Transcript www.ic-hep.com

Catherine Stedman, MD
Christchurch, New Zealand
This activity is supported by an independent medical education
grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences
1
Successful Retreatment of HCV Genotype-1 Infected Patients
Who Failed Prior Therapy with Peg-interferon + Ribavirin Plus
1 or 2 Other Direct-Acting Antiviral Agents with Sofosbuvir
Stanislas Pol1, Mark Sulkowski2, Tarek Hassanein3, Ed Gane4, Liyun Ni5, Hongmei Mo5,
Bittoo Kanwar5, Diana Brainard5, GM Subramanian5, William T. Symonds5,
John G. McHutchison5, Michael Bennett6, Ira M. Jacobson7
1Universite
Paris Decartes, Hopital Cochin, Paris, France; 2John Hopkins University, Baltimore, MD, USA;
3Southern California Liver Center, Coronado, CA, USA; 4Aukland City Hospital, Auckland, NZ; 5Gilead
Sciences, Inc., Foster City, CA, USA; 6Medical Associates Research Group, San Diego, CA, USA;
7Weill Cornell Medical College, New York, NY, USA
2
Wk 12
Wk 0
Wk 24
SOF + PEG/RBV
SVR 12
• All patients were previously treated with PEG+RBV and an investigational
protease inhibitor (GS-9451 or GS-9256) +/- one or two additional DAA
– Tegobuvir (NS5b non-nucleoside polymerase inhibitor)
– Ledipasvir (NS5a inhibitor)
• No patients had documented cirrhosis as per the prior protocols
Pol, S. et al. EASL 2014, Abstract #O55
3
12 weeks
SOF + PEG/RBV
n=80
Mean age, y (range)
Male, n (%)
Black, n (%)
Mean BMI, kg/m2 (range)
IL28B CC, n (%)
Mean ALT, U/L (range)
GT 1a, n (%)
Mean baseline HCV RNA, log10 IU/mL (range)
Mean duration of prior therapy, weeks (range)
Courses of prior therapy, n (%)
1
≥2
Prior DAA Exposure, n (%)
1 DAA
2 DAA
3 DAA
55 (21–72)
60 (75)
11 (14)
28 (21–43)
13 (16)
74 (24-298)
68 (85)
6.6 (5.0–7.3)
25 (1–60)
44 (55)
36 (45)
15 (19)
41 (51)
24 (30)
Patients with ≥1 resistance associated variant (RAV), n(%)
72 (90)
Prior response, n (%)
Relapse
On-treatment failure
48 (48)
36 (45)
Pol, S. et al. EASL 2014, Abstract #O55
4
HCV RNA < LLOQ (%)
100
99
100
74
80
60
40
20
0
66/67
67/67
37/50
Week 4
End of Treatment
SVR12
Pol, S. et al. EASL 2014, Abstract #O55
5
• Three quarters (74%) of DAAs-experienced patients achieved an SVR
with 12 weeks of SOF + PEG/RBV therapy despite multiple resistance
variants and prior courses of therapy
• The presence of baseline RAVs against any or all 3 non structural
proteins (NS3, NS5a, NS5b) did not impact overall SVR
• The 12-week SOF + PEG/RBV regimen was safe and well tolerated
• Sofosbuvir-containing regimens are effective in these patients with no
other currently approved alternatives
Pol, S. et al. EASL 2014, Abstract #O55
6
Successful Retreatment With Sofosbuvir-containing Regimens
for HCV Genotype 2 or 3 Infected Patients who Failed Prior
Sofosbuvir Plus Ribavirin Therapy
Rafael Esteban1, Lisa Nyberg2, Jay Lalezari3, Liyun Ni4, Brian Doehle4, Bittoo Kanwar4, Diana
Brainard4, GM Subramanian4, William T. Symonds4, John G. McHutchison4,
Maribel Rodriquez-Torres5, Stefan Zeuzem6
d’Hebron Hospital, Barcelona, Spain; 2Kaiser Permanente, San Diego, CA, USA;
3Quest Clinical Research, San Francisco, CA, USA; 4Gilead Sciences, Inc., Foster City, CA, USA;
5Fundacion de Investigacion, San Juan, Puerto Rico; 6JW Goethe University Hospital, Frankfurt, Germany
1Vall
7
Wk 0
Wk 12
Wk 24
SOF + PEG/RBV
SOF + RBV
Wk 36
SVR 12
SVR 12
• Open-label study offered to all GT 2 or 3 treatment failures from FISSION,
POSITRON and FUSION
• Patients offered 2 possible treatment options
– Choice based on patient’s eligibility for IFN and patient/investigator recommendation
• Included patients with compensated cirrhosis
Esteban, R. et al. EASL 2014, Abstract #O8
8
12 weeks
SOF + PEG/RBV
n=34
24 weeks
SOF + RBV
n=73
53 (31–70)
53 (38-63)
Male, n (%)
26 (77)
63 (86)
Black, n (%)
1 (1%)
0
29 (22–39)
28 (20-41)
Cirrhosis* n (%)
14 (41)
25 (34)
IL28B CC, n (%)
11 (32)
27 (37)
96 (14-325)
89 (18-310)
2
6 (18)
5 (7)
3
28 (82)
68 (93)
6.3 (4.8-7.8)
6.6 (4.4–7.6)
Mean age, y (range)
Mean BMI, kg/m2 (range)
Mean ALT, U/L (range)
Genotype, n (%)
Mean baseline HCV
RNA, log10 IU/mL (range)
*Cirrhosis status determined in parent protocol.
Esteban, R. et al. EASL 2014, Abstract #O8
9
12 weeks SOF+PEG/RBV
Patients with < LLOQ (%)
100
100
100
100
24 weeks SOF+RBV
100
92
63
80
60
40
20
0
28/28 50/50
28/28 50/50
Week 4
End of Treatment
24/26
25/40
SVR 12
• Relapse accounted for all virologic failures
Error bars represent 95% confidence intervals.
