Highlights of New Developments in HCV Treatment from EASL 2015 April 22-25 Vienna, Austria

Highlights of New Developments in HCV Treatment from EASL 2015

April 22-25Vienna, Austria

Canadian Experts

Curtis CooperOttawa Hospital Research InstituteDirector, Ottawa Hospital and Regional Hepatitis ProgramThe Ottawa HospitalAssociate Professor, Department of MedicineUniversity of Ottawa

Alnoor RamjiClinical Associate ProfessorDivision of GastroenterologyUniversity of British ColumbiaEberhard Renner

Director, GI TransplantationUniversity Health NetworkProfessor, Faculty of Medicine University of Toronto

Giada SebastianiPhysician, Division of GastroenterologyMcGill University Health Centre (MUHC)Assistant Professor, Department of MedicineMcGill UniversityMontreal, QC

Table of Contents (1 of 3)

1st Author Title Slides

Zeuzem SThe Phase 3 C-EDGE Treatment-naive (TN) Study of a 12-week Oral Regimen of Grazoprevir (GZR, MK-5172)/Elbasvir (EBR, MK-8742) in Patients with Chronic HCV Genotype (GT) 1, 4, or 6 Infection

7-11

Poordad F Daclatasvir, Sofosbuvir, and Ribavirin Combination for HCV Patients with Advanced Cirrhosis or Posttransplant Recurrence: Phase 3 ALLY-1 Study 13-17

Manns MLedipasvir/Sofosbuvir with Ribavirin is Safe and Efficacious in Decompensated and Post Liver Transplantation Patients with HCV Infection: Preliminary Results of the Prospective SOLAR 2 Trial

18-23

Faisal N Sofosbuvir-based Antiviral Therapy is Highly Effective in Recurrent Hepatitis C in Liver Transplant Recipients: A "Real-life" Canadian Multicenter Experience 24-29

Foster GRSofosbuvir + PegInterferon / Ribavirin for 12 Weeks vs. Sofosbuvir + Ribavirin for 16 or 24 Weeks in Genotype 3 HCV Infected Patients and Treatment-experienced Cirrhotic Patients with Genotype 2 HCV: The BOSON Study

30-36

Forns XC-SALVAGE: Grazoprevir (GZR; MK-5172), Elbasvir (EBR; MK-8742) and Ribavirin (RBV) for Chronic HCV-Genotype 1 (GT1) Infection After Failure of Direct-acting Antiviral (DAA) Therapy

37-41

Studies of greatest clinical importance, as assessed by Canadian Scientific Reviewers



Lawitz E Retreatment of Patients Who Failed 8 or 12 Weeks of Ledipasvir / Sofosbuvir-based Regimens with Ledipasvir / Sofosbuvir for 24 Weeks 42-47

Pockros PJSafety of Ombitasvir / Paritaprevir / Ritonavir Plus Dasabuvir for Treating HCV GT1 Infection in Patients with Severe Renal Impairment or End-stage Renal Disease: The RUBY-1 Study

48-52

Cooper CA Single Tablet Regimen of Ledipasvir/Sofosbuvir for 12 Weeks in HCV Genotype 1 or 4 Infected Patients with HIV-1 Co-infection: The Phase 3 ION-4 Study

53-58

Alqahtani SSafety and effectiveness of sofosbuvir-based regimens for the treatment of hepatitis C genotype 3 and 4 infections: Interim analysis of a prospective, observational study.

61

Foster GRTreatment of decompensated HCV cirrhosis in patients with diverse genotypes: 12 weeks sofosbuvir and NS5A inhibitors with/without ribavirin is effective in HCV Genotypes 1 and 3.

62

Hezode CDaclatasvir plus sofosbuvir with or without ribavirin in patients with HCV genotype 3 infection: Interim analysis of a French multicenter compassionate use program.

63




Krishnan PLong-term Follow-up of Treatment-emergent Resistance-associated Variants in NS3, NS5A and NS5B with Paritaprevir/R-, Ombitasvir- and Dasabuvir-based Regimens

66-69

Wyles D Long-term Persistence of HCV NS5A Variants After Treatment with NS5A Inhibitor Ledipasvir 70-74

Poordad FC-SWIFT: Grazoprevir / elbasvir + Sofosbuvir in Cirrhotic and Noncirrhotic, Treatment-naive Patients with Hepatitis C Virus Genotype 1 Infection, for Durations of 4, 6 or 8 Weeks and Genotype 3 Infection for Durations of 8 or 12 Weeks

76-80

Van Der Ree M

A Single Subcutaneous dose of 2 mg/kg or 4 mg/kg of RG-101, a GalNAc-conjugated Oligonucleotide with Antagonist Activity Against MIR-122, Results in Significant Viral Load Reductions in Chronic Hepatitis C Patients

82-86

Machouf N Low Incidence of Reinfection with Hepatitis C Virus After Successful Treatment in Montreal 88-90


New European Guidelines for HCV

Updated HCV treatment guidelines were presented at EASL 2015– Simultaneously

published in J Hepatol These are available free

of charge on-line at www.easl.eu

Studies of DAA Efficacywith New Combinations

The Phase 3 C-EDGE Treatment-naive (TN) Study of a 12-week Oral Regimen of Grazoprevir (GZR, MK-5172)/Elbasvir (EBR, MK-8742) in Patients with Chronic HCV Genotype (GT) 1, 4, or 6 Infection

Zeuzem S, et al. Oral Presentation, EASL 2015.

