The Changing Face of

Hepatitis C Treatment

Nezam H. Afdhal M.D

Professor of Medicine,

Harvard Medical School,

Chief of Hepatology,

Beth Israel Deaconess Medical Center, Boston

2

AMMI Canada

CONFLICT OF INTEREST DISCLOSURE SLIDE

2

In the past 2 years I have been an employee of: BIDMC, HMS

In the past 2 years I have been a consultant of:Gilead, Merck, Echosens, GSK,Vertex, Novartis, Boehringer Ingelheim, Ligand, Springbank, Medgenics, Kadmon, Quest

In the past 2 years I have held investments in the following pharmaceutical organizations, medical devices companies or communications firms:

Springbank, Medgenics

In the past 2 years I have been a member of the Scientific advisory board of:

Gilead, Novartis, Merck, Vertex

In the past 2 years I have been a speaker for: N/A

In the past 2 years I have received research support (grants) from:

Merck, BMS, GSK, Abbott, Gilead

In the past 2 years I have received honoraria from:

Gilead, Merck, Echosens, GSK,Vertex, Novartis, Boehringer Ingelheim, Ligand, Springbank, Medgenics, Kadmon, Quest

I agree to disclose approved and non-approved indications for medications in this presentation:

YES

I agree to use generic names of medications in this presentation:

YES

The Goal of Combination

Regimens

• Different drugs can contribute variably to each goal. Not all components must be direct-acting antivirals (DAAs).

B

C

Prevention of emergent resistance

(pre-existing or de novo)

+

+

AProfound suppression of broad range of viral

variants, including pre-existing variants

3

Milestones in Therapy of CHC:

Average SVR Rates from Clinical Trials

IFN

6m

IFN/RBV

6m

Peg-IFN/

RBV 12m

IFN

12m

IFN/RBV

12m

Peg-IFN

12m

70+%

55%

39%42%34%

16%

6%

0

20

40

60

80

100

2001

1998

2011

Standard

Interferon

Ribavirin

Peginterferon

1991

Direct Acting

Antivirals

Peg-IFN/

RBV/DAA

Adapted from US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD.

Predictors of Response

• Viral Factors

– HCV genotype

– HCV RNA

• Patient Factors

– Race/ethnicity

– Metabolic

– Obesity

– Age

– Advanced disease

• Genetic Contributions

– IL28B polypmorphism

• On treatment Factors

– Selection of regimen

– Duration of regimen

– Expected cumulative dose

exposure / adherence

– Viral response

SVR Rates With BOC or TVR in Genotype 1 Treatment-Naive Patients

0

20

40

60

80

100S

VR

(%

)

PegIFN/RBV BOC or TVR + PegIFN/RBV

38-44

63-75

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

BOC + PR: Adverse Events

Significantly higher rates of anemia, neutropenia and dysgeusia in BOC arms vs control

Adverse event BOC + PR RGT/48n = 1225

PR48 n = 467

Anemia* 50% 30%

Neutropenia 25% 19%

Dysgeusia 35% 16%

Boceprevir capsules. Prescribing information, May 2011.

*Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% PR)

What’s In Our Near Future? More Triple Therapy

• Single DAA plus IFN backbone plus ribavirin (RBV)

– Second-generation PIs

– Nucleoside polymerase inhibitors

– Nonstructural protein (NS)5A inhibitors

• Considerations

– RVR > 90%

– Sustained virologic response (SVR): 80%

– Tolerability and side effects

– RGT

– 12–16 weeks of therapy for IL-28B CC genotype

8

PILLAR Study: TMC435 + Peg-IFN + RBV in

treatment-naïve G1 patients

� Phase IIb, randomized, double-blind study in treatment-naïve, HCV G1, TMC435 (QD oral HCV NS3/4A PI) + Peg-IFNα-2a/RBV (PR)

• Very high SVR in PR group, European study, low BMI

• For PR: Very poor RVR in CC patients, very high SVR in CT and TT >50%

• Hyperbilirubinemia noted especially in 150 mg group

• High RVR rate in TMC 435 groups, appropriate to move to Phase III

• Needs combination information

Fried M et al. AASLD 2011, San Francisco, #LB-5

Response, n/N (%)

