update on the hcv antiviral pipeline todd s. wills, md spns hcv treatment expansion initiative...
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Update on the HCV Antiviral Pipeline
Todd S. Wills, MDSPNS HCV Treatment Expansion Initiative
Evaluation and Technical Assistance CenterInfectious Disease Specialist
HCV Response Rates in HIV+ and HIV- Patients Treated With PegIFN/RBV
APRICOTHIV Positive
Overall SVR: 40%
PRESCOHIV Positive
Overall SVR: 50%
176 95 191 152 298 140
Soriano V, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV–HIV International Panel AIDS. 2007;21:1073-1089.
Pat
ient
s W
ith S
VR
(%
)
29
62
36
72
46
76
FRIEDHIV NegativeOverall SVR: 56%
GT1/4 GT2/3GT1/4 GT2/3GT1/4 GT2/3
48 Wks of Therapy,600 mg RBV
24, 48, or 72 Wks of Therapy,
Weight-Based RBV
48 Wks of Therapy,Weight-Based RBV
0
20
40
60
80
100
n =
Potential HCV antiviral targets
NS4AC E1 E2/NS1 NS2 NS3 NS5A NS5BNS4B5’ 3’
RNAbindingsite
Envelopeglyco-proteins
Signalpeptide
Serine protease/helicase
RNA dependentRNA polymerase
Internalribosomalentry site
telaprevir, boceprevir
Response TerminologyTerm Time Point HCV RNA Level
Rapid virologic response (RVR)
Wk 4 of therapy Undetectable
Early virologic response (EVR)
Wk 12 of therapy ≥ 2 log10 IU decrease from baseline
Complete early virologic response (cEVR)
Wk 12 of therapy Undetectable
Slow to respond Wk 24 of therapy Undetectable (but with detectable HCV RNA at Wk 12)
End of treatment response (EOT or ETR)
End of therapy Undetectable
Sustained virologic response (SVR)
6 mos posttherapy Undetectable
Adherence• Triple therapy presents
challenges with already busy schedules[143]
– TID dosing– Food requirements
• Data show pegIFN/RBV adherence decreases over time[5]
– Addition of PIs may exacerbate this trend
1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011. 3. EMA. Boceprevir [package insert] 2011.4. EMA. Telaprevir [package insert] 2011. 5. Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.
6:00 AM
7:00 AM
8:00 AM
9:00 AM
10:00 AM
11:00 AM
12:00 PM
1:00 PM
2:00 PMTVR/BOC
(with food)TVR/BOC
(with food)TVR/BOC (with
food)
3:00 PM
4:00 PM
5:00 PM
6:00 PM Dinner RBV RBV RBV
7:00 PM
8:00 PM
9:00 PM
10:00 PM
Dinner
Dentist Appt
Travel to and Meet With
Clients
Patient Appointments
Study Group
Chemistry Lab
Biology
English Composition
Lunch
TVR/BOC (with food) + RBV
Monday
Work
Monday
TVR/BOC (with food) + RBV
Lunch
TVR/BOC (with food)
Daily Team Conference Call
Typical Student Busy Sales Professional Mother With Small Children and Full-time Nurse
Monday
TVR/BOC (with food) + RBVWake, feed, and dress children
for schoolSchool and daycare drop-off,
commute to work
Patient Appointments
Lunch
TVR/BOC (with food)
Travel to and Meet With Client
Calls to Clients
Running Club
Researching Trade Articles
Dinner
TVR/BOC (with food)
Dinner cleanup, make lunches for next day
Pick up kids, commute home
Get children ready for and in to bed
from Clinical Care Options
Sulkowski M, et al. CROI 2011. Abstract 146LB.
