Final Results SVR 24 Boceprevir plus PegIFN a-2b/Ribavirin

HCV SPRINT-1
Final Results SVR 24
Boceprevir plus PegIFN a-2b/Ribavirin
HCV Genotype 1 Treatment Naive Patients

EASL April 23-26, 2009 Copenhagen, Denmark
Reported by Jules Levin

P. Kwo1, E. Lawitz2, J. McCone3, E. Schiff4, J. Vierling5, D. Pound6, M. Davis7, J. Galati8, S. Gordon9, N. Ravendhran10, L. Rossaro11, F. Anderson12, I. Jacobson13, R. Rubin14, K. Koury15, C. Brass15, E. Chaudhri15, J. Albrecht15

1Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 2Alamo Medical Research, San Antonio, TX, 3Mount Vernon Endoscopy Center, Alexandria, VA, 4Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, 5Professor of Medicine and Surgery, Baylor College of Medicine, Houston, TX, 6Indianapolis Gastroenterology Research Foundation, Indianapolis, IN, 7Digestive Care/South Florida Center of Gastroenterology, Wellington, FL, 8Liver Specialists of Texas, Houston, TX, 9Department of Hepatology, Henry Ford Health Systems, Detroit, MI, 10Digestive Disease Associates, Baltimore, MD, 11Internal Medicine, University of California-Davis Medical Center, Sacramento, CA, USA, 12The Liver & Intestinal Research Center, Vancouver, BC, Canada, 13Weill Cornell Medical College, New York, NY, 14Digestive Healthcare of Georgia, Atlanta, GA, 15Schering-Plough Research Institute, Kenilworth, NJ, USA

AIMS OF THE STUDY
Evaluate safety/efficacy of PegIFN alfa-2b (PegIntron) 1.5 ug/kg plus RBV in combination with boceprevir

Assess impact on SVR
--RVR and EVR

--Effect of the 4-week lead-in of Peg/RBV which allows:
Achievement of steady state drug levels
Alpha interferon-mediated immune system activation
Lower HCV burden
Potentially decreased pool of pre-existing viral quasi-species
--24 vs 48 week treatment duration
--decreased ribavirin from 800-1400 mg/day to 400-1000 mg/day (the low dose was explored to see the affect on anemia)

SVR
LINK TO SEE SOME BUT NOT ALL SLIDES:

Schering's protease boceprevir phase 2; Schering symposium - (04/27/09)

Peg/RBV Control group 48 weeks (=104): 38% SVR (But, 86% with EVR (32/37) had SVR; 8/8 with RVR had SVR)

Peg/RBV 28 weeks (n=107): 54% (74% of patients with RVR had SVR, 32/43; 68% with EVR had SVR, 58/85)
Peg/RBV 4 weeks - then P/R/B 24 weeks (n=103): 56% (82% with RVR had SVR, 54/68; 68% with EVR had SVR, 58/85)
P/R/B 48 weeks (n=103): 67% (84% wit RVR had SVR, 32/38; 84% with EVR had SVR, 68/81)
P/R 4 weeks then P/R/B 44 weeks (n=105): 75% (94% with RVR achieved SVR, 62/68; 91% with EVR achieved SVR, 77/85)

WHEN USING LOW-DOSE RBV:
Peg/RBV 48 weeks (n=50) Overall SVR: 36% comparable to control arm
P/R/B 48 weeks (n=16): 50%

PREDICTABILITY OF SVR: RVR and EVR
RVR
- 8 patients in the control group Peg/RBV achieved RVR and all went on to SVR (100%)
- 82% of patients with 4-week P/R lead-in and 24 weeks P/R/B who had RVR achieved SVR

- 94% of patients with 4 week P/R lead-in and 44 weeks P/R/B achieved SVR

EVR
- 86% of patients (n=37) who achieved EVR went on to SVR in the Peg/RBV control group
- 68% of patients receiving 4 week lead-in followed by 24 weeks P/R/B who had EVR achieved SVR
- 91% of patients receiving 4 week Peg/RBV lead-in followed by 44 weeks P/R/B who achieved EVR went on to SVR

Kwo then showed a chart called Effect of Treatment Duration on SVR.
- If time to 1st PCR-neg was 4 or less weeks 8/8 in control 48 wks, 54/66 (82%) in PR4/PRB 24 wks, and 62/66 94% had SVR.