C-EDGE: Study Design

Grazoprevir: NS3/4A protease inhibitor Elbasvir: NS5A inhibitor N=421

– GT1a, n=211; GT1b, n=171; GT4, n=26; GT6, n=13– Cirrhosis, n=92 (22%)

Study drugs: Fixed-dose, combination tablet Primary endpoint: SVR12

Adapted from Zeuzem S, et al. Presented at EASL 2015; Oral presentation #G07.

Grazoprevir (GZR) 100 mg+ Elbasvir (EBR) 50 mg

GZR 100 mg+ EBR 50 mgPlacebo

N = 316

N = 105

D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW16

FUW12

Follow-up

8/1018/18129/131144/157

C-EDGE: Primary Endpoint (SVR12)

Overall SVR12 in Cirrhotics: 97%; Non-cirrhotics: 94%


299/316

All Patients GT1a GT1b GT4 GT6

Patie

nts,

%

0%

25%

70%

100%

50%

95% 92% 99% 100% 80%

Non-virologic failure 4 3 1 0 0

Breakthrough 1 1 0 0 0

Relapse 12 9 1 0 2

C-EDGE: Authors' Conclusions


SVR12 was achieved by 95% of patients– High efficacy across GT1, GT4, and GT6 infection– High efficacy in cirrhotics (SVR12 = 97.1%)– Overall virologic failure rate was 4%; lower efficacy observed

only among patients with high viral load and primarily with baseline GT1a RAVs that cause >5-fold potency reduction to elbasvir

Grazoprevir/elbasvir was generally well-tolerated, with a similar safety profile in cirrhotic and non-cirrhotic patients

These results are consistent with those from the comprehensive grazoprevir/elbasvir clinical study program, in which SVR12 rates of 94-100% were achieved in diverse patient population1

Commentary from Canadian Scientific Reviewers

The SVR12 rates with this combination were high– No definitive conclusions can be made regarding genotype

6 (80% SVR12 among 6 patients) The observation that the few treatment failures

seen in this study were associated with baseline resistance-associated variants conferring a >5-fold potency reduction to elbasvir may be important

Commentary on Zeuzem S, et al. Presented at EASL 2015; Oral presentation #G07.

Studies Investigating DAA Therapies in Populations with High Unmet Medical Need• Severe renal impairment• Decompensated cirrhosis• Post liver transplantation• Retreatment after DAA failure• Treatment-experienced genotype 2• Genotype 3• HIV co-infection

Daclatasvir, Sofosbuvir, and Ribavirin Combination for HCV Patients with Advanced Cirrhosis or Posttransplant Recurrence: Phase 3 ALLY-1 Study

Poordad F, et al. Oral presentation, EASL 2015.

ALLY-1 Study Design

Treatment-naive or experienced Advanced cirrhosis: Child-Pugh scores A,B &C,

MELD scores 8-40, HCC allowed Post-transplant: ≥3 months post-transplant,

no evidence of rejection, any immunosuppressant Primary endpoint: SVR12

DCV 60 mg QD +SOF 400 mg QD + RBV

DCV 60 mg QD +SOF 400 mg QD + RBV

Week 12 Week 24SVR12a

Week 0 Week 36

Follow-upPost-liver transplant

N = 53

Advanced cirrhosisN = 60

Adapted from Poordad F, et al. Presented at EASL 2015; Oral presentation #L08.

ALLY-1 Study: SVR 12

All patients GT1a GT1b GT2 GT3 GT4 GT60%

20%

40%

60%

80%

100%

83%76%

100%

80% 83%

100%94% 97%

90% 91%100%

Advanced cirrhosis Post-transplant

50/60

50/53

26/34

30/31

11/11

9/10 5/64/5

10/11 4/4 1/1


A B C0%

20%

40%

60%

80%

100%92% 94%

56%

ALLY-1 Study: SVR 12 by Child-Pugh Class and by Albumin Level

By Child-Pugh Class By Albumin Level

11/12 30/32 9/16

>3.5 2.8 to 3.5 <2.80%

20%

40%

60%

80%

100%91%

97%

56%

10/11 30/31 10/18


ALLY-1 Study: Authors' Conclusions

SVR12 achieved by 94% of liver transplant recipients with HCV recurrence

SVR12 in 92%, 94% & 56% of patients with Child-Pugh class A, B & C cirrhosis, respectively

High SVR rates in GT-3 patients; 83% in advanced cirrhosis, 91% post-transplant

Patients who had treatment interrupted for liver transplantation achieved SVR12 after post-transplant treatment extension for 12 weeks


Ledipasvir/Sofosbuvir with Ribavirin is Safe and Efficacious in Decompensated and Post Liver Transplantation Patients with HCV Infection: Preliminary Results of the Prospective SOLAR 2 Trial

Manns M, et al: Oral Presentation, EASL 2015.

