post conference hcv update 49 th annual meeting of the european association for the study of the...
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Post Conference HCV Update
49th Annual Meeting of the European Association for the Study of the Liver
Supported by an independent educational grant from Gilead Sciences Medical Affairs
Co-provided for CME/CE credit by theUniversity of Nebraska Medical Center
and Practice Point Communications
Simply Speaking® Hepatitis “Post Conference HCV Update: 49th Annual Meeting of the European Association for the Study of the Liver” isCopyrighted 2014 by Practice Point Communications, unless otherwise noted. All rights reserved.
2
Content Development & Training Faculty
Tram Tran, MDMedical Director, Liver Transplantation
Cedars-Sinai Medical CenterHepatology and Liver TransplantAssociate Professor of Medicine
UCLA School of MedicineLos Angeles, CA
● Disclosures- Grants/Research Support: Bristol-Myers Squibb
- Consultant: Bristol-Myers Squibb, Enanta, Gilead Sciences
- Speakers’ Bureau: None
- Stock Shareholder: None
- Other Financial or Material Support: None
3
Learning Objectives(CME/CNE/CPE)
● Upon completion of this educational activity, participants should be able to:- Screen for hepatitis C virus (HCV) infection according to the
recommendations from the American Association for the Study of Liver Diseases (AASLD) and the Centers for Disease Control and Prevention (CDC)
- Appropriately select antiviral HCV treatment strategies according to the recommendations from the AASLD/IDSA guidelines
- Manage safety and tolerability problems with antiviral HCV agents, including side effect, drug-drug interactions, and resistance
- Evaluate new agents being investigated for HCV therapy to optimize information-based decision making about therapy
4
Program Overview
● HCV epidemiology and public health considerations
● Interferon-free regimens for HCV
- Treatment-naïve patients
- Treatment-experienced patients
- Retreatment for prior DAA failures
- Difficult-to-cure and liver transplant patients
- HCV/HIV coinfection
5
Global Burden of Disease Study 2010:Causes of Death From Chronic Liver Disease
● In 2010, HIV-related mortality in the EU/EFTA countries never reached those of HCV or HBV
● HCV is the predominant cause of death due to blood-borne viruses in the EU/EFTA
- Approximately 10 times to that of HIV/AIDS
- Greater than HBV and HIV combined
● Majority of HCV-related mortality due to cirrhosis
Cowie BC, et al. J Hepatol. 2014;60(suppl 1):S35-S36. Abstract O86.
Dea
ths
(nu
mb
er)
EU/EFTA (2010)
HCV HBV HIV
2010 Global deaths: HIV (1.47 million), HCV and HBV (1.29 million).
6
Impact of Comorbid Conditions on HCV Treatment Decisions (2002-2012)
● Retrospective cohort study (Kaiser Permanente Southern California) (n=32,283 HCV patients with prescription benefits)
- Received HCV therapy (17%)
• PegIFN + RBV + telaprevir or boceprevir
● Comorbid conditions (relative or absolute contraindications to IFN-based therapy): 50%
- 15% of these patients were treated
● Factors significantly associated with receiving therapy (P<0.01)
- Younger age (<45 versus >65 years and 45-65 versus >65 years), male gender, presence of cirrhosis, HIV coinfection, NAFLD/NASH, depression, prior liver transplant
Nyberg LM, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O67.
AdjustedOdd Ratio
Anemia 0.32*
Autoimmune disorder 0.78†
Renal dysfunction 0.66†
Cardiovascular disease 0.60*
Psychosis/bipolar 0.68†
Severe lung disease 0.56*
Substance abuse 0.54*
MELD >12 0.39*
Factors Associated With Not Achieving HCV Therapy
*P<0.0001 and †P<0.01.
7
Program Overview
● HCV epidemiology and public health considerations
● Interferon-free regimens for HCV
- Treatment-naïve patients
- Treatment-experienced patients
- Retreatment for prior DAA failures
- Difficult-to-cure and liver transplant patients
- HCV/HIV coinfection
8
Sofosbuvir-Based Regimens in Treatment-Naïve Patients
● Sofosbuvir/ledipasvir + RBV
- ION-1 (12 versus 24 weeks)
- ION-3 (8 versus 12 weeks)
● Sofosbuvir long-term, follow-up registries
● Sofosbuvir + GS-5816
9
ION-1: Sofosbuvir/Ledipasvir + RBV in Treatment-Naïve, HCV Genotype 1
Afdhal N, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].
Sofosbuvir/Ledipasvir qd(n=214)
Phase 3Open-label, randomizedGenotype 1Treatment-naïveTarget 20% cirrhoticsNo upper age or BMI criteriaPlatelets >50K/mm3
No neutrophil minimum
Week 0 12 24
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor)/ledipasvir 90 mg (NS5A inhibitor) + RBV (1000-1200 mg).Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 55% to 64%. Age: 52-53 years. Black: 11%-15%. Genotype 1a: 66%-68%. IL28B non-CC: 64% to 76%. HCV RNA (log10 IU/mL): 6.3-6.4. HCV RNA >800K IU/mL: 77%-80%.
Sofosbuvir/Ledipasvir qd+ RBV (n=217)
Sofosbuvir/Ledipasvir qd(n=217)
Sofosbuvir/Ledipasvir qd+ RBV (n=217)
10
ION-1: SVR12 Rates With Sofosbuvir/Ledipasvir+ RBV in Treatment-Naïve, HCV Genotype 1
Overall No cirrhosis Cirrhosis
SV
R12
(%
)
99% 97%100% 100% 100%100%
12-Week Arm
No RBV(n=214/179/33)
RBV(n=217/178/33)
Sofosbuvir/Ledipasvir qd
Overall No cirrhosis Cirrhosis
SV
R12
(%
)
99% 97%99% 100% 100%100%
24-Week Arm
No RBV(n=217/182/32)
RBV(n=217/179/36)
Sofosbuvir/Ledipasvir qd
Afdhal N, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].
11
ION-1: Non-SVR12 Achievers, Resistance, and Safety Results
● Non-SVR12 achievers
- Virologic breakthrough (n=1 due to noncompliance)
- Relapse
• 12-week arm (n=1)
• 24-week arm (n=1)
● No S282T detected at baseline or at time of virologic failure
● Higher incidence of adverse events and laboratory abnormalities in the RBV-containing arms
- Fatigue, insomnia, asthenia, irritability, rash, cough, pruritus, and anemia
● Adverse events rates were generally higher in the 24-week arm
NoRBV
(n=214)RBV
(n=217)
NoRBV
(n=217)
NoRBV
(n=217)
Adverse events (%) Grade 3/4 Discontinuations
20
60
102
63
Death (number) 0 0 0 0
Laboratory abnormalities (%) Grade 3/4 Hemoglobin <10 g/dL <8.5 g/dL
5
00
10
9<1
10
00
12
70
Safety Summary for Sofosbuvir/Ledipasvir qd
12 Weeks 24 Weeks
Afdhal N, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].
12
ION-3: Sofosbuvir/Ledipasvir + RBV in Treatment-Naïve, HCV Genotype 1
Kowdley KV, et al. N Engl J Med. 2014;April 10. [Epub ahead of print].
