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Ronald D’Amico, DO, MSc
10th Annual Health Disparities Summit April 22, 2013
Interferon-free, oral DAA therapy for HCV Infection
Outline
Epidemiology of HCV in African Americans
Protease Inhibitor based Standard of Care (SOC)
Interferon free therapy
• PILOT/CO-PILOT
• AVIATOR
• ELECTRON and SPARE trials
• DCV/SOF and DCV/ASV/BMS791325
• SOUND-C2
Presentation Title | Date xx.xx.xx | Company Confidential © 2012 2
Epidemiology of HCV in African Americans
• The NHANES III survey estimated that 1.8% (3.9 million) of the U.S. population had a positive HCV antibody test with a rate significantly higher in blacks compared to whites (3.2% versus 1.5%).
• 74% of the 3.9 million individuals in the US had chronic infection with the rate of viremia higher in blacks compared to whites (86% versus 68%) and the rate of clearance lower.
• African Americans were more likely to be infected with genotype 1 virus (88%) than were non-African Americans (67%).
– Although HCV RNA levels were similar, liver enzymes (ALT) were lower in African Americans
• Black men had higher rates of infection with the highest prevalence rate (9.8%) among black males ages 40 to 49 years.
– After adjusting for socioeconomic status and high-risk behaviors, race was not a risk factor for HCV infection.
• Although the prevalence of HCV is greater in African Americans, natural history data has suggested a more favorable outcome for African Americans.
– African Americans had less inflammation and fibrosis in their liver biopsies, and there was a trend toward less cirrhosis (22% versus 30%).
Alter et al, NEJM 1999; 341: 556-62; Wiley et al, Am J Gastroenterol 2002;97:700-706;Pearlman et al. CID 2006; 42:82-91
Rates of HCV Seroprevalence among African Americans and White Populations
Pearlman B L Clin Infect Dis. 2006;42:82-91
Cirrhosis
Liver failure HCC Death
Acute infection
Chronic infection
Viral clearance
~80%
~20%
~20%
Stable or slowly progressive
Natural History of HCV Infection
Factors associated with accelerated progression:
• Alcohol • HIV co-infection • Fatty liver • Older age at infection • Duration of infection • Being Caucasians or Hispanic
compared to African Americans Kohla M Dig Dis Sci 2012; 57:771-76
What is the effect of race on treatment outcomes?
African Americans with lower SVR rates compared to Caucasians with IFN-based therapy
Conjeevaram H et al,Gastroenterology 2006; 131:470-477; Muir A NEJM 2004; 350:22:2265
Host genetics and responsiveness to interferon-containing therapy
Favorable genetic change near IFN gene (IL-28bCC): predictive of response - regardless of race
Ge et al, Nature 2009
Why do African Americans have lower treatment responses to interferon?
Ge et al, Nature 2009
Low prevalence of favorable
genotype (IL-28b-CC)
Do directly-acting agents on the hepatitis C virus make a difference in treatment response rates?
Higher SVR rates with PI based triple therapy compared to dual therapy among blacks
P/R/BOC24
...but still lower response rates compared to non-black
cohort
...and optimal responses require a longer duration of
therapy in AAs
Poordad NEJM 2011; 364:1196
FDA approved in 2011 Boceprevir Telaprevir
Adverse events associated with PEG-IFN/Ribavirin
•Fatigue and flu-like symptoms
•Loss of appetite/weight loss
•Thyroid abnormalities
•Nausea, diarrhea, headache
•Risk of teratogenicity with ribavirin
Low enrollment rates of African-Americans in clinical trials
•Barriers:
•Constitutional neutropenia seen in blacks
•Abnormal creatinine
•Uncontrolled diabetes
Melia M et al. Hepatology 2011; 54:70-78
IFN free, all oral DAA combinations for HCV Infection Clinical Trial Results
Life Cycle of HCV (+ Strand, Enveloped RNA Virus)
HCV NS3 protease inhibitors
HCV NS5B polymerase inhibitors
Moradpour, D., Penin, F., & Rice, C.M. 2007. Replication of hepatitis C virus. Nature Reviews Microbiology 5: 453-463.