SOLAR 2 Study Design

• Objective: To evaluate safety and efficacy of LDV/SOF + RBV for 12 or 24 weeks in HCV GT 1 (n=291) or GT 4 (n=37) decompensated cirrhosis and/or recurrent HCV post-transplantation

• Primary efficacy endpoint: SVR12• N = 329

Adapted from Manns M, et al. Presented at EASL 2015; Oral presentation #G02.

Pre-Transplant

SVR12

SVR12

Wk 0 Wk 12 Wk 24 Wk 36

Post-Transplant

CPT B/C (7-12)

Fibrosis (F0-F3)

CPT A (5-6)

CPT B/C (7-12)

FCH

LDV/SOF + RBV

LDV/SOF + RBV

SOLAR 2 Primary Endpoint Results (SVR12)

SOLAR 2 Study


F0-F3 & CPT A Post-Transplant

CPT B & C Pre and Post0%

20%

40%

60%

80%

100%95%

85%

98%88%

12 Weeks 24 Weeks

SVR1

2 (%

)

LDV/SOF + RBV

27 subjects in the 24 week arm have not reached SVR12.7 subjects who were transplanted and 3 subjects did not meet inclusion criteria are excluded.

Error bars represents 2-sided exact 90% confidence intervals.

SOLAR 2: Primary Endpoint Results(SVR12) by Subgroup

Pre-transplant

CPT B CPT C0%

20%

40%

60%

80%

100%87% 85%

96%

72%

12 weeks 24 weeks

Post-transplant

20/23 17/2022/23 13/18

CPT B CPT C0%

20%

40%

60%

80%

100% 95%

50%

100%

75%

12 weeks 24 weeks

19/20 1/216/16 3/4


SOLAR 2 Study:Authors' Conclusions


LDV/SOF + RBV resulted in high SVR12 rates in HCV patients with advanced liver disease, irrespective of transplantation status

For genotype 1 patients, no difference in SVR12 rates between 12 and 24 weeks

Too few genotype 4 patients for meaningful comparisons Among patients with cirrhosis, virologic responce was associated

with improvements in MELD and CPT scores largely due to decreases in bilirubin and improvement in synthetic function (eg, albumin)

LDV/SOF + RBV for 12-24 weeks was generally safe and well tolerated in patients with advanced liver disease, pre and post liver transplantation


In studies investigating DAA combinations for patients with advanced cirrhosis / post transplant (e.g., ALLY-1, SOLAR 2):– Patients with Child-Pugh C status have considerably

lower cure rates– Low albumin(<2.8 g) seems to be the best single laboratory

predictor of treatment failure– At this time, we do not know how to predict which patients

with decompensated cirrhosis will improve on treatment and which will get worse

– This is a topic for future research, to determine who gets DAAs and who should be transplanted

Commentary on: Poordad F, et al. Presented at EASL 2015; Oral presentation #L08; and

Manns M, et al. Presented at EASL 2015; Oral presentation #G02.

Sofosbuvir-based Antiviral Therapy is Highly Effective in Recurrent Hepatitis C in Liver Transplant Recipients: A "Real-life" Canadian Multicenter Experience

Faisal N, et al. Poster presented at EASL 2015.

Sofosbuvir-based Therapy for Recurrent HCV in Liver Transplant Recipients:

"Real-life" Canadian Experience

Prospective, observational study

120 patients from outside of clinical trials– 73 with complete

12 weeks follow-up Primary endpoint:

SVR 12

Adapted from Faisal N, et al. Presented at EASL 2015; Poster #P0059.

30%

21%

44%

5%

Treatment Regimens

SOF+RBV SOF+PEG+RBV SOF+SIM±RBV SOF+LED

SVR12 Rates in Liver Transplant Recipients in the "Real-life" Canadian Experience

All GT1* GT1a GT1b GT2 GT3 GT40%

20%

40%

60%

80%

100%93% 92% 92%

100%

80%

100%

75%

68/73 11/12 25/27 20/20 4/5 5/5 3/4

* Subtype unspecifiedAdapted from Faisal N, et al. Presented at EASL 2015; Poster #P0059.

SVR12 Rates by Previous Treatment in the "Real-life" Canadian Experience

100

80

60

40

20

0

SVR1

2, %

of p

atien

ts

Overall SOF + RBV SOF + SIM± RBV

SOF + PEG+ RBV

Sofosbuvir-based Therapy for Liver Transplant Recipients: Conclusions

from the "Real-life" Canadian Experience

High overall efficacy (>90%), including cirrhotic patients

SVR rates were comparable with respect to age, gender, cirrhosis and HCV RNA

Sofosbuvir-based antiviral therapy for HCV recurrence after liver transplant is well tolerated

Adapted from Faisal N, et al. Presented at EASL 2015; Poster #P0059.


The data from this Canadian real-life study1 are similar to real-life data from a French observational study presented at EASL 20152

However, not all studies have been similar: a real-life study from the United States showed lower eradication rates with simeprevir + sofosbuvir (71%)3

Commentary on:1. Faisal N, et al. Presented at EASL 2015; Poster #P0059.

2. De Ledinghen V, et al. Presented at EASL 2015; Poster #P0795.3. Te H, et al. Presented at EASL 2015; Oral Presentation #O110.

Sofosbuvir + PegInterferon / Ribavirin for 12 Weeks vs. Sofosbuvir + Ribavirin for 16 or 24 Weeks in Genotype 3 HCV Infected Patients and Treatment-experienced Cirrhotic Patients with Genotype 2 HCV: The BOSON Study

Foster GR, et al. Oral Presentation, EASL 2015.

