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How Will New HCV Therapies Overcome the Challenges of Current Regimens?. Jordan J. Feld, MD, MPH Assistant Professor of Medicine University of Toronto Hepatologist Toronto Western Hospital Liver Centre McLaughlin-Rotman Centre for Global Health Toronto, Ontario, Canada.

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How will new hcv therapies overcome the challenges of current regimens

How Will New HCV Therapies Overcome the Challenges of Current Regimens?

Jordan J. Feld, MD, MPH

Assistant Professor of Medicine

University of Toronto

Hepatologist

Toronto Western Hospital Liver Centre

McLaughlin-Rotman Centre for Global Health

Toronto, Ontario, Canada

Supported by an educational grant from Gilead Sciences

Supported by an educational grant from Janssen Therapeutics


About these slides
About These Slides Current Regimens?

  • Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent

  • These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])

DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.


Faculty disclosures
Faculty Disclosures Current Regimens?

Jordan J. Feld, MD, MPH, has disclosed that he has received consulting fees from Abbott, Boehringer Ingelheim, Gilead Sciences, Merck, Roche, and Vertex and fees for non-CME services from Abbott and Merck.


A major advance
A Major Advance Current Regimens?

DAAs

100

2011

PegIFN

2001

RBV

80

70+

Standard

IFN

1998

55

60

1991

SVR (%)

42

39

40

34

16

20

6

0

IFN

12 mos

IFN/RBV

6 mos

IFN/RBV

12 mos

PegIFN

12 mos

PegIFN/ RBV 12 mos

IFN

6 mos

PegIFN/

RBV/

DAA

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


A major step forward svr rates with boc or tvr in gt1 treatment naive patients
A Major Step Forward: SVR Rates With BOC or TVR in GT1 Treatment-Naive Patients

100

80

63-75

60

SVR (%)

38-44

40

20

0

PegIFN/RBV

BOC or TVR + PegIFN/RBV

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


Svr rates with boc or tvr in gt1 treatment experienced patients
SVR Rates With BOC or TVR in Treatment-Naive PatientsGT1 Treatment-Experienced Patients

100

PegIFN/RBV

69-83

BOC or TVR + pegIFN/RBV

80

40-59

60

SVR (%)

29-40

40

24-29

20

7-15

5

0

Relapsers[1,2]

Partial Responders[1,2]

NullResponders[2,3]

1. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 2. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 3. Bronowicki JP, et al. EASL 2012. Abstract 11.


Challenges of current pi based therapy
Challenges of Current PI-Based Therapy Treatment-Naive Patients

  • Efficacy

    • Very dependent on the IFN response

  • Tolerability

    • Additional AEs beyond pegIFN/RBV

  • Regimens

    • Complicated (lead-in, RGT)/pill burden

  • DDIs

    • Many with both agents to common drugs

  • Genotype/special populations

    • Limited activity in non-GT1, limited data HIV/OLTx, ESRD


Likelihood of svr and risk of resistance related to ifn responsiveness
Likelihood of SVR and Risk of Resistance Related to IFN Responsiveness

HCV RNA Reduction After 4-Wk Lead-in

≥ 1 log decline

< 1 log decline

100

100

82

80

76

80

60

60

SVR (%)

SVR (%)

40

33

40

33

20

20

0

0

REALIZE (TVR)[2]

RESPOND-2* (BOC)[1]

*Pooled data from RGT and 48-wk therapy.

1. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 2. Foster G, et al. EASL 2011. Abstract 6.


Il28b genotype predicts likelihood of achieving svr in treatment naive patients
IL28B Responsiveness Genotype Predicts Likelihood of Achieving SVR in Treatment-Naive Patients

ADVANCE: T12PR48*[2]

SPRINT-2: BOC + PR48[1]

100

100

SVR (%)

SVR (%)

90

80

80

80

73

71

71

59

60

60

40

40

20

20

n/N =

n/N =

45/50

48/68

16/22

44/55

82/115

26/44

0

0

CC CT TT

CC CT TT

*IL28B testing in ADVANCE was in whites only.

