Evolution of Therapy in HCV

Transcription

1 Hepatitis C: Update on New Therapies and AASLD 13 David Bernstein, MD, FACP, AGAF, FACP Professor of Medicine Hofstra North Shore-LIJ School of Medicine Evolution of Therapy in HCV (%) SVR IFN IFN 6m 12m IFN/ 6m 25 IFN/ 12m PEG/ 12m PEG/R/PI 6-12m 1

2 New Therapies for Genotype 1 IFN IFN Free Naïve Treatment experienced Cirrhosis Classes of New Therapies Liver International pages 93-14, 3 JAN 13 DOI: /liv

3 DAAs in Late-Stage Clinical Development for Chronic HCV Infection NS3/4A Protease Inhibitors Nucleotide NS5B Polymerase Inhibitors Non-Nucleoside NS5B Polymerase Inhibitors NS5A Replication Complex Inhibitors Approved Boceprevir Telaprevir Simeprevir Sofosbuvir Phase 3 ABT-45* Asunaprevir* Faldaprevir ABT-333 BI 7127 Daclatasvir* ABT-267* GS-5885* Phase 2 Danoprevir GS-9256 GS-9451 MK-5172 Sovaprevir Filibuvir Mericitabine ABT-72 BMS Setrobuvir Tegobuvir VX-222 IDX719 MK8742 NEW INTERFERONS 3

4 PEGLAMBDA INTERFERON REDUCED SIDE EFFECTS Lambda Alpha Headache Arthralgia 6 33 Myalgia 6 Fever 8 33 Insomnia Chills 4 21 Rash Itching Irritability AJ Muir et al Gastroenterol 13: (in press) PEGLAMBDA INTERFERON REDUCED SIDE EFFECTS AJ Muir et al Gastroenterol 13: (in press) 4

5 COMBINING NEW APPROVED THERAPIES FOR GENOTYPE 1 COSMOS: Genotype 1 Week N=14 Arm 1 SMV + SOF + Post-treatment follow-up N=24 Arm 2 SMV + SOF Post-treatment follow-up N=14 Arm 3 SMV + SOF + Post-treatment follow-up N=27 Arm 4 SMV + SOF Post-treatment follow-up Enrolment ratio 2:1:2:1 Cohort 1: Prior null responders (METAVIR F-F2) Final SVR12 for all arms Cohort 2: Treatment-naïve and prior null responders (METAVIR F3-F4) Interim SVR4 for Arms 3 and 4 Jacobson et al AASLD 13 5

6 Patients (%) 24 week treatment 1/ / /24 1 SMV/SOF SMV/SOF/ 24 wks 24 wks 12 week treatment 7.8 1/ / /14 26/27 SMV/ SMV/SOF SOF SMV/ SMV/SOF/ SOF/ 12 wks 12 wks SVR12 (SMV/SOF) SVR12 (SMV/SOF/) Non-virologic failure Relapse Jacobson et al AASLD week treatment Patients (%) 1/ /14 26/27 7/7 12/12 7/7 14/15 Total Naives Nulls 9 naïve and 9 null responders METAVIR F4 patients Only relapser was a F4 prior null responder 1/15 SVR4 (SMV/SOF) SVR4 (SMV/SOF/) Relapse Jacobson et al AASLD 13 6

7 NEW THERAPIES FOR GENOTYPE 1: IFN FREE SVR12 Rates (ITT) for 8- and 12-Week Arms Perce entage of patients (ITT) achieving SVR 12 N= N=41 N=79 N=79 N=79 N=45 N=45 8 weeks 12 weeks 12 weeks ABT-45 ABT-267 ABT-333 ABT-45 ABT-333 ABT-45 ABT-267 ABT-45 ABT-267 ABT-333 Treatment-naϊve Patients ABT-45 ABT-267 ABT-333 ABT-45 ABT-267 ABT-45 ABT-267 ABT-333 Null Responders Kowdley K, et al. 63rd AASLD; Boston, MA; November 9-13, 12. Abst. LB-1. 7

