how will new hcv therapies overcome the challenges of current regimens?

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

Supported by an educational grant from Gilead Sciences

Supported by an educational grant from Janssen Therapeutics

Jordan J. Feld, MD, MPHAssistant Professor of MedicineUniversity of TorontoHepatologistToronto Western Hospital Liver CentreMcLaughlin-Rotman Centre for Global HealthToronto, Ontario, Canada

clinicaloptions.com/hepatitis

Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future

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Faculty Disclosures

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

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

SV

R (

%)

IFN6 mos

PegIFN/ RBV

12 mos

IFN12 mos

IFN/RBV12 mos

PegIFN12 mos

2001

1998

2011

StandardIFN

RBV

PegIFN

1991

DAAs

PegIFN/RBV/DAA

IFN/RBV6 mos

6

16

3442 39

55

70+

0

20

40

60

80

100



A Major Step Forward: SVR Rates With BOC or TVR in GT1 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.



SVR Rates With BOC or TVR in GT1 Treatment-Experienced Patients

0

20

40

60

80

100

SV

R (

%)

Relapsers[1,2] Partial Responders[1,2]

69-83PegIFN/RBV

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.

NullResponders[2,3]

BOC or TVR + pegIFN/RBV

24-29

40-59

7-15

29-40

5



Challenges of Current PI-Based Therapy

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

≥ 1 log decline< 1 log decline

0

20

40

60

80

100

SV

R (

%)

33

REALIZE (TVR)[2]

82

*Pooled data from RGT and 48-wk therapy.

0

20

40

60

80

100

SV

R (

%)

33

RESPOND-2* (BOC)[1]

76

HCV RNA Reduction After 4-Wk Lead-in

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

1. Poordad F, et al. Gastroenterology. 2012;143:608-618. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

SPRINT-2: BOC + PR48[1] ADVANCE: T12PR48*[2]

*IL28B testing in ADVANCE was in whites only.

SV

R (

%)

44/55

82/115

26/44

CC CT TT

80

100

80

60

40

20

0

71

59

n/N =

SV

R (

%)

45/50

48/68

16/22

CC CT TT

90100

80

60

40

20

0

71 73

n/N =



Limited Data and Lower SVR Rates With Advanced Fibrosis

SV

R (

%)

123/328

213/319

211/313

48 PR

38

100

80

60

40

20

0

67 67

n/N =

SV

R (

%)

9/24

14/34

22/42

38

100

80

60

40

20

0

41

52

n/N =

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

F0-2 F3/4

BOCRGT

BOC48

48 PR BOCRGT

BOC48



REALIZE: Very Low SVR in Cirrhotic Previous Null Responders

Previous Relapsers Previous Partial Responders

Previous Null Responders

2/15

n/N = 53/62

144/167

12/38 0/5

10/18

34/47

3/17 0/9

15/38

11/32

1/5

No, Minimal, or

Portal Fibrosis

Cirrhosis

Stage

Pooled T12/PR48

Pbo/PR48

2/15

48/57

24/59

1/18 7/

50

1/10

BridgingFibrosis

No, Minimal, or

Portal Fibrosis

CirrhosisBridgingFibrosis

No, Minimal, or

Portal Fibrosis

CirrhosisBridgingFibrosis

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

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

100

0

60

SV

R (

%)

80

40

20

86

32

85

13

84

13

72

18

56

0

34

20

41

6

39

014

10



Efficacy Limitations

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




Efficacy


Tolerability


Regimens


DDIs






Adverse Effects



Safety Outcome, n (%) TVR-Based Treatment (n = 292)

BOC-Based Treatment(n = 205)

Serious AEs 132 (45.2) 67 (32.7)

Premature discontinuation From serious AEs

66 (22.6)43 (14.7)

54 (26.3)15 (7.3)

Death* 5 (2.6) 1 (0.5)

Infection (grade 3/4) 19 (6.5) 5 (2.4)

RashGrade 3/SCAR 14 (4.8) 0

Hepatic decompensation 6 (2.0) 6 (2.9)

Blood transfusions 47 (16.1) 13 (6.3)

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

*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.

Preliminary Real-World Safety Findings: CUPIC—PIs in Patients With Cirrhosis



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

50

40

30

20

10

0

Pat

ien

ts (

%)

n/N =

18

498 GT1 Patients Evaluated[1]

Started Therapy

2217

1169/407

89/407

43/407

Did Not Start

PatientChoice

Wait forBetter

Therapies

MildDisease

Higher Discontinuation Rates in Real-World Settings Than in Clinical Trials

D/CBeforeWk 12

21

40

30

20

10

0

91/498

D/C TVR < 12 wks

58/174

33[2]

21

36/174

174 GT1 Patients StartedTVR-Based Triple Therapy[2]

Due to AEs



Tolerability

Multiple AEs

Some severe, but mostly manageable

Creates issues with capacity and experience

“Discouraging” to some low volume treaters




Efficacy


Tolerability


Regimens


DDIs






Regimens—Many Challenges

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

BOC = 12/dayRBV = 4-7/day

TVR = 6/dayRBV = 4-7/day

Pill Burden Food RequirementFor our patients . . .




Efficacy


Tolerability


Regimens


DDIs






Drug–Drug Interactions

CYP3A4PI Metabolites

Substrates and Inhibitors of CYP3A4

Interactions with many common drugsStatinsOCPSSRISildenafilMany more

www.hep-druginteractions.org




Efficacy


Tolerability


Regimens


DDIs




The future looks bright,but some challenges remain . . .



