6/2/2015
1
Formatted: 05-14-2015
Chicago, IL: May 19, 2015
Interactive Case-Based Presentations
and Audience Discussion
Michael R. Charlton, MBBS, FRCPHepatology Director
Medical Director of Liver Transplantation
Intermountain Medical Center
Salt Lake City, Utah
Slide 2 of 72
Case 1. Cirrhosis
Slide 3 of 72
Case 1.
62 yr old man
Long history of HCV infection (diagnosed 1992).
– “I did it all in the 60s.”
HCV genotype 1a, HCV RNA 112,000 IU/ml
ALT 53, AST 61, total bilirubin 3.7, albumin 2.9
– Cr 1.12mg/dl, INR 1.2
Exam notable for spider angiomata, mild emaciation, small amount of ascites.
Meds: carvedilol, spironolactone and furosemide
U/S – ascites, nodular liver, splenomegalyAuthor’s Last Name, Conference Name, Year, Presentation #
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Slide 4 of 72
Case 1.
Virological nonresponse to PEG/RBV in 2001
Should we treat HCV infection?
If so, with what?
Are there any special considerations?
Author’s Last Name, Conference Name, Year, Presentation #
Slide 5 of 72
Foster G, EASL, 2014, O66
SVR Rates of SOF-Based Regimens Across Genotypes and Among Patients with Multiple Negative Predictive Factors
Retrospective analysis of data from Phase 2 and 3 SOF studies to identify variables associated with relapse
Effect of Negative Predictors on SVR Rates Across SOF Studies
SV
R1
2 (
%)
Number of Negative Predictors
SVR12 Rates by Number of Negative Predictors and Genotype
4/4
5/5
26/26
22/22
22/22
69/69
69/70
43/43
114/122
78/81
55/59
89/104
65/69
57/66
11/18
26/33
23/37
4/6
8/15
Negative predictors: Male gender, body weight ≥ 75kg, IL28B nonCC, baseline HCV RNA ≥ 800,000 IU/mL, prior treatment failure, cirrhosis
89% of patients in the Phase 3 program had ≤4 negative predictors
Slide 6 of 72
Foster G, EASL, 2014, O66
SVR Rates of SOF-Based Regimens Across Genotypes and Among Patients with Multiple Negative Predictive Factors
Retrospective analysis of data from Phase 2 and 3 SOF studies to identify variables associated with relapse
Effect of Negative Predictors on SVR Rates Across SOF Studies
SV
R1
2 (
%)
Number of Negative Predictors
SVR12 Rates by Number of Negative Predictors and Genotype
4/4
5/5
26/26
22/22
22/22
69/69
69/70
43/43
114/122
78/81
55/59
89/104
65/69
57/66
11/18
26/33
23/37
4/6
8/15
Negative predictors: Male gender, body weight ≥ 75kg, IL28B nonCC, baseline HCV RNA ≥ 800,000 IU/mL, prior treatment failure, cirrhosis
89% of patients in the Phase 3 program had ≤4 negative predictors
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Slide 7 of 72
All oral therapy for HCV Genotype 1 infection in Cirrhosis
Slide 8 of 72
Target Profile
FDC paritaprevir/RTV/ombitasvir dosed QD (2 pills)
dasabuvir dosed BID
12 week treatment duration for non-cirrhotic patients
GT1a TN, GT1 TE, and cirrhotic patients require RBV in regimen
Generic Drug Names
ABT-333 = Dasabuvir (NNI)
ABT-267 = Ombitasvir (NS5A)
ABT-450 = Paritaprevir (PI)
AM PM
450/r/267 450/r/267 333
333
RBVRBVRBV
RBV
RBVRBV
RBV
RBV
AbbVie HCV Clinical Development Program
ABT-450/RTV/ABT-267+ABT-333±RBV in GT 1 Patients ‡
Slide 9 of 72ABBV DDI Exclusion Criteria – Phase 3 Medications Contraindicated for Use with the Study Drug Regimen1
Citeline.com (TrialTrove); accessed 2-19-20141- Drug regimen: ABT-450 (PI) + RTV; ABT-267 (NS5a); ABT-333 (non-nuc NS5b) +/- RBV, 6 pills, BID dosing
Not all medications contraindicated with ritonavir and ribavirin are listed below. Refer to the most current package inserts or product labeling of ritonavir and ribavirin for a complete list of contraindicated medications
Drug Class Drug
Antiarrhythmic Dronedarone, Amiodarone, Propafenone, Quinidine
Anti-asthmatic Montelukast, Salmeterol
Anticonvulsant Carbamazepine, Phenobarbital, Phenytoin
Antidepressant Nefazodone
Antidiabetic Pioglitazone, Rosiglitazone, Troglitazone
Antifungal Itraconazole, Ketoconazole, Voriconazole
Antihistamine Astemizole, Terfenadine
Antihyperlipidemic Lovastatin, Gemfibrozil, Simvastatin
Antihypertensive Bepridil, Eplerenone
Anti-infective Clarithromycin, Fusidic Acid, Telithromycin, Trimethoprim, Troleandomycin
