Bruce R. Bacon, MD, FACG
Hepatitis C: Update in Clinical Management
Bruce R. Bacon, M.D.James F. King M.D. Endowed Chair in Gastroenterology
Professor of Internal MedicineDivision of Gastroenterology and Hepatology
S i t L i U i it Li C tSaint Louis University Liver CenterSaint Louis University School of Medicine
St. Louis, Missouri
Disclosure Slide
• Dr. Bacon has a financial relationship with Merck Kadmon Vertex Gilead AbbottMerck, Kadmon, Vertex, Gilead, Abbott, Roche/Genentech, ISIS, and Bristol-Myers Squibb.
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Bruce R. Bacon, MD, FACG
The Hepatitis Epidemic
• US prevalence of chronic hepatitis C
5 million exposed– 5 million exposed
– 3.5 million with chronic viremia
• Worldwide prevalence of chronic hepatitis C-170 million
• Most patients with hepatitis C are asymptomatic until irreversible liver damage occurs
• Diagnosis depends upon a high index of suspicion and proper screening
• New guidelines from CDC for screening
Why Treat Chronic Hepatitis C?• The disease
– Common, chronic, and potentially progressivep y p g– Complications are becoming more common Liver failure Hepatocellular carcinoma (HCC)
• The treatment– Viral cure, or sustained virologic response (SVR), is
achievableachievable– SVR associated with histologic improvement and
gradual regression of fibrosis1
– SVR leads to lower risk for liver failure and HCC, and improved survival2,3
1. Poynard T, et al. Gastroenterology 2002;122:1303-1313. 2. Craxi A, et al. Clin Liver Dis 2005;9:329-346. 3. Shiratori Y, et al. Ann Intern Med 2005;142:105-114.
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Bruce R. Bacon, MD, FACG
Histologic Improvement After Successful Anti-HCV Therapy
Long-term, follow-up biopsy obtained from the same patient 57 months after end of treatment:Trichrome stain with Ishak stage 1 fibrosis
Pretreatment biopsy:Trichrome stain with Ishak stage 3 fibrosis(portal-to-portal bridging)
George S, et al. Hepatology 2009;49:729-738.
SVR Is Equivalent to Viral Cure
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Bruce R. Bacon, MD, FACG
The Evolution of HCV Therapy
80
100
%)
1986 1998 2001 2002
70 75
2011-13
20
40
60
80
SV
R (
%
16
34
42 39
54-56
70-75
Modified from Strader DB, et al. Diagnosis, Management, and Treatment of Hepatitis C. Hepatology 2004;39:1147-1171.
0IFN6 mo
IFN/RBV6 mo
PEG-IFN /RBV12 mo
IFN12 mo
IFN/RBV12 mo
PEG-IFN12 mo
6
PEG-IFN /RBV + PI6-12 mo
Is Risk-Based HCV Screening the Best Approach?
• High HCV prevalence in “baby boomer” population (born 1946-1964) )
– HCV may have been acquired decades ago
– Individuals no longer identified as high risk
– Aging of population anticipated to yield ↑ advanced liver disease
• Study investigated impact of targeted “birth cohort screening”
– 1-time screening of all US persons born 1946-1964 vs risk-based screening through 70 yrs of age
– Utilized Markov model of natural history of HCV and liver disease, incorporating diagnosis and treatment, to estimate HCV-associated outcomes for both screening approaches
McGarry L, et al. Digestive Disease Week 2011. Abstract 477.
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Bruce R. Bacon, MD, FACG
Birth Cohort vs Risk-Based HCV Screening
Outcome Estimate, n Birth Cohort Screening
Risk-BasedScreening
DifferenceScreening Screening
Total screened 78,700,000 8,000,000 +70,700,000
Diagnosed 1,312,391 427,030 +885,361
Treated 742,329 234,689 +507,640
SVR 404,274 124,650 +279,624
Decompensated cirrhosis
238,500 291,200 -52,700
HCC 137,400 166,000 -28,600
• Limitations of analysis: model is simplified view of disease and treatment; validity dependent on model assumptions; data combined from various sources; incident infection and transmission not included in model; new HCV treatments not considered
McGarry L, et al. Digestive Disease Week 2011. Abstract 477.
