Clinical Virology Results from Telaprevir Phase 3 Study ADVANCE
T. L. Kieffer; D. J. Bartels; J. Sullivan; B. S. Adiwijaya; E. Z. Zhang; A. Tigges; J. Dorrian; J. Spanks; S. De Meyer; G. Picchio; N. Adda; A. D. Kwong
Background: The ADVANCE Phase 3 study assessed telaprevir (TVR)-based regimens in treatment-naïve patients with genotype 1 HCV infection. Patients were randomized to 48 wks of PR (control arm), or TVR for 8 wks (T8/PR) or 12 wks (T12/PR) in combination with PR for 24 or 48 wks based on eRVR (undetectable HCV RNA at wks 4 and 12). AEs in ADVANCE were similar in frequency and severity to those presented for Phase 2 studies.
Methods: HCV RNA measurements (LOQ 25 IU/mL) and population sequencing of NS3-4A (LOD >1000 IU/mL) were performed at baseline, during treatment, and follow-up in patients who did not achieve SVR. Amino acid substitutions potentially associated with TVR resistance were identified. On-treatment virologic failure was defined as HCV RNA >1000 IU/mL at wks 4 or 12, and detectable HCV RNA at wks 24-48. Viral dynamic modeling analyses were developed from Phase 2 data (PROVE1, PROVE2).
Results: The SVR rate for T8/PR (n=364) and T12/PR (n=363) arms was 69% and 75%, respectively, which was significantly higher (p<0.0001) than the PR control arm (44%, n=361). Virologic failure at wks 4 and 12 during TVR/placebo treatment was similar between arms (T8; 2.7% and T12; 3.3%). In contrast, the rate of virologic failure after wk 12 during PR treatment was somewhat higher in T8/PR (10.2%) compared to T12/PR (5.0%), and associated with wild-type (WT) and lower-level TVR-resistant variants, which suggest that 4 additional wks of TVR may further reduce virologic failure. Consistent with these results, modeling analyses suggested 12 wks of TVR may be sufficient to clear all WT and low-level resistant variants, but that a small population of these variants may still exist after 8 weeks of treatment.
Of 91 patients with sequencing data available and having TVR-resistant variants after not achieving SVR, 55 (60%) no longer had resistant variants detected at the end of study (median follow-up = 45 wks). The median time to loss of detectability of resistant variants for T54, A156, V36, and R155 variants was 13, 24, 36 and 44 wks, respectively.
Conclusions: The SVR rates in the T8/PR (69%) and T12/PR (75%)regimens were significantly higher than PR alone (44%). There was a ~5% higher rate of on-treatment virologic failure during the PR treatment phase in the T8/PR arm compared to the T12/PR arm, predominantly with lower-level TVR-resistant variants. These results suggest that TVR continued to exert antiviral pressure on WT and lower-level variants between wks 8 and 12, thus reducing subsequent virologic failure during the PR treatment phase in the T12 arm. Additionally, the majority of patients no longer had detectable TVR-resistant variants at the end of study.