simply speaking hepatitis february 7 2014
TRANSCRIPT
New and Emerging Strategiesto Simplify the Cure of
Chronic Hepatitis C Infection
Sponsored for CME credit by Rush University Medical Center
Supported by an independent educational grant from Gilead Sciences Medical Affairs
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CME Disclosure and Slide HandoutsCME Disclosure and Slide HandoutsWe Are Eliminating Hard Copy Evaluations!● CME DisclosureCME Disclosure
- These slides may not be videotaped, published, posted online, and/or presented for Continuing Medical Education credit without written permission from Rush University Medical Center and Practice Point Communications
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- It is the policy of the Rush University Office of Interprofessional Continuing Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME
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● Slide HandoutsSlide Handouts
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● Disclosures- Grants/Research Support: list here
- Consultant: list here
- Speakers’ Bureau: list here
- Stock Shareholder: list here
- Other Financial or Material Support: list here
Educator Title, DegreeAffiliationCity, State
EDUCATOR TO COMPLETE
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Accreditation and DesignationAccreditation and Designation
Supported by an independent educational grant fromGilead Sciences Medical Affairs.
Rush University (OH-390, 8/25/2014) is an approved provider of continuing education by the Ohio Nurses Association (OBN-001-91), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. Rush University designates this live activity for one (1) Continuing Nursing Education credit.
Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this live activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only credit commensurate with the extent of their participation in the activity.
The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UAN #0012-9999-13-013-L01-P). This activity is accredited for 1 hour of continuing pharmacy education (CPE) credit. The University of Florida College of Pharmacy will report all credit to CPE Monitor within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form.
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FacultyFaculty
CME Course DirectorCME Course DirectorHarold A. Kessler, MDProfessor of Medicine and Immunology/Microbiology
Associate Director,Section of Infectious Diseases
Rush University Medical CenterChicago, Illinois
Content Development and TrainingContent Development and TrainingMark S. Sulkowski, MD
Professor of MedicineMedical Director, Viral Hepatitis Center
Johns Hopkins Medical InstitutionBaltimore, Maryland
Program ChairProgram ChairS. Martin Cohen, MD
Medical Director, HepatologyProfessor of Medicine
University Hospitals/Case Medical CenterCleveland, Ohio
CME ReviewerCME ReviewerDavid M. Simon, MD, PhDAssociate Professor of MedicineSection of Infectious Diseases
Rush University Medical CenterChicago, Illinois
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Faculty DisclosuresFaculty Disclosures
CME Course Director:Harold A. Kessler, MD
Program Chair:S. Martin Cohen, MD
Content Developmentand Training:
Mark S. Sulkowski, MD
Grants/research support
None None Anadys, BIPI, Genentech, Gilead Sciences, Merck, Tibotec,
Vertex
Consultant None Bristol-Myers Squibb, Gilead
Sciences, Vertex
AbbVie, Anadys, BIPI, Genentech, Gilead Sciences,
Merck, Tibotec, Vertex
Speakers’ bureau
None Bristol-Myers Squibb, Genentech,
Gilead Sciences, Vertex
None
Stock shareholder
AbbVie, GlaxoSmithKline, Merck
None None
Other financial or material support
None None None
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Faculty DisclosuresFaculty Disclosures
CME Reviewer:David M. Simon, MD, PhD
Medical Editor:Peter Pinkowish
Grants/research support
None None
Consultant None None
Speakers’ bureau None None
Stock shareholder None None
Other financial or material support
None None
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Opinions and Off-Label DiscussionsOpinions and Off-Label Discussions
The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions
or recommendations of Gilead Sciences Medical Affairs,Rush University Medical Center, Rush University College of Nursing,
or the University of Florida College of Pharmacy
The faculty may have included discussion on unlabeled usesof a commercial product or an investigational use of a
product not yet approved for this purpose
Please consult the full prescribing information before usingPlease consult the full prescribing information before usingany medication mentioned in this programany medication mentioned in this program
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Learning ObjectivesLearning Objectives(CME/CNE and CPE)(CME/CNE and CPE)
We Are Eliminating Hard Copy Evaluations!
● Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine:
- Assess my hepatitis C (HCV)-infected patients on their chances of achieving a successful outcome after failing to respond to either PI-based therapy of a peginterferon-based initial regimen
- Appropriately select specifically targeted antiviral HCV therapies agents for my HCV-infected patients who are not responding to current standard of care, as they become available
- Appropriately select targeted antiviral HCV therapies agents for my HCV-infected patients who are not candidates for initial therapy with PI-based therapy of peginterferon + ribavirin, as they become available
CME/CNECME/CNE● Upon completion of this activity, the
pharmacist should be able to:
- Assess my hepatitis C (HCV)-infected patients on their chances of achieving a successful outcome after failing to respond to either PI-based therapy of a peginterferon-based initial regimen
- Review and discuss specifically targeted antiviral HCV therapies agents for my HCV-infected patients who are not responding to current standard of care, as they become available
- Review and discuss targeted antiviral HCV therapies agents for my HCV-infected patients who are not candidates for initial therapy with PI-based therapy of peginterferon + ribavirin, as they become available
CPECPE
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Chronic HCV Therapy (Genotype 1):Advances in Raising Cure Rates
SV
R (
%)
16%
44%
~70%
35%1991
1998
2001
2011
IFN
IFN/RBV
PegIFN/RBV
Telaprevir orBoceprevir +PegIFN/RBV
>90%
>20132nd Generation DAAs
PegIFN-Free Regimens
Schaefer EA, et al. Gastroenterology. 2012;142:1340-1350.Ghany MG, et al. Hepatology. 2009;49:1335-1374.Ghany MG, et al. Hepatology. 2011;54:1433-1444.
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SVR Rates in Treatment-Naïve,Genotype 1 HCV: Telaprevir and Boceprevir
Pat
ien
ts (
%)
T12/PR(n=363)
75%*69%*
44%
T8/PR(n=364)
PR48(n=361)
Pat
ien
ts (
%)
68%* 67%*
40%
LI/B24/PR(n=350)
LI/B44/PR(n=354)
PR48(n=344)
ADVANCE(Telaprevir + PR)
SPRINT-2(LI-PR, Boceprevir + PR)
*P<0.001 versus PR48.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
*P<0.0001 versus PR48.
T:telaprevir 750 mg tid; B:boceprevir 800 mg tid; PR: pegIFN + RBV.
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Toxicities Impacting Completion ofTelaprevir and Boceprevir Based Therapy
Pat
ien
ts (
%)
Discontinuations
10%7%
36%
Hemoglobin (g/dL)
ADVANCE(Telaprevir + PR)
SPRINT-2(LI-PR, Boceprevir + PR)
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Telaprevir 12/PR (n=363)PR48 (n=361)
LI:lead-in; PR: pegIFN + RBV.
AEs Rash <10 <8.5
Pat
ien
ts (
%)
Discontinuations Hemoglobin (g/dL)
AEs Rash <10 <8.5
Pooled boceprevir (n=804)PR48 (n=344)
7%
1%
14%
9%
2%
12%
N/A
16%
29%
6%3%
49%
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Variation in SVR Rates: Previously Treated, HCV Genotype 1 Patients (REALIZE Study)
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Pat
ien
ts (
%)
PriorRelapsers
32%
86% 85%
F2-3(n=62/15)
F0-1(n=167/38)
F4(n=57/15)
T:telaprevir 750 mg q8h; PR: pegIFN + RBV.METAVIR: F0-1 (no, minimal, or portal fibrosis); F2-3 (bridging fibrosis); F4 (cirrhosis).
