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Sprint 1 Study, Phase 2, Boceprevir

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.


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.
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.



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