Antimycobacterial Rifabutin, rifampin
Narcotic analgesic Methadone, Buprenorphine
Sedative/hypnotic Midazolam, Triazolam
Other
Alfuzosin (alpha adrenoreceptor
antagonist)
Cisapride (GI motility agent)
Bosentan (endothelin receptor
antagonist)Conivaptan (cardiovascular agent)
Efavirenz (HIV)
Eleptriptan (selective serotonin
receptor agonist)
Ergot derivatives (neurologics)
Everolimus (anticancer)
Quercetin (anti-inflammatory)
Mifepristone (steroid)
Modafinil (stimulant)
Pimozide (antipsychotic)St. John's Wort (herbal product)
‡
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Slide 10 of 72
Poordad F, EASL, 2014, LB O163
Clinical trials.gov: NCT01704755
Poordad F, et al. N Engl J Med 2014; 2014 Apr 12]
HCV GT 1
Treatment-naïve and exp., cirrhotic
N=380
SVR12
ABT-450+RTV+ombitasvir+dasabuvir+RBV, n=172 SVR12
Week 0 12 24
Paritaprevir/RTV+Ombitasvir+Dasabuvir+RBV for 12 or 24 weeks in GT 1 Treatment-Naïve and -Experienced Cirrhotic Patients
Phase 3, randomized, open-label study
TURQUOISE II: GT1
ABT-450+RTV+ombitasvir+
dasabuvir+RBV, n=208
‡
Slide 11 of 72
Demographics
TURQUOISE II (paritaprevir/RTV+ombitasvir+dasabuvir+RBV): GT1
12 weeksN=208
24 weeksN=172
Mean age, y 57.1 56.5
Male, % 70.2 70.3
White race, % 95.7 93.6
Hispanic or Latino ethnicity, % 12.0 11.6
Mean BMI, kg/m2 27.9 27.9
IL28B non-CC, % 83.2 80.2
GT 1a, % 67.3 70.3
Treatment-naïve, % 41.3 43.0
Treatment experienced, % 58.7 57.0
PegIFN+RBV Relapse 13.9 13.4
PegIFN+RBV Partial responder 8.7 7.6
PegIFN+RBV Null responder 36.1 36.0
Serum albumin, < 3/5 g/L, % 12.0 10.5
Platelet count < 100 x109/L, % 21.6 19.2
Child-Pugh score > 5, % 18.3 18.6
Poordad F, EASL, 2014, LB O163. Poordad F, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]
‡
Slide 12 of 72
Poordad F, EASL, 2014, LB O163
Poordad F, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]
91.8 95.9
0
20
40
60
80
100
12 Weeks 24 Weeks
SV
R12, %
Patients missing data in SVR12 window count as failures
On treatment virologic failure: 1 (0.5%) in 12 week group, 3 (1.7%) in 24 week group
Relapse: 12/203 (5.9%) in 12 week group, 1/164 (0.6%) in 24 week group
SVR and Virologic Failure
191/208 165/172
TURQUOISE II (paritaprevir/RTV+ombitasvir+dasabuvir+RBV): GT1
P=0.089
‡
Twelve in the 12 week group and 1 in the 24 week group relapsed. 7/12 relapsers were geno 1a null responders
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Slide 13 of 72
SVR in HCV Subtype 1a and Prior Treatment Response
88.6 92.2 93.3100
80
94.292.9
100 10092.9
0
20
40
60
80
100
GT 1a Naïve Prior Relapse Prior PartialResponse
Prior NullResponse
SV
R12
12 weeks 24 weeks
TURQUOISE II (ABT-450+RTV+ombitasvir+dasabuvir+RBV): GT1
124/140 114/121 59/64 52/56 14/15 13/13 11/11 10/10 40/50 39/42
Poordad F, EASL, 2014, LB O163
Poordad F, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]
‡
Slide 14 of 72
The most common AEs in the 12 week and 24 week arm were
Fatigue: 32.7% and 46.5%, respectively, P<0.05
Headache: 27.9% and 30.8%, respectively, P=NS
Nausea: 17.8% and 20.3%, respectively, P=NS
Dyspnea: 5.8% and 12.2%, respectively, P<0.05
12 weeks
N=208
24 weeks
N=172
Any AE, % 91.8 90.7
Serious AEs, % 6.3 4.7
Treatment D/C due to AEs, % 1.9 2.3
Adverse Events
TURQUOISE II (paritaprevir/RTV+ombitasvir+dasabuvir+RBV): GT1
Poordad F, EASL, 2014, LB O163
Poordad F, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]
‡
Slide 15 of 72
Ledipasvir + Sofosbuvir
Author’s Last Name, Conference Name, Year, Presentation #
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Slide 16 of 72
Background
Ledipasvir
– Once-daily, oral, 90-mg NS5A
inhibitor
Sofosbuvir
‒ Once-daily, oral, 400-mg
NS5B inhibitor
Ledipasvir/Sofosbuvir FDC
–Once-daily, oral, fixed-dose
(90/400 mg) combination tablet
–Single-tablet regimen for
hepatitis C
SOF nucleotide
polymerase
inhibitor
LDVNS5A
inhibitor
SOF nucleotide
polymerase
inhibitor
SOF nucleotide
polymerase
inhibitor
LDV
NS5A
inhibitor
SOF
nucleotide
polymerase
inhibitor
LDV
NS5A
inhibitor
SOF
nucleotide
polymerase
inhibitor
FDC, fixed-dose combination.