Pat
ien
ts (
%)
Prior PartialResponders
NullResponders
13% 13%
84%
Pooled T12/PRPR48
Pooled T12/PRPR48
Pooled T12/PRPR48
72%
56%
34%
18%
0%
20%
F2-3(n=18/5)
F0-1(n=47/17)
F4(n=32/5)
F2-3(n=38/9)
F0-1(n=59/18)
F4(n=50/10)
41% 39%
14%
6%0%
10%
Pat
ien
ts (
%)
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Treatment of Chronic HCV:Recent Successes
● Telaprevir or boceprevir + PR
- Offer patients an improved chance of cure and the opportunity for a shorter duration of therapy
- SVR rates
• Treatment-naïve patients: 68%-75%
• Prior relapsers, partial responders: 59%-88%
• Null responders: 40%-41%
● Potential for yet another quantum leap in the field
- Recent proof of concept studies demonstrating the capacity to eradicate HCV without interferon
- PegIFN-free regimens for genotypes 1-6Fox AN, et al. Clin Infect Dis. 2012;55(suppl 1):S16-S24.Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
UpdatedSlide
17
Telaprevir or Boceprevir + PR:Shortcomings of the Current Standard of Care
● Only effective in HCV genotype 1 patients
● Require PR therapy
● Thrice-daily dosing
● Cirrhotics not eligible for response-guided therapy
● Side effects
- Both agents: hemoglobin decline (1.0-1.5 g/dL >PR)
- Telaprevir: rash, anorectal discomfort
- Boceprevir: dysgeusia, neutropenia
● Low barrier to resistance, emergence of resistant variants
- >50% who fail to achieve an SVR have detectable variants (wane in frequency over time off-therapy)
- Stopping rules designed to minimize resistance
● Potential for drug-drug interactions
- CYP3A4 inhibition
Fox AN, et al. Clin Infect Dis. 2012;55(suppl 1):S16-S24.
UpdatedSlide
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Chronic HCV Infection:Targets for Direct-Acting Antiviral Agents
● Prevent viral entry
- Polyclonal and monoclonal antibodies
● Prevent translation of viral RNA
- NS3/4 protease inhibitors
● Inhibit HCV-RNA polymerase
- Nucleoside analogue NS5B polymerase inhibitors
- Non-nucleoside analogue NS5B polymerase inhibitors
- Replication complex inhibitor
- Cyclophilin B inhibitors
● Viral assembly/release
- Glucosidase inhibitor
Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.
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Selected Characteristics of Direct-Acting Antiviral Agents for Chronic HCV Infection
ProteaseInhibitors
Nucleos(t)idePolymeraseInhibitors
Non-Nucleoside Polymerase Inhibitors
NS5A Inhibitors
Potency High(varies by HCV genotype)
Moderate-to-high(consistent across HCV
genotypes, subtype)
Variable(HCV genotypes)
High(multiple HCV
genotypes)
Barrier to resistance
Low(1a<1b)
High(1a=1b)
Very low(1a<1b)
Low(1a<1b)
Potential for drug interactions
High Low Variable Low-to-moderate
Toxicity Rash, anemia,↑ Bilirubin
Mitochondrial, NRTI interactions (ART, RBV)
Variable Variable
Dosing qd to tid qd to bid qd to tid qd
Comments 2nd generation PIs(higher barrier to
resistance, pan-genotype)
Single targetActive site
AllostericMany targets
Multiple antiviral MOA
Schaefer EA, et al. Gastroenterology. 2012;142:1340-1350.
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Combination Therapy: Potential for Preventing the Emergence of Resistant Variants
Variant NS3Linear
NS3Macrocytic
NS5AInhibitor
NS5BNuc
NS5BPalm
NS5BThumb
NS5BFinger IFN RBV
NS3 PI V36M R S S S S S S S S
T54A R S S S S S S S S
R155K R R S S S S S S S
A156T R R S S S S S S S
D168V S R S S S S S S S
NS5A L28V S S R S S S S S S
Y93H S S R S S S S S S
NS5B S282T S S S R S S S S S
C316Y S S S S R S S S S
M414T S S S S R S S S S
R422K S S S S S R S S S
M423T S S S S S R S S S
P495S S S S S S S R S S
HCV DrAG ResisSS. 2012;1.2. Available at http://www.hivforum.org. S: susceptible and R: resistant based on arbitrary <4 and >4 fold shift in HCV replicon EC50, respectively.
21
Program Overview
● DAA + pegIFN + ribavirin
● Multiple DAAs + pegIFN + ribavirin
● Interferon-free regimens
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DAA + PegIFN + Ribavirin inLate Stage Clinical Development
NS3/4AProteaseInhibitors
NucleotideNS5B
Polymerase Inhibitors
Non-Nucleoside
NS5B Polymerase Inhibitors
NS5AReplication
Complex Inhibitors PegIFN RBV
Sofosbuvir(genotypes 1-6)
PegIFN RBV
Daclatasvir(genotypes 1-3)
PegIFN RBV
Danoprevir* PegIFN RBV
Simeprevir* PegIFN RBV
Faldaprevir* PegIFN RBV
*Genotype 1.
UpdatedSlide
23
ATOMIC Trial:Sofosbuvir + PR
HCV RNA >50,000 IU/mL, no cirrhosis.BMI: >18 kg/m2.Non-CC IL28B: 72.4%; genotype 1a: 71.4%.
Week 0 12 24 48
PR: pegIFN + RBV (weight-based dosing: 1000 or 1200 mg).
Follow-Up
Sofosbuvir (400 mg) +PR
Stratified by IL28B (CC versus non-CC) and by HCV RNA (<800K and >800K IU/mL).
Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print].
G1(n=52)
G1,4,6(n=125)
GT 1(n=155)
Sofosbuvir (400 mg) +PegIFN + RBV
Sofosbuvir (400 mg) + PR
Sofosbuvir (n=75)
Sofosbuvir + RBV (n=75)
Follow-Up
Follow-Up
Phase 2bTreatment-naïve
UpdatedSlide
24
ATOMIC Trial:Treatment Outcomes
● SVR12 and SVR24
- Similar among sofosbuvir regimens (12 and 24 weeks)
- Genotype 4 (n=11)
• SVR12/SVR24: 82%/82%
- Genotype 6 (n=5)
• SVR12/SVR24: 100%/100%
● Sequence data from 4 patients who relapsed showed no S282T mutation (population sequencing)
- Deep sequencing for all patients with relapse is ongoing
SVR12 and SVR24 (ITT)
Pat
ien
ts (
%)
90% 89%93%
12Sofosbuvir + PR (weeks)
SVR12 SVR24
91%
24 12 + 12
89% 87%
PR: pegIFN + RBV (weight-based dosing: 1000 or 1200 mg).
Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print].
UpdatedSlide
25
ATOMIC Trial:Relapse and Safety and Tolerability
● Relapse: 3%
- No S282T mutation detected (phenotypic data generated in 10/11 relapse patients)
- No change in susceptibility to sofosbuvir
● Safety and tolerability
- Well tolerated up to 24 weeks, with no serious adverse events
• Discontinuation due to adverse events: <5%
● Most common adverse events
- Consistent with those associated with PR
• Constitutional symptoms, influenza-like symptoms, rash, anemia
UpdatedSlide
Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print].
26
NEUTRINO Study: Sofosbuvir + PR in Treatment-Naïve, HCV Genotype 1, 4, 5, and 6
Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Phase 3Open-labelTreatment-Naïve Genotype 1, 4, 5, and 6
Week 0 12 24 36
Sofosbuvir (nucleotide NS5B polymerase Inhibitor).No upper limit to age or BMI.Opioid substitution permitted.Platelets >90,000/mm3, neutrophils >1500/mm3 or 1000/mm3 (blacks).Cirrhosis permitted (17% enrolled).Primary efficacy endpoint: SVR12.Prespecified comparison to historical SVR control rate of 60%.
