NS5A inhibitors: ideal candidates for combination? Professor Vasily Isakov, MD, PhD, AGAF Dep.Gastroentrology & Hepatology, ION, Russian Academy of Sciences, Moscow
Structure and function of NS5A Meigang Gu, Charles M Rice Structures of hepatitis C virus nonstructural proteins required for replicase assembly and function. Current Opinion in Virology, 2013: 3, p.129-136 Mensa et al., EASL 2012
Characteristics of HCV DAA Classes Characteristic Protease Inhibitors Nucleos(t)ide Polymerase Inhibitors Nonnucleoside Polymerase Inhibitors NS5A Inhibitors Potency Barrier to resistance Drug interaction potential Toxicity Pharmacokinetics Comments High; variable among HCV genotypes Low 1a < 1b Moderate-high; consistent across genotype, subtype High 1a = 1b Variable; variable among HCV genotypes Very low 1a < 1b High; multiple HCV genotypes Low 1a < 1b High Low Variable Low to moderate Rash; anemia; bilirubin Variable; QD to TID 2nd-generation PIs: better barrier, pangenotypic Mitochondrial; nuc interactions (ART) QD Single target; good tolerability in agents progressing in PhIII Variable Variable; QD to TID Many targets Variable QD Multiple antiviral MOA
NS5A inhibitors NS5A inhibitor Manufacturer Activity against genotypes Dose Phase Daclatasvir BMS 1a < 1b, o.d. Approved Ledipasvir Gilead 1a<1b, 2-6 o.d. Approved Ombitasvir Abbvie 1a<1b, 2-6 o.d. Approved Second generation NS5A ACH-3102 Achillon 1a=1b, 2-6 o.d. II Elbasvir Merck 1a=1b, 2-6 o.d. III GS-5816 Gilead 1a=1b, 2-6 o.d. II Third generation NS5A MK-8408 Merck 1a=1b, 2-6 o.d. I-II ABT-530 Abbvie 1a=1b, 2-6 o.d. I-II
Currently identified major NS5A inhibitor resistance mutations Colonno R, et al. 45th EASL; April 14-18, 2010; Vienna, Austria. Abstract 33. Gao M, et al. 61st AASLD, October 29-November 2, 2010; Boston, MA, USA. Abstract 1853.
Daclatasvir (DCV): Key properties Highly selective HCV NS5A replication complex inhibitor 1,2 High potency (picomolar EC 50 ) in vitro 1,2 Pangenotypic coverage in vitro 3 Once-daily dosing 2 without need for dose adjustment in hepatically impaired patients 4 Lack of significant drug interactions 5-9 Clinical efficacy has been shown in difficult- to-treat patient populations in combination with a variety of agents targeting different HCV components 10-15 Generally well tolerated 1,2,10-15 1. Gao et al. Nature. 2010;465:96.; 2. Nettles et al. Hepatology. 2011;54:1956; 3. Gao et al. Curr Opin Virol. 2013;3:514; 4. Bifano et al. AASLD 2011, Poster 1362; 5. Bifano et al. AASLD 2010. Abstract 827; 6. Eley et al. 8th Intl Workshop on Clinical Pharmacology of Hepatitis Therapy. 2013. Oral presentation 014 PK; 7. Bifano et al. Antivir Ther. 2013;18:931.; 8. Bifano et al. AASLD 2013. Poster 1081; 9 Bifano et al. EASL 2013. Abstract 794; 10. Everson et al. AASLD 2012. Oral presentation LB-3.; 11. Sulkowski et al. AASLD 2012. Oral presentation LB-2.; 12. Lok et al. N Engl J Med. 2012;366:216.; 13. Chayama et al. Hepatology. 2012;55:742.; 14. Hezode et al. Hepatology. 2012;56(suppl):553A; 15. Sulkowski et al. N Engl J Med 2014;370:211 21
Randomization 2:1 Global Phase 3 Study: HALLMARK-DUAL (AI447-028) Day 1 Week 12 Week 24 Week 48 Treatment-naive DCV 60 mg QD + ASV 100 mg BID 24 weeks (N = 203) a DCV-PBO + ASV-PBO 12 weeks (N = 102) STOP Enter another study: DCV + ASV 24 weeks Follow up 24 weeks Nonresponder Ineligible/intolerant DCV + ASV 24 weeks (N = 205) DCV + ASV 24 weeks (N = 235) Follow up 24 weeks Follow up 24 weeks a Excludes 2 patients inadvertently assigned, instead of randomized, to DCV + ASV; patients were excluded from efficacy analyses but both achieved SVR 12. SVR 12 Primary endpoint: proportion of DCV + ASV-treated patients with SVR 12 Patients infected with HCV genotype 1b Treatment-naive Nonresponders: prior null or partial response to pegifnα/rbv Interferon-ineligible/intolerant (treatment-naive or -experienced) due to Depression Anemia/neutropenia Compensated advanced fibrosis/cirrhosis (F3/F4) with thrombocytopenia
Virologic Response: SVR 12 100 90 82 82 SVR 12 (% of patients) a,b 80 60 40 20 0 182 203 Treatmentnaive 168 205 Nonresponders 192 235 Ineligible/ intolerant SVR 12 rates documented on or after posttreatment Week 12 Treatment-naive: 91% Nonresponders: 82% Ineligible/intolerant: 83% a HCV RNA < lower limit of assay quantitation (25 IU/mL). b Patients with missing SVR 12 data counted as treatment failures.