Slide 17 of 72
Mangia A, EASL, 2014, O164
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
LDV/SOF Single Tablet Regimen in HCV Treatment-Naïve GT 1
Phase 3, randomized, open-label study of LDV/SOF ± RBV for 12 or 24 weeks in HCV GT 1 treatment-naive patients, including compensated cirrhotics
ION-1 (LDV/SOF±RBV)
‡
N = 865
TN GT 1
12 24Study Weeks 36
SVR 12
SVR 12
n=217
n=217
n=214
n=217
RBV 1000-1200 mg/d
HCV RNA analyzed by COBAS® TaqMan® HCV Test v2.0 HPS, with LLOQ of 25 IU/mL
SVR 12
SVR 12
LDV/SOF 90/400 mg
LDV/SOF 90/400 mg + RBV
LDV/SOF 90/400 mg
LDV/SOF 90/400 mg + RBV
0
Slide 18 of 72
Mangia A, EASL, 2014, O164
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
Overall Demographics
ION-1 (LDV/SOF±RBV)
12 Weeks 24 Weeks
LDV/SOF
n=214
LDV/SOF+RBV
n=217
LDV/SOF
n=217
LDV/SOF+RBV
n=217
Mean age, y (range) 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, n (%) 89 (42) 99 (46) 85 (39) 80 (37)
Mean BMI, kg/m2 (range) 27 (18–41) 27 (18–42) 27 (18–48) 26 (18–48)
Cirrhosis, n (%) 34 (16) 33 (15) 33 (15) 36 (17)
IL28B CC, n (%) 55 (26) 76 (35) 52 (24) 73 (34)
Interferon ineligible, n (%) 14 (7) 20 (9) 19 (9) 14 (7)
GT 1a, n (%) 144 (67) 148 (68) 146 (67) 143 (66)
Mean HCV RNA,
log10 IU/mL (range)6.4 (1.6–7.5) 6.4 (4.4–7.6) 6.3 (3.7–7.4) 6.3 (3.2–7.5)
HCV RNA ≥800,000 IU/mL 169 (79) 173 (80) 168 (77) 173 (80)
‡
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Slide 19 of 72
SVR12 – LDV/SOF Single Tablet Regimen in HCV Treatment-Naïve GT 1
99 97 98 99
0
20
40
60
80
100
211/217
12 Weeks 24 Weeks
LDV/SOF + RBV
211/214 212/217
SV
R1
2 (
%)
215/217
LDV/SOF + RBVLDV/SOF LDV/SOF
Error bars represent 95% confidence intervals
Mangia A, EASL, 2014, O164
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
ION-1 (LDV/SOF±RBV)
‡
Slide 20 of 72
SVR12 by Presence of Cirrhosis - LDV/SOF Single Tablet Regimen in HCV Treatment Naïve GT 1
Error bars represent 95% confidence intervals
Mangia A, EASL, 2014, O164
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]
ION-1 (LDV/SOF±RBV)
99 97 98 9994 100 94 100
0
20
40
60
80
100
Absence of Cirrhosis Cirrhosis
179/180 32/34 178/184 33/33 181/184 31/33 179/181 36/36
SV
R1
2 (
%)
12 Weeks 24 Weeks
LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF
‡
Slide 21 of 72
LDV/SOF±RBV Safety Summary
12 Weeks 24 Weeks
Patients, n (%)
LDV/SOF
n=214
LDV/SOF
+ RBV
n=217
LDV/SOF
n=217
LDV/SOF
+ RBV
n=217
Overall
safety
AEs 169 (79) 185 (85) 178 (82) 200 (92)
Grade 3‒4 AEs 4 (2) 14 (6) 21 (10) 12 (6)
Serious AEs 1 (<1) 7 (3) 18 (8) 7 (3)
Treatment D/C due
to AEs0 0 4 (2) 6 (3)
Death 0 0 0 0
Grade 3‒4
laboratory
abnormality
10 (5) 21 (10) 22 (10) 27 (12)
Hb <10 g/dL 0 20 (9) 0 16 (7)
Hb <8.5 g/dL 0 1 (<1) 0 0
Mangia A, EASL, 2014, O164
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
ION-1 (LDV/SOF±RBV)
‡
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Slide 22 of 72
Afdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
LDV/SOF Single Tablet Regimen in Treatment-Experienced GT 1 HCV
Phase 3, randomized, open-label study of LDV/SOF ± RBV for 12 or 24 weeks in HCV GT 1 treatment-experienced patients who previously failed PegIFN + RBV ± PI
ION-2 (LDV/SOF±RBV)
‡
N = 440
TE GT 1
12 24Study Weeks 36
SVR 12
SVR 12
n=109
n=111
n=109
n=111
RBV 1000-1200 mg/d
HCV RNA analyzed by COBAS® TaqMan® HCV Test v2.0 HPS, with LLOQ of 25 IU/mL
SVR 12 LDV/SOF 90/400 mg + RBV
LDV/SOF 90/400 mg
LDV/SOF 90/400 mg + RBV
SVR 12 LDV/SOF 90/400 mg
0
Slide 23 of 72
SVR12 - LDV/SOF±RBV in Treatment-Experienced GT 1 HCV
94 96 99 99
0
20
40
60
80
100
107/111
12 Weeks 24 Weeks
LDV/SOF + RBV
102/109 108/109
SV
R1
2 (
%)
110/111
LDV/SOF + RBVLDV/SOF LDV/SOF
Error bars represent 95% confidence intervalsAfdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
ION-2 (LDV/SOF±RBV)
‡
Slide 24 of 72
Reasons for Not Achieving SVR
Afdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
12 Weeks 24 Weeks
Patients, n (%)
LDV/SOF
n=109
LDV/SOF+RBV
n=111
LDV/SOF
n=109
LDV/SOF+RBV
n=111
SVR12 102 (94) 107 (96) 108 (99) 110 (99)
Breakthrough 0 0 0 1 (<1)