Follow-UpSofosbuvir 400 mg qd + PR (n=327)
NewSlide
27
NEUTRINO Study: SVR12 Ratesby Prespecified Subgroups
Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Pat
ien
ts (
%)
82%
90%*96%
92%
Overall(n=327)
100%96%
89% 92%
80%
98%
1a(n=255)
1b(n=66)
<6(n=71)
>6(n=256)
No(n=273)
Yes(n=54)
Genotype BaselineHCV RNA (log)
Cirrhosis
CC(n=98)
Non-CC(n=232)
IL28B
87%
4(n=28)
5/6(n=7)
*P<0.001 versus historical SVR rate of 60%.
Sofosbuvir 400 mg qd + PR (12 weeks)
NewSlide
28
NEUTRINO Study:Resistance and Safety
● No resistance detected in sofosbuvir + PR virologic failures and 1 relapse patient who discontinued therapy (HCV RNA >1000 IU/mL)
● Safety of sofosbuvir + PR
- Well tolerated and no additive effects of the addition of sofosbuvir to PR
• Discontinuations due to adverse events: 2%
- Most common adverse events
• Fatigue (59%), headache (36%), nausea (34%), insomnia (25%), anemia (21%), rash (18%)
- Safety profile consistent with ribavirin
• Hemoglobin <10 g/dL: 23%
• Hemoglobin <8.5 g/dL: 2%
Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
NewSlide
29
COMMAND-1 Study:Daclatasvir + PR
PR: pegIFN + RBV.All daclatasvir patients not achieving a protocol-defined response at week 12 (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks.HCV RNA: 6.5 log10 IU/mL.Compensated cirrhosis: 7.3%.BMI: >18 kg/m2.Non-CC IL28B: 69%; genotype 1a: 70%; genotype 4: 8%.
Week 0 12 24 48
Follow-UpDaclatasvir (20 mg) +PR (n=159)
PR (n=78)
Daclatasvir 60 mg + PR (n=158)
Daclatasvir + PR
Follow-Up
Phase 2bTreatment-naïveGenotype 1 or 4
Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755.
PR
Daclatasvir + PR
PR
PR (n=78)
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COMMAND-1 Study (ITT):SVR12 Rates (All PDR)
Pat
ien
ts (
%)
Genotype
67%65%
36%
100%
Genotype 1(n=147/146/72)
64%
50%
DCV 20 mg + PRDCV 60 mg + PRPR
Genotype 4(n=12/12/6)
Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755.
Pat
ien
ts (
%)
Genotype 1 Subgroup
78%
59%
38%
87%
Genotype 1a(n=106/113/56)
58%
31%
DCV 20 mg + PRDCV 60 mg + PRPR
Genotype 1b(n=41/31/16)
PDR: week-12 protocol-defined response (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks). PR: pegIFN + RBV.
31
COMMAND-1 Study:SVR12 Rates by IL28B (All PDR)
Pat
ien
ts (
%)
Genotype 1a
51%
85%
45%
31%
CC(n=41/36/18)
61%
36%
CT(n=51/61/26)
Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755.
Pat
ien
ts (
%)
Genotype 1bDCV 20 mg + PR PRDCV 60 mg + PR
PDR: week-12 protocol-defined response (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks). PR: pegIFN + RBV.
TT(n=11/14/9)
78%
22%
CC(n=11/7/4)
CT(n=24/20/10)
TT(n=6/4/2)
71%
40%
85%
67%
0%
75%
100%
25%
DCV 20 mg + PR PRDCV 60 mg + PR
32
COMMAND-1 Study: Treatment Failure and Safety and Tolerability
● Treatment failure
- Overall (daclatasvir versus PR): 35% versus 64%
• Treatment failure rates were lower in daclatasvir-treated patients who achieved PDR (11%-24%)
● Safety and tolerability
- Similar adverse event profile between the daclatasvir + PR and PR treatment arms
• Discontinuation due to adverse events: <5%
- Changes in laboratory parameters were consistent across all treatment arms
● Future clinical trials will be with genotype 1b patients only
Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755.
PR: pegIFN + RBV.PDR: week-12 protocol-defined response.
33
COMMAND-2 Study:Daclatasvir + PR
PR: pegIFN + RBV.All daclatasvir patients not achieving a protocol-defined response at week 12 (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks.HCV RNA: 6.5 log10 IU/mL.Compensated cirrhosis: 7.3%.BMI: >18 kg/m2.Non-CC IL28B: 69%; genotype 1a: 70%; genotype 4: 8%.
Week 0 12 16 24 48
Follow-UpDaclatasvir 60 mg qd
+ PR (n=50)
Daclatasvir 60 mg qd+ PR (n=50) Follow-Up
Follow-Up
Phase 2bTreatment-naïveGenotype 2, 3
Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418.
PR
Daclatasvir + PR
PR
PR (n=51)
Follow-Up
Follow-Up (36 weeks)
NewSlide
34
COMMAND-2 Study (ITT):SVR24 Rates (ITT)
Pat
ien
ts (
%)
Genotype
69%
83%
63%67%
Genotype 2(n=24/23/24)
83%
59%
DCV + PR (12 weeks)DCV + PR (16 weeks)PR
Genotype 3(n=26/27/27)
Pat
ien
ts (
%)
IL28B Genotypes
50%
80%85%
75%
CC
83%
64%
Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418.
100%
Non-CCGenotype 2
CC Non-CCGenotype 3
75%
56%
81%
64%
56%
DCV + PR (12 weeks)DCV + PR (16 weeks)PR
NewSlide
35
COMMAND-2 Study: Treatment Failure and Safety in Genotype 2/3
● Treatment failure (daclatasvir versus PR)
- Genotype 2: 5% versus 5%
- Genotype 3: 25% verus 14%
• With versus without baseline NS5A Y93 and/or A30 polymorphisms (50% versus 19%)
• Cirrhotics versus non-cirrhotics (36% versus 21%)
• No apparent effect of IL28B genotype or baseline HCV RNA on relapse
● Safety and tolerability
- Similar adverse event profile across all arms
• Discontinuation due to adverse events (daclatasvir versus PR): 7% versus 4%)
- Changes in laboratory parameters were consistent across all treatment arms
● Further evaluation of daclatasvir + PR in HCV genotype 2/3 patients is planned
PR: pegIFN + RBV.
NewSlide
Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418.
36
DAUPHINE Study:Danoprevir/r + PR
*RGT (response-guided therapy): week 12 all drugs stopped if eRVR [HCV RNA <15 IU/L achieved during weeks 2-10, if not then continue to week 24.PR: pegIFN + RBV.HCV RNA: >50,000 IU/Ml; fibrosis score: F0-F2; non-CC IL28B: 70%; genotype 1a: 60%; genotype 4: 8%.
Week 0 12 24 48
Follow-UpDanoprevir/r 200/100 mg + PR(n=94)
PR (n=46)
Follow-Up
Phase 2bTreatment-naïveGenotype 1 or 4
Danoprevir/r 100/100 mg+ PR (n=94)* Follow-Up
Danoprevir + PR
Danoprevir/r 100/100 mg + PR(n=93)
Danoprevir/r 50/100 mg + PR(n=94)
Follow-Up
eRVR: Follow-Up
Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
37
DAUPHINE Study:SVR24 Rates
● Dose-dependent increases in SVR24
- Highest SRV24 rates achieved in the danoprevir/r 200/100 mg treatment arm
● Dose-response relationship seen in a harder-to-treat subgroup (genotype 1a, IL28B non-CC)
- 200/100 mg: 88%
- 100/100 mg: 70%
- 50/100 mg: 58%
● Genotype 1b/IL28B CC and genotype 4 patients
- All achieved SVR24 in <12 weeks
Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
SVR24 (ITT)
Pat
ien
ts (
%)
1a(n=56/56/58/49)
4(n=8/8/7/7)
1b(n=29/29/26/37)
84%
60%
70%
97%93%
100%
88%
73%
100%
200/100 mg 50/100 mg100/100 mg 100/100 mg RGT
GenotypeRGT: response-guided therapy.Danoprevir/r was administered with PR (pegIFN + RBV).