BOSON Study Design

Populations selected, enriched to be difficult-to-treat– GT2: treatment-experienced with cirrhosis – GT3: with cirrhosis (treatment-experienced or naive)– Overall: 92% GT3; >50% were treatment-experienced,

37% had cirrhosis Primary endpoint: SVR12

Adapted from Foster GR, et al. Presented at EASL 2015; Oral presentation #L05.

n=196 SVR12

Wk 0 Wk 12 Wk 16 Wk 36

SOF + RBV

Wk 24 Wk 28

SVR12

SVR12n=199

n=197

SOF + RBV

SOF + PEG/RBV

BOSON Study:SVR12 by Genotype

GT2 GT30%

20%

40%

60%

80%

100%

87%

71%

100%

84%

94% 93%

SOF + RBV 16 wks SOF + RBV 24 wks SOF + PEG/RBV 12 wks

13/15 15/1617/17 128/181 168/181153/182


BOSON Study: SVR12 in GT3 Subgroups, by Treatment

No cirrhosis Cirrhosis Treatment-naive Treatment-experienced0%

20%

40%

60%

80%

100%

80%

51%

77%

64%

87%79%

88%80%

95%88%

95%91%

SOF + RBV 16 wks SOF + RBV 24 wks SOF + PEG/RBV 12 wks

99/124

109/126

117/123 29/57 44/56 51/58 70/91 83/94 89/94 58/90 70/88 79/87


BOSON Study: Safety Summary


Patients

SOF + RBV16 weeks

n=196

SOF + RBV24 weeks

n=199

SOF + RBV12 weeks

n=197

Overall Safety

Aes 185 (94) 188 (95) 195 (99)

Grade 3-4 AE 11 (6) 7 (4) 15(8)

Serious AE 8 (4) 10 (5) 12 (6)

Treatment D/C due to AE 3 (2) 2 (1) 1 (<1)

Death 0 0 0

Laboratory Abnormalities

Grade 3-4 30 (15) 29 (15) 74 (38)

Hb <10 g/dL 7 (4) 12 (6) 24 (12)

Hb <8.5 g/dL 0 0 2 (1)

Platelets <50,000/mm3

BOSON Study: Authors' Conclusions

Treatment-experienced HCV GT 2 patients with cirrhosis: High SVR 12 rates with all regimens

GT3 patients:– Higher SVR12 rates with SOF + PEG/RBV than with

SOF + RBV for 16 or 24 weeks– SOF + RBV for 16 or 24 weeks and SOF + PEG/RBV

for 12 weeks were well tolerated, with low rate of treatment discontinuations due to AEs



SOF + PEG/RBV for 12 weeks is more efficacious than sofosbuvir + RBV alone for 16 or 24 weeks

The SOF + PEG/RBV regimen may not be available for this indication in all jurisdictions– However, hopefully it could be made available to clinicians

and their patients across Canada– For those patients who can tolerate interferon, this should

be considered an option until we have a readily available, all-oral regimen that can match these cure rates

Commentary on Foster GR, et al. Presented at EASL 2015; Oral presentation #L05.

C-SALVAGE: Grazoprevir (GZR; MK-5172), Elbasvir (EBR; MK-8742) and Ribavirin (RBV) for Chronic HCV-Genotype 1 (GT1) Infection After Failure of Direct-acting Antiviral (DAA) Therapy

Forns X, et al. Oral Presentation, EASL 2015.

C-SALVAGE Study Design

Objective: To evaluate grazoprevir + elbasvir + RBV in HCV GT 1-infected patients who had failed prior DAA-based therapy (boceprevir, simeprevir or telaprevir)

Primary endpoint: SVR12 N=79

Adapted from Forns X, et al. Presented at EASL 2015; Oral presentation #O001.

D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW16 FUW20 FUW24

Follow-upN = 79

1° Endpoint:SVR12

GZR 100 mg + EBR 50 mg + RBV

C-SALVAGE: Primary Endpoint Results (SVR12)


13/1363/6676/79

All Patients Prior virologicfailure

Prior non- virologic failure

Resp

onse

rate

, % [9

5% C

I]

0

25

75

100

50

96.2%[89.3, 99.2]

95.5%[87.3, 99.1]

100%[75.3, 100.0]

C-SALVAGE: Authors' Conclusion

Grazoprevir + elbasvir + RBV x 12 weeks provides a promising novel treatment option for treatment-experienced patients after failure of triple therapy with PEG/RBV and an earlier generation PI



In this study, patients with prior treatment with a first-generation PI could be salvaged with the grazoprevir + elbasvir + RBV 12-week regimen, irrespective of which PI had been used previously

These are encouraging data and seem to indicate that these patients will not be a difficult-to-treat subgroup of patients with HCV


Retreatment of Patients Who Failed 8 or 12 Weeks of Ledipasvir / Sofosbuvir-based Regimens with Ledipasvir / Sofosbuvir for 24 Weeks

Lawitz E, et al. Oral Presentation, EASL 2015.