Sofosbuvir/Ledipasvir qd(n=215)
Sofosbuvir/Ledipasvir qd(n=216)
Phase 3Open-label, non-inferiorityGenotype 1Treatment-naïveNon-cirrhoticNo upper age or BMI criteriaOpiate substitution allowed
Week 0 8 12 24
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor)/ledipasvir 90 mg (NS5A inhibitor) + RBV (1000-1200 mg).Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 54% to 61%. Age: 51-53 years. Black: 17%-21%. Genotype 1a: 80% IL28B non-CC: 72% to 74%. HCV RNA (log10 IU/mL): 6.4-6.5. HCV RNA >800K IU/mL: 79%-84%.
Sofosbuvir/Ledipasvir qd+ RBV (n=216)
13
ION-3: SVR12 Rates With Sofosbuvir/Ledipasvir+ RBV in Treatment-Naïve, HCV Genotype 1
SV
R12
(%
)
94% 95%
No RBV(n=215)
Sofosbuvir/ledipasvir qd
8 weeks 8 weeks, with RBV 12 weeks
RBV(n=216)
8 Weeks
No RBV(n=216)
93%
*Met non-inferiority criteria (12% margin) for all between group comparisons.
12 Weeks
Overall SVR12*
Sofosbuvir/Ledipasvir qd
SV
R12
(%
)
93% 95%
Genotype 1a(n=171/172/172)
Genotype 1b(n=43/44/44)
92%98% 98%96%
SVR12 by HCV Subtype
Kowdley KV, et al. N Engl J Med. 2014;April 10. [Epub ahead of print].
14
ION-3: SVR12 Rates by Prespecified Subgroups (Treatment-Naïve)
SV
R12
(%
)
97% 96%
<800K(n=34/45/44)
Sofosbuvir/ledipasvir qd
8 weeks 8 weeks, with RBV 12 weeks
96%93% 95%92%
96% 96%95% 93% 95%92% 92%
95%91%
98% 96%96%91%
95%89%
95% 95%94%
>800K(n=181/171/172)
CC(n=56/60/56)
Non-CC(n=159/156/160)
Male(n=130/117/128)
Female(n=85/99/8)
Black(n=45/36/42)
Non-Black(n=170/180/173)
Baseline HCV RNA(IU/mL)
IL28BGenotype
Gender Race
Kowdley KV, et al. N Engl J Med. 2014;April 10. [Epub ahead of print].
15
ION-3: Non-SVR12 Achieversand Safety Results
● Non-SVR12 achievers
- No virologic breakthroughs
- Relapse
• 8-week arm (n=11)
• 8-week (RBV) arm (n=9)
• 12-week arm (n=3)
● Higher incidence of adverse events and laboratory abnormalities in the RBV-containing arms
- Fatigue, headache, nausea, insomnia, irritability, rash, pruritus, and anemia
NoRBV
(n=216)RBV
(n=216)
NoRBV
(n=216)
Adverse events (%) Grade 3/4 Discontinuations
<10
4<1
3<1
Death (number) 0 0 0
Laboratory abnormalities (%) Grade 3/4 Hemoglobin <10 g/dL <8.5 g/dL
3
00
8
50
7
<10
Safety Summary for Sofosbuvir/Ledipasvir qd
8 Weeks12
Weeks
Kowdley KV, et al. N Engl J Med. 2014;April 10. [Epub ahead of print].
16
Long-Term Follow-Up of Sofosbuvir-Treated Patients in Phase 3 Trials
● Long-term follow-up registries (sofosbuvir phase 3 studies)
- SVR registry (achieved SVR24)
- Sequence registry (SVR24 non-achievers)
● SVR24 was durable in all patients in SVR registry after a median follow-up of 170 days
● Grade 3/4 laboratory abnormalities
- Higher incidence among Sequence registry (SVR24 non-achievers)
Cheng W, et al. J Hepatol. 2014;60(suppl 1):S449. Abstract P1112.
SVR24Registry(n=480)
SequenceRegistry(n=116)
Baseline Age (years) Male (%) Black (%) IL28B non-CC (%) Cirrhosis (%) Genotype 1/2/3/4-6 (%)
53598
3517
40/31/25/4
54825
3336
21/7/72/<1
Follow-up (days) 170 204
Outcomes (%) SVR durability Grade 3/4 ALT/AST Grade 3 Albumin Bilirubin Platelets
1000/0
<100
N/A8/8
120
Baseline and Outcomes Data
17
Sofosbuvir + GS-5816 inTreatment-Naïve, HCV Genotypes 1-6
Everson GT, et al. J Hepatol. 2014;60(suppl 1):S46. Abstract O111.
Sofosbuvir + GS-5816 25 mg qd
Phase 2Open-labelTreatment-naïve Genotypes: 1 (n=55) 3 (n=54) 2-6 (n=45)Non-cirrhotic Week 0 12 24
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + GS-5816 (NS5A inhibitor).Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 64%. Age: 50-51 years. Black: 3%-13%. Genotype 1a: 29%. IL28B non-CC: 32%-40%. HCV RNA (log10 IU/mL): 6.4.
Sofosbuvir + GS-5816 100 mg qd
18
Treatment Outcomes With Sofosbuvir +GS-5816 in Treatment-Naïve, HCV Genotypes 1-6
● SVR12 rates >90% in genotypes 1-6
- Presence of pretreatment NS5A variants was not predictive of failure to achieve SVR12
● Non-SVR12 achievers
- Relapse: genotype 1 (n=1), genotype 3 (n=2)
• 2/3 relapsers received GS-5816 25 mg
● Sofosbuvir + GS-5816 was well tolerated
- No discontinuations due to adverse events
- No hemoglobin <10 g/dL
- Grade 3/4
• Adverse events (1.3%)
• Laboratory abnormalities (4.1%)
Pat
ien
ts (
%)
100% 100% 100%
SVR12 Rates
1(n=27/28)
Sofosbuvir + GS-5816 25 mg qdSofosbuvir + GS-5816 100 mg qd
Genotype
Everson GT, et al. J Hepatol. 2014;60(suppl 1):S46. Abstract O111.
100% 100%96%
91% 93%
86%
2(n=11/10)
3(n=27/27)
4(n=7/7)
5(n=1)
6(n=4/5)
19
ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Naïve Patients
● SAPPHIRE-I (genotype 1)
● PEARL-III (genotype 1b)
20
SAPPHIRE-I: ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Naïve, HCV Genotype 1
Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.