1. Poordad F, et al. Gastroenterology. 2012;143:608-618.

2. Jacobson IM, et al. EASL 2011. Abstract 1369.


Limited data and lower svr rates with advanced fibrosis
Limited Data and Lower SVR Rates With Advanced Fibrosis Responsiveness

F0-2

F3/4

100

100

SVR (%)

SVR (%)

80

80

67

67

60

60

52

41

38

38

40

40

20

20

n/N =

n/N =

9/

24

14/

34

22/

42

123/

328

213/

319

211/

313

0

0

BOC48

BOCRGT

BOC48

BOCRGT

48 PR

48 PR

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


Realize very low svr in cirrhotic previous null responders
REALIZE: Very Low SVR in Cirrhotic Previous Null Responders Responsiveness

REALIZE: TVR + PegIFN/RBV in GT1 Previous Relapsers and Nonresponders

Previous Relapsers

Previous Partial Responders

Previous Null Responders

100

86

85

Pooled T12/PR48

84

Pbo/PR48

80

72

56

60

SVR (%)

41

39

40

34

32

10

20

6

18

20

14

1/10

13

13

1/18

0

0

144/167

12/38

53/62

15/38

2/15

48/57

2/15

34/47

3/17

10/18

11/32

1/5

24/59

7/50

n/N =

0/5

0/9

0

No, Minimal, or Portal Fibrosis

BridgingFibrosis

Cirrhosis

No, Minimal, or Portal Fibrosis

BridgingFibrosis

Cirrhosis

No, Minimal, or Portal Fibrosis

BridgingFibrosis

Cirrhosis

Stage

Zeuzem S, et al. EASL 2011. Abstract 5.


Efficacy limitations
Efficacy Limitations Responsiveness

  • Dependent on response to pegIFN/RBV

  • Limited efficacy in poor IFN responders

    • Cirrhosis, IL28B non-CC, black patients

    • Prior nonresponders, particularly nulls

  • Treatment failure—high rate of resistance

    • May affect future treatment options


Challenges of current pi based therapy1
Challenges of Current PI-Based Therapy Responsiveness

  • Efficacy

    • Very dependent on the IFN response

  • Tolerability

    • Additional AEs beyond pegIFN/RBV

  • Regimens

    • Complicated (lead-in, RGT)/pill burden

  • DDIs

    • Many with both agents to common drugs

  • Genotype/special populations

    • Limited activity in non-GT1, limited data HIV/OLTx, ESRD


Adverse effects
Adverse Effects Responsiveness


Preliminary real world safety findings cupic pis in patients with cirrhosis
Preliminary Real-World Safety Findings: CUPIC—PIs in Patients With Cirrhosis

*Causes of death in patients treated with TVR: septicemia, septic shock, pneumopathy, esophageal varices bleeding, endocarditis; causes of death in patients treated with BOC: pneumopathy.

Hezode C, et al. EASL 2012. Abstract 8.


Higher discontinuation rates in real world settings than in clinical trials
Higher Discontinuation Rates in Patients With CirrhosisReal-World Settings Than in Clinical Trials

40

30

498 GT1 Patients Evaluated[1]

174 GT1 Patients StartedTVR-Based Triple Therapy[2]

21

50

20

40

33[2]

10

30

21

Patients (%)

22

0

18

17

20

D/CBeforeWk 12

11

10

91/

498

69/

407

89/

407

43/

407

58/

174

36/

174

n/N =

0

D/C TVR

< 12 wks

Due to

AEs

Started Therapy

PatientChoice

Wait forBetterTherapies

MildDisease

Did Not Start

1. Chen EY, et al. AASLD 2012. Abstract 133. 2. Bichoupan K, et al. AASLD 2012. Abstract 1755.


Tolerability
Tolerability Patients With Cirrhosis

  • Multiple AEs

  • Some severe, but mostly manageable

  • Creates issues with capacity and experience

  • “Discouraging” to some low volume treaters


Challenges of current pi based therapy2
Challenges of Current PI-Based Therapy Patients With Cirrhosis