, , ,
Liver transplantation 28,700 34,700 -6000
HCV death 233,200 281,200 -48,000
Core E1 E2 P7
NS2 NS3 NS4A NS4B NS5A NS5B
Targets for New Hepatitis C Drugs
5′– –3′
Protease Polymerase
Linear TelaprevirBoceprevirACH-1625GS-9256
Macrocyclic Danoprevir (RG7227)TMC 435350BI-201335
BMS-790052
Active site (nucleosides)
RG7128IDX184PSI-7977
Non-nucleosides ABT-333ABT-072
Protease inhibitors
yinhibitorsClemizole
BMS-650032Vaniprevir
GS 9190ANA598VCH-759VCH-916VX-222FilibuvirBI-207127
Cyclophilin Debio 025SCY-635
Not all-inclusive
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Bruce R. Bacon, MD, FACG
To Treat or not to Treat:
A Constellation of Considerations
Duration ofinfection
Genotype virusGenotype Patient (IL28)
Histologic stage20%+ lifetime risk
of cirrhosis
Personal plans(marriage,pregnancy)
Age
Patient
Family and othersupport
ALT
HIV coinfectionExtrahepatic
Features(Fatigue, EMC, PCT)
Patient"mindset"
Contraindications& comorbidities
Insulin Resistance
Occupation
PinK AALSD CME 2009
Boceprevir and Telaprevir Clinical Trials
• Phase III trials leading to approval
Boceprevir plus pegIFN/RBV– Boceprevir plus pegIFN/RBV
SPRINT-2: treatment-naive patients[1]
RESPOND-2: treatment-experienced patients[2]
– Telaprevir plus pegIFN/RBV
ADVANCE: treatment-naive patients[3]
ILLUMINATE: treatment-naive patients[4]ILLUMINATE: treatment naive patients
REALIZE: treatment-experienced patients[5]
1. Poordad F, et al. N Engl J Med 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Sherman KE, et al. 2010 AASLD. Abstract LB2. 5. Zeuzem S, et al. N Engl J Med 2011;364:2417-2428.
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Bruce R. Bacon, MD, FACG
SPRINT-2: Boceprevir in GT1 Treatment-Naive Patients
Wk 72Wk 48Wk 28Wk 4
Treatment-naive patients with
genotype 1 HCV
(2 cohorts: N = 938
PR*(n = 316,
52) Follow-up
Follow-up
BOC + PR*(n = 316 nonblack,
52 black)
BOC + PR*(n = 311 nonblack, 55 black)
PR*(n = 311,
55)
Detectable Wks 8-24:PR*
Undetectable Wks 8-24:Follow-up
nonblack and 159 black)
PR*(n = 311 nonblack, 52 black)
Follow-up
*BOC 800 mg q8h, pegIFN alfa-2b 1.5 µg/kg/wk, weight-based RBV 600-1400 mg/day.
Poordad F, et al. N Engl J Med 2011;364:1195-1206.
PR*(n = 311,
55)
Treatment With Boceprevir
• All patients initiate therapy with 4-wk pegIFN/RBV lead in phasepegIFN/RBV lead-in phase
• After completion of lead-in phase, boceprevir should be added to continued pegIFN/RBV
– Boceprevir: 800 mg TID, every 7-9 hrs
– Boceprevir should be administered with food (li ht k l)(light snack or meal)
Boceprevir [package insert]. May 2011. Boceprevir. European Medicines Agency.
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Bruce R. Bacon, MD, FACG
SVR and Relapse Rates
P < .001 P = .004
SVR Relapse Rate
SPRINT-2: BOC + PegIFN/RBV in GT1 treatment-naïve patients
23
4253
1740
60
80
100
Per
cen
t
40
67 68
2340
60
80
100
Per
cen
t
P < .001P = .04
P .004
125311
211316
213311
2252
2955
14 12 17
0
20
48 P/R BOC RGTBOC/PR48P23
9 8
0
20
48 P/R BOC RGT BOC/PR48
P
Non-Black Patients Black Patients
311
1252
52
37162 21
23218
2302
143
25
635
Poordad F, et al. New Engl J Med. 2011;364:1195-1206.
SPRINT-2 Subanalysis: Response to 4-Wk PegIFN/RBV Lead-in
• Response to 4-wk lead-in phase with pegIFN/RBV strongest di t f SVR i lti i t l i (OR 9 0 P 001)predictor of SVR in multivariate analysis (OR: 9.0; P < .001)
– When 4-wk lead-in phase included as continuous variable, IL28Bgenotype no longer significantly predictive of SVR
81 79
60
80
100 < 1 log10 decline in HCV RNA
≥ 1 log10 decline in HCV RNA
%)
Poordad F, et al. EASL 2011. Abstract 12. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
2838
4
51
0
20
40
60
BOC RGT BOC/PR48 PR48
SV
R (
%
27/97
203/252
36/95
200/254
3/83 133/
260n/N =
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Bruce R. Bacon, MD, FACG
Boceprevir: Duration of Therapy for Noncirrhotic Treatment-Naive Patients
• HCV RNA levels at Wks 8, 12, and 24 used as decision pointspoints
– HCV RNA assay should have 25 IU/mL limit of quantification
Undetectable < 100 IU/mL Undetectable Complete 3-drug regimen at Wk 28
Detectable < 100 IU/mL Undetectable
1) Continue all 3 drugs through Wk 36, then
2) continue pegIFN/RBV through Wk 48
Detectable ≥ 100 IU/mL N/A Discontinue all 3 drugs at Wk 12
Boceprevir [package insert]. May 2011. Boceprevir. European Medicines Agency.