Retreatment of LDV/SOF Failures: Study Design

GT1 patients previously treated with 8 or 12 weeks of LDV/SOF (N=41)– 46% with cirrhosis

Primary endpoint: SVR12

Adapted from Lawitz E, et al. Presented at EASL 2015; Oral presentation #O005.

98% SVR121

Wk 0 Wk 12 Wk 36

LDV/SOF + RBV

Wk 24

SVR12

SVR12

SOF failures(advanced liver disease)

LDV/SOF

LDV/SOF + RBV

LDV/SOF failures(n = 41)

SOF failures(n = 51)

Retreatment of LDV/SOF Failures: Primary Endpoint (SVR12)

Overall No Yes 8 wks 12 wks No Yes0%

20%

40%

60%

80%

100%

71% 68%74%

80%

46%

100%

60%

Cirrhosis Prior Tx duration

29/41 15/22 14/19 5/1124/30

Baseline RAVs?

18/3011/11


Q30R or M28T L31M Y93H/N0%

20%

40%

60%

80%

100%100%

80%

33%

Retreatment of LDV/SOF Failures: SVR12 by Baseline RAVs

Number of NS5A RAV(s)

None 1 ≥20%

20%

40%

60%

80%

100%100%

69%

50%

Type of Single NS5A RAV

11/11 11/16 7/14 5/5 2/64/5


Retreatment of LDV/SOF Failures: Authors' Conclusions


71% of patients who failed prior LDV/SOF-containing regimens achieved SVR12 when retreated with LDV/SOF for 24 weeks

The presence of baseline NS5A RAV(s), which was more likely to develop with longer prior LDV/SOF treatment, was associated with virologic failure

Emergence of S282T was observed in 3 of 12 virologic failure patients

Retreatment with LDV/SOF is feasible in patients who have failed prior LDV/SOF-based regimens


This and other studies have shown that a patient who fails DAA treatment will have RAVs– The particular variants and number

may not always be known This raises an important question: Should we be

screening for baseline RAVs in patients with HCV?– At present, this is impractical, but it may be something

we have to consider as the DAA era moves forward, especially among patients who fail new-generation DAAs

The question of whether or not to use ribavirin in this retreatment regimen remains to be answered


Safety of Ombitasvir / Paritaprevir / Ritonavir Plus Dasabuvir for Treating HCV GT1 Infection in Patients with Severe Renal Impairment or End-stage Renal Disease: The RUBY-1 Study

Pockros PJ, et al. Oral Presentation, EASL 2015.

RUBY-1: Study Design

Multicenter, open-label, phase 3b study 3D: Co-formulated OBV/PTV/r + DSV

– Could be given before or after dialysis, at investigator discretion Ribavirin dose: 200 mg daily, given 4 hours before dialysis 20 GT 1 patients enrolled – interim analysis

– 13/20 on dialysis– No cirrhosis– 4 patients have completed treatment

Adapted from Pockros PJ, et al. Presented at EASL 2015; Oral presentation #L01.

GT1b

Week 24Week 12Day 1

GT1a

3D

3D + RBV

Open-label Treatment SVR4 SVR12

RUBY-1: Interim Analysis,Adverse Events to Date

AE

n

GT1b3D (n=7)

GT1a 3D + RBV

(n=13)

Anemia 0 8

Fatigue 2 4

Diarrhea 1 4

Nausea 0 5

Dizziness 1 2

Headache 0 3

↓Appetite 0 2

Irritability 0 2

Peripheral edema 1 1

↓ Weight 0 2

8/13 patients interrupted RBV while on treatment– 1 patient had

hemoglobin <8 g/dL– No patient had a

transfusion– Of the 8 who interrupted

RBV, 4 started EPO


RUBY-1: Interim Analysis,Antiviral Efficacy to Date

Timepoint NVirologic Response

n %

End of treatment 14 14/14 100%

Post-treatment week 4 10 10/10 100%

Post-treatment week 12 2 2 100%

Authors' conclusions: • 3D has been well tolerated in GT1-infected patients with advanced renal disease,

including those on hemodialysis, with or without RBV• Hemoglobin reductions were managed with monitoring and RBV dose interruption• There have been no virologic failures to date



This is some of the earliest reliable data on the use of DAA ± RBV among patients with advanced renal disease, a relatively common comorbidity in patients with HCV

This study suggests that these patients can be successfully treated, but that on-treatment monitoring is essential and adjustments of the regimen may be necessary

Although the efficacy data appear promising, these are interim data

Commentary on Pockros PJ, et al. Presented at EASL 2015; Oral presentation #L01.

A Single Tablet Regimen of Ledipasvir/Sofosbuvir for 12 Weeks in HCV Genotype 1 or 4 Infected Patients with HIV-1 Co-infection: The Phase 3 ION-4 Study

Cooper C, et al. Poster presented at EASL 2015.

ION-4: Study Design

Phase 3, multicenter, open-label study HCV genotype 1 or 4 (98% GT 1)

– 20% with cirrhosis– HCV Treatment-naive or experienced

HIV-1 co-infection– ART regimens included emtricitabine (FTC) and tenofovir

disoproxil fumarate (TDF) + efavirenz, raltegravir or rilpivirine Primary endpoint: SVR12

Adapted from Cooper C, et al. Presented at EASL 2015; Poster #P1353.