  • Efficacy

    • Very dependent on the IFN response

  • Tolerability

    • Additional AEs beyond pegIFN/RBV

  • Regimens

    • Complicated (lead-in, RGT)/pill burden

  • DDIs

    • Many with both agents to common drugs

  • Genotype/special populations

    • Limited activity in non-GT1, limited data HIV/OLTx, ESRD


Regimens many challenges
Regimens—Many Challenges Patients With Cirrhosis

For us—lead-in, response-guided therapy . . .

For our patients . . .

Pill Burden

Food Requirement

BOC = 12/day

RBV = 4-7/day

TVR = 6/day

RBV = 4-7/day


Challenges of current pi based therapy3
Challenges of Current PI-Based Therapy Patients With Cirrhosis

  • Efficacy

    • Very dependent on the IFN response

  • Tolerability

    • Additional AEs beyond pegIFN/RBV

  • Regimens

    • Complicated (lead-in, RGT)/pill burden

  • DDIs

    • Many with both agents to common drugs

  • Genotype/special populations

    • Limited activity in non-GT1, limited data HIV/OLTx, ESRD


Drug drug interactions
Drug–Drug Interactions Patients With Cirrhosis

Substrates and Inhibitors of CYP3A4

Interactions with many common drugs

  • Statins

  • OCP

  • SSRI

  • Sildenafil

  • Many more

PI

Metabolites

CYP3A4

www.hep-druginteractions.org


Challenges of current pi based therapy4
Challenges of Current PI-Based Therapy Patients With Cirrhosis

  • Efficacy

    • Very dependent on the IFN response

  • Tolerability

    • Additional AEs beyond pegIFN/RBV

  • Regimens

    • Complicated (lead-in, RGT)/pill burden

  • DDIs

    • Many with both agents to common drugs

  • Genotype/special populations

    • Limited activity in non-GT1, limited data HIV/OLTx, ESRD


The future looks bright but some challenges remain
The future looks bright, Patients With Cirrhosisbut some challenges remain . . .


Potent ifn free daa regimens in treatment naive genotype 1
Potent IFN-Free DAA Regimens in Treatment-Naive Genotype 1 Patients With Cirrhosis

ABT-450/r (PI) + ABT-333 (NNI)

+ ABT-267 (NS5A) + RBV x 12 wks

Sofosbuvir (Nuc) + daclatasvir

(NS5A) + RBV x 24 wks

Sofosbuvir (Nuc) + daclatasvir (NS5A) x 24 wks

Sofosbuvir (Nuc) + GS-5885

(NS5A) + RBV x 12 wks

Daclatasvir (NS5A) + asunaprevir (PI) +

BMS 791325 (NNI) x 12 wks

100[2]

100[1]

98[3]

97[1]

100

94[4]

80

60

SVR4, 12, or 24 (%)

40

20

n/N =

15/15

77/79

28/29

15/16

25/25

0

2-3 DAAs + RBV

2-3 DAAs, No RBV

  • Major caveats: small n, no/few patients with cirrhosis

1. Sulkowski M, et al. AASLD 2012. Abstract LB-2. 2. Gane E, et al. AASLD 2012. Abstract 229.3. Kowdley KV, et al. AASLD 2012. Abstract LB-1. 4. Everson G, et al. AASLD 2012. Abstract LB-3.


Cirrhosis
Cirrhosis Patients With Cirrhosis


Cirrhosis still very limited data
Cirrhosis—Still Very Limited Data Patients With Cirrhosis

ASPIRE: Treatment-Experienced[1]

Simeprevir 150 mg QD + PR*

SOUND-C2: IFN-Free, Naive[2]

Faldaprevir 120 mg QD + BI 207127 600 mg TID/BID + RBV x 16-40 wks

All cirrhotics in trial: n = 39

All cirrhotics in trial: n = 33

100

Cirrhosis

100

No cirrhosis

82

80

80

73

70

67

57

60

60

52

SVR12 (%)

SVR24 (%)

40

40

31

20

20

n/N =

11/

15

9/

11

4/

13

n/N =

11/

21

124/

217

6/

9

48/

69

0

0

TID*

Relapser

Partial

Null

BID

*Treatment arms with different durations combined.

