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NS5A and polymerase inhibitors

NS5A and polymerase inhibitors. Mark Sulkowski, MD Professor of Medicine Johns Hopkins University Baltimore Maryland 21212. Case. 57 yo woman with genotype 1a and bridging fibrosis PROVE-1 study – treated with TVR x 12 wks and 48 weeks PR Viral relapse Treatment options?.

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NS5A and polymerase inhibitors

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  1. NS5A and polymerase inhibitors Mark Sulkowski, MD Professor of Medicine Johns Hopkins University Baltimore Maryland 21212

  2. Case • 57 yo woman with genotype 1a and bridging fibrosis • PROVE-1 study – treated with TVR x 12 wks and 48 weeks PR • Viral relapse • Treatment options?

  3. The Goal of Combination Regimens A Profound suppression of broad range of viral variants, including pre-existing variants + B Prevention of emergent resistance (pre-existing or de novo) + C

  4. Polymerase Inhibitors • Non-nucleoside • VX-222 • ANA-598 • ABT-072; ABT-033 • GS-9190 • Nucleos(t)ide analogue • PSI (GS)-7977 • Mericitabine (RG7128)

  5. ZENITH Study: VX-222 + Telaprevir +PegIFN Alfa-2a + RBV in Chronic HCV VX-222 (100 mg bid) + Telaprevir (1125 mg bid) PegIFN + RBV* (n=18) Dual Regimens Terminated VX-222 (400 mg bid) + Telaprevir (1125 mg bid) PegIFN + RBV* (n=29) Quad Regimens (stratified by genotype 1a/1b) VX-222 (100 mg bid) + Telaprevir (1125 mg bid) + PegIFN + RBV (n=29) Phase 2b Treatment-naive Genotype 1 HCV RNA >5 log10 IU/mL No cirrhosis (nonblack: 89%) PegIFN + RBV* VX-222 (400 mg bid) + Telaprevir (1125 mg bid) + PegIFN + RBV (n=30) PegIFN + RBV* Week 0 12 24* 36* Weight-based ribavirin dosing (1000-1200 mg). *Patients undetectable HCV RNA at weeks 2 and 8 discontinue treatment at week 12; patients with detectable HCV RNA at week 2 or 8 started PegIFN + RBV at week 12 (until 24 weeks of PegIFN + RBV are received). Nelson DR, et al. Hepatology. 2011;54(supp):1435A. Abstract LB-14.

  6. ZENITH Study: Virologic Response VX-222 100 mg + telaprevir + PegIFN + RBV VX-222 400 mg + telaprevir + PegIFN + RBV 93% 90% 87% 83% 83% 82% Patients (%) SVR24 (12 total weeks of treatment) (n=11/15) SVR12 (24 total weeks of treatment) (n=18/15) HCV RNA Undetectable Week 24 (n=29/30) Nelson DR, et al. Hepatology. 2011;54(supp):1435A. Abstract LB-14.

  7. Treatment-naïve, non-cirrhotic, age ≥18 years HCV RNA >50,000 IU/mL Allowed concurrent methadone use Stratified by HCV genotype and IL28B genotype Randomized 1:1:1:1 into IFN-sparing or IFN-free 24 8 12 4 Wk 0 PSI-7977 ELECTRON: Study Design for HCV GT2/3 PSI-7977 + RBV + Peg-IFN SVR12 n=10 PSI-7977 +RBV + Peg-IFN PSI-7977 + RBV SVR12 n=10 PSI-7977+RBV+Peg-IFN PSI-7977 + RBV n=10 SVR12 PSI-7977 + RBV n=10 SVR12 Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.

  8. PSI-7977 ELECTRON100% concordance of SVR12 with SVR24 Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.

  9. PSI-7977 monotherapy arm (n=10) 7 Combined IFN Arms 6 PSI-7977/RBV PSI-7977 Monotherapy 5 4 Mean HCV RNA (Log10 IU/mL) 3 2 1 0 0 2 7 14 21 28 Time (Days) PSI-7977 ELECTRONRibavirin may decrease relapse • No on-treatment viral breakthroughsor resistance • 6/10 subjects achieved SVR4 • 4/10 subjects had viral relapse w/o ribavirin Assay LLOD 15 IU/mL Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.

