clinicaloptions.com/hepatitis HCV Investigational Agents April 22-26, 2015 Vienna, Austria Highlights From EASL: HCV Investigational Agents CCO Independent Conference Coverage of the 2015 Annual Meeting of the European Association for the Study of the Liver* *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from AbbVie, Gilead Sciences, and Merck.
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Highlights From EASL: HCV Investigational AgentsCCO Independent Conference Coverage of the 2015 Annual Meeting of the European Association for the Study of the Liver*
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This program is supported by educational grants fromAbbVie, Gilead Sciences, and Merck.
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Andrew J. Muir, MDChief, Division of GastroenterologyAssociate Professor of MedicineDepartment of MedicineDirector, Gastroenterology/ Hepatology ResearchDuke Clinical Research InstituteDuke University School of MedicineDurham, North Carolina
David R. Nelson, MD Professor of Medicine Assistant Vice President for Research University of FloridaGainesville, Florida
Norah Terrault, MD, MPH Professor of Medicine and Surgery
Director, Viral Hepatitis CenterDivision of GastroenterologyUniversity of California, San FranciscoSan Francisco, California
Andrew J. Muir, MD, has disclosed that he has received funds for research support from AbbVie, Achillion, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hologic, Intercept, Janssen, Merck, NGM Biopharm, and Roche and has received consulting fees from AbbVie, Achillion, Bristol-Myers Squibb, Gilead Sciences, Intercept, Janssen, Lumena, Merck, Regulus Therapeutics, Salix, and Theravance.
David R. Nelson, MD, has disclosed that he has received funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck.
Norah Terrault, MD, MPH, has disclosed that she has received funds for research support from AbbVie, Biotest, Esai, Gilead Sciences, Novartis, and Vertex and has received consulting fees from Achillion, Biotest, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck.
Zeuzem Z, et al. EASL 2015. Abstract G07. Reproduced with permission.
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
SV
R12
(%
)
All Pts GT1a GT1b GT4 GT6
95 92 99 10080
299/316
144/157
129/131
18/18
8/10n/N =
SVR12 With 12 Wks of Grazoprevir/Elbasvir According to Genotype
Forns X, et al. EASL 2015. Abstract O001. Reproduced with permission.
Previous TherapyPrevious All-
Cause Treatment Failures, N
Baseline RAVs, % SVR12 in Pts With Baseline RAVs, %
NS3 NS5A
Boceprevir 28 37.0 10.7 90.9*
Telaprevir 43 44.2 10.7 90.0*
Simeprevir 8 62.5 0 100
All pts 79 43.6 10.1 91.7*2 boceprevir-treated pts and 4 telaprevir-treated pts harbored quasispecies at baseline with mutations in both the NS3 and NS5A genes.
C-SCAPE: Grazoprevir ± Elbasvir ± RBV for Pts With GT2/4/5/6 HCV Open-label, randomized, phase II trial
In the GT4/5/6 group, 53% of pts were infected with GT4 HCV
Efficacy reduced in pts infected with GT2 HCV with baseline HCV RNA > 2 million IU/mL
Grazoprevir/elbasvir active in GT5 and 6 HCV, although pt numbers were small
GT2 (n = 56*)
Grazoprevir/Elbasvir + RBV(n = 30)
Grazoprevir + RBV(n = 26)
Grazoprevir/Elbasvir + RBV(n = 18)
Wk 12
Grazoprevir/Elbasvir (n = 18)
GT4 (n = 20)GT5 (n = 8*)GT6 (n = 8*)
Treatment-naive, noncirrhotic, HCV-
infected pts(N = 98)
*mITT population: 6 pts were excluded due to improper genotyping. Grazoprevir dosed 100 mg orally once daily; elbasvir dosed 50 mg orally once daily; RBV dosed at 800-1400 mg/day based on weight.