59%
78%
38
DAUPHINE Study: Treatment Failure and Safety and Tolerability
● Treatment failure: 17.5%
- Relapse: 11%
• Predominately genotype 1a and non-CC IL28G genotype
- Resistance uniquely associated with the NS3 R155K substitution
● Safety and tolerability
- Similar adverse event profile between the danoprevir/r + PR and PR treatment arms
• Discontinuation of danoprevir/r due to adverse events: 5%
- Laboratory abnormalities were not dose related
- Anemia (hemoglobin <8.9 g/dL or any decrease >4.5 g/dL): 7%
Le Pogam, et al. Hepatology. 2012;56(suppl 4):571A-572A. Abstract 782.Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
39
QUEST-1 and -2 Trials: Simeprevir + PR in Treatment-Naïve, HCV Genotype 1
Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425.Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
Week 0 12 24 48 72
Simeprevir (NS3/4A protease inhibitor).HCV RNA >10,000 IU/mL.PR: pegIFN (alpha 2a or 2b) + RBV (weight-based dosing: 1000-1200 mg).Patients stratified by HCV subtype and IL28B genotype.Response-guided therapy criteria: HCV RNA <25 IU/mL at week 4 and undetectable at week 12.METAVIR score: F0-F1 (~50%); >F2 (~50%).Primary efficacy endpoint: SVR12.
Simeprevir150 mg qd + PR
Follow-Up
Follow-Up
Phase 3Treatment-naïveGenotype 1
PRPR
PR (n=134)Follow-Up
NewSlide
40
QUEST-1 and -2 Trials: Overall SVR12 Rates by Genotype 1 Subgroup
Pat
ien
ts (
%)
49%
80%*
71%*
90%*
50%
Overall(n=264/130)
52%
Simeprevir + PRPR
1a(n=147/74)
1b(n=117/56)
Genotype*P<0.01 versus PR.
NewSlide
Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425.Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
QUEST 1
Pat
ien
ts (
%)
46%
81%* 80%* 82%*
50%
Overall(n=257/134)
53%
Simeprevir + PRPR
1a(n=107/57)
1b(n=150/77)
Genotype
QUEST 2
*P<0.01 versus PR.
41
QUEST-1 and -2 Trials: SVR12 Ratesby Prespecified Subgroups
Pat
ien
ts (
%)
42%
94%*
76%*
65%*
78%
24%
Simeprevir + PRPR
83%*
60%
CC(n=77/37)
CT(n=150/76)
TT(n=37/17)
F0-F2(n=183/90)
IL28B Genotype METAVIR Score
F3(n=46/23)
F4(n=37/17)
58%*
29%
78%*
26%
*P<0.01 versus PR.
NewSlide
Pat
ien
ts (
%)
41%
96%*
80%*
58%*
81%
19%
Simeprevir + PRPR
85%*
51%
CC(n=75/42)
CT(n=142/71)
TT(n=40/21)
F0-F2(n=195/102)
IL28B Genotype METAVIR Score
F3(n=37/17)
F4(n=17/15)
65%*
40%
67%*
53%
*P<0.01 versus PR.
QUEST 1 QUEST 2
Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425.Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
42
QUEST-1 and -2 Trials:Resistance and Safety
● NS3 PI mutations were detected in the time of failure for the majority (>90%) of simeprevir-treated patients not achieving an SVR
- Genotype 1: mainly R155 alone
- Genotype 1b: mainly D168V or Q80R + D168E
● Simeprevir + PR was well tolerated
- Simeprevir treatment discontinuations due to adverse events
• QUEST-1: 3%
• QUEST-2: 1.6%
● Adverse event profile of simeprevir + PR was similar to the PR arm
- Headache, pyrexia, fatigue, influenza-like illness, rash, anemia, pruritus
NewSlide
Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425.Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
43
ASPIRE Study:Simeprevir + PR
Week 0 12 24 48 72
SMV 100 mg 12/PR (n=66)
HCV RNA >10,000 IU/mL.PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).
Follow-Up
Phase 2bPreviously failedGenotype 1
PR
SMV (150 mg qd) + PR
Follow-UpPRSMV 150 mg
12/PR (n=66)
SMV 100 mg 24/PR (n=65)
SMV (100 mg qd) + PR Follow-UpPR
SMV (150 mg qd) + PRFollow-Up
PRSMV 150 mg 24/PR (n=66)
Follow-Up
SMV (100 mg qd) + PR
PR
SMV (100 mg qd) + PR
SMV (150 mg qd) + PR
Follow-Up
Follow-Up
Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2.
PR48(n=66)
SMV 100 mg48/PR (n=66)
SMV 150 mg 48/PR (n=65)
44
ASPIRE Trial:SVR24 Rates With Simeprevir + PR
Pat
ien
ts (
%)
Prior Relapsers
85% 85%
100 mg(n=79)
150 mg(n=79)
PR48(n=27)
*Duration pooled. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).
Pat
ien
ts (
%)
Prior PartialResponders Null Responders
37%
75%
57%
9%
51%46%
19%
Pat
ien
ts (
%)
Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2.
Simeprevir + PR48
100 mg(n=68)
150 mg(n=69)
PR48(n=23)
Simeprevir + PR48
100 mg(n=68)
150 mg(n=69)
PR48(n=23)
Simeprevir + PR48
45
ASPIRE Trial: Resistance andSafety and Tolerability
● Viral breakthrough/relapse was usually associated with emerging mutations to simeprevir
- Q80K at baseline did not alter SVR24 rates in the simeprevir 150 mg treatment arms
● Safety and tolerability
- Well tolerated, treatment discontinuations due to adverse events: 7%)
- Hematologic abnormalities were similar across all treatment arms
- Mild and reversible increases in bilirubin were seen in the simeprevir arms
• No other liver changes
Lenz O, et al. J Hepatol. 2012;54(suppl 2):S5. Abstract 9.Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2.
46
STARTVerso1 Trial: Faldaprevir + PRin Treatment-Naïve, Genotype 1
Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.
Week 0 12 24 48 72
ETS, Follow-Up
Follow-Up
Faldaprevir120 mg qd + PR
(n=261)
PR
Faldaprevir240 mg qd + PR
(n=262)PR
ETS, Follow-Up
PRFollow-Up
Faldaprevir (NS3/4A protease inhibitor).Platelets >90,000 cells/mm3.No HBV or HIV coinfection. Fibrosis stage >F3: 17%ETS: early treatment success (HCV RNA <25 IU/mL at week 4 and undetectable at week 8.Primary efficacy endpoint: SVR12
Phase 3Treatment-NaïveGenotype 1
PRFollow-Up
PRFaldaprevir + PR
No ETS
No ETS
NewSlide
47
STARTVerso1 Trial: SVR12 Ratesby Prespecified Subgroups
Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.
Pat
ien
ts (
%)
36%
69%
84%83%76%
Overall(n=259/261/132)
60%
70%
90%
63%69%
95%
51%
Faldaprevir 120 mg qd + PRFaldaprevir 240 mg qd + PRPR
76%
1a(n=87/90/45)
1b(171/171/86)
CC(n=75/42)
CT(n=142/71)
TT(n=40/21)
Genotype IL28B Genotype
ETS Patients
(n=225/232)
86%89%
79%
28%
*P<0.0001 versus PR.
79%*80%*
52%
NewSlide
48
STARTVerso1 Trial:Resistance and Safety
● No significant effect of Q80K on SVR12 in genotype 1a patients
● Faldaprevir + PR was well tolerated
- Discontinuations due to adverse events: 4%
● Adverse event profile of faldaprevir + PR was similar to the PR arm
- Most common adverse events of at least moderate severity
• Rash (8%), anemia (12%)
● Total bilirubin elevations >2.6 x ULN with faldaprevir + PR were benign and transient
- 120 mg qd: 12%
- 240 mg qd: 53%
Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.