Week

SVR12LDV/SOFN = 335

0 12 24

ION-4 Primary Endpoint: SVR12

No significant difference in SVR12 between GT 1a and 1b In multivariate analysis, black race (90% SVR) was the only

subgroup with significantly lower SVR 12Adapted from Cooper C, et al. Presented at EASL 2015; Poster #P1353.

179/185142/150321/335

LDV/SOF 12 Weeks Naïve Experienced

SVR1

2 (%

)*

0

20

60

100

40

96 95 97

80

No Cirrhosis Cirrhosis

96 94

Overall HCV Treatment History Cirrhosis Status

63/67258/268

ION-4 Study: Authors' Conclusions

In this phase 3 study of 335 HIV/HCV-coinfected patients, 96% achieved SVR12 after 12 weeks of a once-daily, single-tablet regimen of LDV/SOF– Prior HCV treatment status or presence of cirrhosis

did not impact outcomes– In contrast to larger studies of HCV mono-infected

patients, a significantly lower SVR12 rate was observed in coinfected black patient treated with LDV/SOF

LDV/SOF was well tolerated, with no treatment discontinuations due to AEs and no adverse impact on HIV or its treatment

Adapted from Cooper C, et al. Presented at EASL 2015; Poster #P1353.

Other Coinfection Studiesat EASL 2015

Sofosbuvir + daclatasvir (ALLY-2) (N=203)1

12 weeks 8 weeks 12 weeks0%

20%

40%

60%

80%

100% 97.0%

76.0%

98.1%

Grazoprevir + elbasvir(C-EDGE) (n=218)2

GT1a GT1b GT40%

20%

40%

60%

80%

100% 94.4% 95.5% 96.4%

Adapted from1. Levin J, et al. Presented at EASL 2015; Poster #P1353.

2. Rockstroh JK, et al. Presented at EASL 2015; Poster #P0887.

Treatment-naive Treatment-experienced


The results from the ION-4 study, together with other studies of DAA combinations presented at EASL 2015, show that: – SVR12 rates are very high (>95%), comparable

to patients without HIV co-infection– For co-infected patients, it seems a 12-week regimen

is most appropriate– Co-infection should not be considered

a difficult-to-treat population in terms of HCV cure

Commentary on: Cooper C, et al. Presented at EASL 2015; Poster #P1353.

Levin J, et al. Presented at EASL 2015; Poster #P1353.Rockstroh JK, et al. Presented at EASL 2015; Poster #P0887.

Real-life Data in Genotype 3

Sofosbuvir-based Regimens in GT-3 and GT-4 Patients ± Cirrhosis in a Real-World Setting (HCV-TARGET

Study)

GT-3 cohort (N=247)– SOF/PEG/RBV (N=21)

• 62% treatment-experienced

• 57% cirrhotic (median MELD=8.0)

– SOF/RBV (N=226)• 45% TE• 52% cirrhotic (median

MELD=10.0)

Adapted from Alqahtani S, et al. Presented at EASL 2015; Poster #P0840.

SOF + PegIFN + RBV SOF + RBV0%

20%

40%

60%

80%

100%89%

65%

30% relapse

12 weeks 24 weeks

16/18 87/133

Sofosbuvir + NS5A Inhibitor for GT-3 with Decompensated Cirrhosis:

Real-life Data from a UK Early Access Program

N=467 patients with decompensated cirrhosis– GT1 (n=235), GT3 (n=189)

or other (n=43)– CTP score ≥7

Treated with sofosbuvir + ledipasvir or daclatasvir ± RBV (clinicians' choice)– Early access program in

England

Adapted from Foster GR, et al. Presented at EASL 2015; Oral presentation #O002.

SOF + LDV SOF + LDV + RBV

SOF + DCV SOF + DCV + RBV

0%

20%

40%

60%

80%

100%

59%

43%

70% 71%

SVR12 Results in GT3 (n=189)

5/73/7 80/11436/61

Sofosbuvir + Daclatasvir for GT-3 Patients: Preliminary Real-life Data from a French Multicenter

Compassionate Use Program

N=601 GT-3 patients– 77% cirrhotic– 73% treatment-

experienced Treated with sofosbuvir

+ daclatasvir for 12 or 24 weeks– Duration at physicians'

discretion

Adapted from Hezode C, et al. Presented at EASL 2015; Poster #LP05.

Cirrhotic patients Non-cirrhotic patients0%

20%

40%

60%

80%

100%

76%

92%88%

83%

SVR4 Results

12 weeks 24 weeks

5/611/1252/5922/29

Studies InvestigatingResistance-associated Variants

Long-term Follow-up of Treatment-emergent Resistance-associated Variants in NS3, NS5A and NS5B with Paritaprevir/R-, Ombitasvir- and Dasabuvir-based Regimens

Krishnan P, et al. Oral Presentation, EASL 2015.

Follow-up of Treatment Emergent RAVs After 3D Treatment (Paritaprevir/RTV, Ombitasvir,

Dasabuvir ± RBV)

Objective: To evaluate persistence of treatment-emergent RAVs (TEVs) in NS3, NS5A or NS5B through post-treatment weeks 24 and 48 following DAA therapy– Pooled data from phase 2 & 3 studies

Analysis methods:– Population sequencing of NS3/4A, NS5A & NS5B– Clonal sequencing conducted if TEVs not detected

by population sequencing

Adapted from Krishnan P, et al. Presented at EASL 2015; Oral Presentation #0057.

