LIVER CENTRE Toronto Western Site David Wong, MD University of Toronto TWH Francis Family Liver...

LIVERCENTRE

Toronto Western Site

David Wong, MDUniversity of Toronto

TWH Francis Family Liver ClinicTGH Immunodeficiency Clinic

SM Positive Care Clinicwww.torontoliver.ca

Will interferon-free strategies be a

reality?

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Disclosures

Principal Investigator in multicenter studies HCV (none for IFN-free strategies)

BI, BMS, Johnson & Johnson, Vertex HBV

BMS, Gilead

NO involvement in Advisory Boards, Consultancy roles,

Stocks

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Outline

IFN free strategies can work Choosing optimal combinations

Exploring weaknesses of individual agents

Access to treatment Need for more drugs in each class Cost of treatment

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HCV genomeCombinations for cure

Protease

Pol

ReplicationComplex

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First reportNaïve x 24 weeks

BMS-790052 (Daclatasvir) 60 mg OD NS5a replication complex inhibitor

BMS-650032 (Asunaprevir) 600 mg BID NS3 protease inhibitor

PegIFNa2a 180 ug weekly Weakness: IL28b, cirrhosis (excluded),

safety Ribavirin 1000-1200 mg OD

Weakness: resistance? AS Lok et al. A60. EASL 2011AS Lok et al. NEJM 2012;336:216

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Results (SVR)

SVR12 SVR240

20

40

60

80

100100

90

36 36

QuadIFN-Free

11 10 11 10

*1 PCR neg 35 days later

Resistance Relapse

AS Lok et al. A60. EASL 2011AS Lok et al. NEJM 2012;336:216

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NS5A + PIDaclatasvir (DCV) Asunaprevir (ASV)

Genotypic coverage Broad G1 and 4

G1b SVR in 2/2 Works Works

G1a SVR in 2/9 Weak? Weakness

Resistance Weakness Weakness

Cirrhosis Not tested Not tested

Adding IFN helps IFN likely small effect (prior null

response) RBV likely even less effect (resistance)

AS Lok et al. A60. EASL 2011AS Lok et al. NEJM 2012;336:216

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INFORM-SVRTreatment naïve x 24 weeks

Mericitabine (MCB) 1000 mg BID Polymerase inhibitor

Danoprevir (DNV) 100 mg BID/ ritonavir 100 mg BID Macrocyclic protease inhibitor - boosted

Ribavirin 1000-1200 mg OD Treatment naïve Cirrhotics excluded

EJ Gane et al. EASL 2012

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Results after 24 weeks

High relapse if 12 weeks treatment RBV not included

Adding IFN helps

Overall CC Non-CC0

20

40

60

80

100

26 27 25

77

50

76

1a 1b

43 21 15 4 28 17


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PI/r + PolI + RBVDanoprevir (DNV)/r Mericitabine (MCB)

Genotypic coverage 1, 4 and 6 Broad?

G1b SVR > 70% Works but moderate Works but moderate

G1a SVR ~ 25% Weakness Weakness


Cirrhosis Not tested Not tested

Ribavirin needed DNV/r + MCB is weak double therapy

Adding another agent (IFN) helps G1b > 90%, G1a > 70%

Matterhorn StudyEJ Gane et al. EASL 2012

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Sound-C2/3PI + NNPolI +/- RBV

Faldaprevir (FDV) 120 mg OD Protease inhibitor (all except 3)

Deleobuvir (DLV) 600 mg BID Non-Nuc Polymerase Inhibitor

Sound-C21

1b >> 1a IL28b CC and Genotype 1a might respond? GI side effects: cannot keep pills down

Sound-C32 (learning from our mistakes) SVR in G1b: 19/20 (95%) SVR in G1a, IL28b CC: 2/12 (17%)

V Soriano et al. EASL 2012S Zeuzem et al. APASL 2013

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PI/r + PolI + RBVFaldaprevir (FDV) Deleobuvir (DLV)

Genotypic coverage 1b>1a, not 3 Broad?