The Q80K mutation is associated with a decreased susceptibility to some NS3/4A protease inhibitors.
NewSlide
49
SILEN-C2 Study:Faldaprevir + PR (Non-Responders)
Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
Week 0 24 48 72
LI/240 mg qd/PR(n=142)
240 mg qd/PR(n=76)
eRVR, Follow-Up
Follow-Up
LI/120 mg qd/PR(n=70)
Faldaprevir 240 mg qd+ PR
LI*PR
Faldaprevir 240 mg qd+ PR
PRFollow-Up
Faldaprevir 120 mg qd+ PRLI* PR
Follow-Up
*LI: 3-day lead-in with PR.Relapsers excluded.HCV RNA >100,000 IU/mL, no cirrhosis.PR: pegIFN + RBV (weight-based ribavirin: 1000-1200 mg).
Phase 2bNon-respondersGenotype 1
50
SILEN-C2 Study: SVR andOverall Relapse With Faldaprevir
Pat
ien
ts (
%)
LI/240 mgqd/PR(n=142)
Sustained Virologic Response
27%
41%
31%
Relapse: rebound from undetectable at end of all treatment.
240 mgqd/PR(n=76)
LI/240 mgbid/PR(n=70)
Pat
ien
ts (
%)
Overall Relapse
25%
9%
19%
LI/240 mgqd/PR(n=142)
240 mgqd/PR(n=76)
LI/240 mgbid/PR(n=70)
Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
51
SILEN-C2 Study: Virologic Failure, Discontinuations, and Adverse Events
LI/240 mg qd/PR(n=142)
240 mg qd/PR(n=76)
LI/240 mg bid/PR(n=70)
Virologic failure (%) During faldaprevir During PR phase
255
287
176
Discontinuation (%) Adverse events 6 4 23
Adverse events (%) Rash Jaundice Nausea Diarrhea Vomiting
3419483217
2821533222
4241643932
Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
52
Program Overview
● DAA + pegIFN + ribavirin
● Multiple DAAs + pegIFN + ribavirin
● Interferon-free regimens
53
Multiple DAA + PegIFN + Ribavirin inLate Stage Clinical Development
NS3/4AProteaseInhibitors
NucleotideNS5B
Polymerase Inhibitors
Non-Nucleoside
NS5B Polymerase Inhibitors
NS5AReplication
Complex Inhibitors PegIFN RBV
Danoprevir Mericitabine PegIFN RBV
Asunaprevir Daclatasvir PegIFN RBV
54
Phase 2aGenotype 1 Prior Partial Responders
Prior Null Responders
MATTERHORN Study:Danoprevir/r + Mericitabine + PR
Week 0 24 48 72
Danoprevir/r + Mericitabine+ PR (n=50)
Danoprevir/r + PR(n=49)
QUAD
Danoprevir/r + Mericitabine + RBV (n=52) IFN Free
Feld JJ, et al. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81.
Triple
Danoprevir/r + Mericitabine+ PR (n=77)
Danoprevir/r + PR(n=77)
Danoprevir/r + Mericitabine + RBV (n=74) QUADPR
HCV RNA >50,000 IU/mL.Absence of cirrhosis.Mericitabine dosed bid. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).
QUAD
IFN Free
55
MATTERHORN Study:Treatment Outcomes
● QUAD regimen produced the highest overall SVR12 rates
- Genotype 1b patients (91% to 100%)
- Genotype 1a
• Adding mericitabine increased SVR12 from 30% to 75%
● Virologic breakthrough was associated with resistance to danoprevir (R155K, D168E/T)
● QUAD, triple, and IFN-free regimens were safe and well tolerated
- Addition of mericitabine did not change the safety profile of danoprevir/r + pegIFN + RBV
Pat
ien
ts (
%)
SVR12
84%86%
39%
N/A
Prior PartialResponders(n=50/48/23)
56% 55%
QUAD IFN freeTriple
Prior NullResponders
(n=74/31)
Feld JJ, et al. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81.
56
Study 011 (Expansion Cohort):Daclatasvir + Asunaprevir + PR
Week 0 24 36 48
Dual-1(n=18)
Daclatasvir 60 mg qd + Asunaprevir 200 mg bid
(Genotype 1b only)
Follow-Up
Lok AS, et al. Hepatology. 2012;56(suppl 4):230A. Abstract 79.
SVR12Primary Endpoint
Dual-2(n=20)
QUAD-1(n=20)
QUAD-2(n=21)
Triple(n=22)
Phase 2aGenotype 1Prior null responders
Daclatasvir 60 mg qd + Asunaprevir 200 mg qd
(Genotype 1b only)
Daclatasvir 60 mg qd + Asunaprevir 200 mg bid + PR
(Genotype 1a/1b)
Daclatasvir 60 mg qd + Asunaprevir 200 mg qd + PR
(Genotype 1a/1b)
Daclatasvir 60 mg qd + Asunaprevir 200 mg bid + RBV
(Genotype 1a/1b)
Follow-Up
Follow-Up
Follow-Up
Follow-Up
Non-cirrhoticPR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).
57
Study 011:Treatment Outcomes
● SVR12 rates higher in the QUAD arm compared with the dual arm
● Virologic breakthrough
- IFN-free arm: 56%
● QUAD, triple, and IFN-free regimens were well tolerated
- Discontinuations due to adverse events: 0%
● Most common adverse events
- Headache, diarrhea, fatigue, and insomnia
SVR12 Rate
Pat
ien
ts (
%)
Dual-1(n=78)
Dual-2(n=65)
78%
97%90%
65%
QUAD-1(n=20)
QUAD-2(n=21)
Lok AS, et al. Hepatology. 2012;56(suppl 4):230A. Abstract 79.
58
Program Overview
● DAA + pegIFN + ribavirin
● Multiple DAAs + pegIFN + ribavirin
● Interferon-free regimens
59
Interferon-Free Regimens inLate Stage Clinical Development
NS3/4AProteaseInhibitors
NucleotideNS5B
Polymerase Inhibitors
Non-Nucleoside NS5B Polymerase
Inhibitors
NS5AReplication
Complex Inhibitors PegIFN RBV
Sofosbuvir
Sofosbuvir RBV
Sofosbuvir Daclatasvir
Sofosbuvir Daclatasvir RBV
Faldaprevir BI 207127
Faldaprevir BI 207127 RBV
Faldaprevir PegIFN RBV
ABT-450/r ABT-333 ABT-267 RBV
ABT-450/r ABT-333 RBV
ABT-450/r ABT-267 RBV
ABT-450/r ABT-333 ABT-267
60
FISSION Trial: Sofosbuvir + RBV in Treatment-Naïve, HCV Genotype 2 or 3
Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Phase 3Open-labelTreatment-Naïve Genotype 2 or 3
Week 0 12 24 36
Sofosbuvir (nucleotide NS5B polymerase inhibitor).No upper limit to age or BMI.Opioid substitution permitted.Platelet >75,000/mm3 (cirrhotic: 20% maximum).Stratified by genotype, HCV RNA, and cirrhosis.Primary efficacy endpoint: SVR12 (non-inferiority margin: 15%).
Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day
(n=256)
PegIFN + RBV (800 mg/day)(n=243)
Follow-Up
NewSlide
61
FISSION Trial: SVR12 Ratesby Prespecified Subgroups
Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Pat
ien
ts (
%)
78%
67%
97%
56%
67%
Overall*(n=253/243)
63%66%
75%
62%
72%67%
74%
Sofosbuvir + RBVPR
47%
38%
2(n=70/67)
3(n=183/176)
<6(n=107/106)
>6(n=146/137)
No(n=204/193)
Yes(n=49/50)
Genotype BaselineHCV RNA (log)
Cirrhosis
Male(n=168/156)
Female(n=85/87)
Gender
79%76%
61% 62%
*Non-inferiority criteria met.
