) in all cphorts. OAS1 mRNA induction is sustained for up to 28 days for single injection doses of 120-600 µg.
Gene expression profiles of study subjects on Day 7 demonstrate response to Albuferon which was consistent with that for pegylated interferon a.
NEXT STEPS
Single injection doses of up to 900 µg and subsequent double injection doses are being studied in IFNa experienced subjects.
Evaluation of Albuferon in treatment naïve subjects and further Phase 2 studies are planned.
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