G1b SVR > 90% Works Works

G1a SVR ~ 17% Weakness Weakness


Cirrhosis Works but moderate Works but moderate

Ribavirin needed FDV and DLV is weak double therapy Replacing RBV with another agent will

likely help


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ABT orals + RBV x 12 weeks

in non-cirrhotics (naïve and nulls) ABT-450/r

Protease inhibitor ABT-267

NS5a inhibitor ABT-333

Non-Nuc Polymerase Inhibitor

KV Kowdley et al. A3. EASL 2013

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SVR24

92 91 9094 95 93 93 91

95 949498

9491 89

97 97 9693

100

KV Kowdley et al. A3. EASL 2013

% S

VR

24

Male

Fem

ale

1a

1b

>7 l

og

<7 l

og

F0-F

1F

2-F

3

Non

-CC

CC

Male

Fem

ale

1a

1b

>7 l

og

<7 l

og

F0-F

1F

2-F

3

Non

-CC

CC

Naïve N=159 Null N=88

7881 10850 35124 11342 11544 56 33 55 33 22 66 41 45 85 3

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Salvage for BOC/TPV failures

SOF+DCV+/-RBV x 24 weeks Sofosbuvir (SOF)

Nuc Polymerase Inhibitor Declatasvir (DCV)

NS5A Replication Complex Inhibitor

MS Sulkowski et al. A1417. EASL 2013

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Week 2 Week 4 EOT SVR4 SVR12

91100 100 100 100

80

95100 100

95

SD SDR

SVR12%

SV

R

21 20 21 20 21 20 21 20 21 20

MS Sulkowski et al. A1417. EASL 2013

1 missed is SVR24

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Gilead Pipeline

Ledipasvir (LDV) NS5A Replication Complex Inhibitor

GS-9669 Non-Nuc Polymerase Inhibitor

Gilead plans SOF + LDV

What about SOF + LDV + GS-9669?

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SOF + RBV + (LDV or GS-9669)

x 12 weeks84

100 92

10

100 100

NaïveNull

% S

VR

12

Electron Study: EJ Gane et al. A14. EASL 2013

N=25 N=10 N=25 N=9 N=25 N=3

IL28b CC 44% 20% 36% 0 28% 13%

Geno 1b 12% 10% 20% 11% 16% 90%

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FISSIONG2/3 Treatment naïve x 12 weeks

Sofosbuvir (SOF) 400 mg OD Polymerase inhibitor

Ribavirin (RBV) 1000-1200 mg OD Treatment naïve Cirrhotics included but Plts > 75

Compared with PegIFN-RBV (800) x 24 weeks

E Gane et al. A5. EASL 2013E Lawitz et al. NEJM 2013;368:1878

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SVR12

Week 2 Week 4 Week 12

Week 24

SVR12

9299 99

NA

67

32

67

9299

67

SOF-R PR

% S

VR

12

251 250 244 253241 236 224 190 243

No

Cirrhos

is

Cirrhos

is

No

Cirrhos

is

Cirrhos

is

9891

61

34

82

62

71

30

SOF-R PR

% S

VR

12

59 11 145 3854 13 139 37

Genotype 2

Genotype 3Fission study: E Gane et al. A5. EASL 2013

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FUSIONG2/3 Difficult to treat

FUSION1 x 12 or 16 weeks IFN failures Cirrhosis 33% (Patelets > 50)

POSITRON2 x 12 weeks IFN intolerant, ineligible or unwilling Cirrhosis 15% (no platelet restriction)

1FUSION: DR Nelson et al. A6. EASL 20132POSITRON: IM Jacobson et al. A61. EASL 2013

IM Jacobson et al. NEJM 2013;368:1867

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SVR12SOF + RBV

No cirrhosis Cirrhosis No cirrhosis Cirrhosis

96

60

37

19

100

78

63 61

92 94

68

21

12 weeks16 weeksPositron

% S

VR

12

Genotype 2

Genotype 3

26 23 10 9 38 40 26 2392 17 84 14

Genotype 3Prior treatment > 12 weeks

1FUSION: DR Nelson et al. A6. EASL 20132POSITRON: IM Jacobson et al. A61. EASL 2013

IM Jacobson et al. NEJM 2013;368:1867

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SummaryIFN-Free is inevitable

Challenging populations Cirrhosis Genotype 3?

Dream combo Choice of agents to

choose from Ribavirin is weak Interferon Lambda?

3 bedroom house PRT ~ 4 years+ rent SVR ~ 10 years+

rent

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Questions?

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