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Interim
Results of Studies of Albuferon plus Ribavirin in Nonresponders and in Treatment-naïve
Patients with HCV Genotype 1 Human
Genome Sciences (HGS) this week reported interim results of two clinical trials
to evaluate the safety, tolerability and efficacy of the experimental
drug Albuferon (albumin-interferon alfa-2b) in combination with ribavirin
for the treatment of chronic hepatitis C.
One study evaluates the drug‘s activity in nonresponders to previous treatment
with conventional
interferon alfa therapy and the other in individuals without any
prior therapy. A product of albumin fusion technology used to improve
the pharmacological properties of interferon alfa, Albuferon is a novel, long-acting
form of interferon alfa. Interim results of the Phase 2 clinical trial in nonresponders
demonstrate that Albuferon in combination with ribavirin is safe, well tolerated
and “shows robust antiviral activity,” according to the company’s announcement.
A presentation of the full interim data will take place on April 30 at the European
Association for the Study of the Liver (EASL) in Vienna,
Austria, April
26-30, 2006 [1]. In a separate press release issued today, HGS announced
the interim results of a larger Phase 2b clinical trial of Albuferon in combination
with ribavirin versus Pegasys
plus ribavirin in treatment-naïve patients with chronic hepatitis
C genotype 1 [2]. Following is the text of the announcement by HGS on the
Phase 2 and Phase 2b studies: David C. Stump, MD, Executive Vice President, Drug Development,
said, “I continue to be encouraged by the growing evidence that Albuferon in combination
with ribavirin is safe and well tolerated, with robust and durable antiviral activity.
The results available from the first three treatment groups for the 48-week treatment
period of the Phase 2 study demonstrate that Albuferon was well tolerated at all
doses administered, with no significant increase in severity of adverse
events between Week 12, Week 24 and Week 48. Decreases in hematologic cell counts were well managed
with dose reductions, and returned to baseline following the completion of therapy.
I am also encouraged by the emerging evidence of clinically significant antiviral
effect. At Week 48, 30% of the patients in the three lower-dose
treatment groups had no detectable hepatitis C RNA viral load. At the 12-week
follow-up point, 18% of the patients continued to have no detectable hepatitis
C RNA viral load. These data are quite positive, considering that they
were observed in a heavily pretreated population, nearly two thirds of whom previously
failed to respond to treatment regimens that included pegylated
interferon alfa-2a (Pegasys) plus ribavirin. The results to date also indicate that both the 1500-mcg
and the 1800-mcg doses were well tolerated, with safety data generally similar
to the lower-dose treatment groups and with greater antiviral activity. Results at the higher doses in the current Phase 2 study
encourage us to evaluate a regimen in interferon-naïve patients that combines
higher doses of Albuferon with ribavirin administered at intervals of 28 days.
We look forward to the complete presentation of these interim data at the EASL
meeting in April, and to continuing the evaluation of Albuferon in combination
with ribavirin at higher doses and over the full term of the current study.” The Phase 2 trial is a randomized, open-label, multi-center,
dose-escalation study, and is being conducted in the United States.
The study design states that approximately 50 percent of the subjects enrolled
should be patients who have failed combination therapy that included pegylated
interferon alfa plus ribavirin. A total of 115 patients have been enrolled into 5 Albuferon
treatment groups that are receiving doses of Albuferon ranging from 900-1800 mcg
[1, 3-5]. Patients were initially randomized into 3 Albuferon treatment
groups (900 mcg at 14-day intervals, 1200 mcg at 14-day intervals, and 1200 mcg
at 28-day intervals). Following evaluation of safety data, 2 additional cohorts
were enrolled sequentially (1500 mcg at 14-day intervals and 1800 mcg at 14-day
intervals). Patients are receiving Albuferon administered subcutaneously, with
all patients receiving weight-based oral ribavirin daily at 1000 or 1200 mg in
two divided doses. Patients in the trial will receive 48 weeks of treatment, with
an additional 24 weeks of follow-up. The primary objective of the Phase 2 study is to evaluate
the safety and tolerability of Albuferon in combination with ribavirin. The study
also is evaluating the efficacy of Albuferon in combination with ribavirin. The
primary efficacy endpoint is sustained virologic response (SVR), defined as undetectable
virus 24 weeks after the end of therapy. Data are available through Week 48 (end of treatment)
on 71 patients who were enrolled in parallel and randomized into three Albuferon
treatment groups: 
900 mcg administered subcutaneously every 14 days;
1200 mcg
administered subcutaneously every 14 days; and
1200 mcg
administered subcutaneously every 28 days.
All patients are receiving weight-based oral ribavirin
daily at 1000 or 1200 mg in two divided doses. Of the subjects in the first three
Albuferon treatment groups, 65% (46/71) were non-responders to pegylated interferon
alfa, and 93% (66/71) were infected with genotype
1 hepatitis C. More than 60% of the study subjects had received more
than one prior interferon alfa-based treatment regimen, and the mean duration
of prior therapy was approximately 15 months. At Week 48, 30% (21/71) of the patients exhibited no
detectable HCV RNA viral load. Antiviral activity was similar for the 14-day and
28-day Albuferon treatment groups. At the Week 12 follow-up after the end of treatment,
18% (13/71) of these heavily pretreated patients had no detectable hepatitis C
RNA viral load. Albuferon in combination with ribavirin was well tolerated.
The incidence of adverse events was similar across the three dose groups for which
48-week data are available, and generally similar to the adverse events observed
in the 2 higher-dose groups (24-Week data for the 1800-mcg and 1500-mcg cohorts).