Study 110: High Rates of Early Response With TVR + PR in Coinfected Patients
• Similar efficacy results observed with or without concurrent ART• Nausea, pruritus, dizziness, fever more common with TVR vs placebo• Pharmacokinetic interactions with ATV or EFV not clinically significant
Undetectable HCV RNA, Week 4 (ITT)
100
80
60
40
20
0
Und
etec
tabl
e H
CV
RN
A (
%)
Telaprevir + PR PR
012
50
71 7564 70
n/N = 5/7 12/16 9/14 26/37 0/6 1/8 0/8 1/22
No ARTEFV-based ART
ATV/RTV-based ARTTotal
Undetectable HCV RNA, Week 12 (ITT)
100
80
60
40
20
0
Telaprevir + PR PR
17 12 1412
71 75
5768
n/N = 5/7 12/16 8/14 25/37 1/6 1/8 1/8 3/22
Und
etec
tabl
e H
CV
RN
A (
%)
Study 110 – SVR 12 Data
Telaprevir Group N=38 Placebo Group
SVR12 28/38 (74) 10/22 (45)
On Treatment Virologic Failure
3/38 (8) 8/22 (36)
Not Suppressed at End of Treatment
5/37 (14) 9/22 (41)
Relapse 1/32 (3) 2/13 (15)
Dieterich D, et al. CROI 2012 Abstract 46
Telaprevir plus PegINF and Ribavirin in HIV/HCV Infected Patients – Side Effects
Adverse Effect TVR+PR PR
Pruritis or Itching 39% 9%
Headache 37% 27%
Nausea 34% 23%
Skin Rash* 34% 23%
Fever 21% 9%
Anemia 13% 18%
Depression 21% 9%
Insomnia 13% 23%
*no cases of severe rash
Sherman, KE et al.. AASLD Conference November 2011 – Late Breaker Abstract 8
Boceprevir in Addition to Pegylated INF alfa 2a in HIV/HCV Patients on ARVs
Sulkowski, M. CROI 2012 Abstract 47
PSI-7977 – Phase II Trial Data HCV uridine nucleotide analogue
12 WEEK Treatment PSI-7977/P/Rn=47
PSI 7977/P/Rn=54
PSI 7977/Rn=10
PSI-7977n=10
EOT 43 54 10 10
Week 1-4 Relapse 1 0 0 4
SVR 4 42 54 10 6
> Wk 4 relapse 0 0 0 0
SVR 12 42 54 10 pending
SVR 24 42 41 (11 pend) 4 (6 pend) pending
Genotype 1
Genotype 2/3
Lawritz, E. et al. J of Hepatology 54 (s1) 2012
TMC-435 – Phase IIb trial data• HCV NS3/4A Protease Inhibitor (Once-Daily)
• Prior Treatment FailuresTMC12/PR48 n=66
TMC24/PR48N=65
TMC48/PR48N=66
TMC12/PR48n-=66
TMC24/PR48N=68
TMC48/PR48N=65
Pbo48/PR48N=66
RVR Total 44/66 (67)
38/65 (59)
35/66 (53)
41/66 (62)
46/68 (68)
43/65 (66)
1/66 (2)
SVR Total 46/66 (70)
43/65 (66)
40/66 (61)
44/66 (67)
49/68 (72)
52/65 (80)
15/66 (23)
SVR Null 6/16 (38)
9/16 (56)
8/18 (44)
9/17 (53)
7/17 (41) 10/17 (59)
3/16 (19)
SVR Partial 16/23 (70)
11/23 (48)
12/22 (55)
15/23 (65)
18/24 (75)
19/22 (86)
2/23 (9)
SVR Relapse
24/27 (89)
23/26 (89)
20/26 (77)
20/26 (77)
24/37 (89)
23/26 (89)
10/27 (37)
100 mg
150 mg
P<0.001 vs placebo
Zeuzem S., et al. J of Hepatology 54 (s1) 2012
Interferon Sparing Strategies
• ABT 450/r – ritonovir boosted HCV PI +• ABT 072 – HCV polymerase inhibitor +
• Weight-based ribavirin
• Open label 12 week treatment trial 11 patients• Interferon sparing
• 91% SVR24• One patient relapsed 8 weeks post Rx
• All patients were IL28B CC
Lawitz, E. et al. Of Hepatology 56(s1) 2012
Interferon AND Ribavirin Sparing Strategies• Daclatasvir (NS5A replication complex inhibitor) +• Asunaprevir (HCV NS3 PI)• Open label trial of both drugs in 43 prior null responders or
with IFN/R intolerance
Null Responders N=21
IFN/R Ineligible or Intolerant N=22
IL28B CC 3/21 (14.3) 16/22 (72.7)
RVR 11/21 (52.4) 19/22 (86.4)
cEVR 19/21 (90.5) 20/22 (90.9)
EOT 18/21 (85.7) 16/22 (72.7)
SVR 12 19/21 (90.5) 14/22 (63.6)
Suzuki, F. et al. J of Hepatology 56 (s1) 2012