NewSlide
62
FISSION Trial: SVR12 Ratesby Genotype and Cirrhosis
Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Pat
ien
ts (
%)
Genotype 2
98%91%
82%
62%
No Cirrhosis(n=59/54)
Cirrhosis(n=11/13)
Pat
ien
ts (
%)
Genotype 3
61%
71%
34%30%
No Cirrhosis(n=145/139)
Cirrhosis(n=38/37)
Sofosbuvir + RBVPR
Sofosbuvir + RBVPR
NewSlide
63
FISSION Trial:Resistance and Safety
● No resistance detected in sofosbuvir + RBV virologic failures
- Relapse accounted for all but 1 virologic failure (nonadherence)
● Safety of sofosbuvir + RBV
- Well tolerated and few adverse events
- Most common adverse events
• Fatigue (36%), headache (25%), nausea (18%), insomnia (12%)
- Safety profile consistent with ribavirinGane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
NewSlide
64
FUSION Trial: Sofosbuvir + RBV for 12 Versus 16 Weeks in
HCV Genotype 2/3, Previously Failed PR Therapy
Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
Phase 3Double-blindFailed Prior PegIFN-Based Therapy Genotype 2 or 3
Sofosbuvir (nucleotide NS5B polymerase inhibitor).No upper limit to age or BMI.Opioid substitution permitted.Platelet >50,000/mm3, no neutrophil minimum.Cirrhosis at baseline (34%). Prior relapsers (76%).Stratified by genotype and cirrhosis.Primary efficacy endpoint: SVR12.
Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day
(n=103)
Week 0 12 16 24
Placebo
Sofosbuvir 400 mg qd +RBV 1000-1200 mg/day (n=98)
Follow-Up
NewSlide
65
FUSION Trial: SVR12 Ratesby Prespecified Subgroups
Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
Pat
ien
ts (
%)
94%
50%
86%
30%
73%*
Overall(n=100/95)
62%*
77%
50% 50%
61%62%
76%
Sofosbuvir + RBV 12 weeks 16 weeks
31%
66%
2(n=36/32)
3(n=64/63)
<6(n=26/29)
>6(n=74/66)
No(n=64/63)
Yes(n=36/32)
Genotype BaselineHCV RNA (log)
Cirrhosis
Male(n=71/64)
Female(n=29/31)
Gender
69%
87%
42%
66%
*P<0.001 versus 12 weeks of active therapy.
NewSlide
66
FUSION Trial: SVR12 Ratesby Genotype and Cirrhosis
Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
Pat
ien
ts (
%)
Genotype 2
96%
60%
100%
78%
No Cirrhosis(n=26/23)
Cirrhosis(n=10/9)
Pat
ien
ts (
%)
Genotype 3
37%
63%
19%
61%
No Cirrhosis(n=38/40)
Cirrhosis(n=26/23)
Sofosbuvir + RBV 12 weeks 16 weeks
Sofosbuvir + RBV 12 weeks 16 weeks
NewSlide
67
FUSION Trial:Resistance and Safety
● No resistance detected in sofosbuvir + RBV virologic failures
● Safety of sofosbuvir + RBV
- Well tolerated and few adverse events
• No discontinuations due to adverse events
- Most common adverse events
• Fatigue (46%), headache (27%), nausea (21%), insomnia (24%)
- Safety profile consistent with ribavirin
• Hemoglobin <10 g/dL: 7.5%
• Hemoglobin <8.5 g/dL: 1%
Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
NewSlide
68
POSITRON Trial: Sofosbuvir + RBV in HCV Genotype 2 or 3 With Limited Options
Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
Phase 3Double-blind, placebo-controlledInterferon-Ineligible, Intolerant, or unwilling Genotype 2 or 3
Sofosbuvir (nucleotide NS5B polymerase inhibitor).No upper limit to age or BMI.Opioid substitution permitted.No lower limit to platelet or neutrophil count.Cirrhosis at baseline (16%). Prior relapsers (76%).Stratified by presence or absence of cirrhosis.Primary efficacy endpoint: SVR12.
Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day
(n=207)
Week 0 12 24
Placebo (n=71)Follow-Up
NewSlide
69
POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Prespecified Subgroups
Pat
ien
ts (
%)
93%
78%
Overall(n=207)
61%
79%76%81%
61%
2(n=109)
3(n=98)
<6(n=67)
>6(n=140)
No(n=176)
Yes(n=31)
Genotype BaselineHCV RNA (log)
Cirrhosis
Male(n=117)
Female(n=90)
Gender
84%
73%
SVR12 rate was 0% in the placebo arm.
Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
NewSlide
70
POSITRON Trial: SVR12 Rates WithSofosbuvir + RBV by Genotype and Cirrhosis
Pat
ien
ts (
%)
Genotype 2
92% 94%
No Cirrhosis(n=92)
Cirrhosis(n=17)
Pat
ien
ts (
%)
Genotype 3
68%
21%
No Cirrhosis(n=84)
Cirrhosis(n=14)
SVR12 rate was 0% in the placebo arm.
Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
NewSlide
71
POSITRON Trial:Resistance and Safety
● No resistance detected in sofosbuvir + RBV virologic failures
● Safety of sofosbuvir + RBV
- Well tolerated and few adverse events
• Treatment discontinuations due to adverse events: 2%
- Most common adverse events
• Fatigue (44%), headache (21%), nausea (22%), insomnia (19%)
- Safety profile consistent with ribavirin
• Hemoglobin <10 g/dL: 7%
• Hemoglobin <8.5 g/dL: 1%
Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
NewSlide
72
ELECTRON Study:Sofosbuvir + Ribavirin
Week 0 4 8 12 24
Follow-Up
Treatment-NaïveGenotype 2, 3
(n=10)
Sofosbuvir (nucleotide NS5B polymerase Inhibitor). PR: pegIFN + RBV.HCV RNA >50,000 IU/mL. No cirrhosis.Weight-based ribavirin dosing (800-1200 mg).
Sofosbuvir 400 mg qd + PR
Follow-Up
Sofosbuvir 400 mg qd + RBVNull Responders
Genotype 1(n=10)
Sofosbuvir 400 mg qd + RBVFollow-Up
Treatment-NaïveGenotype 1
(n=25)Sofosbuvir 400 mg qd + RBV
Follow-Up
Treatment-ExperiencedGenotype 2, 3
(n=25)
Gane EJ, et al. N Engl J Med. 2013;368:34-44.
Phase 2b
73
ELECTRON Study:SVR Rates in HCV Genotype 2/3 and 1
Pat
ien
ts (
%)
Genotype 2/3SVR12SVR24
100%
68%
100%
NR
PR: pegIFN + RBV; NR: not reported.
Treatment-NaïveSofosbuvir + PR8 weeks (n=10)
Treatment-ExperiencedSofosbuvir + RBV12 weeks (n=25)
Pat
ien
ts (
%)
Genotype 1SVR12SVR24
84%
10%NR NR
Null RespondersSofosbuvir + RBV12 weeks (n=10)
Treatment-NaïveSofosbuvir + RBV12 weeks (n=25)
Gane EJ, et al. N Engl J Med. 2013;368:34-44.
74
ELECTRON Study: Sofosbuvir + RBV + Either Ledipasvir (NS5A Inhibitor) or GS-9669 (NS5B Non-Nucleoside Inhibitor)
Week 0 4 8 12 24
Follow-Up
Treatment-Naïve(n=25)
Sofosbuvir (nucleotide NS5B polymerase Inhibitor).No cirrhosis. Weight-based ribavirin dosing (1000-1200 mg).
Sofosbuvir 400 mg qd + RBV
Sofosbuvir 400 mg qd + RBVNull Responders
(n=10)
Sofosbuvir 400 mg qd + Ledipasvir+ RBV
Follow-Up
Treatment-Naïve(n=25)
Sofosbuvir 400 mg qd + Ledipasvir+ RBV
Follow-Up
Null Responders(n=9)
Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.