TMC435 12WPR RGT

TMC435 24WPR RGT

TMC435 12WPR RGT

TMC435 24WPR RGT

Placebo/PR 48W

75 mg 150 mgN=77

N=78 N=75 N=77 N=79

RVR 59/78 (75.6) 51/75 (68.0) 58/77 (75.3) 59/79 (74.7) 4/77 (5.2)

EOT 72/78 (92.3) 73/75 (97.3) 71/77 (92.2) 74/79 (93.7) 61/77 (79.2)

SVR24 64/78 (82.1)* 56/75 (74.7) 62/77 (80.5)* 68/79 (86.1)** 50/77 (64.9)

SVR W72 63/78 (80.8)* 53/75 (70.7) 60/77 (77.9)* 67/79 (84.8)** 50/77 (64.9)

Viral relapse 8/72 (11.1) 14/72 (19.4) 6/69 (8.7) 6/75 (8.0) 11/62 (17.7)

*p<0.05, **p<0.005, significant difference vs control

12 24

N=327

Sofosbuvir + PEG/RBV: GT 1,4,5,6

Sofosbuvir 400 mg QD + PEG 180 µg/week +

RBV

Study Weeks

SVR 12

NEUTRINO:Treatment-naïve patients, multicenter, open-label study

NEUTRINO SVR12 Results

Overall GT4/5/6GT1

Pa

tie

nts

Ac

hie

vin

g S

VR

12

(%

)

•No on-treatment virologic failure (all relapses)•Most common AEs occurring in ≥20% subjects were fatigue, headache, nausea, insomnia, and anemia

All Oral Therapies: The Drug classes - 2013

12

Efficacy Genotype

independency

Barrier to

resistance

NS3/4A(protease inhibitors) +++ + - ++ + - ++

NS5A +++ + - ++ + - ++

NS5B(nucleosides) + - +++ +++ +++

NS5B(non-nucleosides) + - ++ + +

Cyclophilin

Inhibitors ++ +++ +++

All Oral Therapies: The Drug classes – 2013 - 16

13

Efficacy Genotype

independency

Barrier to

resistance

NS3/4A(protease inhibitors) +++ ++ - +++ ++ - +++

NS5A +++ ++ - +++ ++ - +++

NS5B(nucleosides) + - +++ +++ +++

NS5B(non-nucleosides) ++ + +

Cyclophilin

Inhibitors ++ +++ +++

All Oral Combinations - Timelines

� 2013/14

– NI + RBV (GT 2,3)

� 2014/15

– PI + NNI + RBV (GT 1b)

– PI + NS5A-I + NNI ± RBV (GT 1)

– PI + NS5A-I (GT 1b; off-label ?)

– NI + NS5A-I (pan-GT; off-label)

– NI + PI (GT 1,2,4-6; off-label)

� 2015/16

– NI + NS5A-I (FDC, pan-GT)

– NI + NS5A-I + X

NS5A-Inhibitor

Protease-

Inhibitor (N)NI

Ribavirin

DAA Combination Therapy

Ribavirin

Protease-

Inh.NNI

32

SV

R (

%)

1a non-CC All 1b and 1a-CC

All groups received faldaprevir 120 mg QD for the same duration as BI 207127 (16, 28 or 40 weeks)

TID

16

+

TID

28

+

TID

40

+

BID

28

+

TID

28

-

BI 207127 dosing

Duration (weeks)

RBV +/-

SOUND-C2: SVR according to IL28B and HCV subtype: All groups (ITT)

8/25n/N 40/56 9/24 38/56 9/24 29/53 7/22 47/56 0/11 18/34

ABT-450/r + ABT-333 + RBV for12 weeks in GT1-infected patients

Poordad et al., N Engl J Med 2013;368:45-53.