HCV NS5A inhibitors
(a) Virus binding and internalization (liver cell)
(b) Uncoating and cytoplasmic release of viral RNA
(c) Protein translation and polyprotein processing
(d) RNA replication (e) Packaging and assembly
(f) Virion maturation and release
Characteristics of HCV DAA Classes
Characteristic Protease
Inhibitors
Nucleos(t)ide
Polymerase
Inhibitors
Nonnucleoside
Polymerase
Inhibitors
NS5A
Inhibitors
Potency High; variable among HCV genotypes
Moderate-high; consistent across genotype, subtype
Variable; variable among HCV genotypes
High; multiple HCV
genotypes
Barrier to
resistance
Low 1a < 1b
High 1a = 1b
Very low 1a < 1b
Low 1a < 1b
Drug interaction
potential
High Low Variable Low to moderate
Toxicity
Rash; anemia; bilirubin
Mitochondrial; nuc interactions
(ART)
Variable
Variable
Pharmacokinetics Variable; QD to TID
QD Variable; QD to TID
QD
Comments 2nd-generation PIs: better barrier,
pangenotypic
Single target; good tolerability in agents progressing in PhIII
Many targets
Multiple antiviral MOA
Direct Acting Antivirals (DAA) for HCV Infection
Protease inhibitors
• Telaprevir • Boceprevir • Simeprevir • Faldaprevir (BI-201335) • Vaniprevir • Narlaprevir • Danoprevir • GS-9256 • BMS-650032 • ACH-1625 • VX-500 • BIT-225 • ABT-450
NS5A inhibitors • daclatasvir
• BMS-824383
• PPI-461
• GS-5885
• ABT-267
Entry inhibitors • ITX-5061
NS4B inhibitors • Clemizole
Polymerase inhibitors • sofosbuvir
• Filibuvir
• ANA-598
• BI-207127
• BMS-791325
• GS-9190
• RG7129
• VX-222
• VX-759
• VX-916
• TMC-649128
• MK-3281
• IDX-375
• ABT-072
• ABT-333
• cyclophilin inhibitor • Alisporivir
• miR-122 as target • Miravirsen
. Data to be discussed
Critical questions
• Will we be able to use oral direct-acting agents (DAAs) without interferon?
• Will we be able to use oral DAAs without ribavirin?
• Will response rates be comparable or improved in all patients, including prior null responders and those with traditionally lower SVR (eg, African-Americans)?
• How many DAAs will be required? Will the regimen vary for different patients?
• Will DAAs be effective in special populations? (eg, cirrhotics, HIV-co-infected)
• Will overall treatment “effectiveness” improve?
Co-Pilot Study Phase 2a
Presentation Title | Date xx.xx.xx | Company Confidential © 2012 21 21 21
ABT-450/r ABT-333 RBV Cohort 1 Treatment-naïve
ABT-450/r ABT-333 RBV Cohort 2 Treatment-naïve
ABT-450/r ABT-333 RBV Cohort 3 Prior P/R non-responders
*Enrollment was limited to patients with the IL28B SNP rs12979860 CC genotype
ABT-333 400mg BID; RBV weight-based 1000-1200 mg daily dose divided BID Patients followed through 48 weeks post-treatment
250/100
150/100
150/100
19
14
17
Co-pilot Study Design
Poordad F, et al NEJM 2013; 368: 45-53
ABT-450/r 250/100 mg + ABT-333 + RBV
Treatment-naïve (n=19)
ABT-450/r 150/100 mg + ABT-333 + RBV
Treatment-naïve (n=14)
ABT-450/r 150/100 mg + ABT-333 + RBV
Treatment-experienced (n=17)
Sust
ain
ed V
iro
logi
c R
esp
on