3D + RBV(n=473)
Phase 3Double-blindGenotype 1Treatment-naïveNon-cirrhotic18 to 70 years of age
Week 0 12 24
3D: ABT-450 (NS3/4A inhibitor)/r/ombitasvir (NS5A inhibitor) 150/100/25 mg qd; dasabuvir (non-nucleoside NS5B polymerase inhibitor) 250 mg bid. RBV (1000-1200 mg).Primary endpoint: SVR12 versus historical control SVR rate: 78% (telaprevir + pegIFN + RBV).Baseline demographics and disease characteristics: Male: 46% to 57%. Age: 52 years. Black: 5%-6%. Genotype 1a: 67%-68%. IL28B non-CC: 68%-70%. HCV RNA (log10 IU/mL): 6.5-6.6. Fibrosis stage F0-F1: 77%
Placebo(n=158)
3D + RBV
21
SAPPHIRE-I: SVR12 Rates With 3D + RBVin Treatment-Naïve, HCV Genotype 1
● Non-inferiority and superiority criteria met for overall SVR12 and superiority criteria met for SVR rate for genotype 1a and 1b
● SVR12 rates were similar across patient subgroups
- Baseline HCV RNA, IL28B, BMI, fibrosis stage, gender, race
● SVR12 non-achievers
- Virologic breakthrough (n=1)
- Relapse (n=7)
• Genotype 1a
- All had >1 RAV at time of virologic failure
*
SV
R12
(%
)
96% 98%
Overall(n=473)
1a(n=322)
HCV Subtype
1b(n=151)
95%
SVR12Non-inferioritythreshold
Superioritythreshold
Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.
22
SAPPHIRE-I: Safety of 3D + RBVin Treatment-Naïve, HCV Genotype 1
● Most common adverse events associated with 3D + RBV versus placebo (P<0.05)
- Nausea, pruritus, insomnia, diarrhea, asthenia
● Serious adverse events possibly related to 3D + RBV (n=2)
- Patient 1: acute respiratory failure and hypoxia
- Patient 2: abdominal pain, sinus tachycardia, diarrhea, chiles, vomiting, nausea, and ventricular extrasystoles
● RBV dose modification due to adverse events (5.5%)
3D + RBV(n=473)
Adverse events (%) Grade 3/4 Discontinuations
2.10.6
Death (number) 0
Laboratory abnormalities (%) ALT >5x ULN AST >5x ULN Alkaline phosphatase >5x ULN Total bilirubin >3x ULN Hemoglobin <10-8.0 g/dL <8.0 g/dL
0.90.60
2.8
5.80
Safety Summary
Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.
23
PEARL-III: ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Naïve, HCV Genotype 1b
Ferenci P, et al. N Engl J Med. 2014;May 4. [Epub ahead of print].
3D + RBV(n=210)
Phase 3Double-blindGenotype 1bTreatment-naïveNon-cirrhotic18 to 70 years of ageBMI >18-<38 kg/m2
HCV RNA >10K IU/mLWeek 0 12 24
3D: ABT-450 (NS3/4A inhibitor)/r/ombitasvir (NS5A inhibitor) 150/100/25 mg qd; dasabuvir (non-nucleoside NS5B polymerase inhibitor) 250 mg bid. RBV (1000-1200 mg).Primary endpoint: SVR12 versus historical control SVR rate: 73% (telaprevir + pegIFN + RBV).Baseline demographics and disease characteristics: Male: 41% to 51%. Age: 48-49 years. Black: 5%. IL28B non-CC: 79%. HCV RNA (log10 IU/mL): 6.3. HCV RNA >800K IU/mL: 71%-76%. Fibrosis stage F0-F1: 68%-71%.
3D + Placebo(n=209)
24
PEARL-III: SVR12 Rates With 3D + RBVin Treatment-Naïve, HCV Genotype 1b
● Non-inferiority and superiority criteria met versus historical control
● Non-inferiority criteria (10.5% margin) met for 3D + RBV versus 3D without RBV
● SVR12 rates in both arms were similar across patient subgroups
- Baseline HCV RNA, IL28B, fibrosis stage, gender, race
● SVR12 non-achievers
- Virologic breakthrough (n=1)
• Emergent NS5A Y93H at failure
*
SV
R12
(%
)
99%
3D + RBV(n=210)
3D(n=209)
99%
SVR12
Non-inferiority (73%)
Superiority (84%)
Ferenci P, et al. N Engl J Med. 2014;May 4. [Epub ahead of print].
25
PEARL-III: Safety of 3D + RBVin Treatment-Naïve, HCV Genotype 1b
● Higher incidence of adverse events and laboratory abnormalities in the RBV-containing arm (P<0.05)
- Pruritus (12%), nausea (11%), asthenia (11%), anemia (9%)
● Serious adverse events possibly related to 3D (n=1)
- Arthritis of hands and feet (ANA and RF positive)
● RBV dose modification due to adverse events (9%)
- All patients achieved SVR12
3D + RBV
(n=210)3D
(n=209)
Adverse events (%) Grade 3/4 Discontinuations
30
20
Death (number) 0 0
Laboratory abnormalities (%) ALT >5x ULN Total bilirubin >3x ULN Hemoglobin <10 g/dL (%)
1.05.79.0
00.50
Safety Summary
Ferenci P, et al. N Engl J Med. 2014;May 4. [Epub ahead of print].
26
Daclatasvir + Asunaprevir in Patients With Varying Previous Treatment Exposures
● HALLMARK-DUAL (genotype 1b)
27
HALLMARK-DUAL Study: Daclatasvir + Asunaprevir in HCV Genotype 1b
Manns M, et al. J Hepatol. 2014;60(suppl 1):S524-S525. Abstract O166.Kao J-H, et al. J Hepatol. 2014;60(suppl 1):S527-S528. Abstract P1300.
Daclatasvir 60 mg (NS5A inhibitor; asunaprevir 100 mg (NS3 inhibitor).Primary endpoint: SVR12.Baseline characteristics: Age: 54-60 years; male: 42%-54%; black: 4%-7%. HCV RNA >800K IU/mL: 74%-87%. Cirrhosis: 16%-47%. IL28B non-CC: 61%-84%.
Daclatasvir qd + Asunaprevir bidTreatment-naïve (n=203)
Phase 3Genotype 1bCirrhotics allowedNon-cirrhotic18 to 70 years of age
Week 0 12 24
PlaceboTreatment-Naïve (n=158)
Daclatasvir qd + Asunaprevir bidPrior PR Partial/Null Responders (n=205)
Daclatasvir qd + Asunaprevir bidPR Ineligible/Intolerant (n=235)
28
HALLMARK-DUAL Study: Daclatasvir + Asunaprevir in HCV Genotype 1b
● SVR12 rates were similar
- Non-cirrhotic (85%) and cirrhotic (84%)
- Age, gender, race, IL28B genotype
● SVR12 rates were lower with baseline thrombocytopenia (<90 versus >90 x 109 cells/L)
- Overall: 71% versus 86%
- Advanced fibrosis/cirrhosis: 69% versus 78%
● Non-SVR12 achievers (3 treatment arms)
- Breakthroughs (4%, 13%, 9%)
- Relapse (3%, 4%, 6%)
- All had detectable RAVs at time of virologic failure
● Discontinuations due to adverse events: 1.5%
● Most common adverse events
- Headache, fatigue, diarrhea, nausea, asthenia
Manns M, et al. J Hepatol. 2014;60(suppl 1):S524-S525. Abstract O166.Kao J-H, et al. J Hepatol. 2014;60(suppl 1):S527-S528. Abstract P1300.