Patients Without SVR 12 Patients, n (%) Treatment-naive (N = 203) Nonresponder (N = 205) Ineligible/intolerant (N = 235) All 21 (10) 37 (18) 43 (18) On-treatment failures Virologic breakthrough 9 (4) 26 (13) 20 (9) Futility ( LLOQ at Week 8) 0 0 1 (0.4) Detectable or missing RNA at end of treatment 4 (2) 3 (1) 8 (3) Posttreatment failures Relapse a 5 (3) 7 (4) 12 (6) Missing RNA at posttreatment Week 12 a 3 (2) 1 (1) 2 (1) a Percentages based on number of patients with undetectable HCV RNA at end of treatment (treatment-naive, n = 189; nonresponder, n = 174; ineligible/intolerant, n = 204).
Observed Resistance-Associated Variants (RAVs) Percentage of Patients With Baseline NS5A and/or NS3 Sequences (N = 637) a 0,5 0,2 0,2 7 4 No RAVs NS5A-Y93 NS5A-L31 NS3-D168 88 NS5A-L31 + -Y93 NS5A-L31 + -Y93 + NS3-D168 At baseline, signature NS5A and/or NS3 RAVs were observed in 76 ( 12%) patients with available sequences 28 of 73 patients with NS5A-L31 and/or -Y93 variants achieved SVR 12 2 of 4 patients with NS3-D168E achieved SVR 12 Other baseline NS5A and NS3 RAVs did not appear related to virologic outcome At virologic failure, in patients with detectable RAVs, 61 of 79 had the three variants (NS5A-L31, NS5A-Y93, and NS3-D168) a Sequences were not available for 8 patients.
Resistance-associated variants (RAVs) in studies 026, 028, 031 NS5A/NS3A RAVs AI447026 AI447028 AI447031 NS5A RAVs at baseline 17% 12% 18% NS3A RAVs at baseline 1% 1% 1% SVR in patients with RAVs at baseline NS5A RAVs 40% NS3A RAVs 50% NS5A RAVs 38% NS3A RAVs 50% NS5A RAVs 48% NS3A RAVs 50% SVR in patients without RAVs at baseline (cumulative data) Asian patients Non-Asian patients Non-cirrhotic 94% Non-cirrhotic 94% Cirrhosis 94% Cirrhosis 92% Chayama et al. AASLD 2014 Poster 1937; Friborg et al. Journal of Infectious Disease and Therapy 2015 Kumada et al. Hepatology 2014; 59:2083 2091; Manns et al. Lancet 2014; 384:1597-1605 11
Ombitasvir (ABT-267) Low-picomolar EC 50 values and superior pharmacokinetics. Pangenotypic activity with an EC 50 range of 1.7 19.3 pm against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pm against GT6a. Decreased HCV RNA up to 3.10 log 10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects DeGoey D., et al. Discovery of ABT-267, a Pan-Genotypic Inhibitor of HCV NS5A. J. Med. Chem., 2014, 57 (5), pp 2047 2057
SVR12 (% pts), ITT SAPPHIRE II: Phase 3 study of 12-wk regimen of Paritaprevir/R-/ombitasvir, and Dasabuvir (3D) + RBV in treatment-experienced G1 patients 100 96.3 96.0 96.7 95.3 100 95.2 80 60 40 20 0 286/297 All patients 166/173 G1a 119/123 G1b 82/86 Prior relapse 65/65 Prior partial response 139/146 Prior null response VF in 7/297 (2.4%) 5 of these pts had 1 RAV at time of VF Pts,n VF All pts (n=297) Prior relapsers (n=86) Prior partial responders (n=65) Prior null responders (n=146) Breakthrough 0 0 0 0 Relapse 7 1 0 6 Study drug d/c* 4 3 0 1 Zeuzem S, et al. EASL 2014, London, O1 *Ptswho prematurely d/c withoutbreakthrough; 3 due to AEs, 1 withdrew consentduring Wk 11
GIFT-1: Ombitasvir/Paritaprevir/Ritonavir for GT1b HCV International, part-randomized phase III trial conducted in Japanese pts Double-blind period Wk 12 Open-label period Wk 24 Noncirrhotic pts with GT1b HCV (N = 321) Arm A Arm B Ombitasvir/Paritaprevir/Ritonavir (n = 215) Placebo (n = 106) Ombitasvir/Paritaprevir/Ritonavir (n = 106) Cirrhotic pts with GT1b HCV (N = 42) Arm C Open label Ombitasvir/Paritaprevir/Ritonavir (n = 42) Coformulated ombitasvir/paritaprevir/ritonavir dosed orally 25/150/100 mg once daily. Pts in Arms A and B more likely to be treatment-naive at baseline than those in Arm C (65% and 64% vs 21%, respectively) Baseline BMI (all arms): 22.4-23.6 Baseline IL28B CC: Arm A, 56%; Arm B, 51%; Arm C, 64% Chayama K, et al. EASL 2015. Abstract G13. Reproduced with permission.