se (
SVR
12)
rate
s CO-PILOT: SVR12 rates in treatment-naive and experienced patients on ABT-450/r plus ABT-333 plus Ribavirin
100
RBV=Ribavirin SVR= Sustained Virologic Response
23
Conclusions:
23
Among treatment-naïve HCV genotype 1 patients:
• There were no virologic breakthroughs on treatment
• SVR12 rates were 93-95% for naïve patients
• ABT-450/r 250/100 mg and 150/100 mg doses showed comparable response rates
Among previous P/R non-responders:
• 47% achieved SVR12
• All patients who relapsed did so by their first post-treatment visit
• Relapse after PTW12 was infrequent (1/61, 1.6% of patients)
The combination of ABT-450/r + a non-nucleoside inhibitor + RBV was associated with a low rate of discontinuation (1.6%) due to adverse events during 12 weeks of treatment
Aviator Study Phase 2b
M11-652 Study Design Tr
eatm
ent-n
aïve
N
ull
Res
pond
er
ABT-450/r Dose (QD)
ABT-450 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333
ABT-450 ABT-267 RBV
ABT-450 ABT-267 RBV
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
N
ABT-267 25mg QD; ABT-333 400mg BID; RBV weight-based 1000-1200 mg daily dose divided BID All patients to be followed through 48 weeks post-treatment
ABT-450 ABT-267 ABT-333 RBV
Wk 0 Wk 8 Wk 12 Wk 24
80
79
79
79
80
41
45
45 43
Regimen/Duration
150/100
150/100
100/100,200/100
150/100
100/100,150/100
100/100,150/100
200/100
100/100,150/100
100/100,150/100
SVR12 Rates (ITT) in the AVIATOR Study
88 8591 89
9989
93
0
20
40
60
80
100
26
Perc
en
tage
of
pat
ien
ts (
ITT)
ac
hie
vin
g SV
R1
2
Treatment-naϊve patients Null Responders
8 weeks 12 weeks 12 weeks
N=80 N=41 N=79 N=79 N=79 N=45 N=45
ABT-450/r ABT-267
RBV
ABT-450/r ABT-267 ABT-333
ABT-450/r ABT-267 ABT-333
RBV
ABT-450/r
ABT-333 RBV
ABT-450/r ABT-267 ABT-333
RBV
ABT-450/r ABT-267 ABT-333
RBV
ABT-450/r ABT-267
RBV
Adapted from King M et al, CROI 2013 Presentation
Response Rates Treatment-naïve Patients Null Responders
Duration 8 wks 12 wks 12 wks
Regimen
450/r 267 333 RBV
450/r
333 RBV
450/r 267
RBV
450/r 267 333
450/r 267 333 RBV
450/r 267
RBV
450/r 267 333 RBV
Number dosed 80 41 79 79 79 45 45 Breakthroughs (N) 0 1 1 1 0 0 3 Relapses (N) 9 3 5 5 1 5 0 Lost to follow-up or
withdrawn consent prior
to SVR12
1 2 2 4 1 0 0
SVR12 rate (ITT)a, % (n/N)
88% (70/80)
85% (35/41)
91% (72/79)
89% (70/79)
99% (78/79)
89% (40/45)
93% (42/45)
SVR12 rate (Observed
data)b,
% (n/N)
89% (70/79)
88% (35/40)
92% (71/77)
93% (69/74)
99% (77/78)
89% (40/45)
93% (42/45)
aITT: Intent-to-treat population, includes all patients who received at least one dose of study drug bObserved data: Excludes patients with values missing for reasons other than virologic failure or discontinuation due to AEs
Conclusions:
• The 12-week 3 DAA + RBV regimens showed the greatest efficacy in both treatment-naïve and null responder populations
– SVR12 (ITT) in 99% of GT1treatment-naïve patients on three DAA/RBV and 93% of GT1-infected null responders receiving three DAA/RBV.