Esteban, R. et al. EASL 2014, Abstract #O8
10
No Cirrhosis
Patients with < LLOQ (%)
100
93
Cirrhosis
88
80
74
60
47
40
20
13/14
7/8
17/23
7/15
0
12 weeks SOF + PEG/RBV
24 weeks SOF+RBV
Esteban, R. et al. EASL 2014, Abstract #O8
11
• Retreatment with an extended duration of SOF + RBV to 24 weeks or
the addition of IFN to a 12 week regimen resulted in high SVR rates in
GT 2 and GT 3 patients who previously failed SOF+RBV-containing
regimens
• The 12-week regimen containing IFN had higher overall rates of SVR
and was more effective in patients with cirrhosis
• The 24-week IFN-free regimen was safe and well tolerated and offers a
retreatment option for those ineligible to receive IFN
Esteban, R. et al. EASL 2014, Abstract #O8
12
Simeprevir Plus Sofosbuvir With/Without Ribavirin in
HCV Genotype-1 Prior Null-responder /
Treatment-naïve Patients (COSMOS Study): Primary Endpoint
(SVR12) Results in Patients With METAVIR F3-4 (Cohort 2)
E. Lawitz1, R. Ghalib2, M. Rodriguez-Torres3, Z.M. Younossi4, A. Corregidor5, M.S. Sulkowski6,
E. DeJesus7, B. Pearlman8, M. Rabinovitz9, N. Gitlin10, J.K. Lim11, P.J. Pockros12, B. Fevery13,
T. Lambrecht14, S. Ouwerkerk-Mahadevan13, K. Callewaert13, W.T. Symonds15, G. Picchio16,
K. Lindsay16, M. Beumont-Mauviel13, I.M. Jacobson17
1Texas
Liver Institute, San Antonio, 2Medicine and Gastroenterology and Hepatology, The Liver Institute,
Dallas, TX, 3Fundacion de Investigacion, San Juan, PR, 4Department of Medicine, Inova Fairfax Hospital,
Falls Church, VA, 5Borland-Groover Clinic, 4800 Belfort Rd, Jacksonville, FL, 6Johns Hopkins University
School of Medicine, Baltimore, MD, 7Orlando Immunology Center, Orlando, FL, 8Atlanta Medical Center,
Atlanta, GA, 9University of Pittsburgh Medical Center, Pittsburgh, PA, 10Atlanta Gastroenterology
Association, Atlanta, GA, 11Yale School of Medicine, New Haven, CT, 12Scripps Clinic, La Jolla, CA, United
States, 13Janssen Research & Development, Beerse, 14Novellas Healthcare, Zellik, Belgium, 15Gilead
Sciences Inc, Foster City, CA, 16Janssen Research & Development LLC, Titusville, NJ, 17Weill Cornell
Medical College, New York, NY, United States
13
0
4
12
24
36
48
Week
Randomised
2:1:2:1
Arm 1
SMV + SOF + RBV
Post-treatment follow-up
Arm 2
SMV + SOF
Post-treatment follow-up
Arm 3
SMV + SOF
+ RBV
Post-treatment follow-up
Arm 4
SMV + SOF
Post-treatment follow-up
SMV 150 mg QD + SOF 400 mg QD±RBV 1000/1200 mg/day (BID)
• Cohort 1: METAVIR F0-F2, prior null responders
• Cohort 2: METAVIR F3-F4, prior null responders or treatment-naïve
– Stratified by treatment history, HCV GT 1a/1b
• Primary endpoint: SVR12
• Secondary endpoints: RVR, on-treatment failure, relapse rate, safety and tolerability
BID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; RVR, rapid virologic response;
SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatment
Lawitz, E. et al. EASL 2014, Abstract #O165
14
SVR12
Proportion of patients (%)
100
7%
2/30
Non-VF
7%
Relapse
2/27
7%
1/14
3%
2%
3/87
2/87
80
60
93%
100%
93%
93%
94%
40
20
0
28/30
SMV/SOF + RBV
16/16
SMV/SOF
24 weeks
25/27
SMV/SOF + RBV
13/14
SMV/SOF
12 weeks
82/87
SMV/SOF±RBV
Overall
Non-VF, patients who did not achieve SVR12 for reasons other than virologic failure
ITT, intent-to-treat; Non-VF, Non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12,
sustained virologic response 12 weeks after planned treatment end
BID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; RVR, rapid virologic response; SMV, simeprevir;
SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatment
Lawitz, E. et al. EASL 2014, Abstract #O165
15
GT 1b
100
100
100
100
100
100
SVR12 (%)
80
60
40
20
0
6/6
11/11 11/11
SMV/SOF + RBV
4/4
7/7
4/4
SMV/SOF
5/5
13/14
7/8
SMV/SOF + RBV
24 weeks
GT, genotype; non-VF, non-virologic failure; RBV, ribavirin
SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic
response 12 weeks after planned treatment end
Lawitz, E. et al. EASL 2014, Abstract #O165
3/3
7/8
3/3
SMV/SOF
12 weeks
18/18 38/40 25/26
SMV/SOF±RBV
Overall
*Excluding patients who discontinued
for non-virologic reasons
16
GT 1b
100
100 100 100
GT 1a without Q80K
100 100 100
100
100
100
100
95
93
96
88
88
SVR12 (%)
80
60
40
20
0
6/6
11/11 11/11
SMV/SOF + RBV
4/4
7/7
4/4
SMV/SOF
5/5
13/14
7/8
SMV/SOF + RBV
24 weeks
GT, genotype; non-VF, non-virologic failure; RBV, ribavirin
SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic
response 12 weeks after planned treatment end
Lawitz, E. et al. EASL 2014, Abstract #O165
3/3
7/8
3/3
SMV/SOF
12 weeks
18/18 38/40 25/26
SMV/SOF±RBV
Overall
*Excluding patients who discontinued
for non-virologic reasons
17
GT 1b
100
100 100 100
GT 1a without Q80K
100 100 100
100
GT 1a with Q80K
100
100
100
95
93
96
88
88
SVR12 (%)
80
60
40
20
0
6/6
11/11 11/11
SMV/SOF + RBV
4/4
7/7
4/4
SMV/SOF
5/5
13/14
7/8
SMV/SOF + RBV
24 weeks
GT, genotype; non-VF, non-virologic failure; RBV, ribavirin
SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic
response 12 weeks after planned treatment end
Lawitz, E. et al. EASL 2014, Abstract #O165
3/3
7/8
3/3
SMV/SOF
12 weeks
18/18 38/40 25/26
SMV/SOF±RBV
Overall
*Excluding patients who discontinued
for non-virologic reasons
18
Null responders
100
100
100
100
Treatment naïves
100
100
100
96
94
80
80
SVR12 (%)
67
60
40
20
0
9/9
3/3
4/4
SMV/SOF + RBV
5/5
SMV/SOF
4/5
6/6
4/4
SMV/SOF + RBV
24 weeks
GT, genotype; non-VF, non-virologic failure; RBV, ribavirin
SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic
response 12 weeks after planned treatment end
Lawitz, E. et al. EASL 2014, Abstract #O165
2/3
SMV/SOF
12 weeks
21/22
16/17
SMV/SOF±RBV
Overall
*Excluding patients who discontinued
for non-virologic reasons
19
• SMV/SOF QD led to SVR12 rates of 93-100% (ITT)
in HCV GT 1 infected treatment-naïve and prior
null-responder patients with METAVIR F3-4
• SVR12 rates were high, regardless of baseline
characteristics:
– HCV GT 1 subtype, Q80K polymorphism, METAVIR score,
IL28B GT, prior treatment history
• SMV/SOF QD +/- RBV was safe and well tolerated
• Two Phase 3 trials investigating SMV/SOF without
RBV are ongoing (OPTIMIST-1 and -2)
GT, genotype; ITT, Intent-to-treat; QD, once daily; RBV, ribavirin; SMV, simeprevir;
SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatment
Lawitz, E. et al. EASL 2014, Abstract #O165
20
All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With
Or Without Ribavirin for 12 or 24 Weeks in
Treatment-Naive Genotype 1 HCV-Infected Patients: the
Phase 3 ION-1 Study
Alessandra Mangia,1 Patrick Marcellin,2 Paul Kwo,3
Graham R. Foster,4 Maria Buti,5 Norbert Bräu,6 Andrew Muir,7
Jenny C. Yang,8 Hongmei Mo,8 Xiao Ding,8 Phil S. Pang,8
William T. Symonds,8 John G. McHutchison,8 Stefan Zeuzem,9 Nezam Afdhal10
1Casa
Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy; 2Centre Hospitalier Universitaire
Beaujon, Clichy-sous-Bois, France; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4Queen
Mary’s University of London, Barts Health, UK; 5Hospital Universitario Valle de Hebrón, Barcelona, Cataluña,
Spain; 6Mount Sinai School of Medicine, New York, NY, USA; 7Duke University Medical Center, Durham, NC,
USA;6Gilead Sciences, Inc., Foster City, CA; 9Johann Wolfgang Goethe University, Frankfurt, Germany;
10Beth Israel Deaconess Medical Center, Boston, MA, USA
21
Wk 12
Wk 0
Wk 24
LDV/SOF
SVR12
LDV/SOF + RBV
SVR12
Wk 36
LDV/SOF
SVR12
LDV/SOF + RBV
SVR12
• GT 1 HCV treatment-naïve patients in Europe and USA
• Broad inclusion criteria
– Targeted 20% enrollment of patients with cirrhosis
– No upper age or BMI limit
– Platelet count ≥50,000/mm3, no neutrophil minimum
• 865 patients randomized 1:1:1:1 across four arms
• Stratified by HCV subtype (1a or 1b) and cirrhosis
Lawitz, E. et al. EASL 2014, Abstract #O109
22
12 Weeks
24 Weeks
LDV/SOF
n=214
LDV/SOF+RBV
n=217
LDV/SOF
n=217
LDV/SOF+RBV
n=217
52 (18–75)
52 (18–78)
53 (22–80)
53 (24–77)
Male, n (%)
127 (59)
128 (59)
139 (64)
119 (55)
Black, n (%)
24 (11)
26 (12)
32 (15)
26 (12)
Hispanic, n (%)
26 (12)
20 (9)
29 (13)
26 (12)
Region Europe
89 (42)
99 (46)
85 (39)
80 (37)
27 (18–41)
27 (18–42)
27 (18–48)
26 (18–48)
Cirrhosis
34 (16)
33 (15)
33 (15)
36 (17)
IL28B CC, n (%)
55 (26)
76 (35)
52 (24)
73 (34)
Interferon ineligible
14 (7)
20 (9)
19 (9)
14 (7)
144 (67)
148 (68)
146 (67)
143 (66)
6.4 (1.6–7.5)
6.4 (4.4–7.6)
6.3 (3.7–7.4)
6.3 (3.2–7.5)
169 (79)
173 (80)
168 (77)
173 (80)
Mean age, y (range)
Mean BMI, kg/m2 (range)
GT 1a, n (%)
Mean HCV RNA,
log10 IU/mL (range)
HCV RNA ≥800,000 IU/mL
• Arms were balanced with respect to demographics and baseline characteristics
Mangia, A. et al. EASL 2014, Abstract #O109
23
100
99
97
98
99
211/214
211/217
212/217
215/217
LDV/SOF
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
SVR12 (%)
80
60
40
20
0
12 Weeks
24 Weeks
Error bars represent 95% confidence intervals.