TEVs at Post-Treatment Week 48 in GT1a-infected Patients

TEVs in NS3 declined: detectable in 9% of patients at post-treatment week 48 (PTW48)

TEVs in NS5A persisted through PTW48 TEVs in NS5B generally persisted through PTW48


3-Targets NS3 + NS5A NS5A + NS5B NS5A NS5B0

20

40

60

80

100

Post-Treatment Week 48

% o

f GT1

a-in

fect

ed

Patie

nts

with

TEV

s

1/43 2/43

14/4320/43

3/43

Follow-up of Treatment Emergent RAVs After 3D Treatment: Authors' Conclusions


Virologic failure was uncommon in the development of 3D ± RBV.

Persistence of TEVs varies by DAA target TEVs in NS3 declined and detectable in only 9% of the patients at PTW48.

The main TEVs selected by PTV, at D168, were detected in only 2 patients (4%) at PTW48

TEVs in NS5A persisted through PTW48, consistent with the date for other NS5A inhibitors

TEVs in NS5B generally persisted through PTW48. TEVs selected by DSV are not cross-resistant to other available NS5B inhibitors (sofosbuvir) or Nucs/NNPIs in late development

Trent in persistence for GT1b could not be determinated due to the small number of failures

Ongoing studies are evaluating the long-term persistence of these variants, as well as re-treatment options

Long-term Persistence of HCV NS5A Variants After Treatment with NS5A Inhibitor Ledipasvir

Wyles D, et al. Oral Presentation, EASL 2015.

Persistence of RAVs After Ledipasvir Treatment: Study Design

Patients who did not achieve SVR in studies of regimens including LDV but not SOF were enrolled in a 3-year registry study

Deep sequencing was used for all samples

Adapted from Wyles D, et al. Presented at EASL 2015; Oral Presentation #0059.

LDV + VDV + TGV + RBV

(n = 50)

LDV ± VDV ± TGV + PEG + RBV (n = 26) Plasma samples for sequence analysis

BL FU-12 FU-24 FU-36 FU-48 FU-96

Sequence Registry Study

Persistence of RAVs Over 96 Weeks After Ledipasvir Treatment: Primary Findings

Proportion with any NS5A RAV persisting post treatment

VF parent study Baseline FU-12 FU-24 FU-48 FU-960%

20%

40%

60%

80%

100% 98% 100% 98% 100% 95%86%

Registry study

Adapted from Wyles D, et al. Presented at EASL 2015; Oral Presentation #O059.

0 RAVs 1 RAV 2 RAVs ≥3 RAVs

Registry baseline 0 16% 22% 62%

96 weeks post treatment 14% 19% 33% 34%

Persistence of RAVs After Ledipasvir Treatment: Authors' Conclusions

Patients who failed treatment with LDV-containing regimens without SOF had a high prevalence of NS5A RAVs at virologic failure

NS5A RAVs persisted in >95% of patients through week 48 and in 86% through week 96– L31 and H58 RAVs most likely to persist– A decline in the number of RAVs per patient was observed– Decrease in overall NS5A RAVs viral population through

follow-up week 96 Optimum retreatment regimen requires investigation

Adapted from Wyles D, et al. Presented at EASL 2015; Oral Presentation #O059.


Data up to 96 weeks post-therapy in treatment failures suggest that:– RAVs in NS5A tend to persist– RAVs in NS5B are somewhat less persistent– RAVs in NS3A are much less persistent– Not all RAVs are created equal, in terms of impact

on treatment The presence of RAVs may impact future options Bear in mind that different studies use different

thresholds for definition of RAVsCommentary on:

Krishnan P, et al. Presented at EASL 2015; Oral Presentation #O057.Wyles D, et al. Presented at EASL 2015; Oral Presentation #O059.

Studies EvaluatingDAA Treatment Durations

C-SWIFT: Grazoprevir / elbasvir + Sofosbuvir in Cirrhotic and Noncirrhotic, Treatment-naive Patients with Hepatitis C Virus Genotype 1 Infection, for Durations of 4, 6 or 8 Weeks and Genotype 3 Infection for Durations of 8 or 12 Weeks

Poordad F, et al. Oral Presentation, EASL 2015.

C-SWIFT: Grazoprevir/Elbasvir + Sofosbuvir in Treatment-naive GT 1

and GT 3 – Study Design

Adapted from Poordad F, et al. Presented at EASL 2015; Oral Presentation #O006.