• The combination of ABT-450/r, ABT-267 and ABT-333 will be studied both with and without RBV in phase 3 trials
• An ABT-450/r/ABT-267 co-formulated tablet will be used in phase 3
• All DAA combinations studied were well tolerated through 8-12 weeks of treatment
– Fatigue, headache, insomnia, and nausea were seen most frequently
– 1% of patients discontinued due to adverse events
Electron Study Phase 2b
Overall Study Design in HCV GT 1,2 3: ELECTRON
n=10
n=10
n=11
n=10
GS-7977 + RBV n=10
GS-7977 + RBV n=25
GS-7977 + RBV n=25
n=9
Treatment-Naïve GT 2/3 Patients
Wk 4
GS-7977 + RBV GS-7977 + RBV
GS-7977 + P/R
Wk 8
GS-7977
GS-7977 + RBV GS-7977 + P/R
GS-7977 + RBV
Treatment-Naïve GT 2/3
Null Responders GT 1
Treatment-Naïve GT 1
Treatment-Experienced GT 2/3
n=10 GS-7977 + P/R
Wk 0 Wk 12
100% SVR24
100% SVR24
100% SVR24
100% SVR24
60% SVR24
100% SVR24
10% SVR12
84% SVR12
68% SVR12
Gane EJ, et al. AASLD 2012. Abstract 229
ELECTRON: Sofosbuvir ± GS-5885 + RBV in Naive and Previous Null Responders (GT1 Results)
Pts with poor prognostic indicators: GT1a (86%), male (54%), nonwhite (12%), IL28B CT/TT (68%)
Mean BMI: 26; mean HCV RNA: 6.2 log
Study Design:
SVDF
Sofosbuvir + RBV 1000/1200 mg (GT1; naive) (n = 25)
Sofosbuvir + RBV 1000/1200 mg (GT1; null responders) (n = 10)
Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; naive) (n = 25)
Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; nulls) (n = 9)
*Data reported for 3 pts only then 9/9 Subjects SVR4 reported in Jan2013 press release
Gane EJ, et al. AASLD 2012. Abstract 229; SVR12 results for SOF+5885 arm reported in Feb2013 press release
Wk 12
ELECTRON Results
SOF + RBV* SOF + LDV + RBV**
Naïve (n=25) Null Responder (n=10) Naïve (n=25) Null Responder (n=9)
GT1a 88% 90% 80% 89%
SVR 4 88% 11% 100% 100%
SVR 12 21/25 (84%) 1/10 (10%) 25/25 (100%) 9/9 (100%)
SAEs 1 (4%) 0 2 (8%) 9
AEs that led to DC 0 0 1(4%) 0
> Grade 2 Anemia 0 1 (10%) 5 (20%) 0
Grade 3: Urine Occult
Blood** 5 (20%) 4 (40%) 13 (52%) 2 (22%)
**Majority of occult blood findings unconfirmed or in females. *SAE: urethral injury unrelated to SOF LDV= Ledipasvir= GS5885
Gane EJ, et al. AASLD 2012. Abstract 229; Gane EJ et al. CROI 2013; Abstract 41LB
Conclusions
Genotype 1 Patients
• 12 weeks SOF + RBV provided SVR12 in 84% of treatment-naïve patients and 10% of null responders.
• Addition of GS-5885 to SOF + RBV provided SVR4 and SVR12 in 100% of treatment-naïve patients and 100% of null responders
Regimen is safe and well tolerated
Gane EJ, et al. AASLD 2012. Abstract 229; Gane EJ et al. CROI 2013; Abstract 41LB
Spare Study Phase 2
GS-7977 + Low or Full dose RBV for 24 weeks In Difficult To Treat HCV Infected Genotype 1 Patients : Interim Analysis: SPARE Trial.
