Simply Speaking Hepatitis February 7 2014

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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● Disclosures- Grants/Research Support: list here

- Consultant: list here

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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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address provided within 1 business day

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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

18

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

22

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).


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


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


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%


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)


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)


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%)


- 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


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%


83%

59%

DCV + PR (12 weeks)DCV + PR (16 weeks)PR


Pat

ien

ts (

%)

IL28B Genotypes

50%

80%85%

75%

CC

83%

64%


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


- 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


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


- 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


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


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


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


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 (

%)


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


- 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


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%


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


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)


51

SILEN-C2 Study: Virologic Failure, Discontinuations, and Adverse Events


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


52

Program Overview




53

Multiple DAA + PegIFN + Ribavirin inLate Stage Clinical Development


NucleotideNS5B


Non-Nucleoside

NS5B Polymerase Inhibitors

NS5AReplication


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



- 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




59

Interferon-Free Regimens inLate Stage Clinical Development


NucleotideNS5B


Non-Nucleoside NS5B Polymerase

Inhibitors

NS5AReplication


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


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)


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


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%


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


• 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.


(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


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)


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


Pat

ien

ts (

%)

Genotype 2

96%

60%

100%

78%


Cirrhosis(n=10/9)

Pat

ien

ts (

%)

Genotype 3

37%

63%

19%

61%


Cirrhosis(n=26/23)



NewSlide

67

FUSION Trial:Resistance and Safety




• No discontinuations due to adverse events




• Hemoglobin <10 g/dL: 7.5%



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.


(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)


Cirrhosis

Male(n=117)

Female(n=90)

Gender

84%

73%

SVR12 rate was 0% in the placebo arm.


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.


NewSlide

71

POSITRON Trial:Resistance and Safety




• Treatment discontinuations due to adverse events: 2%




• Hemoglobin <10 g/dL: 7%



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


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


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


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)

NewSlide

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


NewSlide

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.


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



Follow-Up


LI*

Follow-Up


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)


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



- 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


80

Study 040 (12-Week Treatment):SVR4 Rate and Safety


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



Follow-Up

Follow-Up


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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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%


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).

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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.

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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

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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)


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)


TID28W(n=26/6)

TID40W (n=29/5)

BID28W (n=25/5)


44%

14%

40%

67%

45%

60%

44%40%

13%

0%

Pat

ien

ts (

%)

Genotype 1bMETAVIR Score F0-F2 F3-F4

TID16W(n=36/10)


TID28W(n=33/15)

TID40W (n=33/10)

BID28W (n=32/16)

78%

70%64%

80%

52%

70%

91%

75%

63%

44%

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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)


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


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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.

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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)


--(n=79)


RBV(n=79)


89%96%

90%

99%93%

87% 90%


RBV(n=80)

24 Weeks

SVR12SVR24

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AVIATOR Study: SVR24 by Baseline Subgroups (Treatment-Naïve Cohort)

Pat

ien

ts (

%)

98%92% 91%

94%

Male(n=78)


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

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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)


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)

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AVIATOR Study (ITT): OverallSVR Rates (Null Responders Cohort)

Pat

ien

ts (

%)

89% 89%

12 Weeks

ABT-450/rABT-267

--RBV

(n=45)


RBV(n=45)



RBV(n=43)

24 Weeks

SVR12SVR24

93% 93%98% 95%

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AVIATOR Study: SVR24 by Baseline Subgroups (Null Responders Cohort)

Pat

ien

ts (

%)

97%93% 93%

97%

Male(n=55)


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

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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


- Headache (31%), fatigue (30%), nausea (23%), insomnia (20%), diarrhea (15%)

- Bilirubin increase: 2.4%

- Anemia (hemoglobin 6.5 to <8 g/dL): 2.4%


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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

• Completion Is Required for CME/CNE/CPE credit and future attendance

• Incomplete evaluations will preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area

99

Outcomes Measurement ReminderOutcomes Measurement Reminder

• We are required to assess “changes in learners’ competence, performance or patient outcomes achieved as a result of their participation in a CME/CNE/CPE sponsored educational activity”

• As a result of this requirement you will receive a short survey via email 8 to 12 weeks after completing this course

• We consider the survey to be an additional component of your overall participation in this educational activity and would urge you to reflect on what you learned in the activity and then complete this survey

Simply Speaking Hepatitis February 7 2014

Health & Medicine

Transcript of Simply Speaking Hepatitis February 7 2014