GIFT-1: Efficacy With 12 Wks OBV/PTV/RTV in GT1b HCV NR, not reported. *Includes treatment-naive, interferon-eligible patients with HCV RNA > 100,000 copies/ml in Substudy 1. Chayama K, et al. EASL 2015. Abstract G13. Reproduced with permission.
GIFT-1: Treatment failures with 12 wks OBV/PTV/RTV in GT1b HCV 17 patients did not achieve SVR12, of whom 3 experienced on-treatment virologic failure and 8 relapsed by post treatment Week 12 NS3/4A RAVs detected in 0 patients, NS5A RAVs in 14% (50/357) patients at baseline All patients with virologic failure had RAVs at failure 10 of 11 had NS3 and NS5A RAVs 1 of 11 had NS5A RAVs only 8 of 11 had NS5A Y93H at baseline Chayama K, et al. EASL 2015. Abstract G13. Reproduced with permission.
Ledipasvir (LDV, GS-5885) HCV NS5A inhibitor Potent activity against GT1a and 1b GT 1a GT 1b GT 2a GT 3a GT 4a EC 50 (nm) 0,031 0,004 10,8 10,1 0,045 Picomolar potency Potency maintained against cross-class resistant mutants (NS3: A156T, R155K, D168E, NS5B: S282T, Y448H) Safe and well tolerated in clinical studies to date Once daily Limited drug interactions
SVR12 (%) All oral FDC LDV/SOF ± RBV for 12 or 24 weeks in treatment-experienced HCV G1 patients: Phase 3 ION-2 study AIM: Evaluate LDV/SOF ± RBV for 12 and 24 wks in HCV Tx-experienced G1 pts 440 pts randomized to LDV/SOF or LDV/SOF + RBV for 12 or 24 wks SVR12 LDV/SO F LDV/SOF+RBV 12wks 94% 96% 24wks 99% 99% 100 80 PR vs PI + PR failures 93 94 96 97 100 98 98 100 95 Presence vs absence of cirrhosis 100 99 100 99 100 86 82 60 40 20 0 40/43 62/66 45/47 62/64 LDV/SOF LDV/SOF + RBV 12 wks Failed PR Failed PI 58/58 49/50 58/59 51/51 83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22 LDV/SOF LDV/SOF LDV/SOF LDV/SOF LDV/SOF LDV/SOF + RBV + RBV + RBV 24 wks 12 wks* 24 wks No cirrhosis Cirrhosis *Statistically significant when arms combined Afdhal N, et al. EASL 2014, London, O109
All oral FDC LDV/SOF ± RBV for 12 or 24 weeks in treatment-experienced HCV G1 patients: Phase 3 ION-2 study 12wks Reasons for not achieving SVR12 24wks Pts n(%) LDV/SOF n=109 LDV/SOF+RBV n=111 LDV/SOF n=109 LDV/SOF+RBV n=111 SVR12 102(94) 107(96) 108(99) 110(99) Breakthrough 0 0 0 1(<1)(noncompliance) Relapse 7(7) 4(4) 0 0 Lost to f/u 0 0 1(<1) 0 7/11 pts who relapsed had cirrhosis No SOF-associated S282T variants were detected at BL or at VF All 11 pts with relapse had detectable NS5A RAVs at time of VF 6/11 had NS5A RAVs at BL AEs more common: 24 wks vs 12 wks +RBV vs RBV RBV did not alter efficacy but resulted in higher AEs No benefit of 24-week regimen for cirrhotic patients Afdhal N, et al. EASL 2014, London, O109
Elbasvir (MK-8742) MK-8742 exhibits antiviral activity against several HCV genotypes (including 1a, 1b, 2a, 3a, 4a) with decreased potency against genotype 2b and retain significant activity against many resistant HCV mutants in both the GT1a and GT1b backgrounds. Coburn C. A. et al., Discovery of MK-8742: An HCV NS5A Inhibitor with Broad Genotype Activity. ChemMedChem 2013, 8, 1930 1940