Relapse 7 (7) 4 (4) 0 0
Lost to Follow-Up 0 0 1 (<1) 0
Single on-treatment breakthrough was due to non-compliance
– Patient had no detectable levels of LDV or SOF at multiple time points prior to and at the time of virologic failure
ION-2 (LDV/SOF±RBV)
‡
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Slide 25 of 72
95 100 99 9986 82100 100
0
20
40
60
80
100
Absence of Cirrhosis Cirrhosis
SV
R1
2 (
%)
83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22
12 Weeks 24 Weeks
LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF
SVR12: Absence of Cirrhosis vs. Cirrhosis
Error bars represent 95% confidence intervals
Afdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
ION-2 (LDV/SOF±RBV)
‡
Slide 26 of 72
Pre-Liver Transplantation
Slide 27 of 72
Phase 2 Pre-Liver Transplant Pilot StudySOF + RBV to Prevent HCV Recurrence Post-Transplant
SOF + RBV (n=61)
Male, n (%) 49 (80)
Median age, y (range) 59 (46–73)
White, n (%) 55 (90)
BMI < 30 kg/m2, n (%) 43 (70)
HCV RNA > 6 log10 IU/mL, n (%) 41 (67)
Genotype, n (%)
1a
1b
2
3a
4
24 (39)
21 (34)
8 (13)
7 (12)
1 (2)
Non-CC allele, n (%) 47/60 (78)
CTP score, n (%)
5
67
8
26 (43)
18 (30)14 (23)
3 (5)
Median MELD score, (range) 8 (6–14)
Prior HCV treatment, n (%) 46 (75)
SOF 400 mg + RBV 1000–1200 mg
0 Liver transplant
(up to 48 weeks)
Time
Undergoing LT
for HCC 2° to
HCV, N=61
12 weeks
Post-transplant
virologicalresponse
(pTVR)
Pre-Liver Transplant Study (SOF+RBV)
LT, liver transplantation.Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation
6/2/2015
10
Slide 28 of 72
Results: Post-Transplant Virologic Response
93
70
0
20
40
60
80
100
Transplant pTVR12
43/46* 30/43*
*3 patients were >LLOQ at transplant.
Vira
l R
esp
on
se
Ra
te (
%)
ITT analysis: 30/61 (49%) pTVR
Slide 29 of 72
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480
Days with HCV RNA Continuously TND Prior to Liver Transplant
Days Continuously TND Prior to Transplant: No Recurrence vs Recurrence in GT 1–4
No Recurrence (n=30) Recurrence (n=10)
Median days TND
• No recurrence: 99
• Recurrence: 5.5
p <0.001*
>30 days TND
*Wilcoxon rank sum test.
Slide 30 of 72
Results: Adverse Events
*No SAEs were deemed related to SOF.
n (%)
SOF + RBV
(N=61)
SAEs* 11 (18)
Deaths
Pre transplant 2 (3)
Post transplant 3 (5)
AEs leading to DC of study treatment 2 (3)
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Slide 31 of 72
Liver Levels in Humans
Liver levels of triphosphate formed by sofosbuvir in excess of the inhibition constant for the HCV NS5B RNA-dependent RNA polymerase (Ki = 0.42 µM)
In vitro studies show that triphosphate is the predominant metabolite in hepatocytes for both sofosbuvir and ribavirin
Total U-metabolites0.01
0.1
1
10
100
1000
10000
Sofosbuvir
Liv
er
Co
nc
(µM
)
Total RBV-metabolites0.01
0.1
1
10
100
1000
10000
Ribavirin
Human liver explant total metabolite concentrations following between
3 and 32 weeks of sofosbuvir + ribavirin treatment
73 (0.2, 205)
Ki
356 (82, 1,800)
Indicated total concentrations are median (min, max)
of n = 25 subjects
Babusis D. et al. AASLD 2013. November 1-5, 2013. Washington DC, USA
HCV RNA < LLOQ 12 wk post-transplant
Reoccurrence post-transplantHCV RNA > LLOQ @ time of transplant
Slide 32 of 72
Ledipasvir/Sofosbuvir With Ribavirin for the Treatment of HCV in Patients With
Decompensated Cirrhosis: Preliminary Results of a Prospective, Multicenter Study
Michael R. Charlton3, Steven L. Flamm1, Gregory T. Everson2, Jill M. Denning4, Sarah Arterburn4, Theo Brandt-Sarif4, Phillip S. Pang4, John
G. McHutchison4, K. Rajender Reddy5, Nezam H. Afdhal6
1Northwestern Feinberg School of Medicine, Chicago, IL; 2University of Colorado Denver, Aurora, CO; 3Intermountain Medical Center, Murray, UT; 4Gilead Sciences, Inc.,
Foster City, CA; 5University of Pennsylvania School of Medicine, Philadelphia, PA; 6Beth Israel Deaconess Medical Center, Boston, MA
Slide 33 of 72
Study Design
GT 1 and 4, CPT Class B and C
108 patients randomized 1:1 to 12 or 24 Weeks of Treatment