Mangia, A. et al. EASL 2014, Abstract #O109
24
• LDV/SOF for 12 weeks achieved SVR12 rate of 99% in
treatment-naive GT 1 patients
– Adding RBV and/or extending LDV/SOF treatment duration to 24 weeks did not
increase SVR12 rates
– Cirrhotic patients achieved SVR12 rates of 94 - 100% with 12-24 weeks of
treatment with LDV/SOF with or without RBV
• LDV/SOF with or without RBV was safe and well tolerated
– Addition of RBV contributed to higher incidence of AEs and laboratory
abnormalities
• A single tablet regimen with the fixed-dose combination LDV/SOF for
12 weeks achieved SVR in most GT 1 previously un-treated patients
Mangia, A. et al. EASL 2014, Abstract #O109
25
All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir
With or Without Ribavirin for 12 or 24 Weeks in TreatmentExperienced Genotype 1 HCV-Infected Patients:
The Phase 3 ION-2 Study
Nezam Afdhal1, Rajender K. Reddy2, Paul Pockros3, Adrian M. Di Bisceglie4, Sanjeev Arora5,
Jenny C. Yang6, Hadas Dvory-Sobol6, Yanni Zhu6, Phil S. Pang6, William T. Symonds6,
John G. McHutchison6, Mark Sukowski7, Paul Kwo8
1Beth
Israel Deaconess Medical Center, Boston, MA, USA; 2University of Pennsylvania, Philadelphia, PA,
USA; 3Scripps Clinic, La Jolla, CA; 4St Louis University, Saint Louis, MO, USA; 5University of New Mexico,
Albuquerque, NM; 6Gilead Sciences, Inc., Foster City, CA; 7Johns Hopkins Medical Center, Baltimore, MD,
USA; 8Indiana University School of Medicine, Indianapolis, IN, USA
26
Wk 0
Wk 12
Wk 24
LDV/SOF
SVR12
LDV/SOF + RBV
SVR12
Wk 36
LDV/SOF
SVR12
LDV/SOF + RBV
SVR12
•
GT 1 HCV patients who had failed prior IFN-based therapy, including regimens containing a NS3/4A
protease inhibitor
• Broad inclusion criteria
– Targeted 20% enrollment of patients with cirrhosis
– No upper age or BMI limit
– Platelet count ≥50,000/mm3, no neutrophil minimum
•
•
440 patients randomized 1:1:1:1 across four arms
Stratified by HCV subtype (1a or 1b), cirrhosis, prior treatment response
Afdhal, N. et al. EASL 2014, Abstract #O164
27
12 Weeks
LDV/SOF
n=109
LDV/SOF+RBV
n=111
LDV/SOF
n=109
LDV/SOF+RBV
n=111
56 (24–67)
57 (27–75)
56 (25–68)
55 (28–70)
Male, n (%)
74 (68)
71 (64)
74 (68)
68 (61)
Black, n (%)
24 (22)
16 (14)
17 (16)
20 (18)
7 (6)
12 (11)
11 (10)
11 (10)
29 (19–47)
28 (19–45)
28 (19–41)
28 (19–50)
IL28B CC, n (%)
10 (9)
11 (10)
16 (15)
18 (16)
GT 1a, n (%)
86 (79)
88 (79)
85 (78)
88 (79)
6.5 (5.0–7.5)
6.4 (4.6–7.3)
6.4 (4.7–7.4)
6.5 (3.1–7.4)
HCV RNA ≥800,000 IU/mL
103 (95)
98 (88)
93 (85)
96 (87)
Prior non-responders, n (%)
49 (45)
46 (41)
49 (45)
51 (46)
Prior protease inhibitor
failures, n (%)
66 (61)
64 (58)
50 (46)
51 (46)
Cirrhosis, n (%)
22 (20)
22 (20)
22 (20)
22 (20)
Mean age, y (range)
Hispanic, n (%)
Mean BMI, kg/m2 (range)
Mean HCV RNA,
log10 IU/mL (range)
•
24 Weeks
Arms were balanced with respect to demographics and baseline characteristics
Afdhal, N. et al. EASL 2014, Abstract #O164
28
100
96
99
99
102/109
107/111
108/109
110/111
LDV/SOF
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
94
SVR12 (%)
80
60
40
20
0
12 Weeks
24 Weeks
Error bars represent 95% confidence intervals.
Afdhal, N. et al. EASL 2014, Abstract #O164
29
Failed PEG/RBV
100
93
94
40/43
62/66
Failed Protease Inhibitor
96
97
100
98
98
100
45/47
62/64
58/58
49/50
58/59
51/51
SVR12 (%)
80
60
40
20
0
LDV/SOF
LDV/SOF + RBV
12 Weeks
LDV/SOF
LDV/SOF + RBV
24 Weeks
Error bars represent 95% confidence intervals.
Afdhal, N. et al. EASL 2014, Abstract #O164
30
Absence of Cirrhosis
100
95
100
86
82
Cirrhosis
99
100
99
100
86/87
22/22
88/89
22/22
SVR12 (%)
80
60
40
20
83/87
19/22
89/89
18/22
0
LDV/SOF
LDV/SOF + RBV
12 Weeks
LDV/SOF
LDV/SOF + RBV
24 Weeks
Error bars represent 95% confidence intervals.
Afdhal, N. et al. EASL 2014, Abstract #O164
31
• Single tablet fixed dose combination of LDV/SOF with or without RBV
in treatment-experienced GT 1 patients resulted in an SVR of 94 -99%
• Baseline NS5a or NS3/4 mutations had no effect on SVR
• RBV did not enhance SVR rates, alter viral kinetics or prevent relapse
• The majority of subjects who relapsed had cirrhosis
• LDV/SOF ± RBV was safe and well tolerated
– Addition of RBV contributed to higher incidence of AEs and laboratory
abnormalities
Afdhal N, et al. NEJM In Press
Afdhal, N. et al. EASL 2014, Abstract #O164
32
Ledipasvir/Sofosbuvir With and Without Ribavirin for 8
Weeks Compared to Ledipasvir/Sofosbuvir for 12 Weeks in
Treatment-Naïve Noncirrhotic Genotype-1
HCV-Infected Patients: The Phase 3 ION-3 Study
Kris V. Kowdley1, Stuart C. Gordon 2, K. Rajender Reddy3, Lorenzo Rossaro4, David E. Bernstein5,
Di An6, Evguenia S. Svarovskaia6, Robert H. Hyland6, Phillip S. Pang6,
William T. Symonds6, John G. McHutchison6, Andrew J. Muir7, Paul J. Pockros8,
David C. Pound9, Michael W. Fried10
1Virginia
Mason Medical Center, Seattle, WA, USA; 2Henry Ford Health System, Detroit, MI, USA;
3Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA; 4University of
California Davis Medical Center, Sacramento, CA, USA; 5North Shore University Hospital, Manhasset, NY,
USA; 6Gilead Sciences, Inc., Foster City, CA; 7Division of Gastroenterology and Duke Clinical Research
Institute, Duke University School of Medicine, Durham, NC, USA; 8Scripps Clinic, La Jolla, CA; 9Indianapolis
Gastroenterology Research Foundation, Indianapolis, IN, USA; 10University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA
33
Wk 8
Wk 0
Wk 12
Wk 20
LDV/SOF
SVR12
LDV/SOF + RBV
SVR12
LDV/SOF
Wk 24
SVR12
• GT 1 treatment-naïve patients without cirrhosis
• Broad inclusion criteria
– No upper age or BMI limit
– Opiate substitution therapy allowed
• 647 patients randomized 1:1:1 across three arms
• Stratified by HCV subtype (1a or 1b)
Kowdley, K. et al. EASL 2014, Abstract #O56
34
p=0.52
p=0.70
100
p=0.30
95
94
93
202/215
201/216
LDV/SOF
LDV/SOF + RBV
SVR12 (%)
80
60
40
20
0
8 Weeks
206/216
206/216
LDV/SOF
12 Weeks
Error bars represent 95% confidence intervals.
