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COMBINATION THERAPY WITH NUCLEOSIDE POLYMERASE (RG7128) AND PROTEASE (RG7227) INHIBITORS IN GENOTYPE 1 HCV INFECTED PATIENTS: INTERIM RESISTANCE ANALYSIS OF INFORM-1 COHORTS A-D
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Reported by Jules Levin
AASLD Nov 2 2009, Boston, MA
S. Le Pogam1, M. Chhabra1, S. Ali1, J.M. Yan1, M. Ilnicka1 H. Kang1, J. Wong1, A. Kosaka1, A. Ewing1, A. Seshaadri1, A. De La Rosa2, S. Seiwert3, K. Klumpp1, N. Shulman1,P. Smith1, N. Cammack1 and I. Nájera1
1Roche Palo Alto, Virology Therapy Area, Palo Alto, CA, 94304, USA, 2Pharmasset Inc., Princeton, NJ, 08540, USA, 3InterMune, Inc., Brisbane, CA, USA
Author Summary of Result
-- An all oral regimen comprised of a nucleoside polymerase inhibitor (RG7128) and a NS3/4A protease inhibitor (RG7227) results in continual decline in viral load through 13 days of treatment
-- Viral rebound in a single patient in a low dose cohort of INFORM-1 is not correlated with RG7227 or RG7128 drug resistance
-- Robust viral suppression is provided by combination of RG7128 and RG7227 even when RG7227-resistant viral population exists at baseline
-- Both population and clonal sequence analysis of NS3/4A and NS5B suggest drug resistant viral variants are not selected when a nucleoside inhibitor is combined with a protease inhibitor
Author Conclusions
Low dose combination therapy of the nucleoside polymerase inhibitor RG7128, that presents a high barrier to resistance, with the protease inhibitor RG7227, achieves rapid and sustained antiviral activity without apparent selection of resistance for up to 13 days of treatment
The ability of this DAA combination to rapidly reduce HCV RNA even in the presence of pre-existing RG7227 resistant virus indicates that a nucleoside analog with high barrier to resistance (RG7128) may provide unique contributions to a DAA regimen
Introduction
Direct acting antivirals (DAAs) (i.e. NS5B polymerase and NS3/4A protease inhibitors) have demonstrated the ability to reduce HCV RNA several orders of magnitude in short duration studies and enhance sustained virologic response in chronic HCV patients when combined with pegylated interferon and ribavirin (SOC) for longer durations.
RG7128 is a novel nucleoside polymerase inhibitor. RG7128 displays a high barrier to the development of drug resistance both in monotherapy studies and in combination with SOC.
RG7227 (ITMN-191) is a novel NS3 protease inhibitor (PI). Like other PIs, viral resistance is observed in a subset of patients treated with monotherapy. For RG7227, viral rebound during monotherapy is associated with R155K in NS3. In monotherapy, D168E was observed in a single rebound patient that also carried R155K. Combination of RG7227 with SOC suppressed viral rebound in all patients.