8 AVIATOR: SVR12 Rates With ABT-45/RTV, ABT-267, ABT-333, and No drug-related SAEs reported SV VR12 (%) Treatment-Naive Patients 98 Observed data (above bar) ITT (within bar) n = a 1b 1a 1b 1a 1b 1a 1b 1a 1b ABT-45 ABT-267 ABT-333 ABT-45 ABT-333 ABT-45 ABT wks 12 wks ABT-45 ABT-267 ABT-333 ABT-45 ABT-267 ABT-333 Kowdley KV, et al. AASLD 12. Abstract LB-1. Aviator: Null response results Kowdley KV, et al. AASLD 12. Abstract LB-1. 8

9 Sapphire 1 Trial: ABT-45/r, ABT-267, ABT-333, Naïve, Genotype 1a and 1b Non-cirrhotic 631 patients ABT 45/r, ABT-267 co-formulated into 1 pill ABT-333, dosed twice daily AE s fatigue, headache, nausea Enanta/ABBVIE Press release 11/18/13 Sapphire 1 Trial: SVR d/c rate in all arms 1.7% relapse rate All n=473 G 1a n=322 G 1b n=151 Placebo n=218 Enanta/Abbvie Press Release 11/18/13 9

10 Direct-Acting Antiviral Agents Daclatasvir (DCV) NS5A replication complex inhibitor with potent, pan-genotypic activity in vitro Studied in over 55 patients Asunaprevir (ASV) NS3 protease inhibitor active against genotypes (GT) 1, 4, 5, and 6 in vitro Studied in over patients BMS Non-nucleoside, NS5B polymerase inhibitor active against GT 1, 3, 4, 5, and 6 in vitro Studied in over 5 patients Everson et al AASLD 13 Randomized, Phase 2b Open-Label Study (AI443-14) Primary endpoint: SVR 12 N = N = 86 DCV 3 mg BID + ASV mg BID + BMS mg BID DCV 3 mg BID + ASV mg BID + BMS mg BID 12-week follow-up Additional follow-up to SVR 48 Week Patients: treatment-naive, stratified by GT 1a/1b and presence of biopsy- confirmed cirrhosis i (82% GT1a and 9% cirrhotics). Primary end point: HCV RNA < LLOQ 12 weeks post-treatment (SVR 12 ) Observed analysis: breakthrough, relapse, addition of pegifnα/ = failure Modified intent-to-treat analysis: missing, breakthrough, relapse or addition of pegifnα/ = failure Everson et al AASLD 13 1

11 Efficacy Through SVR 12 (Observed) Res sponse, % of patients 78/ 81/86 73/79 77/84 71/77 77/84 DCV + ASV mg DCV + ASV mg End of Treatment SVR 4 SVR 12 Everson et al AASLD 13 Event, n (%) Safety Outcomes DCV + ASV + DCV + ASV mg mg N = N = 86 Total N = 166 Serious AEs 1(13) (1.3) 2(23) (2.3) 3(16) (1.6) AEs leading to discontinuation 1 (1.3) 1 (1.2) 2 (1.1) Grade 3/4 AEs 1 (1.2) 1 (.5) Most frequent on-treatment AEs ( 1%) Headache 17 (21.3) 24 (27.9) 41 (24.7) Diarrhea 12 (15.) 13 (15.1) 25 (15.1) Fatigue 12 (15.) 7 (8.1) 19 (11.4) Nausea 1 (12.5) 7 (8.1) 17 (1.2) Grade 3/4 lab abnormalities Aspartate aminotransferase (AST) 1 (1.3) 1 (.5) Glucose, fasting serum (high) 1 (1.3) 1 (1.2) 2 (1.2) Phosphorus, inorganic 1 (1.2) 1 (.5) Bilirubin, total 1 (1.2) 1 (.5) Everson et al AASLD 13 11

12 NEW THERAPIES FOR GENOTYPE 1: COFORMULATED AGENTS Direct Acting Antiviral Agents Sofosbuvir/Ledipasvir FDC Once daily, oral fixed-dose (/9 mg) combination tablet No food effect > patients treated SOF Nucleotide Polymerase inhibitor LDV NS5A inhibitor GS-9669 HCV NS5B non-nucleoside inhibitor, binding at thumb site II of the polymerase Potent antiviral activity with QD dosing Nanomolar potency against GT 1a and 1b Gane et al AASLD 13 12