C-EDGE TN: 12-Wk Grazoprevir/Elbasvir for Treatment-Naive Pts With GT1/4/6 HCV International, randomized, blinded, placebo-controlled, parallel-group phase III trial Treatment Wk 12 Randomized period Follow-up Wk 4 Follow-up Wk 16 Treatment-naive GT1, 4, or 6 HCV infected pts (N = 421) Grazoprevir/Elbasvir (n = 316) Placebo (n = 105) Open-label period Grazoprevir/Elbasvir Coformulated grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily. Pts well matched at baseline: 91% infected with GT1a or 1b HCV, 68% HCV RNA > 800,000 IU/mL, 22% cirrhotic Fewer white pts in immediate vs deferred treatment arm (60% vs 70%, respectively) Zeuzem Z, et al. EASL 2015. Abstract G07.
SVR12 (%) C-EDGE TN: Efficacy Results SVR12 With 12 Wks of Grazoprevir/Elbasvir According to Genotype 100 80 60 40 20 299/ 144/ 129/ 18/ 8/ n/n = 316 157 131 18 10 0 All Pts GT1a GT1b GT4 GT6 Non-virologic failure 4 3 1 0 0 Subgroup analysis: significantly lower SVR12 rates in pts with baseline HCV RNA > 800,000 IU/mL No differences according to race, IL28B status, presence of cirrhosis Lower SVR12 rates in pts having baseline NS5A RAVs associated with > 5-fold loss of susceptibility to elbasvir Zeuzem Z, et al. EASL 2015. Abstract G07. 95 92 99 100 Breakthrough 1 1 0 0 0 Relapse 12 9 1 0 2 80
SVR12 (%) C-WORTHY: GRZ + EBR ± RBV for 8 weeks in GT1b patients: baseline demographics and SVR12 GRZ + EBR + RBV (n=30) GRZ + EBR (n=31) Male, n (%) 16 (53) 13 (42) White, n (%) 25 (83) 25 (81) Baseline HCV RNA, IU/mL 4,954,362 8,220,775 IL28B CC, n (%) 11 (37) 3 (10) METAVIR F0 F2 27 (90) 29 (94) METAVIR F3 3 (10) 2 (7) One SAE in the RBV-arm (non-drug-related cholangitis) One patient in the RBV-arm experienced hemoglobin decline to <8.5 g/dl No discontinuations or deaths 100 80 60 40 20 0 n N 93 94 27 29 8 weeks + RBV 29 31 8 weeks RBV All failures were due to relapse One of the 4 patients who relapsed failed with a pre-existing Y93H NS5A RAV Vierling J, et al. EASL-ILC 2015; Poster presentation, P0769.
Future NS5A 2017 and beyond Pangenotypic Active against known NS5A RAVs Highly synergistic with novel protease and polymerase inhibitors, providing near 100% efficacy in all genotypes. Excellent safety and DDI profile
MK-8408 is a next generation NS5A inhibitor with activity against known clinically relevant G1a RAVs Asante-appiah E. et al. AASLD 2014
ABT-530 Has Potent Activity Against Common HCV Genotype 1 NS5A Resistance-associated Variants in Vitro Ng T. et al., AASLD 2014
Combination of ABT-530 and ABT-493: high efficacy in all genotypes of HCV Ng T. et al. AASLD 2014 Lawitz E. et al., AASLD 2014
Conclusions NS5A inhibitors are key part of DAA combinations for the treatment of hepatitis C with high potency and good safety. The efficacy of the first generation of NS5A inhibitors is dependent on RAVs to NS5A Number and type of RAVs are important Potency and genetic barrier to resistance of the second/third drug in combination are important Next generation of NS5A inhibitors will be pangenotypic and active against the majority of known RAVs and if combined with other potent DAA in one tablet with fixed dose it can help to realize the one pill for all strategy with near 100% efficacy in a real life setting.