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

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Presentation transcript:

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?

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

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

ZENITH Study: VX Telaprevir + PegIFN Alfa-2a + RBV in Chronic HCV Phase 2b Treatment-naive Genotype 1 HCV RNA >5 log 10 IU/mL No cirrhosis (nonblack: 89%) Nelson DR, et al. Hepatology. 2011;54(supp):1435A. Abstract LB-14. Week * 36* (n=18) Weight-based ribavirin dosing ( 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). (n=29) (n=30) PegIFN + RBV* (n=29) VX-222 (100 mg bid) + Telaprevir (1125 mg bid) PegIFN + RBV* VX-222 (400 mg bid) + Telaprevir (1125 mg bid) PegIFN + RBV* VX-222 (100 mg bid) + Telaprevir (1125 mg bid) + PegIFN + RBV VX-222 (400 mg bid) + Telaprevir (1125 mg bid) + PegIFN + RBV Dual Regimens Terminated Quad Regimens (stratified by genotype 1a/1b)

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

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 PSI RBV PSI RBV + Peg - IFN PSI RBV PSI RBV + Peg-IFN PSI RBV PSI RBV + Peg-IFN n=10 SVR12 n= Wk PSI-7977 ELECTRON: Study Design for HCV GT2/3 Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, Abst. 34.

Time Wk PSI-7977 RBV 12 weeks PEG PSI-7977 RBV 8 weeks PEG PSI-7977 RBV 4 weeks PEG PSI-7977 RBV NO PEG n%<LODn n n 29/11827/8888/9898/ / /101009/910010/ / /101009/910010/ / / / / SVR4 11/ /101009/910010/10100 SVR8 11/ /101009/910010/10100 SVR12 11/ / / / SVR24 6/ / / /4 100 PSI-7977 ELECTRON 100% concordance of SVR12 with SVR24 Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, Abst. 34.

Assay LLOD 15 IU/mL PSI-7977 ELECTRON Ribavirin may decrease relapse PSI-7977 monotherapy arm (n=10) No on-treatment viral breakthroughs or resistance 6/10 subjects achieved SVR4 4/10 subjects had viral relapse w/o ribavirin PSI-7977/RBV PSI-7977 Monotherapy Combined IFN Arms Time (Days) Mean HCV RNA (Log 10 IU/mL) Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, Abst. 34.

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

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

Virologic Responses Through Week 12 in Patients With Genotype 1 Infection LLQ, lower limit of quantitation = 25 IU/mL Undetectable < 10 IU/mL HCV RNA <LLQ and Detectable HCV RNA Undetectable 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 4Weeks 4 and 12Week 12 Percentage of Patients n = Hezode C, et al. 62nd AASLD; San Francisco, CA; November 4-8, Abst. 277.

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

Dual Therapy Group: Resistance Variants in Patients with Viral Breakthrough 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 Patient #123456* Week tested NS3 protease variants (%) D168Y (87) D168A (13) R155K (100)D168Y (100)D168E (100)R155K (100)D168V NS5A variants (%) Y93N (100)L31V (100)Q30R (100) L31M (100) Q30R (76) L31V (100) Y93C (17) Q30R (45) L31V (77) H58P (39) Y93C (16) Y93N (13) Q30R L31V H54Y Y93C IU/mL LOQ LOD HCV RNA (log 10 IU/mL) Week BL *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.

Present study: dual therapy in 10 G1b null responders, non-cirrhotic Treated for 24 weeks Dose of BMS 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 (%) Chayama K, et al. 62nd AASLD; San Francisco, CA; November 4-8, Abst. LB-4 Dual oral combination therapy with the NS5A inhibitor BMS and the NS3 PI BMS achieved 90% SVR24 in HCV G1b-infected null responders 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).

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. Applicable in difficult-to-treat populations:  Transplant  Coinfection  End-stage renal disease, etc. Combination therapy