Potent IFN-Free DAA Regimens in Treatment-Naive Genotype 1

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.

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

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

100

80

60

40

20

0

SV

R4,

12,

or

24 (

%)

n/N =

100[1]

15/15

2-3 DAAs + RBV

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

Daclatasvir (NS5A) + asunaprevir (PI) +BMS 791325 (NNI) x 12 wks

2-3 DAAs, No RBV

28/29

97[1]

94[4]

15/16

98[3]

77/79

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

25/25

100[2]

Sofosbuvir (Nuc) + GS-5885 (NS5A) + RBV x 12 wks

Cirrhosis



Cirrhosis—Still Very Limited Data

*Treatment arms with different durations combined.

Very limited data in patients with cirrhosis Limited safety profile looks promising

7382

0

20

40

60

80

100

Relapser Partial

SV

R24

(%

)

n/N =

11/15

9/11

Null

31

4/13

All cirrhotics in trial: n = 39

52

0

20

40

60

80

100

TID*

SV

R12

(%

)n/N =

11/21

BID

67

6/9

CirrhosisNo cirrhosis

57

124/217

70

48/69

All cirrhotics in trial: n = 33

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

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

Previous Null Responders



Previous Null Responders: Triple Therapy

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

*Treatment arms with different durations combined.

PR48

8576

37

9

0

20

40

60

80

100

Relapser Partial

SV

R24

(%

)

10/27

n/N =

67/79

52/69

Null

51

193/16

26/51

31

4/13

Null F4

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

Faldaprevir 240 mg QD 24 wks + PR 48 wks

50

0

20

40

60

80

100

Partial

SV

R (

%)

n/N =

13/26

Null

35

14/40

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

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

Simeprevir 150 mg QD + PR*

2/23



84

62/74

93*[2]

38/41

Previous Null Responders: Quad Therapy

100

80

60

40

20

0

SV

R12

or

24 (

%)

90[1]

9/10

Quad therapy may be a good option for null responders Well tolerated BUT cirrhotics excluded

*Asunaprevir QD and BID combined.

88% GT1a

n/N =

100

80

60

40

20

0S

VR

12 (

%)

61% GT1a

n/N =

Daclatasvir (NS5A) + Asunaprevir (PI) + PegIFN/RBV x 24 wks (Quad)

Danoprevir/r (PI) + Mericitabine (Nuc)+ PegIFN/RBV x 24 wks (Quad)[3]

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

First IFN-free SVRs in null responders Likely adequate for GT1b but not for GT1a No data in cirrhotics

US Study9/11 GT1a

Japanese Study10/10 GT1b

AASLD 2012GT1b only

100

80

60

40

20

0

36

SV

R4,

12,

or

24 (

%)

United States[1]

90Japan[2]

9/104/11

78

14/18

AASLD 2012*[3]

n/N =

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

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.

*Includes only asunaprevir BID dosing arm.



Past Treatment May Affect Future Response…

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

6

35

94*

47

0

20

40

60

80

100

Naive Nonresponders

SV

R (

%)

31/34n/N = 8/17 6/170 3/34

27

3/11

3/6 null5/11 partial

Statistical fluke ordue to previous NR,

RBV resistance?

98

0

20

40

60

80

100

NaiveS

VR

(%

)n/N = 77/79

Nulls

93

42/45

7

3/45

11/790 0

SVR NR Relapse

*Different doses of ABT450/r combined.

Very high SVR rates in 12 wks Potent combination may overcome null response to PR

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]

IFN Ineligible/Intolerantor Unwilling



64

14/22

IFN Ineligible/Intolerant or Unwilling

100

80

60

40

20

0

SV

R 2

4 (%

)

91

19/21

PreviousNulls

IFNIntolerant/Ineligible

Breakthrough correlated with low plasma drug concentrations

Challenges beyond AEs of IFN Therapy only works if you take your medications

n/N =

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

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

HC

V R

NA

(lo

g10

IU

/mL

)

876543210

N = 21

Null Responders

480 2 4 6 8 10121620242836EOT SVR24

LLOQ = 15 IU/mL Time (wks)

Daclatasvir + Asunaprevir Follow-up

876543210

N = 22

PegIFN/RBV Ineligible/Intolerant

480 2 4 6 8 10121620242836EOT SVR24

Daclatasvir + Asunaprevir Follow-up

Below LLOQ Undetectable

Non–Genotype 1 HCV



Non-GT1: Options IncreasingSofosbuvir (Nuc) + RBV x 12 wks + pegIFN x 4-12 wksSofosbuvir (Nuc) + RBV x 12 wks

Sofosbuvir (Nuc) + Daclatasvir (NS5A) ± RBV x 24 wks

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

Major caveat: no patients with cirrhosis included

100

80

60

40

20

0

SV

R12

or

24 (

%)

n/N = 17/25

68[1]

GT2/3 Experienced

100[1] 100[1]

29/29 11/11

GT2/3 Naive

96[2]

27/28

88[3]

14/16

GT4/6Naive

GT4Naive

97[4]

29/30

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.

Sofosbuvir (Nuc) + RBV + pegIFN x 24 wks



Advantages of Future Therapies

Once-daily dosing

Shorter duration

Simpler regimens—no RGT

Fewer AEs

IFN free

High efficacy



Caveats to Future Therapies

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

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