GT 1 or 4 treatment-naïve or -experienced patients with decompensated cirrhosis (CPT class B [7-9] or C [score 10–12])
Broad inclusion criteria
– No history of major organ transplant, including liver
– No hepatocellular carcinoma (HCC)
– Total bilirubin ≤10 mg/dL, Hemoglobin ≥ 10 g/dL
– CLcr ≥ 40 mL/min, platelets > 30,000 x 103/µL,
Stratified by CPT score B or C
LDV/SOF + RBV
LDV/SOF + RBV
Wk 0 Wk 12 Wk 24
SVR12
SVR12
Wk 36
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12
Slide 34 of 72
CPT B CPT C
12 Weeks
n=30
24 Weeks
n=29
12 Weeks
n=23
24 Weeks
n=26
MELD score, n (%)
<10 6 (20) 8 (28) 0 0
10‒15 21 (70) 16 (55) 16 (70) 13 (50)
16-20 3 (10) 5 (17) 7 (30) 12 (46)
21-25 0 0 0 1 (4)
Ascites, n (%) 17 (57) 17 (59) 22 (96) 25 (96)
Encephalopathy, n (%) 20 (67) 16 (55) 21 (91) 23 (88)
Median bilirubin, mg/dL (range) 2.0 (0.6-5.5) 1.4 (0.8-4.5) 2.9 (1.2-14.5) 3.8 (1.1-5.7)
Median albumin, g/L (range) 2.9 (2.1-3.7) 3.0 (2.2-3.4) 2.6 (1.6-3.5) 2.6 (2.0-3.3)
Median INR, (range) 1.3 (1.0-1.5) 1.3 (1.0-2.6) 1.4 (1.2-1.9) 1.4 (1.1-2.2)
Median platelets, x 103µL (range) 88 (36-212) 73 (30-154) 81 (39-177) 71 (32-179)
Results: Baseline CharacteristicsGT 1 and 4, CPT Class B and C
Slide 35 of 72Results: SVR12
GT 1 and 4, CPT Class B and C
6 subjects (2 CPT B/24 Wk, 1 CPT C/12 Wk and 3 CPT C/24 Wk) excluded (transplant on study); 3 subjects CPT C/24 Wk have not reached SVR12.Error bars represent 90% confidence intervals.
87 87 8689 89 90
0
20
40
60
80
100
CPT B CPT C
SV
R1
2 (
%)
26/30 19/22 18/20
Overall
24/2745/52 42/47
LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks
Slide 36 of 72
Does cirrhosis get better?
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Slide 37 of 72
Laboratory Results: Change in MELD Score From Baseline Through Follow-up Week 4
37
-6
-4
-2
0
2
4
-6
-4
-2
0
2
4
n=5 n=5 n=2 n=3
(-8)
(+10)
CPT B CPT C
12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*
*Missing FU-4: n=2 CPT B 12 wks; n=4 CPT B 24 wks; n=2 CPT C 12 wk; n=7 CPT C 24 wk.
Slide 38 of 72
HC
V R
NA
(lo
g10
IU/m
L)
< L
LO
Q
Week
56
100 100 100 100
44
75
94 94 93
0
20
40
60
80
100
2 4 8 12 24
CPT A
CPT B
5/
9
9/
9
8/
8
8/
8
7/
7
7/
16
12/
16
15/
16
15/
16
14/
15
*
Afdhal N, EASL, 2014, O68
SOF+RBV for Treatment of Chronic HCV with Cirrhosis and Portal HTN ± Decompensation: Week 24 Interim Results
Randomized, open-label, safety and efficacy study of SOF+RBV for 48 weeks compared to observation for 6 months in patients with HCV cirrhosis and portal HTN (CPT 5–9)
SOF 400 mg + RBV
1000‒1200 mg
SVR1
2
ObservationSOF 400 mg + RBV
1000‒1200 mg
SVR
12
Wk 0 Wk
24
Wk
48
Wk
96
Wk
72
Arm 1
n=25
Arm 2
n=25
HVPG at Day 0 and Week 48
HVPG at Day 0, and Weeks 24 and 72
Preliminary results
*1 patient was a non-responder at Week 8
Slide 39 of 72
Laboratory and Clinical Event Changes
Ascites Hepatic Encephalopathy
Patients, n
SOF + RBV
n=25
Observation
n=25
SOF + RBV
n=25
Observation
n=25
Baseline 6 9 5 2
Week 12 5 8 3 3
Week 24 0 7 0 4
Cirrhosis and Portal Hypertension Study (SOF+RBV)
17
1
-9
-1
-15
-10
-5
0
5
10
15
20
CTP A CTP B
0.50.4
-0.1
0
-0.2-0.1
00.10.20.30.40.50.6
Platelets (103/µL) Albumin (g/dL)
SOF+RBV Observation 24 weeks
-72 -75
130
-80
-60
-40
-20
0
20
CTP A CTP B
ALT (U/L)
CTP A CTP B
Afdhal N, EASL, 2014, O68
6/2/2015
14
Slide 40 of 72
Conclusions
GT 1 and 4, CPT Class B and C
LDV/SOF + RBV for 12 weeks resulted in a high SVR12 rate in HCV patients with GT 1 and 4 and advanced liver disease
– Extending treatment duration to 24 weeks did not increase the response rate
Virologic response was associated with improvements in bilirubin, albumin, MELD and CPT scores in both CPT class B and C patients
LDV/SOF + RBV for 12-24 weeks was generally safe and well tolerated in CPT class B and C patients
Slide 41 of 72
Post-Liver Transplantation
Slide 42 of 72
Case 2. Liver Transplantation
6/2/2015
15
Slide 43 of 72
HCV RNA 19,000;
Total bili 5.6; AST
291; ALT 182; INR 1.7; Cr 0.73
(9/18/2013)
Biopsy = Cirrhosis
(donor liver Hep C +
and fibrosis)(9/24/2013)
Underwent Liver
Transplantation
(9/19/2013)
Case 2.