Phase 2bGenotype 1 Follow-Up
Sofosbuvir 400 mg qd + GS-9669+ RBV
Follow-Up
Treatment-Naïve(n=25)
Sofosbuvir 400 mg qd + GS-9669+ RBV
Follow-Up
Null Responders(n=9)
NewSlide
75
ELECTRON Study (Genotype 1 Cohort):Interim Analysis of SVR12 Rates
Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.
Pat
ien
ts (
%)
Treatment-Naive
84%92%
Sofosbuvir + RBV(n=25)
Null Responders100%
Sofosbuvir + Ledipasvir
+ RBV(n=25)
Sofosbuvir + GS-9669
+ RBV(n=25)
Pat
ien
ts (
%)
10%
100%
Sofosbuvir + RBV(n=10)
100%
Sofosbuvir + Ledipasvir
+ RBV(n=9)
Sofosbuvir + GS-9669
+ RBV(n=3)
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76
ELECTRON Study(Genotype 1 Cohort): Safety
● Adding ledipasvir to sofosbuvir + RBV
- No additional safety or tolerability issues
● Adding GS-9669 to sofosbuvir + RBV
- No additional safety or tolerability issues
● Fix-dose combination of sofosbuvir/ledipasvir
- Undergoing phase 3 trial in patients with and without cirrhosis
- Additional studies exploring shorter duration of therapy
Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.
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77
Phase 2aTreatment-naïve Genotype 2/3
Genotype 1
Study 040:Sofosbuvir + Daclatasvir + Ribavirin
Week 0 12 24 48
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd (n=16)
Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd (n=14)
Follow-Up
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd + RBV (n=14)
*LI: 7-day lead-in with sofosbuvir 400 mg qd. HCV RNA >50K IU/mL, no cirrhosis. Primary outcome: SVR12.
LI*
Follow-Up
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd (n=15)
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd (n=14)
Follow-Up
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd + RBV (n=15)
LI*
Follow-Up
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd (n=14)
Follow-Up
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd
+ RBV (n=15)
Follow-Up
78
Study 040 (24-Week Treatment):SVR12 and SVR24 Rates
Pat
ien
ts (
%)
Genotype 2/3SVR12SVR24
88% 86%
93% 93%
LI/SOF/DCV
(n=16)
Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
100%
SOF/DCV(n=14)
SOF/DCV+ RBV(n=14)
LI: 7-day lead-in with sofosbuvir 400 mg qd.
Pat
ien
ts (
%)
Genotype 1SVR12SVR24
100%
93%
100%
LI/SOF/DCV
(n=15)
100%
SOF/DCV(n=14)
SOF/DCV+ RBV(n=15)
79
Study 040 (24-Week Treatment):Safety and Tolerability
● Sofosbuvir + daclatasvir + RBV was well tolerated
- Discontinuations due to adverse events: 3%
● Most common adverse events
- Fatigue (36%)
- Headache (27%)
- Nausea (26%)
● No grade 3/4 elevations in ALT, AST, or total bilirubin
● Anemia (hemoglobin <9 g/dL): 7%
• All in the RBV-containing arms
Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
80
Study 040 (12-Week Treatment):SVR4 Rate and Safety
Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
Pat
ien
ts (
%)
Genotype 1: SVR4
98% 95%
SOF/DCV(n=41)
SOF/DCV+ RBV(n=41)
● No virologic failure reported
● SVR12 evaluable for 68 of 82 patients: 100%
● Safety
- No discontinuations due to adverse events
- Hemoglobin <9 g/dL
• Without ribavirin: 0%
• With ribavirin: 12%
81
Phase 2aPrior Nonresponse, Relapse, or Breakthrough with Telaprevir or Boceprevir With PRGenotype 1
Study 040: Sofosbuvir + Daclatasvir + RBV in Previous Telaprevir or Boceprevir Failures
Week 0 12 24 48
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd (n=21)
Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd + RBV (n=20)
Follow-Up
Follow-Up
Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417.
Sofosbuvir (nucleotide NS5B polymerase inhibitor).Daclatasvir (NS5A replication complex inhibitor).HCV RNA >105 IU/mL.No upper limit to age or BMI.METAVIR score: F0-F1 (12%), >F2 (88%).NS3 polymorphisms conferring resistance to boceprevir or telaprevir as baseline: 46%NS5A polymorphisms conferring resistance to daclatasvir: 7%Excluded: patients who discontinued telaprevir or boceprevir due to an adverse event.Primary efficacy endpoint: SVR12.
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82
Study 040 (24-Week Treatment):SVR4 and SVR12 Rates
● No virologic failures
● Neither baseline NS3 PI resistance nor use of RBV influenced response
● Sofosbuvir + daclatasvir + RBV was well tolerated
- No discontinuations due to adverse events
● Most common adverse events (without RBV)
- Fatigue (29%), headache (33%), arthralgia (14%)
● No grade 3/4 elevations in ALT, AST, or total bilirubin
● Anemia (hemoglobin <9 g/dL): 0%
Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417.
Pat
ien
ts (
%)
Genotype 1SVR4 SVR12
100% 100%95%*
Sofosbuvir +Daclatasvir
(n=21)
100%
Sofosbuvir +Daclatasvir + RBV (n=20)*1 patient missing at post-treatment 12 weeks,
HCV RNA undetectable at post-treatment week 24 (preliminary).
NewSlide
83
Study 014: Asunaprevir +Daclatasvir + BMS-791325
● Phase 2a, open-label study in treatment-naïve, HCV genotype 1 patients (n=32)
- Non-cirrhotic
- HCV RNA 6.3 log10 IU/mL
- Genotype 1b (75%)
- IL28B CC genotype: 28%
● Asunaprevir + daclatasvir + BMS-791325 75 mg
- 24 or 12 weeks of therapy
● Primary outcome: SVR12
- Interim analysis
• SVR4: 24 and 12-week arms
• SVR12: 12-week arm only)
24-WeekTreatment
(n=16)
12-WeekTreatment
(n=16)
SVR4 (%) Overall Genotype 1a
9492
94100
SVR12 (%) N/A 94
Safety (%) Discontinuations due to adverse events Grade 3/4 laboratory abnormalities Headache Diarrhea Asthenia
0
0
251313
0
6
383819
Interim Outcomes
Everson GT, et al. Hepatology. 2012;56:1517A-1518A. Abstract LB-3.
84
SOUND-C2 Study:Faldaprevir + BI 207127 + Ribavirin
Week 0 16 28 40
TID16W(n=81)
Follow-Up
TID28WNo RBV
(n=46)
TID28W(n=80)
Follow-Up
Faldaprevir + BI 207127 TID+ RBV
Follow-UpTID40W (n=77)
BID28W (n=78)
Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232.
Faldaprevir + BI 207127 TID+ RBV
Faldaprevir + BI 207127 BID+ RBV
Follow-Up
Follow-UpFaldaprevir + BI 207127 TID
HCV RNA >100K IU/mL, cirrhotic patients permitted.Faldaprevir (NS3/4A inhibitor), BI 207127 (non-nucleoside NS5B inhibitor).
Phase 2bTreatment-naïveGenotype 1 Faldaprevir +
BI 207127TID + RBV
85
SOUND-C2 Study:Final SVR12 Results
Pat
ien
ts (
%)
Overall
69%
59%52%
39%
59%
Pat
ien
ts (
%)
Genotype 1 Subtypes
Genotype 1aGenotype 1b
TID16W(n=81)
TID28WNo RBV(n=46)
TID28W(n=80)
TID40W (n=77)
BID28W (n=78)
TID16W(n=34/47)
TID28WNo RBV(n=18/28)
TID28W(n=32/48)
TID40W (n=34/43)
BID28W (n=30/48)
Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232.