Virolo

gic

response

rate

s(%

)

Tx-naive (n=19) Tx-naive (n=14) Tx-exp. (n=17)

DAA Combination Therapy

NS5A-I

Ribavirin

Protease-

Inh.NNI

Treatment regimen with ABT-450/r, ABT-267,

ABT-333 and RBV: Study design

• 448 patients

– 358 naive• G1a: 66–70%

• Viral load 6.5 log

• IL28B CC: 27–34%

• No cirrhosis

– 90 null responders

• G1a: 59–62%

• Viral load 6.5 log

• IL28B CC: 2–4%

• No cirrhosis

Kowdley KV, et al. AASLD 2012, Boston, #LB-1

ABT-267 25 mg QD; ABT-333 400 mg BID; RBV weight-based 1000–1200 mg daily doseAll subjects to be followed through 48 weeks post-treatment

n= Wk 0 Wk 8 Wk 12 Wk 24

ABT-450/r Dose (QD)

80

41

79

79

79

80

45

45

43

Tre

atm

ent-

naiv

e

Null

Responders

150/100

150/100

100/100,200/100

150/100

100/100,150/100

100/100,150/100

200/100

100/100,150/100

100/100,150/100

450 267 333 RBV

450 333 RBV

450 267 RBV

450 267 333

450 267 333 RBV

450 267 333 RBV

450 267 333 RBV

450 267 333 RBV

450 267 RBV

12-Week IFN-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and RBV results

Kowdley KV, et al. AASLD 2012, Boston #LB-1

Pro

port

ion o

f patients

(IT

T)

achie

vin

g S

VR

12,

%

Treatment-naive patients Null Responders

8 weeks 12 weeks 12 weeks

ABT-450

ABT-267

ABT-333

RBV

ABT-450

ABT-333

RBV

ABT-450

ABT-267

RBV

ABT-450

ABT-267

ABT-333

ABT-450

ABT-267

ABT-333

RBV

ABT-450

ABT-267

RBV

ABT-450

ABT-267

ABT-333

RBV

DAA Combination Therapy

NS5A-I

Protease-

Inh.

Daclatasvir+Asunaprevir in GT1b ptswith IFN intolerance/null response

• 24 wks of daclatasvir 60 mg QD +

asunaprevir 200 mg BID (N = 43)

– 10 pts received asunaprevir 600 mg BID

• Among pts with virologic breakthrough

(7.0%) or relapse (9.3%), almost all had

trough daclatasvir and asunaprevir

plasma concentrations below median

Suzuki, et al., EASL 2012, A14

Wk 4RVR

Wk 12cEVR

End ofTreatment*

SVR12

HC

V R

NA

Un

de

tec

tab

le (

%)

0

40

60

80

100

20

*End of treatment = Wk 24 or last on-treatment visit for pts who discontinued early.ITT (missing = failure) analysis.

SVR24

Null responders (n = 21)

Ineligible/intolerant (n = 22)

52

86 91 91 91 91 91

6464

86

11/

21

19/

22

19/

21

20/

22

19/

21

19/

21

19/

21

14/

22

14/

22

19/

22

ASV and DCV Trough Plasma Concentrations

in Patients With SVR or Virologic Failure

800

600

400

200

100

100 200 400 600 800 1000

Daclatasvir Ctrough (ng/mL)

Asu

na

pre

vir C

trough

(ng/m

L)

Virologic failures

SVR

Relapse

Breakthrough

*

*

Median 57M

ed

ian

20

1

n/N =

DAA Combination Therapy

NS5A-I

Protease-

Inh.NNI

An IFN-free, RBV-free 12-week regimen of daclatasvir (DCV),

asunaprevir (ASV), and BMS-791325

Everson GT, et al. AASLD 2012, Boston, #LB-3

� AEs

� Headache (31%) and diarrhea (25%) most common

� No grade 3/4 ALT/AST elevations

� Resistance

� No data, no virologic failure to date

HCV RNA

< LLOQTD or TND

24-week (Group 1)

Missing data

HCV RNA

< LLOQTD or TND

12-week (Group 2)

0

20

40

60

80

100

4 12 EOT PT 4(SVR4)

0

20

40

60

80

100

4 12 EOT PT 4 PT 12(SVR4)(SVR12)

Patients

achie

vin

g e

ndpoin

t (%

)