13 Study Design Wk Wk 6 Wk 12 F4 omized Rando SOF/LDV FDC (n=1) SOF/LDV FDC + (n=1) GT 1 Experienced F3/F4 Randomized SOF/LDV FDC + (n=25) SOF/LDV FDC + GS-9669 (n=25) SVR12 GT 1 Naïve F/F1/F2 SOF/LDV FDC + (n=25) Primary endpoint: SVR12 (HCV RNA <LLOQ) Patients enrolled in ELECTRON or ELECTRON 2 (GT1, F3/F4) All groups were open label Gane et al AASLD 13 SVR 12 (%) /1 9/9 25/25* 26/26* SOF/LDV SOF/LDV + SOF/LDV + SOF/LDV + GS9669 Duration (wk) F4 only F3/F4 *From ELECTRON 2 Gane et al AASLD 13 13

14 SVR 12 (%) /25 21/21 17/25 SOF + LDV + * SOF/LDV + SOF/LDV + Duration (wk) *Gane et al. EASL 13. Lawitz et al AASLD 13 (LONESTAR) Conclusions In treatment-experienced patients with advanced fibrosis/cirrhosis, either or GS may enhance the efficacy of SOF/LDV given for 12 weeks The optimal duration of SOF/LDV in treatmentnaïve GT 1 patients (even with the addition of ) is more than 6 weeks Regimens of SOF/LDV alone, or with or with GS-9669, were safe and well tolerated Gane et al AASLD 13 14

15 n=25 MK-5172 ( mg) + MK-8742 ( mg) + ; G1a & G1b Follow-up n=27 MK-5172 ( mg) + MK-8742 (5 mg) + ; G1a & G1b Follow-up n=13 MK-5172 ( mg) + MK-8742 (5 mg); G1b Follow-up D1 TW4 TW12 SVR4 SVR8 SVR12 SVR24 Lawitz et al AASLD 13 % HCV-RNA <25 IU/mL TW4 TW12 SVR4 SVR MK-5172 ( mg) + MK ( mg) + (n=25) MK-5172 ( mg) + MK (5 mg) + (n=27) MK-5172 ( mg) + MK (5 mg) (n=13) Lawitz et al AASLD 13 Treatment Follow-up 15

16 Number of patients (%) MK-5172 Common MK-5172 MK-5172 mg mg Adverse mg + MK MK Event mg + MK All arms mg mg + N=65 + n=25 n=28 n=12 Fatigue 8 (32) 5 (18) 4 (33) 17 (26) Headache 4 (16) 5 (18) 5 (42) 14 (22) Nausea 3 (12) 7 (25) 2 (17) 12 (18) Diarrhea 3 (12) 4 (14) 1(8) 8 (12) Dizziness 4 (16) 2 (7) 1 (8) 7 (11) Rash 1 (4) 5 (18) 1 (8) 7 (11) * Incidence 1% in all arms Lawitz et al AASLD 13 Study Design and Methods Treatment Period PostTreatment Period Cohort 1 (n=12) mg BID DBV + 1 mg QD FDV* + mg QD Cohort 2 (n=12) mg BID DBV + 1 mg QD FDV* + mg QD Cohort 3 (n=12) mg BID DBV + 1 mg QD FDV* + mg QD 668 (no ) Day Week 12 Week 16 SVR4 Week 24 SVR12 Week 36 SVR24 *FDV loading dose (2 mg) on Day 1 Lalezari et al AASLD 13 16

17 <LLOQ/<LLOD (%) 1 Cohort Cohort Cohort 3 (- All Time 1 n 2 n free) n Cohorts n Week 2 92/ / / /42 36 Week 4 92/75 12 / 12 / /81 36 Week 6 / 11 2 /92 12 / 1 /97 33 Week 8 / 11 2 / 11 / 4 / 26 Week 12 / 9 2 / 8 N/A 3 / 17 SVR4 / 7 2 / 6 N/A 3 / 13 Overall, 97% of patients across all three cohorts achieved HCV RNA <LLOQ (81% <LLOD) at week 4, regardless of use NEW THERAPIES FOR GENOTYPE 1: IFN AND FREE 17