  • Very limited data in patients with cirrhosis

  • Limited safety profile looks promising

1. Zeuzem S, et al. EASL 2012. Abstract 2. 2. Soriano V, et al. AASLD 2012. Abstract 84.


Previous null responders
Previous Null Responders Patients With Cirrhosis


Previous null responders triple therapy
Previous Null Responders: Triple Therapy Patients With Cirrhosis

ASPIRE: Simeprevir (PI) + PegIFN alfa-2a + RBV[1]

SILEN-C2: Faldaprevir (PI) + PegIFN alfa-2a + RBV[2]

Simeprevir 150 mg QD + PR*

PR48

Faldaprevir 240 mg QD 24 wks

+ PR 48 wks

100

100

85

76

80

80

60

60

51

50

SVR24 (%)

SVR (%)

37

40

40

35

31

19

20

20

13/

26

14/

40

n/N =

9

67/

79

52/

69

26/

51

4/

13

n/N =

10/

27

3/

16

2/23

0

0

Null

F4

Null

Relapser

Partial

Null

Partial

*Treatment arms with different durations combined.

Modest benefit in efficacy—but once-daily dosing/fewer AEs

1. Jacobson IM, et al. IDSA 2012. 2. Sulkowski M, et al. EASL 2011. Abstract 66.


Previous null responders quad therapy
Previous Null Responders: Quad Therapy Patients With Cirrhosis

Daclatasvir (NS5A) + Asunaprevir (PI)

+ PegIFN/RBV x 24 wks (Quad)

Danoprevir/r (PI) + Mericitabine (Nuc)

+ PegIFN/RBV x 24 wks (Quad)[3]

88% GT1a

61% GT1a

100

100

93*[2]

90[1]

80

84

80

60

60

SVR12 (%)

SVR12 or 24 (%)

40

40

20

20

n/N =

n/N =

9/10

38/41

0

62/74

0

*Asunaprevir QD and BID combined.

  • Quad therapy may be a good option for null responders

  • Well tolerated BUT cirrhotics excluded

1. Lok AS, et al. N Engl J Med. 2012;366:216-224. 2. Lok AS, et al. AASLD 2012. Abstract 79.

3. Feld JJ, et al. AASLD 2012. Abstract 81.


Previous null responders ifn free
Previous Null Responders: IFN Free Patients With Cirrhosis

Daclatasvir (NS5A) + Asunaprevir (PI) x 24 wks

Japan[2]

100

90

AASLD 2012*[3]

78

80

US Study

9/11 GT1a

Japanese Study

10/10 GT1b

AASLD 2012

GT1b only

United States[1]

60

SVR4, 12, or 24 (%)

36

40

20

n/

N =

14/18

4/11

9/10

0

  • First IFN-free SVRs in null responders

  • Likely adequate for GT1b but not for GT1a

  • No data in cirrhotics

*Includes only asunaprevir BID dosing arm.

1. Lok AS, et al. N Engl J Med. 2012;366:216-224. 2. Chayama K, et al. AASLD 2011. Abstract LB-4.

3. Lok AS, et al. AASLD 2012. Abstract 79.


Past treatment may affect future response
Past Treatment May Affect Future Response… Patients With Cirrhosis

ABT450/r (PI) + ABT-333 (NNI) + RBV x 12 wks[1]

ABT-450/r (PI) + ABT-333 (NNI) +ABT-267 (NS5A) + RBV x 12 wks[2]

SVR NR Relapse

98

100

94*

100

93

Statistical fluke or

due to previous NR,

RBV resistance?