Gen

otyp

e 3

D1

SVR12*:Primary

EndPoint

TW4 TW6 TW8 TW12 SVR4 SVR8 SVR12

Gen

otyp

e 1

4 wk; n = 31Non-

cirrhotic

Cirrhotic

Non-cirrhotic

Cirrhotic

*SVR12 = Primary End Point (HCV RNA < 15 IU/mL), COBAS TaqMan v2.0

12 wk; n = 12

12 wk; n = 14

8 wk; n = 15

8 wk; n = 21

6 wk; n = 20

6 wk; n = 30

C-SWIFT: Primary Endpoint (SVR12)

Genotype 1

4 wks 6 wks 6 wks 8 wks0%

20%

40%

60%

80%

100%

33%

87%80%

94%

Genotype 3

Non-cirrhotic Cirrhotic

8 wks 12 wks 12 wks0%

20%

40%

60%

80%

100% 93%100%

91%

Non-cirrhotic Cirrhotic

10/30 26/30 16/20 17/18 14/15 14/14 10/11


C-SWIFT: Authors' Conclusions


A novel regimen of grazoprevir/elbasvir with sofosbuvir was able to shorten treatment duration to 8 weeks or less among cirrhotic and non-cirrhotic HCV Genotype 1-infected patients

Genotype 3 patients achieved high SVR12 rates with 8-12 weeks of therapy, including patients with cirrhosis

All virologic failures were due to relapse Patients relapsed most commonly with either wild-type

virus or with RAVs already present at baseline A regimen of grazoprevir/elbasvir with sofosbuvir

was generally safe and well tolerated


This important proof-of-concept study clearly shows that four weeks is not an optimal duration for this DAA regimen (33% SVR12)

The results suggest that an 8-week regimen for cirrhotic patients with GT1 and a 12-week regimen for cirrhotic patients with GT3 may be sufficient

Patients undergoing shorter durations of therapy are less prone to developing RAVs– The mechanisms of failure may be different with short- vs.

longer duration DAA therapy

Commentary on Poordad F, et al. Presented at EASL 2015; Oral Presentation #O006.

Study EvaluatingNovel Treatment for HCV

A Single Subcutaneous dose of 2 mg/kg or 4 mg/kg of RG-101, a GalNAc-conjugated Oligonucleotide with Antagonist Activity Against MIR-122, Results in Significant Viral Load Reductions in Chronic Hepatitis C Patients

Van Der Ree M, et al. Oral Presentation, EASL 2015.

RG-101: Single-dose MIR-122 Antagonist for HCV Infection

Multicenter, phase 1 study in 32 patients with HCV– GT 1, 3 and 4– Treatment-naive or –experienced– None with cirrhosis

RG-101 administered as single s.c. injection

Adapted from Van Der Ree M, et al. Presented at EASL 2015; Oral Presentation #L07.

D1 W1 W2 W3 W4 W5 W8

RG-101 study

Single s.c.dose RG-101

Randomizedn = 32

2 mg/kgn = 16

4 mg/kgn = 16

RG-101n = 14

Placebon = 2

RG-101n = 14

Placebon = 2

HCV RNA Levels During Extended Follow-up After Single RG-101 Dose


Single Dose of RG-101 for HCV Infection: Authors' Conclusions


Original study Single dose RG-101 was safe and well tolerated in HCV patients AE’s were generally mild and transient; no SAE and discontinuations Pharmacokinetic profile in HCV patients was similar to healthy volunteers 15/28 (54%) patients had HCV RNA levels BLOQ 8 weeks after RG-101 dosing Viral load reductions observed in HCV genotype 1, 3 and 4 patients

Extended follow-up 7 patients had HCV RNA levels BLOQ 20 weeks after RG-101 dosing Follow-up is extended to 1 year to assess if viral cure can be established

Future plans Phase II studies to combine RG-101 with direct acting antivirals Investigation of multiple doses as monotherapy in certain patient populations


This is an early-phase study of this novel approach to HCV treatment

Should future studies show that this therapy is safe and effective, it could be a useful adjunct to DAA therapy– Might be helpful in combination to help shorten

the required duration of DAA therapy– The single s.c. dosing makes it appealing in terms

of adherence

Commentary on Van Der Ree M, et al. Presented at EASL 2015; Oral Presentation #L07.

Sustainabilityof HCV Cure

Low Incidence of Reinfection with Hepatitis C Virus After Successful Treatment in Montreal

Machouf N, et al. Oral Presentation, EASL 2015.

Reinfection After HCV Cure: Montreal's Experience1

338 men cured from HCV infection 77% men, mean age 46 years Median follow-up 2.7 years (1175 patient-years)

Reinfection Rates Over Timen/N %

1 year 2/265 1%

2 years 8/210 4%

3 years 11/169 7%

4 years 10/123 8%

5 years 10/88 11%

Risk factor Incidence / 100 pt-years p

Non-IDU 0.43

0.056IDU in remission 1.90

Active IDU 3.60

Reinfection Rates by IDU Status

Also at EASL 2015:A Norwegian study with 7-year follow-up reported similar rates of re-infection.2

Adapted from EASL 2015 presentations: 1. Machouf N, et al. Poster #P1250.; and 2. Midgard H, et al. Oral Presentation #O061.


Re-infection after HCV cure is a concern among individuals who re-engage in risky behaviour (e.g., IDU)

These studies were performed among patients who were treated with interferon-based regimens; these are often highly motivated patients– The landscape of re-infection may change in light

of the ease of use and tolerability of newer DAAs Counseling on risk of re-infection needs to be an

important component of the treatment processCommentary on:

Machouf N, et al. Presented at EASL 2015; Poster #P1250 and Midgard H, et al. Presented at EASL 2015; Oral Presentation #O061.

Documents

Highlights of New Developments in HCV Treatment from EASL 2015 April 22-25 Vienna, Austria