Kowdley, K. et al. EASL 2014, Abstract #O56
35
• LDV/SOF ± RBV for 8 or 12 weeks results in high
SVR12 rates
• No difference in efficacy among the groups was observed
• Host and viral factors traditionally associated with lower
SVR rates did not affect SVR12 rates
• LDV/SOF ± RBV was safe and well tolerated
– RBV contributed to a higher incidence of AEs and laboratory
abnormalities
• An 8 week LDV/SOF treatment regimen is a safe and
effective treatment for treatment-naïve non-cirrhotic
patients with HCV GT 1 infection
Kowdley K, et al. NEJM In Press
Kowdley, K. et al. EASL 2014, Abstract #O56
36
Sofosbuvir/Ledipasvir Fixed Dose Combination is Safe and
Effective in Difficult-to-treat Populations Including Genotype-3
Patients, Decompensated Genotype-1 Patients, and Genotype-1
Patients With Prior Sofosbuvir Treatment Experience
E.J. Gane1, R.H. Hyland2, D. An2, P.S. Pang2, W.T. Symonds2, J.G. McHutchison2, C.A. Stedman3
1Auckland
Clinical Studies, Auckland, New Zealand; 2Gilead Sciences, Inc., Foster City, CA, United States;
3Christchurch Clinical Studies Trust, Christchurch, New Zealand
37
Wk 12
Wk 0
SVR12
LDV/SOF + RBV, n=19
GT 1
CPT class B
LDV/SOF, n=20
Randomized
GT 1
Prior SOF exposure
GT 3
Treatment naïve
Wk 24
LDV/SOF, n=25
LDV/SOF + RBV, n=26
1. HCV GT 1, relapsed after previous treatment with
SOF-containing regimens in ELECTRON-1
2. HCV GT 1 decompensated cirrhosis (Child Pugh Turcotte B)
3. HCV GT 3, treatment naïve
Gane, E. et al. EASL 2014, Abstract #O6
38
Re-treatment
100
SOF+RBV 12 wk
Prior Null
Responders
100
SOF+RBV 12 wk
Treatment Naïve
n=4
80
SVR12 (%)
n=6
n=1
GS-9669 + SOF
+RBV 12 wk
Treatment Naïve
n=8
LDV/SOF +RBV
6 wk
Treatment Naïve
• All 19 previous SOF-regimen failures had relapsed
60
40
20
0
19/19
19/19
LDV/SOF +
RBV
12 Weeks
Gane, E. et al. EASL 2014, Abstract #O6
39
GT 1
CPT Class B
100
1.5 (0.7-3.7)
3.1 (2.3-3.8)
Median INR
(range)
1.2 (1.0-3.0)
Ascites, n (%)
4 (20)
Hepatic encephalopathy,
n (%)
6 (30)
Median platelet count,
103/µL (range)
65
80
Median serum albumin,
g/dL (range)
84 (44-162)
SVR12 (%)
Median total bilirubin,
mg/dL (range)
7 relapsers
60
40
20
0
13/20
LDV/SOF 12 Weeks
Error bar represents the 95% confidence interval.
Gane, E. et al. EASL 2014, Abstract #O6
40
100
100
64*
SVR12 (%)
80
60
40
20
0
16/25
26/26
LDV/SOF 12 Weeks
LDV/SOF + RBV 12 Weeks
*Failure due to relapse (n=8) or discontinuation due to AE (n=1)
Gane, E. et al. EASL 2014, Abstract #O6
41
LDV/SOF regimens for 12 weeks are safe and
effective IFN-free treatments for many diverse and
difficult-to-treat patient populations including:
• Patients infected with HCV GT 1 who have failed
previous SOF-containing regimens
• Patients infected with HCV GT 1 with
decompensated cirrhosis
• Patients infected with HCV GT 3
Gane, E. et al. EASL 2014, Abstract #O6
42
SAPPHIRE I: Phase 3 Placebo-Controlled Study of
Interferon-Free, 12-Week Regimen Of ABT-450/r/ABT-267,
ABT-333, and Ribavirin in 631 Treatment-Naïve Adults With
Hepatitis C Virus Genotype 1
J.J. Feld1, K.V. Kowdley2, E. Coakley3, S. Sigal4, D. Nelson5, D. Crawford6,7, O. Weiland8, H. Aguilar9,
J. Xiong3, B. DaSilva-Tillmann3, L. Larsen3, T. Podsadecki3
1Toronto
Western Hospital Liver Centre, Toronto, ON, Canada; 2Digestive Disease Institute, Virginia Mason
Medical Center, Seattle, WA; 3AbbVie Inc., North Chicago, IL; 4NYU Langone Medical Center, New York, NY;
5University of Florida College of Medicine, Gainesville, FL, United States; 6Gallipoli Medical Research
Foundation; 7The University of Queensland, Brisbane, QLD, Australia; 8Karolinska University Hospital
Huddinge, Karolinska Institutet, Stockholm, Sweden; 9Louisiana Research Center, LLC, Shreveport, LA,
United States
43
Double-Blind
Treatment Period
Open-Label
Treatment Period
3D + RBV
(n=473)
Placebo
(n=158)
Week 0
48-Week
Follow-Up
48-Week
Follow-Up
3D + RBV
Week 12
Week 24
Week 60
Week 72
Primary Analysis:
SVR12
• 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25
mg QD; dasabuvir, 250 mg BID
• RBV: 1000-1200 mg daily according to body weight (<75 kg
and >75kg, respectively)
Feld, J. et al. EASL 2014, Abstract #O60
44
Male, n (%)
Race, n (%)
White
Black
Hispanic/Latino ethnicity, n (%)
Median age, years (range)
Median BMI, kg/m2 (range)
Fibrosis stage, n (%)
F0-F1
F2
F3
IL28B non-CC genotype, n (%)
HCV subtype, n (%)
1a
1b
Median HCV RNA, log10 IU/mL (range)
3D + RBV
(N=473)
271 (57.3)
Placebo
(N=158)
73 (46.2)
428 (90.5)
26 (5.5)
27 (5.7)
52.0 (18.0-70.0)
25.2 (18.0-38.4)
144 (91.1)
8 (5.1)
5 (3.2)
52.0 (21.0-70.0)
25.5 (18.5-39.4)
363 (76.7)
70 (14.8)
40 (8.5)
329 (69.6)
116 (73.4)
27 (17.1)
15 (9.5)
108 (68.4)
322 (68.1)
151 (31.9)
6.51 (3.58-7.60)
105 (66.5)
53 (33.5)
6.64 (3.71-7.51)
HCV genotype and subtype were assessed using the Versant HCV Genotype Inno-LiPA Assay, v2.0.