SV
R12
(%
)
90%
82%
Treatment-Naïve(n=203)
Prior PRPartial/NullResponder
(n=205)
PRIneligible/Intolerant
(n=235)
82%
SVR12
29
MK-5172 + MK-8742 + RBV inTreatment-Naïve Patients
● C-WORTHY (non-cirrhotic, genotype 1)
30
C-WORTHY Trial: MK-5172 + MK-8742+ RBV in Treatment-Naïve Patients
● Phase 2b study
- Non-cirrhotic, genotype 1
● MK-5172 + MK-8742 treatment arms
- Part A (12-week regimens)
• 100/20 mg + RBV (n=25)
• 100/50 mg + RBV (n=27)
• 100/50 mg (genotype 1b) (n=13)
- Part B (100/50 mg)
• 8 weeks (genotype 1a) (n=30)
• 12 weeks (n=33)
• 12 weeks (genotype 1a (n=31)
● Safety
- No deaths, discontinuations due to adverse events, grade 3/4 laboratory abnormalities
- Most common adverse events: fatigue, headache, nausea, diarrhea, insomnia
NoRBV(n=30)
WithRBV(n=85)
NoRBV(n=44)
SVR4-24* (%) Overall Genotype 1a (n=30/52/30)
Genotype 1b (n=0/33/14)
8383--
949494
9897
100
No SVR (%) Breakthrough Relapse Non-virologic
0170
114
020
Preliminary Outcomes:MK-5172 + MK-8742
8Weeks
12Weeks
*Part A: 12-week arms (100% completed SVR24); Part B:8 week arm (93% completed SVR8), 12-week arms (100% completed SVR8).
Hezode C, et al. J Hepatol. 2014;60(suppl 1):S5. Abstract O10.
31
Program Overview
● HCV epidemiology and public health considerations
● Interferon-free regimens for HCV- Treatment-naïve patients
- Treatment-experienced patients
- Retreatment for prior DAA failures
- Difficult-to-cure and liver transplant patients
- HCV/HIV coinfection
32
Sofosbuvir-Based Studies in Treatment-Experienced Patients
● Sofosbuvir/ledipasvir
- ION-2: previous PR and DAA + PR failures
● Sofosbuvir + simeprevir
- COSMOS: previous PR failures
33
ION-2: Sofosbuvir/Ledipasvir + RBV in Treatment-Experienced, HCV Genotype 1
Sofosbuvir/Ledipasvir qd(n=109)
Phase 3Open-label, randomizedGenotype 1Treatment-experiencedTarget 20% cirrhoticsNo upper age or BMI criteriaPlatelets >50K/mm3
No neutrophil minimum
Week 0 12 24
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor)/ledipasvir 90 mg (NS5A inhibitor) + RBV (1000-1200 mg).Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 61% to 68%; age: 55-57 years; black: 14%-22%. Genotype 1a: 78%-79%. IL28B non-CC: 84% to 91%. Cirrhosis: 20%. HCV RNA (log10 IU/mL): 6.4-6.5. HCV RNA >800K IU/mL: 85%-95%. Prior non-responders: 41%-46%. Prior PI failures: 46%-61%.
Sofosbuvir/Ledipasvir qd+ RBV (n=111)
Sofosbuvir/Ledipasvir qd(n=109)
Sofosbuvir/Ledipasvir qd+ RBV (n=111)
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
34
ION-2: SVR12 Rates With Sofosbuvir/Ledipasvir+ RBV in Treatment-Experience, HCV Genotype 1
Overall Failed PR Failed PI + PR
SV
R12
(%
)
94% 96%93% 96% 97%94%
12-Week Arm
No RBV(n=109/43/47)
RBV(n=111/66/64)
Sofosbuvir/Ledipasvir qd
SV
R12
(%
)
99% 98%100% 99% 100%98%
24-Week Arm
No RBV(n=109/58/59)
RBV(n=111/50/51)
Sofosbuvir/Ledipasvir qd
PR: pegIFN + RBV.
Overall Failed PR Failed PI + PR
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
35
ION-2: SVR12 Rates by Presence of Cirrhosis With Sofosbuvir/Ledipasvir + RBV
No cirrhosis Cirrhosis
SV
R12
(%
)
95%86%
100%
82%
12-Week Arm
No RBV(n=87/22)
RBV(n=89/22)
Sofosbuvir/Ledipasvir qd
SV
R12
(%
)
99% 100% 99% 100%
24-Week Arm
No RBV(n=87/22)
RBV(n=89/22)
Sofosbuvir/Ledipasvir qd
PR: pegIFN + RBV.
No cirrhosis Cirrhosis
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
36
ION-2: Non-SVR12 Achievers, Resistance, and Safety Results
● Non-SVR12 achievers
- Virologic breakthrough (n=1 due to noncompliance)
- Relapse in 12-week arm
• No RBV (n=7), RBV (n=4)
● Resistance
- No S282T variant at baseline or at time of virologic failure
- NS5A RAVs at baseline (n=62)
• Achieved SVR12: 89%
● Higher incidence of adverse events and laboratory abnormalities in the RBV-containing arms
- Fatigue, nausea, insomnia, irritability, rash, dry skin, dyspnea, and anemia
NoRBV
(n=109)RBV
(n=111)
NoRBV
(n=109)
NoRBV
(n=111)
Adverse events (%) Grade 3/4 Discontinuations
20
30
90
70
Death (number) 0 0 0 0
Laboratory abnormalities (%) Grade 3/4 Hemoglobin <10 g/dL <8.5 g/dL
5
00
14
20
8
00
24
82
Safety Summary for Sofosbuvir/Ledipasvir qd
12 Weeks 24 Weeks
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
37
COSMOS Subgroup Analysis:Genotype 1 Prior Null Responders (F0-F2)
Simeprevir + Sofosbuvir qd (n=14)
Simeprevir + Sofosbuvir qd+ RBV (n=27)
Phase 2aOpen-labelGenotype 1Prior PR null responderNon-cirrhotic (F0-F2)
Week 0 12 24
Simeprevir + Sofosbuvir qd (n=15)
Simeprevir + Sofosbuvir qd + RBV (n=24)
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor); simeprevir 150 mg (NS3/4A Inhibitor).Weight-based ribavirin dosing (1000-1200 mg).Baseline demographics and disease characteristics: Male: 61%; age: 56 years; black: 29%. Genotype 1a: 78%. Genotype 1a with Q80K: 39%. IL28B non-CC: 94%. METAVIR F2: 59%. HCV RNA (log10 IU/mL): 6.8.
Sulkowski MS, et al. J Hepatol. 2014;60(suppl 1):S4. Abstract O7.
38
COSMOS Subgroup Analysis: SVR12 inGenotype 1 Prior Null Responders (F0-F2)
SV
R12
(%
)
SVR12
93%
24 Weeks(n=15/24)
12 Weeks(n=14/27)
Simeprevir + sofosbuvir No RBV With RBV
96%93%
79%
SV
R12
(%
)
SVR12 by Subgroups
100%
Genotype(n=17/30/27)
1b
100%
89%
Simeprevir + sofosbuvir + RBV
Sulkowski MS, et al. J Hepatol. 2014;60(suppl 1):S4. Abstract O7.