80

80

3/6 null

5/11 partial

60

60

SVR (%)

47

SVR (%)

40

35

40

27

20

20

7

1

6

n/N =

n/N =

0

0

0

77/79

42/45

3/45

1/79

31/34

3/34

8/17

6/17

3/11

0

0

Naive

Nulls

Naive

Nonresponders

  • Very high SVR rates in 12 wks

  • Potent combination may overcome null response to PR

*Different doses of ABT450/r combined.

1. Poordad, et al. EASL 2012. Abstract. 2.Kowdley KV, et al. AASLD 2012. Abstract LB-1.


Ifn ineligible intolerant or unwilling
IFN Ineligible/Intolerant Patients With Cirrhosisor Unwilling


Ifn ineligible intolerant or unwilling1
IFN Ineligible/Intolerant or Unwilling Patients With Cirrhosis

Daclatasvir (NS5A) + Asunaprevir (PI) x 24 Wks (IFN Free)

100

PegIFN/RBV Ineligible/Intolerant

91

Null Responders

Daclatasvir + Asunaprevir

Follow-up

Daclatasvir + Asunaprevir

Follow-up

80

8

8

64

N = 22

N = 21

7

7

6

6

60

5

5

SVR 24 (%)

4

4

HCV RNA (log10 IU/mL)

3

3

40

2

2

Below LLOQ Undetectable

1

1

20

0

0

0

2

4

6

8

10

12

16

20

24

28

36

48

0

2

4

6

8

10

12

16

20

24

28

36

48

n/N =

19/21

14/22

EOT

SVR24

EOT

SVR24

0

Time (wks)

LLOQ = 15 IU/mL

PreviousNulls

IFN

Intolerant/

Ineligible

Breakthrough correlated with low plasma drug concentrations

  • Challenges beyond AEs of IFN

  • Therapy only works if you take your medications

Suzuki F, et al. EASL 2012. Abstract 14.


Non genotype 1 hcv
Non–Genotype 1 HCV Patients With Cirrhosis


Non gt1 options increasing
Non-GT1: Options Increasing Patients With Cirrhosis

Sofosbuvir (Nuc) + RBV + pegIFN x 24 wks

Sofosbuvir (Nuc) + RBV x 12 wks + pegIFN x 4-12 wks

Danoprevir (PI)/ritonavir + pegIFN + RBV x 12-24 wks

Sofosbuvir (Nuc) + RBV x 12 wks

Sofosbuvir (Nuc) + Daclatasvir (NS5A)

± RBV x 24 wks

100[1]

100[1]

97[4]

100

96[2]

88[3]

80

68[1]

60

SVR12 or 24 (%)

40

20

n/N =

29/29

11/11

27/28

17/25

14/16

29/30

0

GT2/3 Naive

GT2/3

Experienced

GT4/6

Naive

GT4

Naive

  • Major caveat: no patients with cirrhosis included

1. Gane EJ, et al. AASLD 2012. Abstract 229. 2. Sulkowski M, et al. AASLD 2012. Abstract LB-2. 3. Hassanein T, et al. AASLD 2012. Abstract 230. 4. Hezode C, et al. AASLD 2012. Abstract 760.


Advantages of future therapies
Advantages of Future Therapies Patients With Cirrhosis

  • Once-daily dosing

  • Shorter duration

  • Simpler regimens—no RGT

  • Fewer AEs

  • IFN free

  • High efficacy


Caveats to future therapies
Caveats to Future Therapies Patients With Cirrhosis

  • Very small studies

  • Potential for toxicity remains

    • Agents from multiple classes (nucs, nonnucs, PI, alisporivir) pulled for toxicity

  • Efficacy and safety in cirrhosis largely unknown

  • Minimal data—DDIs, special populations (OLTx, HIV, ESRD)

  • Timelines uncertain

    • Not just approval, but availability and reimbursement

  • Costs uncertain, but likely an issue in many regions


Go online for more cco programming on hcv
Go Online for More CCO Patients With CirrhosisProgramming on HCV

clinicaloptions.com/hepatitis


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