Feld, J. et al. EASL 2014, Abstract #O60
45
95.3%
98.0%
455/473
307/322
148/151
All
Patients
GT1a
GT1b
SVR12, % Patients
96.2%
Feld, J. et al. EASL 2014, Abstract #O60
46
The ITT SVR12 rate was 96.2% (455/473) for treatmentnaïve GT1-infected patients receiving 12 weeks of coformulated ABT-450/r/ombitasvir + dasabuvir + RBV
SVR12 rates (ITT) were high regardless of HCV subtype
The rate of virologic failure was low:
– 0.2% breakthrough rate
– 1.5% relapse rate
The regimen was generally well-tolerated, with a low rate
of study drug discontinuation due to AE(s) (0.6%)
Feld, J. et al. EASL 2014, Abstract #O60
47
SAPPHIRE II: Phase 3 Placebo-Controlled Study Of
Interferon-Free, 12-Week Regimen Of ABT-450/r/ABT-267,
ABT-333, And Ribavirin In Treatment-Experienced Adults With
Hepatitis C Virus Genotype 1
S. Zeuzem1, I. Jacobson2, T. Baykal3, R.T. Marinho4, F. Poordad5, M. Bourliere6, M. Sulkowski7, H.
Wedemeyer8, E. Tam9, P. Desmond10, D. Jensen11, A.M. Di Bisceglie12, P. Varunok13, T. Hassanein14, J.
Xiong3, B. DaSilva-Tillmann3, L. Larsen3, T. Podsadecki3
1J.W.
Goethe University, Frankfurt, Germany, 2Weill Cornell Medical College, New York, NY, 3AbbVie Inc.,
North Chicago, IL, United States, 4Centro Hospitalar de Lisboa Norte, Lisbon, Portugal, 5The Texas Liver
Institute, University of Texas Health Science Center, San Antonio, TX, United States, 6Hopital Saint Joseph,
Marseille, France, 7Johns Hopkins University, Baltimore, MD, United States, 8Medizinische Hochschule
Hannover, Hannover, Germany, 9LAIR Centre, Vancouver, BC, Canada, 10St Vincent's Hospital (Melbourne),
Fitzroy, VIC, Australia, 11Center for Liver Diseases, University of Chicago Medical Center Chicago, Chicago,
IL, 12Saint Louis University, St. Louis, MO, 13Premier Medical Group of the Hudson Valley, PC,
Poughkeepsie, NY, 14Southern California Liver Centers and Southern California Research Center, Coronado,
CA, United States
48
Double-Blind
Treatment Period
Open-Label
Treatment Period
3D + RBV
(n=297)
Placebo
(n=97)
Week 0
48-Week
Follow-Up
48-Week
Follow-Up
3D + RBV
Week 12
Week 24
Week 60
Week 72
Primary Analysis:
SVR12
• 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir,
250 mg BID
• RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg,
respectively)
Zeuzem, S. et al. EASL 2014, Abstract #O1
49
Male / female, n (%)
White, n (%)
Median age, years (range)
Median BMI, kg/m2 (range)
Fibrosis stage, n (%)
F0-F1
F2
F3
IL28B* non-CC genotype, n (%)
HCV subtype, n (%)
1a
1b
Median HCV RNA, log10 IU/mL (range)
Prior pegIFN/RBV response, n (%)
Relapse
Partial response
Null response
3D + RBV
(N=297)
167 (56.2) / 130 (43.8)
269 (90.6)
54.0 (19.0-71.0)
26.0 (18.1-38.1)
Placebo
(N=97)
60 (61.9) / 37 (38.1)
86 (88.7)
56.0 (30.0-69.0)
26.1 (18.5-36.7)
202 (68.0)
53 (17.8)
42 (14.1)
263 (88.6)
65 (67.0)
17 (17.5)
15 (15.5)
90 (92.8)
173 (58.2)
123 (41.4)
6.66 (4.61-7.70)
57 (58.8)
40 (41.2)
6.55 (5.20-7.55)
86 (29.0)
65 (21.9)
146 (49.2)
29 (29.9)
21 (21.6)
47 (48.5)
*IL28B rs12979860
HCV genotype and subtype assessed using the Versant HCV Genotype Inno-LiPA Assay, v2.0.
HCV RNA level measured by COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, v2.0 (Roche).
