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
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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.
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A Major Advance
DAAs
100
2011
PegIFN
80
Standard
IFN
60
2001
RBV
70+
1998
55
1991
42
40
34
39
16
20
6
0
PegIFN/
PegIFN/
RBV
RBV/
12 mos
DAA
Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,
April 27-28, 2011, Silver Spring, MD.
IFN
6 mos
IFN
12 mos
IFN/RBV IFN/RBV
6 mos
12 mos
PegIFN
12 mos
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A Major Step Forward: SVR Rates With BOC
or TVR in GT1 Treatment-Naive Patients
100
SVR (%)
80
63-75
60
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.
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SVR Rates With BOC or TVR in
GT1 Treatment-Experienced Patients
100
PegIFN/RBV
69-83
BOC or TVR + pegIFN/RBV
SVR (%)
80
40-59
60
29-40
40
24-29
20
7-15
5
0
Relapsers[1,2]
Partial
Responders[1,2]
Null
Responders[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;364:24172428. 3. Bronowicki JP, et al. EASL 2012. Abstract 11.
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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
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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
60
33
20
0
80
SVR (%)
SVR (%)
80
40
82
76
60
40
33
20
RESPOND-2* (BOC)[1]
0
REALIZE (TVR)[2]
*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.
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IL28B Genotype Predicts Likelihood of
Achieving SVR in Treatment-Naive Patients
ADVANCE: T12PR48*[2]
SPRINT-2: BOC + PR48[1]
100
100
80
80
71
59
60
40
SVR (%)
SVR (%)
80
20
0
90
71
73
45/
50
48/
68
16/
22
CC
CT
TT
60
40
20
n/
N=
44/
55
82/
115
CC
CT
26/
44
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.
0
n/
N=
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Limited Data and Lower SVR Rates With
Advanced Fibrosis
F0-2
100
80
80
67
SVR (%)
SVR (%)
67
60
38
40
20
0
F3/4
100
60
52
38
40
41
20
n/
N=
123/
328
213/
319
211/
313
48 PR
BOC
RGT
BOC
48
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
0
n/
N=
9/
24
14/
34
22/
42
48 PR
BOC
RGT
BOC
48
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REALIZE: Very Low SVR in Cirrhotic
Previous Null Responders
REALIZE: TVR + PegIFN/RBV in GT1 Previous Relapsers and Nonresponders
Previous Relapsers
Previous Partial
Responders
100
86
85
Pooled T12/PR48
Pbo/PR48
84
80
SVR (%)
Previous Null
Responders
72
56
60
41
40
32
20
n/N =
0
53/
62
2/
15
No,
Bridging
Minimal, or Fibrosis
Portal Fibrosis
48/
57
2/
15
Cirrhosis
20
18
13
13
144/ 12/
167 38
39
34
34/
47
3/
17
10/
18
0/5
No,
Bridging
Minimal, or
Fibrosis
Portal Fibrosis
Stage
Zeuzem S, et al. EASL 2011. Abstract 5.
0
11/
32
1/
5
Cirrhosis
10
6
24/
59
1/
18
14
15/
38
0
0/9
No,
Bridging
Minimal, or Fibrosis
Portal Fibrosis
7/
50
1/
10
Cirrhosis
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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
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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
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Adverse Effects
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Preliminary Real-World Safety Findings:
CUPIC—PIs in Patients With Cirrhosis
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)
Rash
 Grade 3/SCAR
14 (4.8)
0
Hepatic decompensation
6 (2.0)
6 (2.9)
47 (16.1)
13 (6.3)
Blood transfusions
*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.
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Higher Discontinuation Rates in
Real-World Settings Than in Clinical Trials
40
50
Patients (%)
30
498 GT1 Patients
Evaluated[1]
21
20
40
33[2]
10
30
20
22
18
17
11
10
n/N =
0
69/
407
Mild
Disease
89/
407
Patient
Choice
43/
407
Wait for
Better
Therapies
91/
498
174 GT1 Patients Started
TVR-Based Triple Therapy[2]
21
0
D/C
Before
Wk 12
Started Therapy
58/
174
36/
174
D/C TVR Due to
< 12 wks
AEs
Did Not Start
1. Chen EY, et al. AASLD 2012. Abstract 133. 2. Bichoupan K, et al. AASLD 2012. Abstract 1755.
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Tolerability
 Multiple AEs
 Some severe, but mostly manageable
 Creates issues with capacity and experience
 “Discouraging” to some low volume treaters
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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
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Regimens—Many Challenges
For us—lead-in, response-guided therapy . . .
For our patients . . .
Pill Burden
BOC = 12/day
RBV = 4-7/day
Food Requirement
TVR = 6/day
RBV = 4-7/day
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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
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Drug–Drug Interactions
PI
CYP3A4
Metabolites
Substrates and Inhibitors of CYP3A4
Interactions with many common drugs
 Statins
 OCP
 SSRI
 Sildenafil
 Many more
www.hep-druginteractions.org
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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
The future looks bright,
but some challenges remain . . .
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Potent IFN-Free DAA Regimens in
Treatment-Naive Genotype 1
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
SVR4, 12, or 24 (%)
100
Daclatasvir (NS5A) + asunaprevir (PI) +
BMS 791325 (NNI) x 12 wks
100[1]
100[2]
98[3]
97[1]
15/15
25/25
77/79
28/29
94[4]
80
60
40
20
n/N =
0
15/16
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
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Cirrhosis—Still Very Limited Data
SOUND-C2: IFN-Free, Naive[2]
Faldaprevir 120 mg QD + BI 207127
600 mg TID/BID + RBV x 16-40 wks
ASPIRE: Treatment-Experienced[1]
Simeprevir 150 mg QD + PR*
All cirrhotics in trial: n = 39
100
100
82
80
73
60
40
31
20 n/
0
11/
15
9/
11
4/
13
Relapser
Partial
Null
N=
SVR12 (%)
SVR24 (%)
80
All cirrhotics in trial: n = 33
Cirrhosis
No cirrhosis
70
67
60
52
57
40
20
0
n/
N=
11/
21
124/
217
6/
9
TID*
*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.
48/
69
BID
Previous Null Responders
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Previous Null Responders: Triple Therapy
ASPIRE: Simeprevir (PI) +
PegIFN alfa-2a + RBV[1]
100
SILEN-C2: Faldaprevir (PI) +
PegIFN alfa-2a + RBV[2]
Simeprevir 150 mg QD + PR*
PR48
100
85
76
80
60
40
51
37
20
0
n/ 10/ 67/
N = 27 79
Relapser
31
9
52/
2/23 69
Partial
19
3/
16
SVR (%)
SVR24 (%)
80
Faldaprevir 240 mg QD 24 wks
+ PR 48 wks
60
40
20
26/
51
4/
13
Null Null
F4
50
0
35
13/
n/
N = 26
Partial
14/
40
Null
*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.
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Previous Null Responders: Quad Therapy
Daclatasvir (NS5A) + Asunaprevir (PI)
+ PegIFN/RBV x 24 wks (Quad)
90[1]
88% GT1a
93*[2]
61% GT1a
100
84
80
80
SVR12 (%)
SVR12 or 24 (%)
100
Danoprevir/r (PI) + Mericitabine (Nuc)
+ PegIFN/RBV x 24 wks (Quad)[3]
60
40
60
40
20
20
n/N =
9/10
38/41
0
n/N =
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.
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Previous Null Responders: IFN Free
Daclatasvir (NS5A) +
Asunaprevir (PI) x 24 wks
Japan[2]
90
SVR4, 12, or 24 (%)
100
80
2012*[3]
AASLD
78
Japanese Study
10/10 GT1b
United
States[1]
36
60
40
20
n/
N=
0