100% 100%
83%
1a 1a +Q80K IL28B Genotype
(n=4/52/18)
CC CT TT
39
COSMOS Subgroup Analysis:Genotype 1 Prior Null Responders (F0-F2)
● SVR12 non-achievers
- No virologic breakthroughs
- Relapse (n=3)
• 12-week arm (n=2, with and without RBV)
• 24-week arm (n=1 with RBV)
• All with Q80K at baseline
• Achieved undetectable HCV RNA at week 4
• No sofosbuvir RAVs at time of virologic failure
- Non-virologic (n=5)
• Due to adverse event (n=1), withdrew consent (n=1), noncompliance (n=1), lost to follow-up (n=1), non-treatment related death (n=1)
Sulkowski MS, et al. J Hepatol. 2014;60(suppl 1):S4. Abstract O7.
40
ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Experienced Patients
● SAPPHIRE-II
- Previous PR failures
41
SAPPHIRE-II: ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Experienced, HCV Genotype 1
Zeuzem S, et al. N Engl J Med. 2014;370:1604-1616.
3D + RBV(n=297)
Phase 3Double-blindGenotype 1Prior relapse, partial response, and null response to PRNon-cirrhoticHCV RNA >10K IU/mL18-70 years of age Week 0 12 24
3D: ABT-450 (NS3/4A inhibitor)/r/ombitasvir (NS5A inhibitor) 150/100/25 mg qd; dasabuvir (non-nucleoside NS5B polymerase inhibitor) 250 mg bid. RBV (1000-1200 mg). PR: pegIFN + RBV.Primary endpoint: SVR12 versus historical control SVR rate: 65% (telaprevir + pegIFN + RBV).Baseline demographics and disease characteristics: Male: 58% to 59%; age: 54-56 years; black: 9%-11%. Genotype 1a: 67%-68%. IL28B non-CC: 89%-93%. HCV RNA (log10 IU/mL): 6.5-6.6. Fibrosis stage F0-F1: 68%. Prior PR response: Relapse: 29%. Partial response: 22%. Null response: 49%.
Placebo(n=97)
3D + RBV
42
SAPPHIRE-II: SVR12 Rates With 3D + RBVin Treatment-Experienced, HCV Genotype 1
● Non-inferiority and superiority criteria met for overall SVR12 and superiority criteria met for SVR rate for genotype 1a and 1b
● SVR12 rates were similar across prior PR response subgroups
- Relapse (95%), partial response (100%), null response (95%)
● SVR12 non-achievers
- Virologic breakthrough (n=0)
- Relapse (n=7)
• Prior relapser (n=1), prior null responder (n=6)
- >1 RAV at time of virologic failure (n=5)
*
SV
R12
(%
)
96% 97%
Overall(n=297)
1a(n=173)
HCV Subtype
1b(n=123)
96%
SVR12Non-inferioritythreshold
Superioritythreshold
PR: pegIFN + RBV.
Zeuzem S, et al. N Engl J Med. 2014;370:1604-1616.
43
SAPPHIRE-II: Safety of 3D + RBV inTreatment-Experienced, HCV Genotype 1
● Pruritus was more common in the 3D + RBV arm versus placebo (P<0.05)
● Serious adverse events possibly related to 3D + RBV (n=1)
- Transient ischemic attack in patients with hypertension, older age, atrial septal defect with shunt
● RBV dose modification due to adverse events (6.4%)
3D + RBV(n=297)
Adverse events (%) Grade 3/4 Discontinuations
2.11.0
Death (number) 0
Laboratory abnormalities (%) ALT >5x ULN AST >5x ULN Alkaline phosphatase >5x ULN Total bilirubin >3x ULN Hemoglobin <10-8.0 g/dL <8.0 g/dL
1.71.00
2.4
4.70.3
Safety Summary
Zeuzem S, et al. N Engl J Med. 2014;370:1604-1616.
44
Program Overview
● HCV epidemiology and public health considerations
● Interferon-free regimens for HCV- Treatment-naïve patients
- Treatment-experienced patients
- Retreatment for prior DAA failures
- Difficult-to-cure and liver transplant patients
- HCV/HIV coinfection
45
Retreatment for Prior DAA Failures
● Sofosbuvir + RBV or PR
- Prior sofosbuvir + RBV failures
● Sofosbuvir/ledipasvir
- Prior sofosbuvir + RBV relapsers
● Sofosbuvir + PR
- Prior failures of PR + either GS-9451 or GS-9256 + ledipasvir or tegobuvir
46
Retreatment With Sofosbuvir-Based Regimens for Prior Sofosbuvir + RBV Failures (Interim Analysis)
Esteban R, et al. J Hepatol. 2014;60(suppl 1):S4-S5. Abstract O8.
Sofosbuvir qd + PR(n=34)
Open-LabelPrior relapsers of 12- or 16-weeks sofosbuvir + RBV in phase 3 studies (FISSION, FUSION, POSITRON) Genotype 2 or 3Compensated cirrhosis allowed
Week 0 12 24
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + RBV (1000-1200 mg) + pegIFN.PR: pegIFN + RBV.Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 77%-86%; age: 53 years; black: 1%. IL28B non-CC: 63%-68%. Mean ALT: 89-96 U/L. HCV RNA: 6.3-6.6 log10 IU/mL. Genotype 2/3: Sofosbuvir + PR: 18%/82%. Sofosbuvir + RBV: 7%/93%. Cirrhosis: Sofosbuvir + PR: 41%. Sofosbuvir + RBV: 34%.
Sofosbuvir qd + RBV(n=73)
47
SVR12: Retreatment With Sofosbuvir-Based Regimens for Prior Sofosbuvir + RBV Failures (Interim Analysis)
Esteban R, et al. J Hepatol. 2014;60(suppl 1):S4-S5. Abstract O8.
SV
R12
(%
)
100%
91%
50%
63%
Overall SVR12(Observed)
12-Week ArmSofosbuvir + PR
(n=4/22)
PR: pegIFN + RBV.
Genotype 2Genotype 3
24-Week ArmSofosbuvir + RBV
(n=2/38)
SV
R12
(%
)
93%88%
74%
47%
Genotype 3: SVR12(Observed)
12-Week ArmSofosbuvir + PR
(n=14/8)
No cirrhosisCirrhosis
24-Week ArmSofosbuvir + RBV
(n=23/15)
48
Safety: Retreatment With Sofosbuvir-Based Regimens for Prior Sofosbuvir + RBV Failures
● No deaths or discontinuations due to adverse events
- Grade 3/4 adverse events (sofosbuvir + PR versus sofosbuvir + RBV): 6% versus 1%
● Common adverse events
- Fatigue, headache, insomnia, irritability, depression, arthralgia, dry skin, pruritus, nausea
● Laboratory abnormalities (sofosbuvir + PR versus sofosbuvir + RBV)
- Grade 3/4: 38% versus 16%
- Hemoglobin <10 g/dL: 15% versus 0%
- Neutrophils <750/mm3: 9% versus 0%
- Platelets <50,000/mm3: 9% versus 0%
Esteban R, et al. J Hepatol. 2014;60(suppl 1):S4-S5. Abstract O8.
49
NIAID SPARE Study: Sofosbuvir/Ledipasvir Retreatment of Prior Sofosbuvir + RBV Relapsers
● Pilot study in genotype 1 (n=17)*
- Sofosbuvir + RBV relapsers from the NIAID SPARE
● Retreatment regimen (n=14)
- Sofosbuvir/ledipasvir (400/90 mg qd) for 12 weeks
● Primary endpoint: SVR12 (ITT analysis)
● Detection of S282T mutation during prior therapy with sofosbuvir + RBV
- End of treatment: 0%
- Week 28 post-treatment: 7% (1/14), reverted to wild type by week 36
Osinusi A, et al. J Hepatol. 2014;60(suppl 1):S5-S6. Abstract O11.