Cr increase (1.79)
led to decrease
TAC dosing and levels
(10/5/2013)
Sept 2013
Started Compassionate
Use
SOF + RBV 200 mg/day
(anemia limiting dose)
(9/29/2013)
HCV RNA undetectable (Wk 8)
Total bili, AST and ALT normal(11/12/2013)
Nov 2013
Patient discharged
from hospital
(11/14/2013)
Biopsy- acute cellular
rejection, treated with
mycophenolate and increasing TAC dosing
(10/16/2013)
51 yo female with cirrhosis secondary to HCV GT 1b, complicated by hepatopulmonary syndrome
HCV RNA 456,000;
Total bili 19.1; AST
56; ALT 55; Cr 1.26(9/28/2013)
Oct 2013
Hypoxic on maximal
oxygen support. No
embolizable lesions on pulmonary
angiography.
Blood type O+
MELD score 29 by
exception
Cholestatic from
outset, ascites,
encephalopathy
Slide 44 of 72
Slide 45 of 72
45
6/2/2015
16
Slide 46 of 72
0
5
10
15
20
25
0
50
100
150
200
250
300
350
400
450
500
AST
ALT
Total Bilirubin
Tota
lBil
iru
bin
(mg/
dL)
AST &
ALT (IU
/L)
Sep-19 Oct Nov Nov-13
Compassionate use began
Case 2.
Slide 47 of 72
Charlton M, Gastroenterology, 2014.
0 24 36Study Week
SOF 400 mg + RBV 400–1200 mg SVR 12
TN & TE with
recurrent
HCV
SOF+RBV for Established Recurrent HCV Post-Liver Transplant
Post-Liver Transplant Study (SOF+RBV)
n=40
Low, ascending-dose RBV regimen starting at 400 mg/day, escalated based on hemoglobin levels
Slide 48 of 72
Samuel D, EASL, 2014, P1232
100 100
7370 70
0
20
40
60
80
100
Week 4 EOT SVR4 SVR12 SVR24
HC
V R
NA
< L
LO
Q (
%)
LLOQ, lower limit of quantification (25 IU/mL)
40/40 40/40 29/40 28/40 28/40
Virologic ResponsePost-Liver Transplant Study (SOF+RBV)
Twenty-four weeks of SOF+RBV resulted in high SVR rates in this difficult-to-treat post-transplant population, including many cirrhotics and treatment-experienced patients
Relapse was not influenced by RBV dose or exposure
SOF + RBV in patients with recurrent HCV after liver transplantation was safe and well tolerated
6/2/2015
17
Slide 49 of 72
Kwo P, NEJM, 2014.
ABT-450+RTV+Ombitasvir+Dasabuvir+RBV in LT Recipients with Recurrent HCV GT 1
M12-999 (ABT-450+RTV+ombitasvir+dasabuvir+RBV)
Adjusted doses of TAC: 0.5mg/wk or 0.2mg every 3 days
Adjusted dose of CYA: 1/5th
daily dose
One patient D/C due to AEs (rash, memory impairment, and anxiety) after Week 18
Anemia Grade 3 (6.5–8 g/dl) in one patient, and 5 patients received EPO
Phase 2 single-arm trial assessing a NS3/4A/5A/5B inhibitor plus RBV for 24 weeks in 34 adult liver transplant recipients with recurrent HCV GT1 infection, fibrosis stage ≤ F2, excluding post-transplant treatment experience
* 4 patients experienced a TAC level > 15 ng/mL (15.7–34.0 ng/mL); All 4 patients had TAC dosing errors; 2 patients had associated creatinine increases (1.8 and 1.4 mg/dL), which normalized when dosing was corrected
0
2
4
6
8
10
12
14
16
Ta
cro
lim
us
Co
nc
en
tra
tio
n (
ng
/mL
) *
Pre-Rx on-Rx
SVR12 of 96%
Slide 50 of 72
Study Design
GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
223 patients randomized 1:1 to 12 or 24 weeks of treatment
GT 1 or 4 treatment-naïve or -experienced post-transplant patients
Broad inclusion criteria
– ≥ 3 months from liver transplant
– No hepatocellular carcinoma (HCC)
– Total bilirubin ≤10 mg/dL
– CLcr ≥ 40 mL/min
– Platelets >30,000 x 103/µL
– Hemoglobin ≥10 g/dL
Stratified at screening: F0–F3, CPT A, B, C
RBV dosing
– F0–F3/CPT A cirrhosis: weight-based
– CPT B and C cirrhosis: dose escalation, 600–1200 mg/d
LDV/SOF + RBV
LDV/SOF + RBV
Wk 0 Wk 12 Wk 24
SVR12
SVR12
Wk 36
Slide 51 of 72
Results: Baseline Characteristics – 12 and 24 Weeks
GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
F0-F3
n=111
CPT A
n=51
CPT B
n=52
CPT C
n=9
MELD (n, %)
<10 N/A 28 (55) 13 (25) 1 (11)
10-15 N/A 20 (39) 33 (63) 5 (56)
16-20 N/A 3 (6) 4 (8) 2 (22)
21-25 N/A 0 2 (4) 1 (11)
Ascites, n (%) 2 (2) 2 (4) 40 (77) 9 (100)
Encephalopathy, n (%) 1 (1) 3 (6) 23 (44) 7 (78)
Median bilirubin,
mg/dL (range)0.7 (0.3-3.6) 0.8 (0.2-2.9) 1.2 (0.5-3.7) 2.1 (0.7-9.9)
Median albumin,
g/L (range)3.8 (2.4-4.6) 3.7 (2.6-4.5) 3.2 (2.3-4.2) 2.4 (1.6-2.9)
Median INR (range) 1.0 (0.9-1.3) 1.1 (0.9-2.4) 1.2 (0.9-3.4) 1.3 (1.0-1.5)
Median platelets,
x 103/µL (range)146 (71-429) 108 (41-358) 93 (32-225) 79 (54-189)
Median hemoglobin,
g/dL (range)14.0 (10.1-18.3) 13.6 (11.2-17.9) 12.9 (9.6-17.0) 11.5 (9.6-14.2)
Median CLCr,
mL/min (range)
65.0
(20.4-116.8)
62.1
(26.8-110.9)
58.9
(29.0-118.9)
66.6
(39.5-72.1)
6/2/2015
18
Slide 52 of 72
Results: Mean HCV RNA Change During TreatmentGT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
0
1
2
3
4
5
6
7F0-F3 (n=111)
CPT A (n=51)
CPT B (n=52)
CPT C (n=9)
Mean H
CV
RN
A (
log
10
IU/m
L)
Week
Baseline 1 2 4 6
LLOQ
Slide 53 of 72
96 96
85
60
98 96
83
67
0
20
40
60
80
100
F0–F3
SV
R1
2 (
%)
53/55 22/26 15/18
CPT B
55/56 25/26 24/25 2/3
CPT A
Results: SVR12
GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
Error bars represent 2-sided 90% exact confidence intervals.8 CPT B 24 Week and 1 CPT C 24 Week subjects still to reach Week 12 posttreatment.
LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks
3/5
CPT C
Slide 54 of 72
96 96
85
60
98 96
83
67
0
20
40
60
80
100
F0–F3
SV
R1
2 (
%)
53/55 22/26 15/18
CPT B
55/56 25/26 24/25 2/3
CPT A
Results: SVR12GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
Error bars represent 2-sided 90% exact confidence intervals.8 CPT B 24 Week and 1 CPT C 24 Week subjects still to reach Week 12 posttreatment.
LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks
3/5
CPT C
2 relapses
1 relapse 1 death 1 death
1 relapse
2 deaths
1 consentwithdrawn
3 deaths 2 relapses 1 relapse
6/2/2015
19
Slide 55 of 72
Laboratory Results: Change in MELD Score From Baseline Through Follow-up Week 4
CPT A Patients (n=48) CPT B Patients (n=41)
n=4 n=1
-8
-6
-4
-2
0
2
4
n=9 n=4
(-11)
12 Wk (n=23) 24 Wk (n=25) 12 Wk (n=21) 24 Wk (n=20)
-8
-6
-4
-2
0
2
4
Slide 56 of 72Results: Overall Safety Summary
GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
F0-F3 CPT A CPT B CPT C
Patients, n (%)12 Wk
n=55
24 Wk
n=56
12 Wk
n=26
24 Wk
n=25
12 Wk
n=26
24 Wk
n=26
12 Wk
n=5
24 Wk
n=4
Serious and
related AEs2 (4) 1 (2) 2 (8) 2 (8) 0 1 (4) 0 0
Treatment DC due
to AE0 2 (4) 1 (4) 0 0 3 (12) 0 0
Treatment
emergent Death0 0 1 (4) 0 1 (4) 2 (8) 0 0
AE’s leading to DC: shortness of breath, hemoperitoneum, thoracic
aorta aneurysm dissection, seizure, elevated ALT/AST, dyspnoea,
Deaths: internal bleeding*, intestinal perforation/multi-organ failure,
unknown, sepsis, thoracic aorta aneurysm dissection*, complications
of cirrhosis*, progressive multifocal leukoencephalitis*
Slide 57 of 72Conclusions
GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
In patients with recurrent HCV post
transplantation, treatment with
LDV/SOF+RBV for 12 or 24 weeks resulted
in:
–High rates of SVR12 irrespective of disease
severity or duration of therapy (i.e. 12 = 24 weeks)
–Decreases in MELD scores
No on-treatment virologic failure occurred
Generally safe and well tolerated
6/2/2015
20
Slide 58 of 72
Prior Treatment Failures
Slide 59 of 72
Retreatment with SOF Regimens for HCV GT 2 or 3 Who Failed Prior SOF+RBV Therapy
Retreatment of GT 2/3 Study (SOF+PegIFN±RBV)
Open-label study offered to n=107 GT 2 or 3 treatment failures from FISSION, POSITRON and FUSION who received SOF+RBV
SVR 12
SOF + PegIFN + RBVSVR 12
n=34
SOF + RBVn=73
Wk 0 Wk 12 Wk 24 Wk 36GT 2 or 3
treatment
failures
from
FISSION,
POSITRON
and
FUSION
4/4 1/2 20/22 24/38
13/14 7/8 17/23 7/15
SOF + PegIFN + RBV
n=34
SOF + RBV
n=73
Mean age, y (range) 53 (31–70) 53 (38-63)
Male, n (%) 26 (77) 63 (86)
Black, n (%) 1 (1%) 0
Mean BMI, kg/m2 (range) 29 (22–39) 28 (20-41)
Cirrhosis* n (%) 14 (41) 25 (34)
Genotype 2, n (%) 6 (18) 5 (7)
Genotype 3, n (%) 28 (82) 68 (93)
Mean baseline HCV RNA, log10 IU/mL (range) 6.3 (4.8-7.8) 6.6 (4.4–7.6)
‡
*Cirrhosis status determined in parent protocol
Esteban R, EASL, 2014, O8
Slide 60 of 72
Retreatment with SOF Regimens for HCV GT 2 or 3 Who Failed Prior SOF+RBV Therapy
Retreatment of GT 2/3 Study (SOF+PegIFN±RBV)
13/14 7/8 17/23 7/15
10091
50
63
0
20
40
60
80
100
Genotype 2 Genotype 3
SV
R1
2 (%
)
12 weeks SOF+PegIFN+RBV 24 weeks SOF+RBV
4/4 1/2 20/22 24/38
93
74
88
47
0
20
40
60
80
100
12 weeks SOF +PegIFN+RBV
24 weeks SOF+RBV
SV
R1
2 (
%)