4/11
US Study
9/11 GT1a
AASLD 2012
GT1b only
9/10
14/18
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.
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Past Treatment May Affect Future Response…
ABT450/r (PI) + ABT-333 (NNI)
+ RBV x 12 wks[1]
SVR
NR
Statistical fluke or
due to previous NR,
RBV resistance?
80
3/6 null
5/11 partial
47
35
60
40
98
93
80
60
40
27
20
20
0
100
SVR (%)
SVR (%)
Relapse
94*
100
ABT-450/r (PI) + ABT-333 (NNI) +
ABT-267 (NS5A) + RBV x 12 wks[2]
n/
N=
0
Naive
31/34
6
3/34
8/17
6/17
3/11
Nonresponders
0
n/
N = 77/79
7
1
0 1/79
Naive
42/45
Nulls
 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.
3/45
0
IFN Ineligible/Intolerant
or Unwilling
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IFN Ineligible/Intolerant or Unwilling
Daclatasvir (NS5A) + Asunaprevir (PI) x 24 Wks (IFN Free)
91
SVR 24 (%)
80
64
60
40
20
n/N =
0
19/21
14/22
Previous
Nulls
IFN
Intolerant/
Ineligible


PegIFN/RBV
Ineligible/Intolerant
Null Responders
HCV RNA (log10 IU/mL)
100
Daclatasvir + Asunaprevir
8
7
6
5
4
3
2
1
0
Daclatasvir + Asunaprevir
Follow-up
8
7
6
5
4
3
2
1
0
N = 21
N = 22
Below LLOQ
Undetectable
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
EOT
SVR24
EOT
SVR24
LLOQ = 15 IU/mL
Time (wks)
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.
Follow-up
Non–Genotype 1 HCV
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Non-GT1: Options Increasing
Sofosbuvir (Nuc) + RBV x 12 wks +
pegIFN x 4-12 wks
Sofosbuvir (Nuc) + RBV x 12 wks
SVR12 or 24 (%)
Sofosbuvir (Nuc) + Daclatasvir (NS5A)
± RBV x 24 wks
100[1]
100[1]
100
96[2]
80
Sofosbuvir (Nuc) + RBV + pegIFN x
24 wks
Danoprevir (PI)/ritonavir + pegIFN + RBV
x 12-24 wks
88[3]
97[4]
68[1]
60
40
20
n/N =
0
29/29
11/11
GT2/3 Naive

27/28
17/25
14/16
29/30
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.
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Advantages of Future Therapies
 Once-daily dosing
 Shorter duration
 Simpler regimens—no RGT
 Fewer AEs
 IFN free
 High efficacy
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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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