- If time to SVR was 4-12 weeks 24/29 83% in PR control 48 wks, 4/19 21% in PRB 24 wks, and 15/19 79% in PR4/PRB 44 wks had SVR, and Kwo said extending treatment in this group led to better response. Why is this different in the group above under PREDICTABILITY, is it 12 wks EVR vs between 4-12?

Kwo then showed an interesting table where SVR predictability was based on response during 4 week lead-in Peg/RBV. For patients with <0.5 log reduction, essentially null responders, 2/7 (29%) in PR 4 wks/PRB 24 wks had SVR, and 44% (4/9) in PR 4 wks/PRB 44 wks had SVR. The numbers of patients are small but the suggestion is that 44% of null responders achieved SVR in this group.

In the patients with 0.5-1.0 log reduction 24% (5/21) in the 4 wk leadin/24 wk PRB group and 62% (8/13) in the 4 wk leadin/44 wks PRB group had SVR thus again suggesting that poor responders to Peg/RBV might achieve good SVR rate. For patients with 1 to 1.5 logs reduction, 30% (3/10) and 65% (11/17) had SVR in the 24 & 44 wk groups after leadin, respectively

Patients with 1.5-2.0 logs viral load reduction in leadin- 73% (8/11) in 24 week group and 80% in 44 week group had SVR.

Patients with 2-3 log reduction in leadin - 67% (14/21) & 79% (11/14) had SVR.

Patients with 3-4 log reduction in leadin - 83% (10/12) & 82% (14/17) had SVR.

Patients with >4 logs - 100% (11/11) had SVR in 24 week group & 92% (11/12) in 44 week group had SVR.

Patients who achieved undetectable in leadin: 100% (3/3) in 24 wk & 100% (9/9) in 44 wk groups had SVR.

Kwo presented a table showing patients with anemia had better SVR rates: 88% vs 64% for patients in 4 wk P/R leadin/44 wks P/R/B; 67% vs 47% for patients with 4 wk leadin/24 weeks P/R/B; and for patients in control group 48% vs 35%.

RELAPSE
Kwo reported 24% relapse rates in P/R control 48 weeks similar to that seen in IDEAL he said and similarly 30% and 24% in the 24 wk group and in the 4 week leadin/24 week PRB group. But 7% in the P/R/B 44 wk group & 3% in the PR 4 wk leadin/44 wks P/R.B group. Patients in each group who achieved RVR had lower relapse rates.

ANEMIA
34% on patients in 48 week peg/rbv control group had anemia
And I couldn't read the chart very well but 50-60% in the other 24 and 48 week regimens.
And 24% in the low dose 48 wk RBV group.

EPO USE
26% in the control group used EPO and 50% in the 2 leadin groups both 24 & 44 wks used EPO. Of note EPO use reduced discontinuations quite a lot; in the 24 week with lead in the discontinuation rate was 38% without EPO vs 14% with EPO, and in the 4 wk lead with 44 weeks it was reduced by 50%. The authors summarized "no beceprevir defining toxiity responsible for treatment discontinuation; boceprevir is associated with additional approximate 1 g/dL incremental hemoglobin decrease; anemia management with EPO is associated with increased completion rates.

VIRAL BREAKTHROUGHS
were lower in the leadin groups 7% for PRB 24 weeks vs 4% with leadin; 12% for PRB 48 wks vs 5% with leadin, and 25% with low dose RBV group.

MUTATIONS
Major mutations (>25%): V36M, T54S, R155K
Less common (>5% to <25%): T54A, V55A, R1555T, A156S, V158I, V170A
Infrequent (<5%): V36A, V36L, I170T