Treatement Experienced patients without cirrhosis Rafael Esteban Hospital Universitario Valle Hebron Barcelona
Agenda With IFN PegIFN+ Ribavirin + Simeprevir PegIFN+ Ribavirin+ Sofosbuvir Without IFN Sofosbuvir + Ribavirin Sofosbuvir + Daclastasvir Sofosbuvir + Simeprevir Sofosbuvir + Ledipasvir 3D RegimenAbbvie
Agenda With IFN PegIFN+ Ribavirin + Simeprevir PegIFN+ Ribavirin+ Sofosbuvir
SMV + PR in relapsers: PROMISE Study Phase III randomized study RGT* Relapsers Genotype 1 n=26 n=133 SMV 15 mg QD + PR Pbo + PR PR PR Follow up PR PR Week 12 24 48 15% Patients F4 6% Genotype 1b 11% IL28 TT *RGT: stop all therapy if HCV RNA <25 IU/mL detectable or undetectable at Week 4 and <25 IU/mL undetectable at Week 12 patients who did not qualify for RGT were treated with PR until week 48 Forns X, et al. Gastroenterology 214;146:1669 1679
SVR12 (%) SVR12 rates PROMISE P<.1* 26/26 48/133 RVR in 77% of the patients and SVR among them of 87 % 5 Forns X, et al. Gastroenterology 214;146:1669 1679
SMV + PR in treatment experienced patients : study ASPIRE Phae II b rabdomized study SMV + PR (NCT9833) n=132 SMV (1 ó 15 mg) + PR PR Genotype 1 patients Relapsers n=133 SMV (1 ó 15 mg) + PR PR Partial Responders and null responders n=131 SMV (1 ó 15 mg) + PR n=66 Pbo + PR Semana 12 24 48 Zeuzem S, et al. Gastroenterology, 214;146:43 41
SVR24 (%) SMV + PR: ASPIRE SVR rates 12 15/23 2/23 9/17 3/16 Partial responder Null responder *Análisis de los brazos de 15 mg de SMV QD durante 12 semanas con PR durante 48 semanas Zeuzem S, et al. Gastroenterology, 214;146:43 41
SMV + PR safety First 12 weeks Entire treatment phase SMV + PR (n=924) Pbo + PR (n=54) SMV + PR (n=924) Pbo + PR (n=54) Hyperbilirubinemia, n (%) N 923 538 923 539 Grade 1 (1.1 1.5 x ULN) 237 (25.7) 76 (14.1) 237 (25.7) 8 (14.8) Grade 2 (1.6 2.5 x ULN) 16 (17.3) 5 (9.3) 159 (17.2) 5 (9.3) Grade 3 (2.6 5. x ULN) 41 (4.4) 8 (1.5) 42 (4.6) 9 (1.7) Grade 4 (>5. x ULN) 5 (.5) 5 (.5) n (%) AEs of clinical interest SMV + PR (n=924) First 12 weeks Pbo + PR (n=54) Entire treatment phase SMV + PR (n=924) Pbo + PR (n=54) Rash (any type)* 212 (22.9) 9 (16.7) 259 (28.) 134 (24.8) Pruritus 22 (23.8) 94 (17.4) 272 (29.4) 15 (27.8) Photosensitivity conditions** 43 (4.7) 4 (.7) 44 (4.8) 4 (.9) Manns M, et al. HEPDART 213. Poster 57
Agenda With IFN PegIFN+ Ribavirin + Simeprevir PegIFN+ Ribavirin+ Sofosbuvir
SOF + PEGIFN + RIBA in treatment expereinced patients
SOF + PEGIFN + RIBA in patients with PI failure
Treatment experienced 5% PI Faliures 27% Cirrhosis 3%
Agenda With IFN PegIFN+ Ribavirin + Simeprevir PegIFN+ Ribavirin+ Sofosbuvir Without IFN Sofosbuvir + Ribavirin Sofosbuvir + Daclastasvir Sofosbuvir + Simeprevir Sofosbuvir + Ledipasvir 3D RegimenAbbvie
Sofosbuvir + RBV: QUANTUM study N=25 SOF + RBV (naives) N=25 SOF + RBV (naives) N=132 SOF + RBV (retreatment) Week 12 24 36 Lalezari et al. EASL 213; abstract 845 http://www.natap.org/213/easl/easl_31.htm
Study QUANTUM: SOF + RBV 8/15 7/15 2/4 2/4 4/6 4/6 Lalezari J, et al. EASL 213. Abstract 845