% < LLOQTD or TND

100 94 94 94

100 88 100 94 94

� Limited by small numbers and incomplete SVR12

data, but competitive results

� Addition of a non-nuc. to a NS3 and NS5A adds

incremental benefit in G1a

� Regimen should be evaluated with larger numbers

and more advanced fibrosis

12-week, Group 2, n=16

24-week , Group 1, n=16

DAA Combination Therapy

Ribavirin

Protease-

Inh.NI

COSMOS study: Sofosbuvir + Simeprevir

±±±± RBV in GT1 Null-RespondersWeek 12 Group

96 93

0

25

50

75

100

RBV + RBV -

Sofosbuvir 400 mg QD + Simeprevir 150 mg QD ± RBV x 12 wks

Lawitz et al., CROI 2013, Abstract 155LB

26/27

SVR8wks

(%)

13/14

DAA Combination Therapy

Ribavirin

NI

High efficacy of GS-7977 in combination with low- or full-dose

RBV for 24 weeks in difficult-to-treat G1 patients: SPARE trial

Osinusi A, et al. AASLD 2012, Boston, #LB-4

Part 1: 10 HCV G1 stages 0–2 Part 2: 50 G1 all stages (including CP A)

� In treatment-naive HCV G1, SVR4 in 72% (mITT 75%) who received SOF + full-dose RBV but only in 56% (mITT 64%) in those who received low-dose RBV

� No safety signals or drug-related discontinuations

90 90 90 90 90

0

20

40

60

80

100

Wk 4 Wk 12 ETR SVR4 SVR12

Full-dose RBV (part 1) n=10* 1 drop out at Week 3

96 96 96

72

9688 88

56

0

20

40

60

80

100

Wk 4 Wk 12 ETR SVR 4

Full-dose RBV*1 dropout at Wk 3

Low-dose RBV*3 dropouts by Wk 8

% o

f patients

with

HC

V R

NA

<LLO

Q (

ITT

)

% o

f patients

with

HC

V R

NA

<LLO

Q (

ITT

)

*

*

*

Sofosbuvir Phase 3 Programs: GT2/3

Genotype 2/3(naïve)

Genotype 2/3(IFN ineligible/intolerant)

Sofosbuvir 400mg QD + RBV

Peg-IFN + RBV

N=256

N=243

N=207

N=71

SVR12

SVR12

12 24 36

Sofosbuvir placebo + RBV placebo

SVR12

SVR12

POSITRON

FISSION

Sofosbuvir 400mg QD+ RBV

Study Weeks

Genotype 2/3(treatment-experienced)

N=103

N=98Sofosbuvir 400mg QD +

RBV

SVR12

SVR12

FUSIONSofosbuvir 400mg QD +

RBV

16 28

POSITRON SVR12 Results

overall

Pa

tie

nts

Ac

hie

vin

g S

VR

12

(%

)

GT2 GT3 No Cirrhosis Cirrhosis

•SVR12 rate in placebo recipients was 0%•No on-treatment virologic failure in SOF+RBV arm (all relapses)•Most common AEs occurring in ≥10% subjects were fatigue, nausea, headache, insomnia, pruritus, and anemia

FISSION SVR12 Results

Overall GT2 GT3 No Cirrhosis Cirrhosis

Pa

tie

nts

Ac

hie

vin

g S

VR

12

(%

)

•1 on-treatment virologic failure in SOF+RBV arm due to nonadherence•Most common AEs occurring in ≥20% subjects were fatigue, headache, nausea, and insomnia (all more common in PEG+RBV arm)

FUSION SVR12 Results

Overall GT2 GT3 No Cirrhosis Cirrhosis

Pa

tie

nts

Ac

hie

vin

g S

VR

12

(%

)

•No on-treatment virologic failure (all relapses)•Most common AEs occurring in ≥15% subjects were fatigue, headache, insomnia, and nausea

DAA Combination Therapy

NS5A-I

NI

All-oral combination of daclatasvir plus sofosbuvir

� Adverse events

� Fatigue 29–50%

� Headache 16–38%

� Nausea 16–32%

Sulkowski MS, et al. AASLD 2012, Boston #LB-2

0

20

40

60

80

100

SVR4

HC

V R

NA

<LLO

Q (%

patients

)