• HCV genotype 1a/b, treatment naïve patients
• Part 1: Stage 0-2 fibrosis; Part 2: All stages (including Child Pugh A)
• Study Design
Day 0
GS-7977 400mg daily + ribavirin 1000-1200mg (RBV)
Week 24
Part 1 n=10
n=25
Day 0
GS-7977 400mg daily + RBV1000-1200mg daily
GS-7977 400mg daily + RBV 600mg
Week 24
n=25 Part 2
Osinusi et al. AASLD 2012; LB4
Efficacy Results
90% 96% 96%
88%
72%
56%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Full dose RBV Full dose RBV Low dose RBV
Part 1 Part 2
HC
V R
NA
<LL
OQ
(%
pat
ien
ts)
Treatment Response (ITT Patients)
Week 4
Week 12
ETR
SVR4
SVR12
Osinusi et al. AASLD 2012; LB4
No serious adverse events (AE) or discontinuations due to AEs
No grade 4 events; Two Grade 3 events of nausea and hyperbilirubinemia
Safety Results
Grade 2 Adverse Events n(%)
GS-7977 + Full dose RBV n=35
GS-7977 + Low dose RBV n=25
Headache 0 2 (8) Nausea 1 (3) 1 (4) Fatigue 1 (3) 0 Rash 2 (6) 1 (4) Pruritus 1 (3) 1 (4) Myalgia 0 2 (8) Depression 1 (3) 0 Neutropenia 0 1 (4) Hyperbilirubinemia 4 (11) 1 (4) Decreased Hgb 7 (20) 1 (4)
Osinusi et al. AASLD 2012; LB4
• Early viral decay was rapid and independent of RBV dosing.
• GS-7977 in combination with full dose RBV resulted in high efficacy rates in subjects with early fibrosis
• Low dose RBV with GS-7977 appears to be similarly efficacious in suppressing HCV replication in difficult to treat subjects
• Anemia was more common in patients receiving full dose of RBV(20% vs 4%).
Conclusions
Osinusi et al. AASLD 2012; LB4
Daclatasvir and Sofosbuvir with or without RBV Phase 2
All-Oral Combination of Daclatasvir (NS5A Inhibitor) + Sofosbuvir (NS5B Inhibitor), +/- RBV in Treatment-Naïve Patients Chronically Infected With HCV Genotype 1, 2, or 3
SOF 400 mg QD x 7 days, then add DCV 60 mg QD Follow-up N=15 A
DCV 60 mg QD + SOF 400 mg QD
Follow-up N=14 C DCV 60 mg QD
+ SOF 400 mg QD + RBV Follow-up N=15 E DCV 60 mg QD + SOF 400 mg QD
Follow-up N=41 G DCV 60 mg QD +
SOF 400 mg QD + RBV Follow-up N=41 H
SOF 400 mg QD x 7 days, then add DCV 60 mg QD
Follow-up N=16 B DCV 60 mg QD
+ SOF 400 mg QD Follow-up N=14 D
DCV 60 mg QD + SOF 400 mg QD + RBV Follow-up N=14 F
GT 2/3
GT 1 a/b
Wk 12 Wk 24 SVR48
SVR48
Treatment Naïve, Non-
Cirrhotic Patients
Sulkowski M, et al. AASLD 2012; LB2
Study Design
Efficacy Results
100% 100% 100%
98%
95%
88%
100%
86%
93% 93%
75%
80%
85%
90%
95%
100%
A: SOF LI +DCV
C: DCV + SOF E: DCV + SOF +RBV
G: DCV + SOF(12 wks)
H: DCV + SOF +RBV (12 wks)
B: SOF LI +DCV
D: DCV + SOF F: DCV + SOF +RBV
GT 1a/b GT 2/3
HC
V R
NA
<LL
OQ
(%
Pat
ien
ts)
Virologic Response After Treatment
SVR4
SVR12
SVR24
LI= Lead In
Sulkowski M, et al. AASLD 2012; LB2
No grade 3 or 4 elevations of ALT, AST, and bilirubin
Safety Results
Patients with event, n (%)
24-week Treatment 12-week Treatment A and B
SOF LI + DCV
N=31
C and D DCV + SOF
N=28
E and F DCV + SOF + RBV
N=29
G DCV + SOF
N=41
H DCV + SOF + RBV
N=41
Safety Parameters
Grade 3-4 AEs 0 4 (14) 2 (7) 1 (2) 1 (2) Discontinuations due to AEs 0 1 (4) 1 (3) 0 0
SAEs 2 (6) 4 (14) 2 (7) 1 (2) 0 Hgb <9 g/dL (grade 3-4) 0 0 6 (21) 0 5 (12)
Adverse Events occuring in ≥ 20% of patients total
Fatigue 9 (29) 14 (50) 9 (31) 16 (39) 13 (32) Headache 5 (16) 8 (29) 11 (38) 14 (34) 9 (22) Nausea 5 (16) 9 (32) 9 (31) 8 (20) 8 (20)
Sulkowski M, et al. AASLD 2012; LB2
• 24 weeks of the all-oral, once-daily combination of DCV plus SOF achieved high rates of SVR (more than 93%) in previously untreated patients with HCV genotype 1, 2, or 3.