INFORM-1
First of its kind study to investigate the combined antiviral effects of two DAAs (Figure 1)
- All oral regimen of RG7128 (nucleoside polymerase inhibitor) and RG7227 (NS3 PI)
- Up to 13 Day duration
- Evaluated safety, tolerability, pharmacokinetic interactions, and antiviral effect
Summary of results presented previously (Figure 21)
- No pharmacokinetic interactions
- Promising safety profile
- Robust antiviral effect in lower dose cohorts
Higher dose, twice daily cohorts presented at 2009 AASLD Presidential Plenary Session2
Interim analysis of drug resistance in low dose INFORM-1 cohorts (Cohorts A-D)
Aim: To monitor and evaluate the effect of RG7128 and RG7227 combination on the potential development of drug resistance following up to 13 days of DAA treatment in INFORM-1
Population sequence spanning NS3/4A and NS5B genes was determined for all patientsat baseline
For cohort A, population and clonal sequence was determined for NS3/4A (and/or NS3 protease domain) and NS5B for samples with a viral load ≥ 1000 IU/mL (limit of amplification). Drug susceptibility was determined at baseline (Day 1), at the end of monotherapy (Day 4) and at the end of combination treatment (Day 7) by direct cloning of patient-derived sequences into a shuttle replicon
For cohorts B-D (13 Day combination therapy), sequence and phenotypic studies were performed on any patient that experienced a viral load rebound (defined as ≥ 0.5 log10 increase of viral load above nadir) and had a viral load ≥ 1000 IU/mL
Cohort A: No evidence of drug resistance observed by population, clonal sequencing and phenotypic analysis
Virologic response
All patients (n=17) displayed a continuous decline in viral load, despite low-dose, lead in monotherapy for 3 days with either the nucleoside inhibitor RG7128 or the NS3/4A protease inhibitor RG7227
Sequence analysis
Population sequence spanning NS3/4A and NS5B genes at baseline showed no pre-existing substitutions known to confer reduced susceptibility to RG7128 or RG7227 at baseline
Population sequence analysis of patients with a viral load ≥1000 IU/mL (n=10) did not identify treatment emergent substitutions associated with reduced susceptibility to RG7128 or RG7227 (Day 4, end of monotherapy or Day 7, end of combination therapy) regardless of whether lead in was with RG7128 or with RG7227
Clonal sequence analysis did not identify the selection of mutations known to confer reduced susceptibility to RG7128 or RG7227 either at the end of monotherapy(Day 4) or combination therapy (Day 7)
Drug susceptibility
All samples tested (with a viral load ≥1000 IU/mL) (n=10) were sensitive to RG7128 and to RG7227 both at baseline and after treatment, with no change in susceptibility (within the 2.6-fold variability of the assay) between day 1 and on treatment samples (Figure 3)
Cohort B: No evidence of drug resistance observed by population, clonal sequencing and phenotypic analysis at baseline
Virologic response
All patients (n=8) displayed a continuous decline inviral load
Sequence analysis
Population sequence spanning NS3/4A and NS5B genes at baseline showed no pre-existing substitutions known to confer reduced susceptibility to RG7128 or RG7227
Cohort C: No evidence of drug resistance observed by population or clonal sequencing, and phenotypic analysis
Virologic response
All patients but one displayed a continuous decline in viral load
Single patient receiving 500 mg RG7128 BID/200 mg RG7227 q8h showed a 1.4 log10 IU/mL increase in HCV RNA from nadir to End of DAAtreatment (EOT) (Figure 4)
EOT HCV RNA was 701 IU/mL, that was suppressed by subsequent SOC therapy
Sequence analysis and drug susceptibility
Population sequence spanning NS3/4A and NS5B genes at baseline showed no pre-existing RG7227 or RG7128 resistance mutations
The one patient (Pt 11) who experienced a 1.4 log10 IU/mL viral load rebound while on RG7227 + RG7128 treatment showed:
- No selection of RG7227 or RG7128 resistance mutations was observed at day 15 (wash out period) by population and clonal sequencing studies (viral load of previous on-treatment samples was <1000 IU/mL and below limit of amplification) (Figures 5 and 7)
- Susceptibility to RG7227 did not change from Day 1 (baseline) to Day 15 (washout) in patients experiencing virologic rebound (Figures 6 and 8)
Cohort D: Patient with RG7227 resistance mutation at baseline experienced continuous viral load decline in combination with RG7128 therapy
Virologic response
All patients displayed a continuous decline in viral load, including patients that carried D168E at baseline
Sequence analysis
Population sequence spanning NS3/4A and NS5B genes at baseline showed that two patients carried a pre-existing substitution known to confer reduced susceptibility to RG7227
A DAA-treated patient carried D168E NS3 (Pt 12); clonal sequence analysis showed 92% D168E at baseline- this patient displayed a continual decline in HCV RNA during DAA treatment
A placebo-treated patient carried R155K NS3 (Pt 13)
Drug susceptibility of DAA treated samples
Baseline susceptibility to RG7227 in Pt 12 was compromised (EC50 10.8 ± 0.6 nM), a 27-fold shift compared to WT con-1 NS3 (Figure 9)
Pt 12 was susceptible to RG7128 at baseline (Figure 9)
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