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Design

* Randomisation stratified on cirrhosis (yes or no) and response to prior PEG-IFN + RBV therapy (null response, partial response, relapse)

Grazoprevir (GZR) / Elbasvir (EBR ) 100/50 mg fixed dose combination : 1 tablet QD

Objective

• SVR₁₂ (HCV RNA < 15 IU/ml), with 95% CI, by intention to treat analysis, 99% power to demonstrate superiority to historical rate of 58%

Baseline characteristics and disposition

SVR₁₂ (HCV RNA < 15 IU/ml), ITT, % (95% CI)

SVR₁₂ (HCV RNA < 15 IU/ml) by subgroup, ITT, n/N (%)

SVR₁₂ (HCV RNA < 15 IU/ml) by subgroup, ITT

SVR₁₂ (HCV RNA < 15 IU/ml) by subgroup, Per-protocol, n/N (%)

• The per-protocol analysis excluded 12 patients who discontinued for administrative reasons

Resistance-Associated Variants

• Presence of NS3 RAVs at baseline in genotype 1 by population sequencing: 33.2% (123/170)
  • NS3 variants at positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175, considered for the analysis •
  • SVR₁₂ rates : 97.2% (240/247) and 94.3% (116/123) if baseline NS3 RAVs absent or present, respectively
  • The slightly higher rate of virologic failure among patients with baseline NS3 RAVs is likely explained by the co-existence of baseline NS5A RAVs in these patients. Of the 14 virologic failures in genotype 1, 12 had baseline NS5A RAVs, and of the 2 failures who were wild-type for NS5A, only 1 had a baseline NS3 RAV
• NS5A RAVs at positions 28, 30, 31 and 93 assessed by population sequencing (limit of detection: 25%) and NGS (limit of detection: 1% and 15%)
  • The lower-sensitivity assays (population sequencing and NGS 15%) offer the highest precision in identifying patients with baseline RAVs at risk of virologic failure

Impact of baseline NS3 variants on SVR₁₂ in genotype 1, n/N (%)

* RAP = resistance analysis population excludes patients who discontinued for administrative reasons or did not have sequence data

Impact of baseline NS5a variants on efficacy in genotype 1-infected subjects

* RAP = resistance analysis population excludes patients who discontinued for administrative reasons or did not have sequence data
n/a = not applicable

Impact of baseline NS5a variants on SVR₁₂ in genotype 1a

• The same 10 virologic failures are identified by all 3 assays as having baseline NS5A RAVs
• 7 of the 10 patients with baseline NS5A RAVs who experienced virologic failure received a 12-week regimen

Impact of baseline NS5a variants on SVR₁₂ in genotype 1b

RAVs in patients with genotypes 1 and 1b and virologic failure (all relapses)

Adverse events, N (%)

* Emotional lability D35 ; ** palpitations, suicidal ideation

Summary

• In patients who failed prior PEG-IFN + RBV therapy
  • 12 weeks of EBR/GZR without RBV achieved SVR₁₂ in 100 % of patients with history of relapse to prior PEG-IFN + RBV
  • 12 weeks of EBR/GZR without RBV achieved SVR₁₂ in 100% of genotype 1b
  • 16 weeks of EBR/GZR + RBV achieved SVR 12 of 100% with no virologic failure regardless of prior treatment history or cirrhosis status or NS5A RAV
  • There was no difference in response rates between patients with and without cirrhosis, irrespective of therapy duration and with or without the addition of RBV
• Of the 12 genotype 1a with virologic failure, 10 had a baseline NS5A RAV
• EBR/GZR FDC was generally safe and well tolerated
• Virologic failure was seen in 5.8% of patients treated with 12W of EBR/GZR
• To maximize SVR rates, genotype 1a or 4-infected patients with a prior history of null or partial response to PEG-IFN + RBV
  • may benefit from the addition of RBV and extension of therapy to 16 weeks,
  • alternatively, baseline RAV testing of genotype 1a-infected patients may be used to identify the small subset of patients who can benefit from the addition of RBV and extension of therapy to 16 weeks