Pts well matched at baseline: population primarily white (93% to 100%); of pts with GT1 HCV infection, 76% to 84% had GT1a HCV; IL28B non-CC varied between arms (21% to 50%)
All pts who failed treatment relapsed; among GT1 HCV relapses, 30% developed NS5A RAVs at failure (most in 4-wk treatment group)
Higher baseline HCV RNA (> 2 million IU/mL) and presence of cirrhosis resulted in lower SVR12 rates for pts with GT3 HCV
Poordad F, et al. EASL 2015. Abstract O006. Reproduced with permission.
SV
R12
(%
)
100
80
60
40
20
04 Wks 6 Wks 6 Wks 8 Wks 8 Wks 12 Wks 12 Wks
Genotype 1 Genotype 3
33
26/30
16/20
17/18
14/15
14/14
10/11*
87 8094 93 100 91
10/30*
*Excluded pts who discontinued due to reasons other than virologic failure.
C-SURFER: Grazoprevir/Elbasvir in Pts With GT1 HCV and Stage 4 or 5 CKD Multicenter, part-randomized, parallel-group, placebo-controlled, phase III trial
Treatment arms well matched at baseline
– Pts split evenly by GT1a and 1b infection (52% for GT1a); 6% had compensated cirrhosis
– 75% and 77% were on hemodialysis; 32% to 36% were diabetic
– 81% and 82% were CKD stage 5 (eGFR < 15 mL/min/1.73 m2, or on hemodialysis); 18% and 19% were CKD stage 4 (eGFR 15-29 mL/min/1.73 m2)
Roth D, et al. EASL 2015. Abstract LP02.
Grazoprevir/Elbasvir(n = 111)
Placebo(n = 113)
GT1 HCV-infected pts with
stage 4/5 CKD(n = 224) Grazoprevir/Elbasvir
(n = 113)
Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily. This study also included a pharmacokinetic analysis (n = 11) in which pts were treated as in the randomized grazoprevir/elbasvir study group.
Roth D, et al. EASL 2015. Abstract LP02. Reproduced with permission.
GZR/EBR 12 wks
Modified analysis set: pts in pharmacokinetic substudy and pts randomized to immediate treatment who received ≥ 1 drug dose; excludes pts who died or discontinued where cause not related to study treatment.Full analysis set: all pts receiving ≥ 1 drug dose.*1 pt relapsed on each arm. †6 pts in the full analysis set discontinued unrelated to treatment: lost to follow-up (n = 2), n = 1 each for death, noncompliance, withdrawal by subject, and withdrawal by physician (owing to violent behavior).
SYNERGY: 4-6 Wks of LDF/SOF + GS-9451 ± GS-9669 in GT1 HCV Single-center, open-label, phase IIa trial
At baseline, > 60% GT1a HCV; 76% to 80% black pts, except 6-wk treatment-experienced arm, which had 40% black pts; 4- and 6-wk arms had 40% to 44% and 20% to 24% pts with > 6 million IU/mL, respectively
Most pts in the F3-F4 fibrosis treatment groups had F3 fibrosis (64% to 68%)
Univariate analysis: HCV RNA < 6 million IU/mL and GT1b HCV predicted response
SOF + NS5A Inhibitors ± RBV in Pts With GT1/3 HCV and Decompensated Cirrhosis Observational cohort study of National Health Service of England (N = 467)
At physician’s discretion, pts received 12 wks SOF + LDV or DCV ± RBV
Baseline Characteristic
All Pts(N = 467)
Genotype 1(n = 235)
Genotype 3(n = 189)
Other Genotypes(n = 43)
CTP B, % 66.2 68.5 64.0 62.8
CTP C, % 9.9 8.1 12.7 7.0
Mean MELD score (range)
11.9 (6-36) 11.3 (6-24) 12.6 (6-36) 11.9 (6-22)
Regimen, % of total population
SOF + LDV + RBV 54.0 35.1 13.1 5.8
SOF + DCV + RBV 36.8 9.6 24.4 2.8
RBV-free regimen 9.2 5.6 3.0 0.6
Foster GR, et al. EASL 2015. Abstract O002. Reproduced with permission.