Week 4 SVR12EOT SVR24

9488 88

86 93

88

86Genotype 2/3 results Genotype 1 results

� Ribavirin adds no benefit to SOF+DCV

� No safety signals

� Regimen needs evaluation in cirrhosis

� New bar for other regimens to be

compared

SVR4Week 4 SVR12EOT SVR24

C: DCV + SOFA: SOF LI + DCV E: DCV + SOF + RBVD: DCV + SOFB: SOF LI + DCV

F: DCV + SOF + RBV Missing

93

� Virologic failures

� G1: Reinfection

� G3: 1 relapse (baseline A30K); 1 started IFN for LLQ-TD

G: DCV + SOF (12-wk) H: DCV + SOF + RBV (12-wk)

3 pts missing from SVR4 in G and H were SVR 12

SVR12 in G and H 68/68 to date

3636

8.814.7

23.5

32.4 29.4 26.5

4.7

42.2

59.4

73.465.6

60.7

0

20

40

60

80

100

4 8 12 24 EOT SVR12

Treatment Week

PR B/PR

%

HC

V R

NA

Un

dete

cta

ble

3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64

HIV / HCV Co-infection: Virologic Response Over Time† on Bocepravir

10/34 9/3442/64 37/61

† Three patients undetectable at FW4 have not yet reached FW12 and were not

included in SVR12 analysis.

Follow-up

PRSMV

150 mg/PR

PR

Simeprevir: C212 study design

• Primary endpoint: SVR12, safety, and tolerability

• Secondary endpoints: virologic response at other time points, on-treatment failure, and relapse rates

• Interim analysis: – All patients included in the analysis had completed 24 weeks of treatment

or had discontinued prior to that point

– No. of patients:Week 24: N=100Week 28: N=71 Week 36: N=27

• HCV treatment-naive• Relapse

• Partial response• Null response• Cirrhotic patients (F4)

RGT*

Week

12

Interim analysis 24 36 60

SMV 150 mg/PR

PRSMV

150 mg/PRFollow-up

Follow-up

*Response-guided therapy criteria: HCV RNA <25 IU/mL (detectable

or undetectable) at Week 4 and undetectable at Week 12

48 72

PR, pegIFN-α2a + ribavirin; SMV, simeprevir

C212 interim analysis summary

• Simeprevir 150 mg QD + pegIFN/RBV led to high virologic response rates in co-infected patients, regardless of prior response

– SVR12

• Naïve and relapse 77%

– RVR

• Naïve 71%

• Relapse 93%

• Partial response 80%

• Patients who met RGT criteria 88%

– achieved SVR12 75%

• At Week 24, 64% of null responders had not experienced treatment failure

• HIV virologic failure not observed over the study period

• Simeprevir was well tolerated, with a safety profile similar to HCV mono-infected patients

The Future of All Oral Regimen

All Oral Therapies – How They Differentiate ?

1. Genotype dependency

2. Efficacy

– Standard population

– Special populations

3. Treatment duration

– Standard population

– Special populations

4. Resistance

5. Drug-Drug-Interactions

6. Safety and Tolerability

7. Posology, Pill Burden 41

All Oral Therapies – How They Differentiate ?

1. Genotype dependency

2. Efficacy

– Standard population

– Special populations

3. Treatment duration

– Standard population

– Special populations

4. Resistance

5. Drug-Drug-Interactions

6. Safety and Tolerability

7. Compliance, Pill Burden 42

2 DAAs ± RBV vs 3 DAAs ± RBV

43

2 DAAs 2 DAAs + RBV 3 DAAs 3 DAAs + RBV

„Lag“-phase Similar >> Similar

Slope ++ ++ +++ +++

Efficacy ++ ++(+) +++ +++

Assuming - similar efficacy of individual DAA

- no selection of resistant variants

3 vs. 2 DAAs may allow to shorten therapy and improve SVR rates

(at least in more difficult-to-cure patients)

Little if any role of ribavirin in 3 DAAs regimen

2 DAAs vs 3 DAAs in patients with cirrhosis

44

F0-3 (2 DAAs) F4 (2 DAAs) F4 (3 DAAs)

Slope +++ + ++

Efficacy +++ ++ ++(+)

Duration 12 wks 24 wks 12-24 wks

Assuming - similar efficacy of individual DAA

- no selection of resistant variants

All Oral Therapies: The Combinations

� 2013/14

– NI + RBV (GT 2,3)

� 2014/15

– PI + NNI + RBV (GT 1b)

– PI + NS5A-I + NNI ± RBV (GT 1)

– PI + NS5A-I (GT 1b; off-label ?)