There was no increase in severity of adverse events beyond
Week 12. Hematologic reductions were maximal by Week 8, were well managed with
dose reductions, and returned to baseline following the completion of therapy
(Week 12 follow-up after the end of 48 weeks of treatment). Albuferon appeared to be better tolerated in the treatment
group receiving 1200 mcg administered subcutaneously every 28 days, with fewer
hematologic dose reductions observed in this group. No subject required discontinuation
of either Albuferon or ribavirin for hematological abnormalities. Overall, the rate of treatment-emergent Albuferon antibodies
is 10%, with pre-existing antibodies detected in 17% of study participants. There
was no apparent correlation between the emergence of antibodies and antiviral
response, adverse events or pharmacokinetics. No overall increase in the emergence
of antibodies was observed between Week 12, Week 24 and Week 48, or in administration
of higher doses. Data are available through Week 24 for treatment groups
receiving, in combination with ribavirin, Albuferon doses of 1500 mcg and 1800
mcg, respectively, administered subcutaneously every 14 days. At Week 24, the same percentage of patients in the 1500-mcg
and 1800-mcg Albuferon treatment groups exhibited no detectable hepatitis C RNA
viral load: 32% (7/22) in each of the two groups. Data also are available for the 1500-mcg and 1800-mcg
Albuferon treatment groups on early virologic response (EVR12). EVR12 is defined
as a >2 log (99% or greater) reduction in HCV RNA viral load at Week
12. In the 1500-mcg treatment group, 41% or the patients (9/22) achieved EVR12.
In the 1800-mcg treatment group, 59% (13/22) of the patients achieved EVR12. The 1800-mcg Albuferon treatment group had a higher percentage
of genotype 1 hepatitis C patients who had failed to respond to previous treatment
with a combination of pegylated interferon and ribavirin – 91% (20/22) versus
an average of 66% (61/93) in the other Albuferon treatment groups combined. At Week 24 in this important and most difficult to treat
subgroup, the data show the following percentages of patients with no detectable
HCV RNA viral load: 17% (2/12) in the treatment group receiving 900 mcg of Albuferon
at 14-day intervals; 19% (3/16) in the treatment group receiving 1200 mcg of Albuferon
at 14-day intervals; 15% (2/13) receiving 1200 mcg of Albuferon at 28-day intervals;
27% (4/15) receiving 1500 mcg of Albuferon at 14-day intervals; and 32% (6/19)
receiving 1800 mcg of Albuferon at 14-day intervals. Data also are available for this subgroup on early
virologic response (EVR12). The data show the following percentages
of patients achieving EVR12:
42% (5/12)
in the treatment group receiving 900 mcg of Albuferon at 14-day intervals;
25% (4/16)
receiving 1200 mcg of Albuferon at 14-day intervals;
23% (3/13)
in the treatment group receiving 1200 mcg of Albuferon at 28-day intervals;
33% (5/15)
receiving 1500 mcg of Albuferon at 14-day intervals; and
63% (12/19)
receiving 1800 mcg of Albuferon at 14-day intervals.
Safety data available for the 1500-mcg and 1800-mcg treatment
groups through Week 24 are generally similar to the lower-dose Albuferon treatment
groups. No increase in the emergence of Albuferon antibodies was observed related
to administration of the higher doses. Wall
Street Reaction to Albuferon Results Shares
of Human Genome Sciences (HGS) fell 20 percent on March 14 after interim study
results of Albuferon plus ribavirin drew mixed reactions from Wall Street, according
to an article in the Washington Post. HGS
said in a conference call with analysts that two Phase 2 human studies showed
encouraging results and support the continued development of the drug for chronic
hepatitis C. But the study results left some investors uncertain how well the
drug, even if it wins approval from the Food and Drug Administration (FDA), will
be able to compete with established treatments that have been on the market for
years, i.e. peginterferon
alfa-2a (Pegasys) and peginterferon
alfa-2b (PegIntron). Standard
& Poor's, widely respected on Wall Street for the
impartiality of its research, upgraded the HGS shares to "buy" from
"hold." But Infinium Capital Corp. maintained a negative rating on the
stock. 03/17/06 Sources Human Genome Sciences
J Gillis.
Investors Unhappy With HGS Drug Test Data. Washington Post.
Page D01. March 15, 2006. References
1. V Rustgi and others. A Phase 2 dose-escalation study
of Albuferon combined with ribavirin in non-responders to prior interferon based
therapy for chronic hepatitis C infection. 41st Annual Meeting of the European
Association for the Study of the Liver (EASL), Vienna . Oral Presentation #113. 2. (HGSI Press Release) Human Genome Sciences Announces
Positive Interim Results of Phase 2b Clinical Trial of Albuferon in Combination
with Ribavirin in Treatment-Naïve Patients with Chronic Hepatitis C. March 14,
2006. 3. D R Nelson and others. A Phase 2
study of Albuferon in combination with ribavirin in non-responders to prior interferon
therapy for chronic hepatitis C. 56th Annual Meeting of the American Association
for the Study of Liver Diseases (AASLD), 2005. Oral Presentation #204. 4. (HGSI Press Release) Human Genome Sciences Reports
Interim Results of Phase 2 Clinical Trial of Albuferon in Combination with Ribavirin
in Treatment-Experienced Hepatitis C Patients. November 15, 2005. 5. It is important to note that the method of measurement
for dose determination in the Phase 2 study of Albuferon in combination with ribavirin
in treatment-experienced patients (as well as in other Phase 2 studies of the
compound) is different from the method of measurement in the Phase 1/2 study of
Albuferon. Accordingly, the 900-mcg dose in the current study is equivalent to
a 680-mcg dose in the Phase 1/2 study, and the 1200-mcg dose is equivalent to
900 mcg in the Phase 1/2 study.
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