Compassionate Use Program: SOF + DCV ± RBV for GT3 HCV Infection Interim analysis of nonrandomized, multicenter, compassionate use program
Pts had GT3 HCV infection and ≥ F3 liver disease, extrahepatic manifestation of HCV disease, HCV recurrence following liver transplantation, or indication for liver or kidney transplantation (N = 601)
76% of pts were cirrhotic; 73% were treatment experienced
Pts received sofosbuvir + daclatasvir ± ribavirin for 12 or 24 wks
Treatment discontinuations to date
– Adverse events: n = 1; death: n = 2; pt decision: n = 1
Hezode C, et al. EASL 2015. Abstract LP05.
SVR4, % (n/N)12 Wks of Sofosbuvir + Daclatasvir ± Ribavirin
– 95% and 96% of pts were white, 40% and 42% were treatment naive, 75% and 77% were infected with GT1 HCV
Treatment
– All pts: 12 wks of daclatasvir 60 mg QD + sofosbuvir 400 mg QD + RBV
– Initial RBV dose 600 mg/day, adjusted to 1000 mg/day based on hemoglobin levels and creatinine clearance
– Pts with advanced cirrhosis who interrupted treatment due to liver transplantation could receive 12 additional wks of therapy immediately after transplantation
– Individuals relapsing following 12 wks of daclatasvir + sofosbuvir + RBV offered re-treatment with the same regimen for 24 wks
In subgroup analysis of pts in the advanced cirrhosis group, those who were Child-Pugh class C (n = 16) or had albumin < 2.8 g/dL (n = 18) had SVR12 rates of 56%
10/10 pts who relapsed in the advanced cirrhosis group had NS5A RAVs at virologic failure; 4 of 10 pts had NS5A RAVs at baseline
3/3 pts who relapsed in the posttransplantation group had NS5A RAVs at virologic failure; none had NS5A RAVs at baseline
Poordad F, et al. EASL 2015. Abstract LO8. Reproduced with permission.
ANRS CUPILT: SOF + DCV Treatment for HCV Recurrence After Liver Transplant Multicenter, open-label, nonrandomized study
SOF + DCV (n = 11)
SOF + DCV+ RBV(n = 3)
Pts with HCV recurrence posttransplant,
no coinfection with HIV(N = 130) SOF + DCV
(n = 64)
Wk 12
SOF + DCV+ RBV(n = 52)
Wk 24
SOF dosed 400 mg/day; DCV dosed 60 mg/day; renal function-based RBV dosing.Treatment type and duration at discretion of investigator; 3 pts in 24-wk groups received ≥ 36 wks of treatment.
Coilly A, et al. EASL 2015. Abstract G15.
Most pts were GT1a (27% to 29%) or GT1b (47% to 49%)
ALLY-2: Daclatasvir + Sofosbuvir for HIV/HCV Coinfection Multicenter, randomized phase III study
Treatment arms well matched at baseline and GT1 HCV infection most prevalent (> 80% per arm)
Cirrhosis more common on treatment-experienced arm (29% vs 9% to 10% for treatment-naive arms)
Almost all pts received ART (atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, efavirenz, nevirapine, rilpivirine, raltegravir, dolutegravir, or NRTIs only)
Wyles DL, et al. EASL 2015. Abstract LP01.
Daclatasvir + Sofosbuvir(n = 101)
Daclatasvir + Sofosbuvir(n = 50)
HCV treatment-naive, HCV/HIV-coinfected
pts(n = 151)
Daclatasvir + Sofosbuvir(n = 52)
Daclatasvir 60 mg QD, with dose adjustment for ART use: 30 mg QD with ritonavir-boosted PIs, 90 mg QD with NNRTIs except rilpivirine. Sofosbuvir 400 mg QD.