– NI + NS5A-I (pan-GT; off-label)

– NI + PI (GT 1,2,4-6; off-label)

� 2015/16

– NI + NS5A-I (FDC, pan-GT)

– NI + NS5A-I + X

NS5A-Inhibitor

Protease-

Inhibitor (N)NI

Ribavirin

The future of HCV therapyStatements and predictions

� Ribavirin will disappear

� 3 DAAs (vs 2 DAAs) may

– further shorten therapy

– lead to higher SVR rates (in particular in cirrhosis)

� Response to previous (IFN-based) therapy will be lessrelevant

� Cirrhosis (more granular differentiated) is expected tobecome the key baseline predictor for SVR

� Some patients may relapse with any DAA combinationand require maintenance therapy

� Peg-IFN may remain a pan-genotypic compound for some(rare) rescue options 46

The future of HCV therapyPotential strategies

Option 1

� Simple (e.g. FDC) regimen for every patient

� Rescue for Relapsers

Option 2

� Highly individualized therapy according to

– Geno/subtype

– Fibrosis stage

– Comorbidity and co-medication (DDI)

– Previous drug exposure, potential baseline RAVs

47

Future of HCV therapyIndividualized Approaches and Rescue options

48

Genotype F0-3 F4 F4 + portal

hypertension

Post-Ltx HIV-HCV

coinfection

Rescue

HCV-1a

NI+NS5 x 12

3 DAA x 12

NI+NS5 x 12-24

3 DAA x 12-16

NI+NS5 x 24 NI+NS5 x 24

NI+PI x 24

NI+NS5 x 24

NI+PI x 24

4 DAA x 24

2 DAA+PR x 24

3DAA+P x 24

HCV-1b

NI+NS5 x 12

2 DAA x 12

3 DAA x 8

NI+NS5 x 12-24

3 DAA x 12-16

NI+NS5 x 24 NI+NS5 x 24

NI+PI x 24

NI+NS5 x 24

NI+PI x 24

4 DAA x 24

2 DAA+PR x 24

3DAA+P x 24

HCV-2

NI+RBV x 12

NI+P Ix 12

3 DAA x 6

NI+NS5 x 12-16

3 DAA x 12

NI+NS5 x 24 NI+NS5 x 24

NI+PI x 24

NI+NS5 x 24

NI+PI x 24

4 DAA x 24

2 DAA+PR x 24

3DAA+P x 24

HCV-3

NI+NS5 x 12

CYPI + NS5 x12

NI+NS5 x 12-24

CYPI + NS5 x 24

NI+NS5 x 24 NI+NS5 x 24 NI+NS5 x 24 4 DAA x 24

2 DAA+PR x 24

3DAA+P x 24

HCV-4

NI+NS5 x 12

NI+PI x 12

3 DAA x 8

NI+NS5 x 12

3 DAA x 12-16

NI+NS5 x 24 NI+NS5 x 24

NI+PI x 24

NI+NS5 x 24

NI+PI x 24

4 DAA x 24

2 DAA+PR x 24

3DAA+P x 24

HCV-5

NI+NS5 x 12

NI+PI x 12

3 DAA x 8

NI+NS5 x 12

3 DAA x 12-16

NI+NS5 x 24 NI+NS5 x 24

NI+PI x 24

NI+NS5 x 24

NI+PI x 24

4 DAA x 24

2 DAA+PR x 24

3DAA+P x 24

HCV-6

NI+NS5 x 12

NI+PI x 12

3 DAA x 8

NI+NS5 x 12

3 DAA x 12-16

NI+NS5 x 24 NI+NS5 x 24

NI+PI x 24

NI+NS5 x 24

NI+PI x 24

4 DAA x 24

2 DAA+PR x 24

3DAA+P x 24