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Albuferon: new HCV drug
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Albuferon: new HCV drug
"….mean HCV RNA reduction at week 4 was 3.2 log IU/mL for the 900 & 1200 ug cohorts…..18/26 (69%) subjects in the 900 ug & 1200 ug cohorts achieved a >2 log reduction in HCV RNA at week 4…"
Reported by Jules Levin
Today results from this study were presented at the Hepatitis C oral Session.
"A Phase 2 study to assess antiviral response, safety, and pharmacokinetics of Albuferon, in IFNa Naïve subjects with genotype 1 Chronic Hepatitis C"
Molecular weight: 85.7 kDa. Albuferon is a single polypeptide molecule that combines the therapeutic activity of interferon alpha with the long half-life of human serum albumin, said V Bain, the study investigator who reported results today.
As background, Bain summarized the previously reported phase I/II study.
--open-label, dose escaltion study in IFNa experienced patients with chronic HCV
--one or two subcutaneous injections, administered 14 days apart
--119 subjects enrolled in 22 cohorts (5-6 subjects/cohort).
DOSE RANGE INJECTION SCHEDULE
7-80 ug single & double injections
120-900 ug single injections
400-900 ug double injections
SUMMARY
--Albuferon has a favorable safety & tolerability profile with no discontinuations due to adverse events
--pharmacokinetics supports dosing at a 2-4 week interval
half-life of about 140 hrs
--antiviral response was observed
47% (37/78) of the subjects in single & double injection cohorts (120-900 ug) experienced >1.0 log HCV RNA reduction.
PHASE 2A STUDYy
Study Objectives:
--Evaluate safety, tolerability, and pharmacokinetics
--Evaluate antiviral response
Study Population:
--chronic Hepatitis C patients, genotype 1 and naïve to IFNa.
STUDY DESIGN
Open-label, randomized
Stratified by viral load & body mass index
Two sc injections, administered 14 days apart
5 cohorts (10 subjects/cohort)
--200 ug
--450 ug
--670 ug
--900 ug
--1200 ug
(12 & 14 subjects were enrolled in the 900 & 1200 ug cohorts, respectively.
DEMOGRAPHICS
56 subjects
age: mean 46 yrs
sex: 70% male
baseline viral load: mean=6.72 log IU/mL
--93% had high baseline HCV RNA (>800,000 IU/mL)
baseline ALT: mean 108
BMI: mean 28
There were no significant differences in baseline demographics across the treatment groups, Bain said.
The adverse events profile was similar across dosing groups with 3 possible exceptions. There might be a trend of a dose response for headache, pyrexia & chills.
Mean percent change in absolute neutrophil counts: day 14 -40%, day 28 -40% with dose 200-670 ug; 900-1200 ug dose -50% at day 14 & -5-% at day 28. Mean percent change in platelet count: 200-670 ug dose -10% at day 14, -20% at day 28; 900-1200 ug dose -20% at day 14, -30% at day 28. 22% of subjects had ANC <750 at any time during the study. No subject had a platelet count <50,000 during the study.
SAFETY SUMMARY
Albuferon was well tolerated & adverse events were mostly transient & mild to moderate in severity.
Common adverse events included headache (73%), fatigue (61%), chills (59%), arthalgia (57%), and mylagia (54%)
One serious adverse event
--acute colitis that has resolved
immunogenicity: one subject had predose antibodies to interferon and 1 subject developed antibodies to human serum albumin at day 42
reduction in neutrophil and platelet counts were observed
--23% of subjects had an ANC <750 during the study duration
--1 subject delayed receivingf the second dose till day 21 due to ANC <750 on day 14
PHARMACOKINETICS
PK parameters following the second dose of Albuferon. Cmax increases in a linear manner. The median half-life is 148 hours.
PHARMACOKINETICS SUMMARY
The Cmax increases in a linear manner over the dose range evaluated (200-1200 ug).
Drug is detectable for at least 4 weeks following the second sc injection of Albuferon.
As expected, some drug accumulation was observed following the 2nd dose of Albuferon at all doses.
The median half-life is 148 hrs (about 6 days), so dosing at 2 to 4 week intervals is supported by the pharmacokinetic profile of the drug.
EVALUATION of ANTIVIRAL RESPONSE
HCV RNA reduction at week 4
Viral dynamics over study duration
Viral kinetics
Correlation of HCV RNA reduction with body mass index (BMI)
HCV RNA Reduction at Week 4 in Genotype 1 HCV
Mean HCV RNA reduction
(proportion of subjects with >2 log reduction at day 28)
200 ug: 2/10 patients
450 ug: 7/10
670 ug: 3/10
900 ug: 10/12
1200 ug: 8/14
Bain said: "robust antiviral response at week 4 at the higher doses".
VIRAL KINETICS
Dose dependent 1st phase decline was observed. Mean HCV RNA decline was:
200 ug: -1.0 log
450 ug: -1.2 log
670 ug: -0.9 log
900 ug: -1.8 log
1200 ug: -1.6 log
2nd phase decline. In the 900-1200 ug high dose groups 24/28 (92%)of subjects had a 2nd phase decline in HCV RNA >0.3 log/wk, which is a predictor for SVR during PegIFNtreatment. Mean HCV RNA decline:
200 ug: -0.5 log
450 ug: -0.6 log
670 ug: -0.3 log
900 ug: -0.8 log
1200 ug: -0.7 log
Antiviral response was not found to be affected by BMI at the doses evaluated.
STUDY SUMMARY BY BAIN
Albuferon was well tolerated.
-median adverse events were transienr, mostly mild to moderate
Median terminal half-life was 148 hours.
Robust antiviral activity observed in genotype 1 HCV:
--mean HCV RNA reduction at week 4 was 3.2 log IU/mL for the 900 & 1200 ug cohorts
--18/26 (69%) subjects in the 900 ug & 1200 ug cohorts achieved a >2 log reduction in HCV RNA at week 4
--viral kinetics demonstrated a biphasic response
Further evaluation of Albuferon in combination with ribavirin is warranted for the treatment of HCV.
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