*3 patients did not participate: developed HCC (n=1), opted for telaprevir-based therapy (n=1), declined participation (n=1).Population sequencing (Sanger methodology) was performed for presence of NS5B mutations (sensitivity cut-off: 20%-25%).
Patients(n=14)
Male (%) 93
Age (years) 59.5
Black (%) 93
HCV genotype 1a (%) 57
IL28B non-CC (%) 86
HCV RNA log10 IU/mL 6.45
HAI stage 3-4 fibrosis (%) 50
Baseline Characteristics
50
NIAID SPARE Study: Sofosbuvir/Ledipasvir Retreatment of Prior Sofosbuvir + RBV Relapsers
● SVR12 (n=14): 100%
● Sofosbuvir/ledipasvir retreatment was well tolerated
- No deaths
- No grade 3/4 adverse events
- No discontinuations due to adverse events
● Grade 3 laboratory abnormalities
- Hypophosphatemia (n=2), hypercholesterolemia (n=1), elevated creatinine (n=1)
● Retreatment with sofosbuvir/ledipasvir
- No significant hemoglobin decline from baseline
- Mean 12-week hemoglobin decline versus previous sofosbuvir + RBV (-0.3 versus -1.2 g/dL; P<0.05)
- No changes in serum creatinine and estimated GFROsinusi A, et al. J Hepatol. 2014;60(suppl 1):S5-S6. Abstract O11.
51
Retreatment With Sofosbuvir-Based Regimens for Prior DAA + PR Failures (Interim Analysis)
● Single-arm study in HCV genotype 1 (n=80)
- Prior PR + DAA failures
• Either GS-9451 or GS-9256 and ledipasvir or tegobuvir
● Retreatment with sofosbuvir (400 mg qd) + PR for 12 weeks
● Primary endpoint: SVR12
- Available data (n=50)
- Characterized by NS3, NS5A, and NS5B exposure and RAVs prior to retreatment
Pol S, et al. J Hepatol. 2014;60(suppl 1):S23. Abstract O55.
Patients(n=80)
Male (%) 75
Age (years) 55
HCV genotype 1a (%) 85
IL28B non-CC (%) 84
HCV RNA log10 IU/mL 6.6
Duration of prior therapy (weeks) 25
>2 courses of therapy (%) 45
Number of prior DAAs (%) 1/2/3 19/51/30
Prior relapse (%) 48
Prior on-treatment failure (%) 45
Baseline Characteristics
52
SVR12: Retreatment With Sofosbuvir-Based Regimensfor Prior DAA + PR Failures (Interim Analysis)
Pol S, et al. J Hepatol. 2014;60(suppl 1):S23. Abstract O55.
SV
R12
(%
)
74%
SVR12
50%
75%
93%
Overall(n=50)
NS3(n=12)
NS3NS5a(n=24)
NS3NS5aNS5b(n=14)
Prior DAA + PR
SV
R12
(%
)
25%
SVR12 by Number of RAVs
73%80% 80%
0(n=4)
1(n=11)
2(n=25)
3(n=10)
Number Baseline RAVs Prior to Retreatment With Sofosbuvir + PR
53
Safety: Retreatment With Sofosbuvir-Based Regimens for Prior DAA + PR Failures
● No deaths or discontinuations due to adverse events
● Most common adverse events
- Fatigue (43%), headache (34%), nausea (24%), neutropenia (23%), rash (15%), myalgia (15%), dizziness (13%), pruritus (13%), anemia (13%), insomnia (10%), cough (10%)
● Grade 3/4 adverse events (10%)
● Laboratory abnormalities
- Grade 3/4: 51%
- Hemoglobin <10 g/dL: 8%
- Neutrophils <750/mm3: 21%
- Platelets <50,000/mm3: 0%
Pol S, et al. J Hepatol. 2014;60(suppl 1):S23. Abstract O55.
54
Program Overview
● HCV epidemiology and public health considerations
● Interferon-free regimens for HCV- Treatment-naïve patients
- Treatment-experienced patients
- Retreatment for prior DAA failures
- Difficult-to-cure and liver transplant patients
- HCV/HIV coinfection
55
Sofosbuvir-Based Studies in Difficult-to-Cure and Liver Transplant Patients
● Sofosbuvir/ledipasvir
- ELECTRON-2
● Sofosbuvir + RBV or PR
- Cirrhosis and portal hypertension + decompensation
- Multiple negative predictors
- Post liver transplantation
● Sofosbuvir + simeprevir
- COSMOS (F3-F4)
56
Sofosbuvir/Ledipasvir in Difficult-to-Cure Populations: ELECTRON-2 Study
Gane EJ, et al. J Hepatol. 2014;60(suppl 1):S3-S4. Abstract O6.
Sofosbuvir/Ledipasvir qd + RBV (n=26)
Sofosbuvir/Ledipasvir qd(n=25)
Demographics
Male: 68%, age: 55 yearsWhite: 95%Genotype 1a: 89%Cirrhosis: 0%IL28B CC: 21%HCV RNA: 6.3 log10 IU/mL
12-Week Treatment
Sofosbuvir/Ledipasvir qd + RBV (n=26)
Genotype 1(Prior relapse with sofosbuvir [ELECTRON-1])
SOF + RBV: null responders (n=6); naïve (n=4)SOF/LDV + RBV: naïve (n=6)SOF + GS-9669 + RBV: naïve (n=1)
Sofosbuvir/Ledipasvir qd + RBV (n=26)
Genotype 1Decompensated Cirrhosis (CTP class B)
Total bilirubin 1.5 mg/dL; serum albumin 3.1 g/dL;INR 1.2; ascites 20%; hepatic encephalopathy (30%); platelets 84,000/mm3
Demographics
Male: 85%, age: 56 yearsWhite: 85%Genotype 1a: 90%Cirrhosis: 100%IL28B CC: 35%HCV RNA: 6.0 log10 IU/mL
Genotype 3Treatment-NaïveDemographics
Male: 42%-52%, age: 43-48 yearsWhite: 88%Genotype 3a: 100%Cirrhosis: 12%-19%IL28B CC: 36%-58%HCV RNA: 6.3 log10 IU/mL
SVR12Hemoglobin
<10 g/dL
100% 16%
65% 5%
100% 12%
64% 0%
57
Sofosbuvir-Based Regimens Across Genotypes and Multiple Negative Predictors
Foster GR, et al. J Hepatol. 2014;60(suppl 1):S27. Abstract O66.
Retrospective analysis of predictors of relapse associated with sofosbuvir-based regimens and calculated SVR rates by number of negative predictors (prior treatment, male gender, body weight >75 kg, IL28B non-CC genotype, cirrhosis, baseline HCV RNA >800K IU/mL).