No Cirrhosis Cirrhosis
13/14 7/8 17/23 7/15
Retreatment with a SOF-based regimen was successful in GT2 or GT3 patients who previously failed SOF-containing regimens
12-weeks of SOF+PegIFN+RBV had higher overall SVR rates, including 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
HCV GT 3 by Cirrhosis Status
‡
Esteban R, EASL, 2014, O8
6/2/2015
21
Slide 61 of 72
Sofosbuvir/Ledipasvir FDC with or without RBV for patients with genotype 1 including patients with cirrhosis and prior protease inhibitor failure: LONESTAR
Treatment naïve, n=60– SOF/LDV +/- RBV for 8 or
12 weeks
PI virologic failure, n=40– Cirrhosis, n=22
– SOF/LDV +/- RBV for 12 weeks
Non-SVR, n=3– Lost to follow-up, n=1
– Viral relapse, n=2 Naïve, 8 wks, no RBV
TE cirrhosis, 12 wks, no RBV
TN relapse patient was retreated
No treatment discontinuation due to AE
Lawitz E et al. Lancet 383: 9916, p515-523, 2014.
Slide 62 of 72
0
2
3
4
5
6
7
NS5A: L31M 25.5%
NS5B: No RAVs
NS5A: Q30L (4.50%)
L31M (>99%)
Y93H (96.74%)
NS5B: S282T (91.24%)
NS5A: Q30L (3.47%)
L31M (94.38%)
L31V (4.67%)
Y93H (98.19%)
NS5B: S282T (8.00%)
Retreatment of a single patient who relapsed with multi-DAA resistant virus following 8 weeks of SOF/LDV: Lonestar
LLOQ-TD
LLOQ-TND
HC
V R
NA
(lo
g10 I
U/m
L)
SOF/LDV
8 Weeks
Re-treatment:
SOF/LDV + RBV24 Weeks
Post-
Treatment
Post-
Treatment
SVR12
Lawitz E et al. Lancet 383: 9916, p515-523, 2014.
Slide 63 of 72
Genotype 4
6/2/2015
22
Slide 64 of 72
Wk 0 Wk 24Wk 12
SOF+RBV
(n=31)*
SOF+RBV (n=29)*
SVR12
Wk 36 Wk 48
SVR24SVR4
SVR24
*SOF 400 mg/d; RBV 1000–1200 mg/d
SOF+RBV for GT 4 HCV
Randomized, open-label, single-center study conducted in the US of the safety and efficacy of all-oral SOF + RBV in patients of Egyptian ancestry with HCV GT 4
79
100
59
87
0
20
40
60
80
100
13/15
Treatment Naïve Treatment Experienced
12 Weeks
SOF+RBV
24 Weeks
SOF+RBV
SV
R1
2 (
%)
11/14 10/17
12 Weeks
SOF+RBV
24 Weeks
SOF+RBV
14/14
‡
Ruane P, EASL, 2014, P1243*1 patient had RBV D/C after Day 35 due to AE of dyspnea, and completed SOF 24 wk
SOF/LDV
(n=22)*
SVR12 SVR24SVR4
12 Weeks
SOF/LDV
38% SOF/LDV patients Rx experienced43% bridging fibrosis/cirrhosis
95
Slide 65 of 72
Summary
Slide 66 of 72
Preferred Regimens for Genotype 1 or 4
www.HCVguidelines.org
Compensated Cirrhosis Decompensated or LTx
Naïve SOF/LDV x 12 weeks SOF/LDV + RBV x 12 weeks
3D + RBV x 24 weeks
SIM/SOF x 24 weeks
Experienced
(IFN or PI)
SOF/LDV x 24 weeks SOF/LDV x 24 weeks
SOF/LDV + RBV x 12 weeks SOF/LDV + RBV x 12 weeks
(IFN) 3D + RBV x 24 weeks* SOF + RBV x 24 weeks
(SOF) SOF/LDV + RBV x 24 weeks SOF/LDV + RBV x 24 weeks
* Do not use 3D regimens or SIM in prior protease inhibitor failures
6/2/2015
23
Slide 67 of 72
Preferred Regimens for Genotype 2 or 3
www.HCVguidelines.org
Compensated Cirrhosis Decompensated or LTx
Naïve SOF + PEG x 12 weeks SOF + RBV x 24 weeks
SOF + RBV x 12-16 weeks
(24 weeks for geno 3)
Experienced SOF + PEG x 12 weeks SOF + RBV x 24 weeks
SOF + RBV x 12-16 weeks
(24 weeks for geno 3)
Formatted: 05-14-2015
Chicago, IL: May 19, 2015
Interactive Case-Based Presentations
and Audience Discussion
Michael R. Charlton, MBBS, FRCPHepatology Director
Medical Director of Liver Transplantation
Intermountain Medical Center
Salt Lake City, Utah