SOF + DCV ± RBV: Study AI444-4 Treatment experienced (TVR + PR o BOC + PR) n=21 n=2 SOF + DCV SOF + DCV + RBV 24 weeks Genotypo 1 weeks 24 SOF + DCV SOF + DCV + RBV Median, age 59 57 Male, n (%) 13 (62) 12 (6) Race, n (%) White Black Others 19 (9) 2 (1) 18 (9) 1 (5) 1 (5) HCV RNA, log 1 IU/mL 6.3±.4 6.3±.4 HCV genotype, n (%) 1a 1b Metavir score, n (%) F/F1 F2/F3 F4 16 (76) 5 (24) 2 (1) 14 (67) 3 (14) 17 (85) 3 (15) 3 (15) 11 (55) 6 (3) Sulkowski MS, et al. N Engl J Med 214;37:211 21
Patients with undetectable HCV RNA(%) : SOF + DCV ± RBV: Study AI444-4 SOF + DCV SOF + DCV + RBV 1 8 6 4 2 19/21 16/2 21/2119/2 21/212/2 21/212/2 21/2119/2 Week 2 Week 4 EOT SVR4 SVR12 *Missing data for one patient: patient presented with HCV RNA undetectable 4 weeks post treatment and 24 weeks post treatment Sulkowski MS, et al. N Engl J Med 214;37:211 21
SIMEPREVIR + SOFOSBUVIR: COSMOS Stydy Cohort 1 (n=8): Null responders and Fibrosis F-F2 Cohort 2 (n=87): Naive and Null responders Fibrosis F3 F4 Arm 1 SMV + SOF + RBV Follow up Arm 2 SMV + SOF Follow up Arm 3 SMV + SOF + RBV Follow up Arm 4 SMV + SOF Follow up Week 4 12 24 36 48 1.Sulkowski M, et al. J Hepatol. 214;6:S4. Oral presentation O7. 2. Lawitz E, et al. J Hepatol. 214;6:S524. Late breaking abstract O165. 3. Lawitz E et al. Lancet. 214 Jul 26. pii: S14-6736(14)6136-9 4. SmPC Simeprevir.
Proportion of Patients (%) COSMOS Study Null responders and fibrosis F-F2 24 weeks SVR12 Non-VF* Relapse 12 weeks 1 1/24 1/15 1 1/27 1/14 8 4/24 8 6 6 4 4 2 2 19/24 14/15 26/27 13/14 SMV/SOF + RBV SMV/SOF SMV/SOF + RBV SMV/SOF 1.Sulkowski M, et al. J Hepatol. 214;6:S4. Oral presentation O7. 2. Lawitz E, et al. J Hepatol. 214;6:S524. Late breaking abstract O165. 3. Lawitz E et al. Lancet. 214 Jul 26. pii: S14-6736(14)6136-9 4. SmPC Simeprevir.
OPTIMIST-1 study design SVR12 SVR24 Week 4 8 12 16 24 36 Arm 1 N=155 SMV 15 mg QD + SOF 4 mg QD Follow-up SVR12 SVR24 Week 4 8 12 2 32 Arm 2 N=155 SMV 15 mg QD + SOF 4 mg QD Follow-up Treatment was to be discontinued in patients with viral breakthrough (confirmed >1. log 1 increase in HCV RNA from nadir or confirmed HCV RNA >1 IU/mL in patients who had previously achieved HCV RNA <25 IU/mL) HCV, hepatitis C virus; QD, once daily; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatment; SVR24, sustained virologic response 24 weeks after end of treatment 6/11/215 2
Proportion of patients with SVR12 (%) 6/11/215 2 1 SVR12 rates for patients receiving SMV + SOF for 12 and 8 weeks versus historical control rate 1 8 97 (95% CI: 93.7; 99.9) 87 83 (95% CI: 76.3; 88.9) SMV + SOF Historical control 83 6 4 2 15/155 12-week regimen 128/155 8-week regimen Superior: 93.7>87 Non superior: 76.3>83 The primary objective was tested by means of a closed testing procedure. 95% CIs were constructed using a normal approximation with continuity correction. To conclude superiority of the SMV+SOF arm towards the historical data the 95% lower limit of the CI of the SMV+SOF arm has to be greater than the historical control rate. CI, confidence interval; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatment
Proportion of patients (%) Proportion of patients (%) Proportion of patients (%) Proportion of patients (%) a) SVR12 rates (95% CI) by a) prior treatment history, b) HCV geno/subtype, c) IL28B genotype, and d) baseline HCV RNA (intentto-treat population) 1 8 97 (94.;1) 85 (78.1;92.7) 95 (87.;1) SMV+SOF 12 weeks 77 (64.5;89.3) b) SMV+SOF 8 weeks 1 8 97 (92.8;1) 79 (71.5;87.1) 96 (88.7;1) 73 (6.1;86.9) 97 (92.5;1) 84 (74.;93.2) 97 (91.2;1) 92 (82.7;1) 6 6 4 4 c) 2 1 8 6 112/115 Treatment-naïve 1 (98.8;1) 93 (83.5;1) 88/13 38/4 4/52 97 (92.1;1) 84 (75.3;92.1) Treatment-experienced 92 (8.1;1) 64 (44.8;83.8) d) 2 1 8 6 112/116 92/116 44/46 36/49 68/7 56/67 38/39 36/39 GT1a 96 (9.7;1) GT1a with Q8K 96 (89.1;1) GT1a without Q8K 97 (93.1;1) GT1b 77 (68.2;85.1) 4 4 2 43/43 CC 38/41 83/86 72/86 24/26 18/28 CT TT 2 54/56 Baseline HCV RNA <4 IU/mL 46/48 96/99 82/17 Baseline HCV RNA 4 IU/mL CI, confidence interval; GT, genotype; HCV, hepatitis C virus; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatment 6/11/215 2 2
TARGET Study : SVR-4 SIMEPREVIR/ SOF /RIBA
SOF+ Ledipasvir : ION 2 Study Wk Wk 12 Wk 24 Wk 36 LDV/SOF LDV/SOF + RBV SVR12 SVR12 LDV/SOF LDV/SOF + RBV SVR12 SVR12 Non responders 6% 2% Cirrhosis Genotype 1a : 8 % 25
SVR12 (%) 1 94 96 99 99 8 6 4 2 12/19 17/111 18/19 LDV/SOF LDV/SOF + RBV LDV/SOF 11/111 LDV/SOF + RBV 12 Weeks 24 Weeks Error bars represent 95% confidence intervals. 26
SVR12 (%) SOF+ Ledipasvir : ION 2 Failed PEG/RBV Failed Protease Inhibitor 1 93 94 96 97 1 98 98 1 8 6 4 2 4/43 62/66 45/47 62/64 58/58 49/5 58/59 51/51 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Error bars represent 95% confidence intervals. 27
SVR12 (%) SOF+ Ledipasvir : Estudio ION 2. SVR in relation to fibrosis Absence of Cirrhosis Cirrhosis 1 95 86 1 99 1 99 1 82 8 6 4 2 83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Error bars represent 95% confidence intervals. 28
RVS12 (%) Paritaprevir/R+ Ombitasvir+ Dasabuvir + RBV 12 weeks in Genotype 1 1 SAPPHIRE-I (naïve) SAPPHIRE-II (experienced) 96 95 98 96 96 97 8 6 4 2 455 473 37 322 148 151 286 297 166 173 119 123 Global gen 1a gen 1b global gen 1a gen 1b Zeuzem S. N Engl J Med 214; Online DOI: 1.156/NEJMoa141561 Feld J. N Engl J Med 214; Online DOI: 1.156/NEJMoa1315722
SAPPHIRE-II. SVR 12 by ITT
3D in Genotype 1 b : PEARL Study Open-label Treatment 3D + RBV (N = 91) 3D (N = 95) Assess for SVR12 48-wk follow-up Day Week 12 Week 24 Week 6 3D: coformulated ABT-45/r/ombitasvir, 15 mg/1 mg/25 mg QD; dasabuvir, 25 mg BID RBV: 1 or 12 mg daily according to body weight (<75 kg and 75 kg, respectively)
% Patients SVR 12 in Pearl Study 1 98.9 1 98.9 1 97.7 1 96.6 1 8 Superiority threshold (75%) Noninferiority threshold (64%) 6 4 2 87 88 91 91 87 88 91 91 86 88 91 91 85 88 91 91 RVR (Week 4) ITT GT1b efficacy population EOTR (Week 12) SVR4 SVR12 3D Regimen With RBV No RBV
SAPPHIRE-II. Aes in >1% of patients