  10. NS5A: Replication Complex Inhibitors • Daclatasvir – phase 3 • Others in phase 2 • Abbott, ABT-267 • Gilead, GS-5885

  11. PDR (protocol-defined response): HCV RNA <LLQ (25 IU/mL) at week 4 and undetectable (<10 IU/mL) at week 10. BMS NS5A + PEG / RBV Follow-up from Weeks 24 or 48 Weeks 1-12 Weeks 13-24 Placebo + peg-alfa/RBV (n=60) Placebo + peg-alfa/RBV Peg-alfa/RBV Follow-Up 20 mg BMS-790052 + peg-alfa/RBV Follow-up YES 20 mg BMS-790052 + peg-alfa/RBV (n=180) PDR Follow-up Placebo + peg-alfa/RBV Placebo + peg-alfa/RBV alfa/RBV NO 60 mg BMS-790052 + peg-alfa/RBV Follow-up 60 mg BMS-790052 + peg-alfa/RBV (n=180) YES Follow-up Placebo + peg-alfa/RBV Placebo + peg-alfa/RBV Peg-alfa/RBV NO Week 4 RNA Week 10 RNA Week 12 Interim Efficacy Analysis and Re-randomization Week 24 Interim SafetyAnalysis Hezode C, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 277.

  12. LLQ, lower limit of quantitation = 25 IU/mL Undetectable < 10 IU/mL Virologic Responses Through Week 12 in Patients With Genotype 1 Infection 100 HCV RNA <LLQ and Detectable 84 85 90 84 HCV RNA Undetectable 76 7 25 80 9 78 19 75 70 60 53 54 54 60 57 Percentage of Patients 50 10 40 43 30 24 20 9 14 15 10 0 20 mg + peg-alfa/RBV 60 mg + peg-alfa/RBV Placebo + peg-alfa/RBV 20 mg+ peg-alfa/RBV 60 mg + peg-alfa/RBV Placebo+ peg-alfa/RBV 20 mg + peg-alfa/RBV 60 mg + peg-alfa/RBV Placebo + peg-alfa/RBV Week 4 Week 12 Weeks 4 and 12 n = 146 72 147 146 72 147 146 72 147 Hezode C, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 277.

  13. Dual Oral vs Quad Therapy: BMS-790052 + BMS-650032 ± PR BMS-790052 (60 mg QD) + BMS-650032 (600 mg BID) (n=11) Follow-up x 48 weeks Group A BMS-790052 (60 mg QD) + BMS-650032 (600 mg BID) + PR (n=10) Follow-up x 48 weeks GroupB 24-week treatment Post treatment: Week 24: SVR24 Phase 2a study; N=21; 19 with CT/TT IL28B genotype. BMS-790052=NS5A replication complex inhibitor; BMS-650032=NS3 PI Lok As et al. New Engl J Med 2012

  14. Viral breakthrough in 6 of 11 pts: All G1a; no resistance variants detected at baseline NS3 protease and NS5A resistance variants detected after viral breakthrough Role of emerging variants confirmed by phenotypic analysis NS3:30- to 525-fold resistance NS5A:3400- to >330,000-fold resistance Dual Therapy Group: Resistance Variants in Patients with Viral Breakthrough 8 BL 1 6 2 3 HCV RNA (log10 IU/mL) 4 4 5 1000 IU/mL 6 2 LOQ LOD 0 0 4 6 8 10 12 2 Week *Clonal analysis not performed on patient 6 McPhee F, et al. Presented at: EASL: The International Liver Congress 2011; March 30 - April 3, 2011; Berlin, Germany. Oral Presentation 63.

  15. Dual oral combination therapy with the NS5A inhibitor BMS-790052 and the NS3 PI BMS-650032 achieved 90% SVR24 in HCV G1b-infected null responders • Present study: dual therapy in 10 G1b null responders, non-cirrhotic • Treated for 24 weeks • Dose of BMS 650032 reduced from 600mg bid to 200mg bid secondary to ALT elevations • No viral breakthrough and no effect of pre Existing viral mutants • 2 SAE’s: 1 hyperbilirubineia, 1 pyrexia SVR (%) Confirmation of high SVR in G1b patients with IFN-free regimen despite history of null response to PR. Need for high resistance barrier component of IFN-free regimens may be subtype-dependent (less in G1b than G1a). Chayama K, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. LB-4

  16. Combination therapy • Antiviral activity in all HCV genotypes • No selection of resistance • All-oral combination regimen • Short treatment duration • QD (or BID) dosing Excellent safety and tolerability • Applicable in difficult-to-treat populations: • Transplant • Coinfection • End-stage renal disease, etc.

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