SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

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SPRINT-2: Adding Boceprevir to PegIFN/RBV Significantly Increases SVR in Treatment- Naive Patients With Genotype 1 HCV
Slideset on: Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.

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SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

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Background and Rationale

   ~ 60% of patients with genotype 1 HCV fail to achieve SVR with pegIFN/RBV[1] Boceprevir, potent, oral HCV NS3 serine protease inhibitor approved in 2011 for treatment of genotype 1 chronic hepatitis C Antiviral efficacy of boceprevir in treatment-experienced genotype 1 patients demonstrated in pivotal phase III study in combination with pegIFN/RBV
RESPOND-2: SVR in 59% to 66% of treatment-experienced patients who received 4-wk pegIFN/RBV lead-in followed by boceprevir/pegIFN/RBV triple therapy for 3244 wks[2]

Current phase III study compared safety and efficacy of combination therapy with boceprevir + pegIFN/RBV vs pegIFN/RBV alone in treatment-naive patients with genotype 1 HCV[3]
Blacks and nonblacks enrolled separately into 2 cohorts given historical differences in SVR between racial groups

1. McHutchison JG, et al. N Engl J Med. 2009;361:580-593. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

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Schematic of Study Design

 International, randomized, placebo-controlled, double-blind phase III trial
Stratified by baseline HCV RNA and HCV genotype subtype Wk 4 Wk 24 Wk 28 Wk 48 HCV RNA negative at Wks 8-24 24-wk follow-up Boceprevir 800 mg q8h + PegIFN/RBV* PegIFN/RBV* HCV RNA positive at/after Wk 8, negative at Wk 24 Treatment-naive patients chronically infected with genotype 1 HCV (N = 940 NB) (N = 159 B) B44PR48: PegIFN/RBV* (n = 311 NB) (n = 55 B) PR48: PegIFN/RBV* (n = 311 NB) (n= 52 B) 24-wk follow-up

BPR RGT: PegIFN/RBV* (n = 316 NB) (n = 52 B)

Boceprevir 800 mg q8h + PegIFN/RBV*

24-wk follow-up

Placebo + PegIFN/RBV*

24-wk follow-up

*PegIFN alfa-2b 1.5 g/kg once wkly + weight-based RBV 600-1400 mg/day. Failure assessment: detectable HCV RNA at Wk 24 = treatment failure.

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

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Stopping Rules
 Stopping rule for study therapy
All treatment stopped if HCV RNA detectable at Wk 24

 Boceprevir discontinued and pegIFN/RBV continued through Wk 48 in cases of virologic breakthrough or incomplete virologic response and rebound
Virologic breakthrough: HCV RNA undetectable during treatment, followed by HCV RNA > 1000 IU/mL Incomplete virologic response and rebound: HCV RNA increase 1 log10 IU/mL above nadir, with HCV RNA > 1000 IU/mL
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

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Main Findings
  SVR rates significantly higher with boceprevir-containing arms vs pegIFN/RBV control among nonblacks (P < .001) and blacks (P < .05) Among nonblack cohort, SVR rates high with boceprevir-containing regimens whether analyzed by ITT or modified ITT analyses
Viral breakthrough occurred in 1% to 2% of patients in each treatment group BPR RGT (n = 316) 67 70 B44PR48 (n = 311) 68 71 PR48 (n = 311) 40 42 P Value for BPR RGT vs PR48 < .001 < .001 P Value for B44PR48 vs PR48 < .001 < .001

Virologic Outcome in Nonblack Cohort SVR, %  ITT  Modified ITT* SVR according to HCV RNA response at Wk 4, %  Undetectable or 1 log10 IU/mL decrease  < 1 log10 IU/mL decrease  Undetectable  Detectable Relapse, %

82 29 89 68 9

82 39 90 69 8

52 5 96 36 23

< .001 < .001 .55 < .001 < .001

< .001 < .001 .56 < .001 < .001

*Patients who completed lead-in treatment and received 1 dose of boceprevir or placebo.