Zeuzem, S. et al. EASL 2014, Abstract #O1
50
SVR12, % Patients
100
96.3%
96.0%
96.7%
286/297
166/173
119/123
All
Patients
GT1a
GT1b
80
60
40
20
0
Zeuzem, S. et al. EASL 2014, Abstract #O1
51
100
95.3%
100%
95.2%
82/86
65/65
139/146
Prior
Relapse
Prior
Partial
Response
Prior
Null
Response
SVR12, % Patients
80
60
40
20
0
Zeuzem, S. et al. EASL 2014, Abstract #O1
52
• The ITT SVR12 rate was 96.3% (286/297) for
treatment-experienced GT1-infected patients
receiving 12 weeks of ABT-450/r/ombitasvir +
dasabuvir + RBV
• High SVR12 rates regardless of HCV subtype and
across all prior pegIFN/RBV response groups
• The regimen was generally well-tolerated, with a
low rate of study drug discontinuation due to AE(s)
(1.0%)
Zeuzem, S. et al. EASL 2014, Abstract #O1
53
TURQUOISE-II:
SVR12 Rate of 92-96% in 380 Hepatitis C Virus
Genotype 1-infected Adults With Compensated
Cirrhosis Treated With ABT-450/R/ABT-267 and ABT333 Plus Ribavirin
F. Poordad1, C. Hezode2, R. Trinh3, K.V. Kowdley4, S. Zeuzem5, K. Agarwal6, M.L. Shiffman7, H.
Wedemeyer8, T. Berg9, E.M. Yoshida10, X. Forns11, S.S. Lovell3, B. Da Silva-Tillmann3, A.L. Campbell3,
T. Podsadecki3
1The
Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, United States, 2Henri
Mondor Hospital, APHP, University Paris-Est, Inserm U955, Creteil, France, 3AbbVie Inc., North Chicago, IL,
4Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States, 5J.W. Goethe
University, Frankfurt, Germany, 6Institute of Liver Studies, Kings College Hospital, London, United Kingdom,
7Liver Institute of Virginia, Newport News, VA, United States, 8Medizinische Hochschule Hannover,
Hannover, 9Universit_tsklinikum Leipzig, Leipzig, Germany, 10University of British Columbia, Vancouver, BC,
Canada, 11Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain
54
SVR12
3D + RBV
(N=208)
SVR12
3D + RBV
(N=172)
All patients to be followed through 48 weeks post-treatment
Day 0
Week 12
Week 24
• 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD;
dasabuvir, 250 mg BID
• RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg,
respectively)
Poordad, F. et al. EASL 2014, Abstract #O163
55
3D + RBV
12-Week Arm
24-Week Arm
(N=208)
(N=172)
Male (%)
White race (%)
Hispanic or Latino ethnicity (%)
Mean age (years)
Mean BMI (kg/m2)
IL28B non-CC (%)
HCV genotype 1a (%)
Treatment-naïve (%)
Treatment-experienced (%)
Relapse
Partial responder
Null responder
Platelet count <100 x 109/L (%)
Serum albumin <3.5 g/dL (%)
Child-Pugh score >5 (%)
70.2
95.7
12.0
57.1
27.9
83.2
67.3
41.3
58.7
13.9
8.7
36.1
21.6
12.0
18.3
70.3
93.6
11.6
56.5
27.9
80.2
70.3
43.0
57.0
13.4
7.6
36.0
19.2
10.5
18.6
Poordad, F. et al. EASL 2014, Abstract #O163
56
SVR12, % Patients
100
91.8
P=0.089
95.9
80
60
40
20
0
191/208
165/172
12 Weeks
3D + RBV
24 Weeks
3D + RBV
Poordad, F. et al. EASL 2014, Abstract #O163
57
100
92.2 92.9
93.3 100
100 100
80.0 92.9
3D + RBV
12-week arm
SVR12, % Patients
80
24-week arm
60
40
20
0
59/64 52/56
Naïve
14/15 13/13
11/11 10/10
Prior Relapse Prior Partial
Response
Response
40/50 39/42
Prior Null
Response
HCV Subtype 1a
Poordad, F. et al. EASL 2014, Abstract #O163
58
• First dedicated trial of IFN-free regimen in cirrhotic patients,
including patients often ineligible for clinical trials
(low platelets, low albumin, radiographic ascites)
• SVR rates of 92% to 96% with 12 and 24 weeks of
treatment, with high SVR rates in all subgroups analyzed
• 12 or 24 weeks of treatment were similarly well tolerated,
with low rates of treatment discontinuation
• Efficacy and safety in this large cirrhotic population is similar
to non-cirrhotics treated with the same regimen
59
All-Oral Dual Therapy With Daclatasvir
and Asunaprevir in Patients With
HCV Genotype 1b Infection:
Phase 3 HALLMARK-DUAL Study Results
M. Manns1, S. Pol2, I. Jacobson3, P. Marcellin4, S. Gordon5, C.-Y. Peng6, T.-T. Chang7, G. Everson8, J.
Heo9, G. Gerken10, B. Yoffe11, W.J. Towner12, M. Bourliere13, S. Metivier14, C.-J. Chu15, W. Sievert16, J.P. Bronowicki17, D. Thabut18, Y.-J. Lee19, J.-H. Kao20, F. McPhee21, J. Kopit21, P. Mendez22, M.