• IL28B genotype, genotype 1 subtype, and the use of ribavirin did not influence response.
• 96% of patients with HCV genotype 1 achieved SVR4 following 12-weeks treatment. After 24 -week treatment 98% of patients achieved SVR24.
• The most common adverse events (>20%) were fatigue, headache, and nausea.
Conclusions
Daclatasvir and Asunaprevir + BMS-791325 without RBV Phase 2a
Phase 2a, Safety and Tolerability Study; Part 2 is ongoing.
Treatment-naïve HCV GT1 infected, non-cirrhotic subjects
45
An Interferon-free, Ribavirin-free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 (NS5B inhibitor) in Treatment-Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection
ASV 200mg BID + DCV 60mg QD+ BMS-791325 75mg BID
Follow-up
Follow-up Group 1 n=16
Group 2 n=16
ASV 200mg BID + DCV 60mg QD + BMS-791325 75mg BID
ASV 200mg BID + DCV 60mg QD+ BMS-791325 150mg
Follow-up
Follow-up Group 3
Group 4
Week 12
ASV 200mg BID + DCV 60mg QD + BMS-791325 150mg
Week 24 Day 1
Part 1
Part 2
Everson et al. AASLD 2012; LB3
No virologic breakthrough in either group
Efficacy Results
100%
94% 94% 94%
88%
100%
94%
82%
84%
86%
88%
90%
92%
94%
96%
98%
100%
4 12 EOT PT4(SVR4)
PT12(SVR12)
Pat
ien
ts A
chie
vin
g En
dp
oin
t (%
)
Study Week
HCV RNA < LLOQ (MITT Analysis)
Group 1 (24 week treatment)
Group 2 (12 week treatment)
Everson et al. AASLD 2012; LB3
No Grade 3/4 elevations in ALT/AST or bilirubin were observed.
Renal calculus deemed not-related to study drug.
Safety Results
Number of Patients (%) Group 1 24 Week
Treatment N=16
Group 2 12 Week
Treatment N=16
Total
N=32
Serious AEs 0 1 (5) Renal Calculus
1 (3)
AEs leading to discontinuation 0 0 0 Grade 3-4 AE 0 1 (6)
Grade 3 headache 1 (3)
Grade 3-4 laboratory abnormalities 0 1 (6) Lymphopenia
1 (3)
AE in >10% of patients in combined treatment groups Headache 4 (25) 6 (38) 10 (31) Diarrhea 2 (13) 6 (38) 8 (25) Asthenia 2 (13) 3 (19) 5 (16)
Everson et al. AASLD 2012; LB3
• Twelve weeks of the interferon- and ribavirin-free regimen of DCV + ASV + BMS-791325 was well tolerated and achieved a high rate of SVR4 in chronic HCV GT1-infected patients who were mainly GT1a and IL28B non-CC genotype.
• There was no viral breakthrough and no posttreatment relapse to date.
• Further investigation of this regimen in the treatment of HCV is warranted. Study Part 2 is ongoing.