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

clinicaloptions.com/hepatitis

Main Findings
 Among black cohort, SVR rates high with boceprevir-containing regimens whether analyzed by ITT or modified ITT analyses, but lower than that in nonblack cohort
BPR RGT (n = 316) B44PR48 (n = 311) PR48 (n = 311) P Value for BPR RGT vs PR48 .04 .04 P Value for B44PR48 vs PR48 .004 .001 Virologic Outcome in Black Cohort SVR, %  ITT  Modified ITT* SVR according to HCV RNA response at Wk 4, %  Undetectable or 1 log10 IU/mL decrease  < 1 log10 IU/mL decrease  Undetectable  Detectable Relapse, % 67 25 100 45 12 61 31 0 52 17 46 0 100 22 14 .17 .02 -.03 1.00 .30 .01 -.003 1.00 42 47 53 53 23 26

*Patients who completed lead-in treatment and received 1 dose of boceprevir or placebo. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

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Main Findings
 Among both cohorts, 22% of patients in BPR RGT arm had detectable HCV RNA between Wks 8 and 24 and assigned to 48 total wks of therapy
SVR rates in this subgroup that received 24 weeks of boceprevir and 48 wks of pegIFN/RBV comparable to group that received 44 wks of boceprevir and 48 wks of pegIFN/RBV (74% vs 74%)

SVR rates numerically higher with boceprevir-containing regimens vs pegIFN/RBV control across various subgroups
Nonblack Cohort BPR RGT B44PR48 PR48 Black Cohort BPR RGT 48 12 B44PR48 52 67 PR48

SVR in Patient Subgroups, %

Liver histology  No/minimal portal fibrosis  Bridging fibrosis/cirrhosis Hemoglobin during treatment  Nadir 10 g/dL  Nadir < 10 g/dL 64 72 59 79 33 60 NR NR NR NR NR NR 70* 50 70* 50 40 39 24 0

*P < .001 vs pegIFN/RBV control. P .03 vs pegIFN/RBV control. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

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Main Findings
 Addition of boceprevir to pegIFN/RBV generally well tolerated
Although incidence of anemia more common in boceprevir-containing arms, discontinuation due to anemia infrequent (BPR RGT: n = 6; B44PR48: n = 7; PR48: n = 4) Significantly more patients in boceprevir-containing arms received erythropoietin support (BPR RGT: 43%; B44PR48: 43%) vs control arm (PR48: 24%; P < .001 for both comparisons) BPR RGT (n = 368) 11 53 46 48 49* 2 1 33 36 37* 32 24* 6 B44PR48 (n = 366) 12 57 46 43 49* 3 <1 32 33 43* 33 25* 8 PR48 (n = 363) 9 60 42 42 29 2 0 33 28 18 33 14 4

Safety Outcome, % Serious adverse event Adverse event  Fatigue  Headache  Nausea  Anemia Grade 3 Grade 4  Pyrexia  Chills  Dysgeusia  Insomnia  Neutropenia Grade 3 Grade 4

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

clinicaloptions.com/hepatitis

Main Findings
 Higher rates of boceprevir-resistant variants observed in patients who had < 1 log10 IU/mL decrease vs 1 log10 IU/mL decrease in HCV RNA at Wk 4 regardless of treatment group (40% to 52% vs 4% to 6%) Multivariate analysis identified several factors associated with SVR, including assignment to boceprevir-containing arm
Odds Ratio (95% CI) 9.0 (6.3-12.8) 3.9 (2.1-7.1) P Value < .001 < .001 < .001 < .001 .04 .003 .03 < .001

Factor Response* to pegIFN/RBV lead-in (vs no response) Low baseline HCV RNA ( 400,000 vs > 400,000 IU/mL) Assignment to boceprevir-containing arm  B44PR48 vs PR48  BPR RGT vs PR48 Statin use (vs no use) No cirrhosis (vs cirrhosis) 40 yrs of age or younger (vs older than 40 yrs of age) Black race (vs nonblack)
*HCV RNA decrease from baseline 1 log10 IU/mL.

3.5 (2.6-4.9) 3.1 (2.3-4.3) 3.4 (1.1-10.7) 2.5 (1.4-4.6) 1.5 (1.0-2.1) 0.5 (0.3-0.7)

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2: Boceprevir in Genotype 1 Treatment-naive Patients

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Summary of Key Conclusions

 Combination of boceprevir + pegIFN/RBV significantly increased SVR rates vs pegIFN/RBV alone in treatment-naive patients with genotype 1 HCV
Nonblack patients: 67% to 68% vs 40% Black patients: 42% to 53% vs 23%

 

SVR rates similar between response-guided boceprevir (24 wks) vs 44-wk boceprevir in combination with pegIFN/RBV PegIFN/RBV lead-in allowed for prediction of virologic response
Lower SVR rates achieved if patients had poor response to lead-in

Boceprevir + pegIFN/RBV safe and overall well tolerated

Anemia, dysgeusia, and severe neutropenia more frequent with boceprevir vs pegIFN/RBV alone Discontinuation due to anemia infrequent

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.