Linaberry22, E. Hughes22, S. Noviello22, HALLMARK DUAL Study Team
1Department
of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, 2H_pital Cochin, Paris,
France, 3Weill Cornell Medical College, New York, NY, United States, 4Hopital Beaujon, Clichy, France, 5Henry Ford Health Systems,
Detroit, MI, United States, 6School of Medicine, China Medical University, Taichung, 7National Chen Kung University Hospital, Tainan,
Taiwan, 8University Of Colorado Denver, Aurora, CO, United States, 9Pusan National University Hospital, Busan, Korea, Republic of,
10University of Duisburg-Essen, Essen, Germany, 11VAMC, Baylor College of Medicine, Houston, TX, 12Kaiser Permanente, Los Angeles,
CA, United States, 13H_pital Saint Joseph, Marseille, 14CHU Purpan, Toulouse, France, 15Taipei Veterans General Hospital and National
Yang-Ming University, Taipei, Taiwan, 16Monash Health and Monash University, Melbourne, VIC, Australia, 17INSERM Unit_ 954, Centre
Hospitalier Universitaire de Nancy and Universit_ de Lorraine, Vandoeuvre-l_s-Nancy, 18H_pital Piti_-Salp_tri_re, Paris, France, 19Inje
University Busan Paik Hospital, Busan, Korea, Republic of, 20National Taiwan University Hospital, Taipei, Taiwan, 21Bristol-Myers Squibb
Research and Development, Wallingford, CT, 22Bristol-Myers Squibb Research and Development, Princeton, NJ, United States
60
Treatment-naive
Randomization
2:1
Day 1
Week 12
Week 24
DCV 60 mg QD + ASV 100 mg BID 24 weeks
(N = 203)a
DCV-PBO + ASV-PBO
STOP
12 weeks (N = 102)
Week 48
Follow up 24 weeks
Enter another study:
DCV + ASV 24 weeks
Nonresponder
DCV + ASV 24 weeks
(N = 205)
Follow up 24 weeks
Ineligible/intolerant
DCV + ASV 24 weeks
(N = 235)
Follow up 24 weeks
Excludes 2 patients inadvertently assigned, instead of randomized, to DCV
+ ASV; patients were excluded from efficacy analyses but both achieved
SVR12
a
SVR12
• Primary endpoint: proportion of DCV + ASV-treated patients with SVR12
• Patients infected with HCV genotype 1b
– Treatment-naive
– Nonresponders: prior null or partial response to pegIFN/RBV
– Interferon-ineligible/intolerant (treatment-naive or -experienced) due to
•
•
•
Depression
Anemia/neutropenia
Compensated advanced fibrosis/cirrhosis (F3/F4) with thrombocytopenia
Manns, M. et al. EASL 2014, Abstract #O166
61
Treatment-naive
DCV + ASV
(N = 205)
Treatment-naive
Placebo
(N = 102)
Nonrespondera
(N = 205)
Ineligible/
intolerantb
(N = 235)
55
54
58
60
101 (49)
54 (53)
111 (54)
98 (42)
White
135 (66)
59 (58)
148 (72)
169 (72)
Black
14 (7)
8 (8)
10 (5)
10 (4)
Asian
52 (25)
33 (32)
45 (22)
56 (24)
< 800,000 log10 IU/mL
53 (26)
26 (25)
27 (13)
48 (20)
≥ 800,000 log10 IU/mL
152 (74)
76 (75)
178 (87)
187 (80)
33 (16)
16 (16)
63 (31)
111 (47)
CC
76 (37)
N/A
29 (14)
82 (35)
Non-CC
129 (63)
N/A
173 (84)
143 (61)
Parameter
Age, median years
Male, n (%)
Race, n (%)
HCV RNA, n (%)
Cirrhosis, n (%)
IL28B genotype, n (%)
a
Includes 119 (58%) null responders, 84 (41%) partial responders, and 2 (1%) relapsers.
Includes 71 (30%) patients with depression, 87 (37%) with anemia/neutropenia, and 77 (33%) with compensated advanced
fibrosis/cirrhosis with thrombocytopenia (6 with advanced fibrosis [F3], 70 with cirrhosis [F4], and 1 not reported).
b
Manns, M. et al. EASL 2014, Abstract #O166
62
SVR12 (% of patients)a,b
100
90
82
82
182/203
168/205
192/235
Treatmentnaive
Nonresponders
Ineligible/
intolerant
80
60
40
20
0
•
SVR12 rates documented on or after posttreatment Week 12
– Treatment-naive: 91%
– Nonresponders: 82%
– Ineligible/intolerant: 83%
a
HCV RNA < lower limit of assay quantitation (25 IU/mL)
Patients with missing SVR12 data counted as treatment failures
Manns, M. et al. EASL 2014, Abstract #O166
b
63
Treatment-naive
100
Nonresponder
91
90
82
SVR12 (% of patients)
Ineligible/intolerant
81
80
68/84
57/71
73
80
60
40
20
182/203
98/119
79/87
56/77
0
Null
Partial
Depression Anemia/ Advanced
neutropeniaa fibrosis/cirrhosis
w/ thrombocytopeniab
a
Anemia: screening hemoglobin 8.5 to < 12 (female) or < 13 (male) g/dL and/or history of anemia on pegIFN/RBV;
neutropenia: screening absolute neutrophils 0.5 to < 1.5 x 10 9 cells/L and/or history of neutropenia on pegIFN/RBV
b Screening platelets 50 to < 90 x 109 cells/L and/or history of thrombocytopenia on pegIFN/RBV
Manns, M. et al. EASL 2014, Abstract #O166
64
Patients, n (%)
All
Treatmentnaive
(N = 203)
Nonresponder
(N = 205)
Ineligible/intoler
ant
(N = 235)
21 (10)
37 (18)
43 (18)
9 (4)
26 (13)
20 (9)
0
0
1 (0.4)
4 (2)
3 (1)
8 (3)
5 (3)
7 (4)
12 (6)
3 (2)
1 (1)
2 (1)
On-treatment failures
Virologic breakthrough
Futility
Detectable or missing RNA at end of
treatment
Posttreatment failures
Relapsea
Missing RNA at posttreatment Week
12a
a
Percentages based on number of patients with undetectable HCV RNA at end of treatment (treatment-naive, n = 189;
nonresponder, n = 174; ineligible/intolerant, n = 204).
Manns, M. et al. EASL 2014, Abstract #O166
65
• All-oral DCV + ASV therapy achieved SVR12 rates up to
91% in treatment-naive, 82% in nonresponder, and 83% in
ineligible/intolerant patients with genotype 1b
– SVR12 rates were similar in non-cirrhotic (85%) and cirrhotic (84%)
patients
– No differences by age, gender, race, IL28B genotype, or prior
IFN/RBV treatment experience
• DCV + ASV was generally safe and well tolerated
– Only 2% of patients discontinued treatment due to adverse events
• DCV is being further evaluated in all-oral combinations in
multiple patient populations of high unmet need
Manns, M. et al. EASL 2014, Abstract #O166
66