how will new hcv therapies overcome the challenges of current regimens?
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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
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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
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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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
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
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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.
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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
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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
≥ 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.
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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 =
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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
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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
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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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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
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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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
Adverse Effects
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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
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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
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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
Tolerability
Multiple AEs
Some severe, but mostly manageable
Creates issues with capacity and experience
“Discouraging” to some low volume treaters
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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
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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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
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 . . .
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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
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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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
Drug–Drug Interactions
CYP3A4PI Metabolites
Substrates and Inhibitors of CYP3A4
Interactions with many common drugsStatinsOCPSSRISildenafilMany more
www.hep-druginteractions.org
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Treat or Wait in HCV? Meeting Clinical Challenges as Present Meets Future
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
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
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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
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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
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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.
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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.
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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
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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
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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
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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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