38%
75%
44%
68%
47%
56%
43%
85%
11%
57%
86
SOUND-C2 Study: SVR12 byGenotype Subtype and METAVIR Score
Pat
ien
ts (
%)
Genotype 1aMETAVIR Score F0-F2 F3-F4
TID16W(n=27/7)
TID28WNo RBV(n=16/2)
TID28W(n=26/6)
TID40W (n=29/5)
BID28W (n=25/5)
Zeuzem S, et al. J Hepatol. 2013;58(suppl 1):S498. Abstract 1227.
44%
14%
40%
67%
45%
60%
44%40%
13%
0%
Pat
ien
ts (
%)
Genotype 1bMETAVIR Score F0-F2 F3-F4
TID16W(n=36/10)
TID28WNo RBV(n=19/9)
TID28W(n=33/15)
TID40W (n=33/10)
BID28W (n=32/16)
78%
70%64%
80%
52%
70%
91%
75%
63%
44%
NewSlide
87
SOUND-C2 Study: Virologic Failureand Baseline Predictors of SVR12
● Virologic failure (twice daily, 28-week treatment arm)
- Genotype 1a versus 1b: 47% versus 8%
- Genotype-1a patients had a higher rate of resistance compared with genotype-1b patients
● Baseline predictors of SVR12 (multivariate odds ratio)
- Gender (female:male): 3.99 (P<0001)
- HCV subtype (1b:1a): 7.11 (P<0.0001)
- IL28B genotype (CC:non-CC): 4.94 (P<0.0001)
- GGT (normal:>ULN): 2.08 (P=016)
Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232.
88
SOUND-C2 Study:Safety and Tolerability
● Twice daily, 28-week treatment arm
- Most favorable safety and tolerability profile
• Grade 3/4 bilirubin increase: 39%
• Grade 3/4 hemoglobin decrease: 2%
• No adverse hematologic effects
● The inclusion of ribavirin remains necessary component of treatment
● Future phase 3 studies (genotype 1b only)
- Faldaprevir 120 mg bid + BI 207600 600 mg bid + RBV
Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232.
89
Phase 2Treatment-naïveGenotype 1
AVIATOR Study: ABT-450/r-Based Therapy (Treatment-Naïve Cohort)
Week 0 8 12 24
ABT-450/r 150/100 mg qd +ABT-267 + ABT-333 + RBV (n=80)
Follow-Up
ABT-450/r 150/100 mg qd +ABT-333 + RBV (n=41)
Follow-Up
ABT-450/r 100/100 or 200/100 mg qd +ABT-267 + RBV (n=79)
ABT-450 (NS3/4A protease inhibitor); ABT-267 (NS5A replication complex inhibitor); ABT-333 (non-nucleoside NS5B polymerase inhibitor).HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV.ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid.Primary outcome: SVR24.
Follow-Up
ABT-450/r 150/100 mg qd +ABT-267 + ABT-333 (n=79)
Follow-Up
ABT-450/r 100/100 or 150/100 mg qd +ABT-267 + ABT-333 + RBV (n=79)
Follow-Up
ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=80)
Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
NewSlide
90
AVIATOR Study (ITT): OverallSVR Rates (Treatment-Naïve Cohort)
Pat
ien
ts (
%)
83%89%
85%91%88%
ABT-450/rABT-267ABT-333
RBV(n=80)
8 Weeks 12 Weeks
ABT-450/r--
ABT-333RBV
(n=41)
ABT-450/rABT-267
--RBV
(n=79)
ABT-450/rABT-267ABT-333
--(n=79)
ABT-450/rABT-267ABT-333
RBV(n=79)
Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
89%96%
90%
99%93%
87% 90%
ABT-450/rABT-267ABT-333
RBV(n=80)
24 Weeks
SVR12SVR24
NewSlide
91
AVIATOR Study: SVR24 by Baseline Subgroups (Treatment-Naïve Cohort)
Pat
ien
ts (
%)
98%92% 91%
94%
Male(n=78)
Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
89% 91%94% 94% 95%
89%
ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined)
Female(n=81)
1a(n=108)
1b(n=50)
>7(n=35)
<7(n=124)
F0-F1(n=113)
F2-F3(n=42)
Non-CC(n=115)
CC(n=44)
Genotype HCV RNA(log)
Fibrosis Stage
IL28B Genotype
NewSlide
92
Phase 2Null RespondersGenotype 1
AVIATOR Study: ABT-450/r-Based Therapy (Null Responders Cohort)
Week 0 8 12 24
Received at least 12 weeks of pegIFN + RBV and failed to achieve >2 log10 IU/mL HCV RNA decrease.HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV.IL28B CC genotype (~3%).ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid.Primary outcome: SVR24.
Follow-Up
Follow-Up
ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=43)
Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
ABT-450/r 100/100 or 200/100 mg qd +ABT-267 + RBV (n=45)
ABT-450/r 100/100 or 150/100 mg qd +ABT-267 + ABT-333 + RBV (n=45)
NewSlide
93
AVIATOR Study (ITT): OverallSVR Rates (Null Responders Cohort)
Pat
ien
ts (
%)
89% 89%
12 Weeks
ABT-450/rABT-267
--RBV
(n=45)
ABT-450/rABT-267ABT-333
RBV(n=45)
Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
ABT-450/rABT-267ABT-333
RBV(n=43)
24 Weeks
SVR12SVR24
93% 93%98% 95%
NewSlide
94
AVIATOR Study: SVR24 by Baseline Subgroups (Null Responders Cohort)
Pat
ien
ts (
%)
97%93% 93%
97%
Male(n=55)
Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
91% 93%96% 95% 94%
100%
ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined)
Female(n=53)
1a(n=55)
1b(n=33)
>7(n=22)
<7(n=66)
F0-F1(n=41)
F2-F3(n=45)
Non-CC(n=85)
CC(n=3)
Genotype HCV RNA(log)
Fibrosis Stage
IL28B Genotype
NewSlide
95
AVIATOR Study:Virologic Relapse and Safety
● Virologic relapse in prior null responders
- 8-, 12-, and 24-week arms: 12.5%, 6.3%, 2.5%
● Discontinuations due to adverse events in the 12- and 24-week arms: 2.4%
- Considered related to treatment (n=4/6): hepatitis cholestatic, feeling jittery, homicidal ideation, decreased creatinine clearance
● Most common adverse events
- Headache (31%), fatigue (30%), nausea (23%), insomnia (20%), diarrhea (15%)
- Bilirubin increase: 2.4%
- Anemia (hemoglobin 6.5 to <8 g/dL): 2.4%
Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
NewSlide
96
New and Emerging Strategies:Clinical Considerations
● Recent recommendations from the CDC emphasize the importance to screen and early diagnosis of HCV infection
● Newly diagnosed patients with chronic HCV infection still require comprehensive counseling
● For patients who are candidates for therapy
- Initiate treatment with currently available therapy
- Defer treatment until availability of new antiviral agents with the potential for increased efficacy, decreased adverse events, and shorter duration of therapy over existing regimens
97
New and Emerging Strategies:Conclusions
● Results from phase 2 trials for all oral agents are excellent, with well tolerated regimens and high SVR rates
● High SVR rates with interferon-free regimens are possible in a variety of patient populations, including difficult-to-treat patient populations (prior null responders and cirrhotics)
- Ribavirin and IL28B status remain important for some regimens
● Non-CC and genotype 1a status remain important for DAA + peginterferon + ribavirin regimens
● Further study is needed for DAAs in special patient populations
- Cirrhosis
- HIV coinfection
- Liver transplant recipients
98
New Electronic Evaluation ProcessNew Electronic Evaluation ProcessWe Are Eliminating Hard Copy Evaluations!• You will receive an electronic evaluation to the email
address provided within 1 business day
• Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed
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99
Outcomes Measurement ReminderOutcomes Measurement Reminder
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