Conclusions
Sound-C2 Study Phase 2b
IFN free combination of BI 201335 (Faldaprevir) + BI 207127 (NS5B inhibitor) ± ribavirin (RBV) in treatment-naïve patients with HCV GT 1 infection and compensated liver cirrhosis
Open-Label Phase 2b study
HCV treatment-naïve patients with GT 1a or 1b with IL28B (CC or non-type), compensated cirrhosis (9%)
BI 201335 120 mg QD + BI207127 600 mg TID + RBV
Follow-up
Day 1 Week 16 Week 28 Week 48
Follow-up
Follow-up
Follow-up
Follow-up
n=81
n=80
n=77
n=78
n=46
BI 201335 120 mg QD + BI 207127 600 mg TID + RBV
BI 201335 120 mg QD + BI207127 600 mg TID + RBV
BI 201335 120 mg QD + BI207127 600 mg BID + RBV
BI 201335 120 mg QD + BI207127 600 mg TID + RBV
Soriano et al, AASLD 2012; Abstract #84
Efficacy Results- SVR
43% 50%
0%
43% 42%
11%
57%
80%
33%
68%
86%
60%
0%10%20%30%40%50%60%70%80%90%
100%
TID16, 28, & 48
+
BID28+
TID28-
TID16, 28, & 48
+
BID28+
TID28-
SV
R (
%)
SVR12 Rates by HCV-1 Subtype
GT-1aGT-1b
Cirrhosis No Cirrhosis
BI 207127 Dosing Duration (weeks)
RBV
Soriano et al, AASLD 2012; Abstract #84
Efficacy Results- Failure
19%
33%
67%
21% 26%
44%
6% 0% 0%
8% 0%
10%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
TID16, 28, & 48
+
BID28+
TID28-
TID16, 28, & 48
+
BID28+
TID28-
Failu
re R
ate
(%
)
On-treatment Failure and Relapse Rates
On Treatment Failure
Relapse
BI 207127 Dosing Duration (weeks)
RBV
Cirrhosis No Cirrhosis
Soriano et al, AASLD 2012; Abstract #84
Safety Results
n (%)
TID16W, 28W, & 40W
BID28W TID28W-NR
Cirrhosis (n=21)
No Cirrhosis (n=217)
Cirrhosis (n=9)
No Cirrhosis (n=69)
Cirrhosis (n=3)
No Cirrhosis (n=47)
Overall AEs, n(%) 20 (95) 203 (94) 9 (100) 64 (93) 2 (67) 42 (98) Severe AEs, n(%) 3 (14) 18 (8) 1 (11) 8 (12) 1 (33) 3 (7) Serious AEs, n(%) 4 (19) 12 (6) 1 (11) 7 (10) 0 3 (7) Discontinuation due to AE, n(%) 6 (29) 27 (12) 1 (11) 5 (7) 0 5 (12) Aes at Discontinuation
Rash AEs 3 (14) 4 (2) 0 0 0 1 (2) Photosensitivity AEs 2 (10) 4 (2) 0 0 0 0 Vomiting AEs 1 (5) 7 (3) 0 0 0 0 Asthenia 0 6 (3) 0 0 0 0 Jaundice AEs 2 (10) 2 (1) 0 0 0 0
Soriano et al, AASLD 2012; Abstract #84
Conclusions
• Patients with cirrhosis had lower SVR rates across all dose groups compared with those without cirrhosis.
• High on-treatment failure rate in TID 28 week arm (67% and 44% in cirrhotic and noncirrhotic patients, respectively).
• The most common adverse events (AEs) in patients with cirrhosis were mild rash and gastrointestinal side effects.
• Phase III will evaluate 24 weeks faldaprevir + BI 207127 (BID) + RBV in compensated cirrhosis
AbbVie Phase 3 Clinical Development Program
Phase 3 program – evaluation of 3 DAA regimen in broad range of GT1 patient populations, with and without RBV
M11-646 SAPPHIRE-I (GT1 naïve, placebo controlled) N=600
M13-098 SAPPHIRE-II (GT1 exp, placebo controlled) N=400
M14-002 PEARL-IV (GT1a naive, +/- RBV) N=300
M13-961 PEARL III (GT1b naive, +/- RBV) N=400
M13-099 TURQUIOSE-II (GT1 naïve/exp, cirrhotics) N=300
M13-389 PEARL-II (GT1b exp, +/- RBV) N=200
*M14-004 TURQUOISE-I (GT1 HIV/HCV) N=300 S
peci
al
Pop
ulat
ions
R
BV-
free
3DA
A +
RB
V
* Submitted as a supplement to the NDA 3| 12-18-13 Company Confidential © 2013
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