SPRINT-1
Study Shows Benefits of Response-guided Therapy with Experimental
HCV Protease Inhibitor Boceprevir
By
Liz Highleyman
The
Phase 2 SPRINT-1
study enrolled nearly 600 untreated patients in the
U.S., Canada, and Europe with hard-to-treat HCV genotype
1. Participants were randomly allocated to receive various
schedules of 800 mg boceprevir
3 times daily plus 1.5 mcg/kg once-weekly pegylated
interferon alfa-2b (PegIntron) plus 800-1400 mg/day weight-adjusted
ribavirin.
Some
arms started all 3 drugs at the same time, while others
had a 4-week "lead-in" period with pegylated interferon
plus ribavirin before adding boceprevir. Pegylated interferon
and ribavirin both reach steady-state blood concentrations
by week 4, so patients in the lead-in arms had optimum levels
before starting boceprevir. Furthermore, the lead-in allowed
clinicians to assess rapid virological response (RVR) to
standard-of-care therapy before deciding whether to add
boceprevir.
Overall,
most study participants (about 60%) were men, about three-quarters
enrolled in the U.S., 80% were white, 15% were black (a
group that tends to respond poorly to interferon-based therapy),
and the mean age was about 47 years. At baseline, 7% had
cirrhosis and 90% had high HCV RNA (> 600,000 IU/mL).
An
analysis presented in an oral session at AASLD looked at
206 participants in the 2 treatment arms that received pegylated
interferon plus ribavirin for the lead-in period, then added
boceprevir and continued on all 3 drugs for an additional
24 or 44 weeks (for a total time on treatment of 28 or 48
weeks). The researchers focused on sustained virological
response (SVR) rates among "null responders,"
or patients who had < 1 log decrease in HCV viral load
after the 4-week lead-in.
Results
 |
In
an intent-to-treat analysis, the SVR rate was 56% (58
of 103) in the 28-week lead-in boceprevir arm and 75%
(77 of 103) in the 48-week lead-in arm. |
|
In
the arms without the lead-in, the SVR rates were 54%
(58 of 107) for 28 weeks and 67% (69 of 103) for 48
weeks. |
|
Overall,
38% of null responders achieved SVR after adding boceprevir:
25% (7 of 28) of those treated for 28 weeks and 55%
(12 of 22) of those treated for 48 weeks. |
|
44%
(4 of 9) of the poorest responders who had a < 0.5
log decrease at week 4 achieved SVR with 48 weeks of
triple therapy. |
|
Among
non-null responders, 72% of those treated for 28 weeks
and 81% treated for 48 weeks achieved SVR. |
|
Black
race was the only significant baseline predictor of
null response at week 4. |
|
In
a related poster presentation, the SPRINT-1 researchers
reported that among patients in the lead-in arms who
achieved RVR, 82% of those treated for 28 weeks and
94% of those treated for 48 weeks achieved SVR -- not
a significant difference, suggesting that treatment
might be shortened for good early responders. |
|
However,
patients who still had detectable HCV RNA at week 4
but not at week 16 -- about 18% of the study population
-- did benefit from longer therapy, with 79% who received
triple therapy for 48 weeks achieving SVR, compared
to only 21% who received 28 weeks. |
|
The
response rate for patients in a control group receiving
standard-of-care pegylated interferon plus ribavirin
with no boceprevir was 38%. |
|
The
most common adverse events reported in the boceprevir
arms were fatigue, anemia, nausea, and headache. |
|
Skin
rash or prurtis (itching) occurred with similar frequency
in the boceprevir and control groups. |
|
Anemia
occurred more often in the boceprevir group compared
with the control arm. |
|
The
rate of treatment discontinuation due to adverse events
was 9%-19% in the boceprevir arms versus 8% in the standard
therapy arm. |
Based
on these findings, the study investigators concluded, "Boceprevir
with standard of care for 48 weeks nearly doubles SVR."
"Since
null responders to [pegylated interferon/ribavirin] responded
well to the addition of boceprevir, and benefited from longer
boceprevir/[pegylated interferon/ribavirin] therapy, the
ability to treat these patients for up to 44 weeks with
all 3 drugs is likely an important therapeutic advantage"
they suggested.
"Although
the numbers are small, this analysis of the HCV SPRINT-1
study data showed that it was possible to achieve SVR in
a proportion of null responders to peginterferon and ribavirin
when boceprevir was added to their backbone regimen,"
said lead investigator Paul Kwo, MD, from Indiana University
School of Medicine said in a press release issued by Schering-Plough.
"However, the risk of developing viral resistance to
protease inhibitors in patients who do not achieve SVR must
be carefully weighed against the potential benefits of treatment
with this new class of direct antiviral agents. With the
lead-in strategy, initial peginterferon and ribavirin responsiveness
is determined prior to the addition of a protease inhibitor,
thus allowing the physician to take into account the potential
for the development of resistance."
Phase
3 studies in treatment-naive hepatitis C patients (SPRINT-2)
and people with prior treatment failure (RESPOND-2) -- both
of which include the lead-in period for all boceprevir recipients
-- are currently underway.
Division
of Gastroenterology/Hepatology, Indiana University School
of Medicine, Indianapolis, IN; Alamo Medical Research, San
Antonio, TX; Mount Vernon Endoscopy Center, Alexandria,
VA; University of Miami Center for Liver Diseases, Miami,
FL; Baylor College of Medicine, Houston, TX; Indianapolis
Gastroenterology Research Foundation, Indianapolis, IN;
South Florida Center of Gastroenterology, Wellington, FL;
Liver Specialists of Texas, Houston, TX; Henry Ford Hospital,
Detroit, MI; Digestive Disease Associates, Baltimore, MD;
University of California-Davis, Sacramento, CA; Liver &
Intestinal Research Center, Vancouver, BC, Canada; Weill
Medical College of Cornell University, New York, NY; Digestive
Healthcare of Georgia, Atlanta, GA; Schering-Plough Research
Institute, Kenilworth, NJ.
11/06/09
References
PY
Kwo, E Lawitz, J McCone, and others. High Sustained Virologic
Response (SVR) in Genotype 1 (G1) Null Responders to Peg-Interferon
alfa-2b (P) plus Ribavirin (R) When Treated with Boceprevir
(Boc) Combination Therapy. 60th Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD 2009).
Boston. October 30-November 1, 2009. Abstract 62.
PY
Kwo, E Lawitz, J McCone, and others. Response-Guided Therapy
(RGT) for Boceprevir (Boc) Combination Treatment? - Results
from HCV SPRINT-1. 60th Annual Meeting of the American Association
for the Study of Liver Diseases (AASLD 2009). Boston. October
30-November 1, 2009. Abstract 1582.
Other
source
Schering-Plough.
Data Supporting Boceprevir Response Guided Therapy Presented
at American Association for the Study Of Liver Diseases
(AASLD) Annual Meeting. Press release. November 1, 2009.