SV
R12
(%
)
100%100% 100%99% 100%
93%96%
100%100% 100%
93%
86%
94%
86%
61%
79%
62%
67%
53%
3(n=122/81/59)
0(n=0/4/5)
Number of Negative Predictors
1(n=26/22/22)
2(n=69/70/43)
6(n=0/6/15)
4(n=104/69/66)
5(n=18/33/37)
N/AN/A
Genotype 1 (ATOMIC, NEUTRINO) Genotype 2 (FISSION, POSITRON, FUSION, VALENCE) Genotype 3 (VALENCE)
58
Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation
Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.
Sofosbuvir qd + RBV(n=25)
Observation(n=25)
Open-LabelGenotypes 1-4Treatment-naïve and experiencedCompensated cirrhosis (Child-Pugh 5-6, A)Decompensated cirrhosis (Child-Pugh 7-9, B)Esophageal or gastric varicesHepatic venous gradient (HVPG): >6 mm Hg)
Week 0 24 48 72
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + RBV (1000-1200 mg).HVPG at day 0 and 48 in the sofosbuvir-treated patients.Baseline demographics and disease characteristics: Male: 72%-80%; age: 55-56 years; white: 84%-96%, treatment-naive: 68%-92% . Genotype 1a, 1b, 2, 3, 4: 36%-40%, 24%-36%, 4%-8%, 8%-32%, 4%-8%. IL28B non-CC: 72%-88%. HVPG >12 mm Hg: 76%-80%. CTP score 5-6, 7-9: 36%-44%, 56%-60%. MELD <10, 10-15: 32%, 56%-60%. Albumin: 3.0-3.3 g/dL; platelets: 75-99 x103. ALT, AST: 87-105, 105-128 U/mL. Ascites: 24%-36%. Encephalopathy 8%-20%.
Sofosbuvir qd + RBV
Current Analysis
59
Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation
● High rates of virologic suppression irrespective of severity of liver disease
● Decreased necroinflammation with ALT normalization
● Improvements
- Platelet count and albumin
- Ascites and hepatic encephalopathy
● Low rates of treatment discontinuation due to adverse events (4%)
Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.
Sofosbuvir+ RBV(n=25)
Observation(n=25)
HCV RNA <LLOQ (%) CTP A (n=7) CTP B (n=15)
10090
----
Change Platelets (103/µL) CTP A CTP B Albumin (g/dL) CTP A CTP B Bilirubin (mg/dL) CTP A CTP B ALT (U/L) CTP A CTP B
171
0.50.4
0.5-0.2
-72-75
-9-1
-0.10
0.2-0.1
130
Outcomes at Week 24
60
Sofosbuvir Compassionate Use Program:Recurrent HCV Following Liver Transplantation
● Patients with severe recurrent HCV infection following liver transplantation
- Likely to have <1 year life expectancy
● Sofosbuvir 400 mg qd + RBV + pegIFN for up to 48 weeks
● Recommended time of clinical assessments
- On treatment: weeks 4, 12, 24, 36, and 48
- Follow-up: weeks 4, 12, and 24
Patients(n=104)
Male (%) 73
Age (years) 55
Genotype (%) 1a/1b 2/3/4
28/491/7/8/
ALT (IU/L) 71
Bilirubin (mg/dL) 3.1
Albumin (g/dL) 3.1
INR 1.3
MELD score 15
Time from liver transplantation (months)
17
Baseline Characteristics
PR: pegIFN + RBV.
Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.
61
Sofosbuvir Compassionate Use Program:Initial Treatment Evaluations
● Overall, liver function tests significantly improved over time
● Most patients improved clinically or remained stable
● All serious adverse events (48%)
- Leading to treatment discontinuation (13%)
● Deaths (13%) were mostly a result of disease progression in this very sick population
- On treatment (n=8)
- Post treatment follow-up (n=5)
Pat
ien
ts (
%)
Treatment Outcomes
62% 62%
21%
SVR12(n=85)
Improved* Stable
*Improved: improvement in decompensation events (ie, significant decrease in hepatitic encephalopathy episodes, improvement or disappearance of ascites, and improvement in liver-related laboratory values.
Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.
Worse
Clinical Outcomes(n=104)
21%
62
Sofosbuvir + RBV: Treatment ofRecurrent HCV After Liver Transplantation
● Open-label study
- Genotype 1(83%), 3 (15%), 4 (3%)
- Prior HCV treatment (88%)
- CTP <7 and MELD <17
- Time liver transplantation: 4.3 years
- METAVIR F3/F4: 23%/40%
● Sofosbuvir 400 mg qd + RBV (starting at 400 mg) for up to 24 weeks
● Primary efficacy endpoint: SVR12
● Safety
- No deaths, graft losses, or rejection
- Discontinuations due adverse events: 5%
- RBV dose escalation manageable
- No interactions with common immunosuppressant agents
Patients
(n=40)
HCV RNA <25 IU/mL (%) Week 4 SVR4 SVR12 SVR24
100737070
Concomitant immunosuppression (%) Tacrolimus Mycophenolate mofetil Prednisone Cyclosporin Azathioprine
703528255
Adverse events (%) Fatigue Headache Arthralgia
282523
Grade 3/4 laboratory abnormalities (%) 25/28
Key Results
Samuel D, et al. J Hepatol. 2014;60(suppl 1):S499. Abstract P1232.
63
COSMOS Subgroup Analysis:HCV Genotype 1, METAVIR F3-F4
Simeprevir + Sofosbuvir qd (n=14)
Simeprevir + Sofosbuvir qd+ RBV (n=27)
Phase 2aOpen-labelGenotype 1Prior PR null responder or treatment-naïve METAVIR F3-F4No BMI limit<70 years of age
Week 0 12 24
Simeprevir + Sofosbuvir qd (n=16)
Simeprevir + Sofosbuvir qd + RBV (n=30)
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor); simeprevir 150 mg (NS3/4A Inhibitor).Weight-based ribavirin dosing (1000-1200 mg).Baseline demographics and disease characteristics: Male: 67%; age: 58 years; black: 9%. Genotype 1a: 78%. Genotype 1a with Q80K: 40%. IL28B non-CC: 79%. Cirrhosis: 47%. HCV RNA (log10 IU/mL): 6.6. Prior PR null responders: 54%.
Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.
64
COSMOS Subgroup Analysis:SVR12 in HCV Genotype 1, METAVIR F3-F4
SV
R12
(%
)
SVR12
93%
24 Weeks(n=16/30)
12 Weeks(n=14/27)
Simeprevir + sofosbuvir No RBV With RBV
93%100%
93%
SV
R12
(%
)
SVR12 by HCV Subtype
100%
Genotype(n=18/40/26)
1b
95% 96%
Simeprevir + sofosbuvir + RBV
94%98%
95%
1a 1a +Q80K IL28B Genotype
(n=17/48/19)
CC CT TT
Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.
65
COSMOS Subgroup Analysis:HCV Genotype 1, METAVIR F3-F4
● SVR12 rates were similar regardless of prior treatment exposure or baseline METAVIR score
● Relapse (n=3)
- All were genotype 1a, undetectable at EOT, and in 12-week arm (n=2 with RBV)
- At time of relapse there were no sofosbuvir RAVs
• Simeprevir RAVs: D166E, R155K
● Sofosbuvir + simeprevir + RBV was safe and well tolerated
- Discontinuations due to adverse events (1.1%)
- Higher incidence of adverse events and laboratory abnormalities in the RBV-containing arms
- Most common adverse events
• Fatigue (38%), headache (20%), nausea (17%), anemia (13%), pruritus (13%)
- Grade 3/4 laboratory abnormalities
• Hyperbilirubinemia (8%)
• Hemoglobin (1%) Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.