18 N BL HCV Genotype/Regimen Treatment Experience Week 12 Week 24 Substudy 1: Patients Without Cirrhosis Substudy 2: Patients With Compensated Cirrhosis Group 1 GT4 ABT-45/r + ABT-267 Treatment-naïve Group 2 GT1b ABT-45/r + ABT-267 Treatment-naïve Group 3 GT1b ABT-45/r + ABT-267 Group 4 Null Responders Group 5 GT4 ABT-45/r + ABT rbv Treatment-naïve Group 6 GT4 ABT-45/r + ABT-267 Partial/Null Responders & Relapsers Group 7 GT4 ABT-45/r + ABT rbv Group 8 Partial/Null Responders & Relapsers GT1b ABT-45/r + ABT-267 Treatment-naïve GT1b ABT-45/r + ABT-267 Partial/Null Responders & Relapsers ABT-45/r 15/ mg QD; ABT mg QD; weight based, mg or 1 mg daily divided BID. Patients followed through 48 weeks post-treatment Lawitz et al AASLD 13 ercentage of Patients P /42 41/42 41/42 /42 Week 4 Week 12 SVR SVR EOTR 4 12 Lawitz et al AASLD 13 18

19 ercentage of Patients P Lawitz et al AASLD / 39/ 37/ 36/ Week 4 Week 12 SVR SVR EOTR 4 12 Event, n (%) GT1b-infected Treatment-naïve Patients (N=42) GT1b-infected Prior Null Responders (N=) Headache 14 (3.3) 1 (25.) Nausea 8 (19.) Dry Skin 7 (16.7) Fatigue 6 (14.3) Pruritus 6 (14.3) Diarrhea 6 (14.3) Lawitz et al 13 19

20 HCV RNA < LLOQ, n (%) Ineligible naïve/intolerant (IN/I) Patients n = 135 a Nonresponder (NR) Patients n = 87 b Total N = 222 RVR, Week (84.4) 53 (.9) 167 (75.2) cevr, Week (92.6) 77 (88.5) 2 (91.) SVR (93.3) 71 (81.6) 197 (88.7) SVR 12 1 (88.9) 7 (.5) 19 (85.6) SVR (87.4) 7 (.5) 188 (84.7) a Ineligible naïve: n=; Intolerant: n=35 b Null responders: n=48; Partial responders: n=36; Undetermined: n=3 Abstract #211 Chayama et al AASLD 13 TREATMENT OF PI EXPERIENCED: IFN FREE THERAPIES

21 Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin with HCV Genotype 1, Including Patients with Cirrhosis: the LONESTAR trial Wk Wk 8 Wk 12 Wk Wk 24 COHORT 1 (n=) Treatment Naïve (No cirrhosis) 1:1:1 Randomized SOF/LDV SOF/LDV + SOF/LDV SVR12 SVR12 SVR12 COHORT 2 (n=) PI Failures (5% cirrhosis) Randomized 1:1 SOF/LDV SOF/LDV + SVR12 SVR12 Single center study of GT 1 patients Broad inclusion criteria No upper limit to age or BMI Platelets 5,/mm 3 Lawitz et al AASLD 13 Results: Demographics of Patients Who Previously Failed PI Therapy PI Failures n= Prior treatment with boceprevir 22/ (55) Prior treatment with telaprevir 18/ (45) Cirrhosis, n (%) 22/ (55) Mean platelet count, x 1 3 /µl 17 Mean albumin, g/dl 3.8 All patients were required to have experienced virologic failure Patients who stopped prior therapy due to an AE were excluded Lawitz et al AASLD 13 21

22 Lonestar Results Patients (%) Duration (week) 19/ 21/21 18/19 18/19 21/ Lawitz et al AASLD 13 Treatment Naïve (No Cirrhosis) PI Failures (5% Cirrhosis) Daclatasvir + Sofosbuvir ± in GT 1 Pts With Prior Tx Failure on TVR or BOC Pts with GT 1 HCV and virologic failure on previous TVR- or BOC-based regimen (N = 41) Daclatasvir mg QD + Sofosbuvir mg QD (n = 21) Daclatasvir mg QD + Sofosbuvir mg QD + -1 mg/day (n = ) Wk 24 SVR4, % SVR12, % 95 45% to 48% had TVR/BOC resistance mutations, median 2.4 yrs since previous therapy No difference in response by absence/presence of resistance mutations Both regimens well tolerated; 1 serious AE; no discontinuations due to AEs Sulkowski MS, et al. EASL 13. Abstract

23 Evolution of Therapy in HCV Genotype ? SVR (%) IFN IFN IFN/ IFN/ 6m 12m 6m 12m PEG/ 12m PEG/R/PI 6-12m All Oral DAA weeks 23