66
ABT-450/r/Ombitasvir + Dasabuvir + RBV
● TURQUOISE-II
- Compensated cirrhotics (genotype 1)
67
TURQUOISE-II: ABT-450/r/ABT-267 +ABT-333 + RBV in Compensated Cirrhotics
Poordad F, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].
3D + RBV(n=208)
Phase 3Open-labelGenotype 1Treatment-naïve and PR experienced Child-Pugh APlatelets: >60K/mLSerum albumin: >2.8 g/dLTotal bilirubin: <3 g/dLINR: <2.3AFP: <100 ng/mL Week 0 12 24
3D: ABT-450 (NS3/4A inhibitor)/r/ombitasvir (NS5A inhibitor) 150/100/25 mg qd; dasabuvir (non-nucleoside NS5B polymerase inhibitor) 250 mg bid. RBV (1000-1200 mg). PR: pegIFN + RBV.Primary endpoint: SVR12 versus historical control SVR rate: 43% and 54% for non-inferiority and superiority, respectively (telaprevir + pegIFN + RBV).Baseline demographics and disease characteristics: Male: 70%; age: 57 years; black: 4%-6%. Genotype 1a: 67%-70%. IL28B non-CC: 80%-83%. Treatment naïve: 41%-43%. Prior PR response: Relapse: 13%-14%. Partial response: 8%-9%. Null response: 36%.Child-Pugh score >5: 18%-19%.
3D + RBV(n=172)
68
TURQUOISE-II:SVR12 in Compensated Cirrhotics
SV
R12
(%
)
92%96%
SVR12
12-Week Arm(n=208)
24-Week Arm(n=172)
3D + RBV
SV
R12
(%
)
89%
98%94%
100%
SVR12 by HCV Subtype
1a 1bNon-inferioritythreshold
Superioritythreshold
12-Week Arm(n=140/68)
24-Week Arm(n=121/51)
3D + RBV
Poordad F, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].
69
TURQUOISE-II:SVR12 by Prior Treatment Response
SV
R12
(%
)
92%
100%
12-Week Arm
1a 1b
Naive(n=64/22)
Relapse(n=15/25)
Prior PR Response
Partial(n=11/7)
Null(n=50/14)
93%
100% 100%
86%80%
100%
SV
R12
(%
)
93%100%
24-Week Arm
1a 1b
Naive(n=56/18)
Relapse(n=13/20)
Prior PR Response
Partial(n=10/3)
Null(n=42/10)
100%100% 100%100%93%
100%
PR: pegIFN + RBV.
Poordad F, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].
70
TURQUOISE-II: SVR12 by Baseline Surrogates of Portal Hypertension and Hepatic Function
SV
R12
(%
)
89%
12-Week Arm
<100(n=45)
>100(n=163)
Platelets(x109/L)
<35(n=25)
>35(n=183)
93%84%
93%
24-Week Arm
PR: pegIFN + RBV.
Serum Albumin(g/L)
SV
R12
(%
)
97%
<100(n=45)
>100(n=163)
Platelets(x109/L)
<35(n=25)
>35(n=183)
96%89%
97%
Serum Albumin(g/L)
Poordad F, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].
71
TURQUOISE-II: Safety of 3D + RBVin Compensated Cirrhotics
● Virologic failure (4.5%)
- >1 RAVs at time of virologic
failure (n=15)
● Hepatic decompensation (1.1%)
● Anemia managed with RBV dose reduction
- No impact on achieving SVR12
● Common adverse events
- Fatigue, headache, nausea, pruritus, insomnia, diarrhea, asthenia, rash, cough, irritability, anemia, dyspnea
12 Weeks(n=208)
24 Weeks(n=172)
Virologic failure (%) Breakthrough Relapse
0.55.9
1.70.6
Adverse events (%) Grade 3/4 Discontinuations
131.9
122.3
Death (number) 0 0
Laboratory abnormalities (%) ALT >5x ULN Total bilirubin >3x ULN Hemoglobin <10 g/dL <8.0 g/dL
2.913.5
7.21.4
05.2
11.00.6
Virologic Failure and Safety Summary
Poordad F, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].
72
Program Overview
● HCV epidemiology and public health considerations
● Interferon-free regimens for HCV- Treatment-naïve patients
- Treatment-experienced patients
- Retreatment for prior DAA failures
- Difficult-to-cure and liver transplant patients
- HCV/HIV coinfection
73
NIAID ERADICATE Study: Sofosbuvir/Ledipasvir in HCV Genotype 1 With HIV Coinfection (Interim Analysis)
Osinusi A, et al. J Hepatol. 2014;60(suppl 1):S7. Abstract O14.
Sofosbuvir/Ledipasvir (n=13)SVR12 (interim analysis)
Open-LabelHCV genotype 1HCV treatment-naïveHAI fibrosis stage 0-3ART-naïve: HIV RNA <40 copies/mL and CD4 stable or CD4 >500 cells/mm3
On ART: CD4 >100 cells/mm3 HIV RNA <40 copies/mL Current ART >8 weeks
Week 0 12 24
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor)/ledipasvir 90 mg (NS5A inhibitor).Primary endpoint: SVR12.Allowable ART: emtricitabine/tenofovir DF (100%) plus: efavirenz (41%), raltegravir (27%,), rilpivirine (21%), rilpivirine/raltegravir (8%), efavirenz/raltegravir (3%).Baseline demographics and disease characteristics: Male: 54%-81%; age: 58 years; black: 77%-86%. Genotype 1a: 75%-81%. HAI fibrosis stage 3: 22%-38%. HCV RNA (log10 IU/mL): 5.97-6.07. CD4 cells/mm3: ART-naïve: 687. On ART: 576.
Sofosbuvir/Ledipasvir (n=13)SVR4 (interim analysis)
ART-Naïve
On ART
74
NIAID ERADICATE Study: Sofosbuvir/Ledipasvir in HCV Genotype 1 With HIV Coinfection (Interim Analysis)
● No change within groups
- CD4 counts or CD4 T-cell percentages
- Serum creatinine or estimated GFR
● HIV RNA status during HCV treatment
- ART-naïve: no clinically significant change
- On ART: transient HIV RNA breakthrough (missed ART for 4 days), re-suppressed
- No change within groups
● Sofosbuvir/ledipasvir was well tolerated
- No deaths, grade 4 adverse events or discontinuations due to adverse events
- Laboratory abnormalities
• Grade 3: neutropenia (n=1), AST (n=1)
• Grade 4: creatinine phosphatase (n=1)
Osinusi A, et al. J Hepatol. 2014;60(suppl 1):S7. Abstract O14.
SV
R (
%)
100% 100% 100%
Not YetAvailable
SVR Rates(Interim, Observed)
ART-Naïve(n=12/10)
SVR4SVR12
On ART(n=22/0)