ADVANCE: Telaprevir + PegIFN/RBV in GT1 Treatment-Naive Patients
Wk 12 Wk 72Wk 48Wk 8 Wk 24
Treatment-naive patients withgenotype 1
HCV
TVR + PR*(n = 364)
TVR + PR*(n = 363)
eRVR†: PR* Follow-up
Follow-up
Follow-up
PR*
eRVR†: PR*
PR*
Follow-up
(N = 1088)
PR*(n = 361)
*TVR 750 mg q8h, pegIFN alfa-2a 180 µg/wk, weight-based RBV 1000-1200 mg/day.†eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
Follow-up
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Bruce R. Bacon, MD, FACG
Treatment With Telaprevir
• All patients initiate therapy with 12-wk period of p py ptriple therapy with telaprevir plus pegIFN/RBV
– Telaprevir: 750 mg TID, every 7-9 hrs
– Telaprevir should be administered with food (standard or high fat)
Standard fat meal would be 21 g such as 2Standard fat meal would be 21 g, such as 2 oz of cheese or 1/2 cup of nuts
Telaprevir [package insert]. 2011.
ADVANCE: Overall SVR and Relapse Rates
100 P 0001 f b h8-wk TVR/PR + 16/40-wk PR (n = 364)
40
60
80
100
Pat
ient
s (%
) 6975
44
P < .0001 for both treatment arms vs control
12-wk TVR/PR + 12/36-wk PR (n = 363)
48-wk PR (n = 361)
28
0
20
SVR
Jacobson IM, et al. AASLD 2010. Abstract 211. These data are available in unpresented abstract format only, and will be presented in full during the AASLD meeting. We encourage you to review the presented data before making conclusions.
n = 250 271 158
Relapse
9 9
28
n = 28 27 64
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Bruce R. Bacon, MD, FACG
Response-Guided Approach With TVR in Tx-Naive Patients Supported
by 2 Studies• ADVANCE: suggested 24 wks of therapy sufficient for patients with eRVR
A ti t i T12PR48 h hi d RVR d i d 24 k– Among patients in T12PR48 arm who achieved an eRVR and received 24 wks therapy, SVR was 89%
8997
54
39VR
(%
)
40
60
80
100 T12PRPR
Jacobson IM, et al. N Engl J Med 2011;364:2405-2416.
eRVR Positive(TVR patients
treated for 24 wks)
eRVR Negative(All treated for 48 wks)
SV
0
20
40
189/212
28/29
130/332
82/151n/N =
Response-Guided Approach With TVR in Tx-Naive Patients Supported by 2
Studies• Robustness of response-guided therapy confirmed by ILLUMINATE
– 92% of those who received 24 wks of total therapy following eRVRachieved SVR
100
80
60
R (
%)
∆ 4.5%(2-sided 95% CI: -2.1% to +11.1%)
72
9288
64
eRVR + T12PR24
Sherman K, et al. AASLD 2010. Abstract LB2.
40
20
0
SV
R
ITT eRVR + T12PR48
eRVR + T12PR48
Other
23
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Bruce R. Bacon, MD, FACG
Telaprevir: Duration of Therapy for Treatment-Naive Patients
• After 12 wks, telaprevir should be discontinued and pegIFN/RBV continued
– Cirrhotic patients with undetectable HCV RNA at Wks 4 and 12 may nevertheless benefit from additional 36 wks of pegIFN/RBV (48 wks total) rather than response-guided therapy
Response-Guided Therapy
HCV RNA Triple Therapy:TVR + PegIFN/RBV
Dual Therapy: PegIFN/RBV
Total Treatment Duration
Undetectable at Wks 4 and 12 First 12 wks Additional 12 wks 24 wks
Detectable (but ≤ 1000 IU/mL) at Wks 4 and/or 12
First 12 wks Additional 36 wks 48 wksat Wks 4 and/or 12
Stopping Rules
Time Point Criteria Action
Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue pegIFN/RBV
Any Discontinuation of pegIFN/RBV for any reason Discontinue TVR
Telaprevir [package insert]. 2011.
Retreatment With BOC + PegIFN/RBV in Treatment-Experienced Patients
100
Previous relapse
40
60
80
40
69
52
75
VR
(%
)[3]
Previous partial response
1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology 2011;54:1433-1444. 3. Bacon BR, et al. N Engl J Med 2011;364:1207-1217.
0
20
BOC RGT BOC/PR48
7
29
PR48
n/N = 2/29 15/51 23/57 72/105 30/58 77/103
SV
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Bruce R. Bacon, MD, FACG
SVR in Previous Relapsers, Partial Responders, Null Responders
REALIZE: TVR + PegIFN/RBV in G1 Previous Relapsers and Partial/Null Responders
100
60
R (
%)
80
Previous Relapsers Previous Partial Responders
Previous Null Responders
83*88*
59*54*
T12/PR48PR48 LI T12/PR48
0
SV
R
40
n/N=
*P < .001 vs PR48.
20
121/145 124/14116/68
24
29/49 26/484/27
15
21/72 25/75
29*33*
2/37
5
Zeuzem S, et al. N Engl J Med 2011;364:2417-2428.
SVR in Poorly IFN-Responsive Patients by Wk 4 PR Lead-in Response
RESPOND-2: BOC + PegIFN/RBV in GT 1 Treatment-Experienced Patients
VR
(%
)
100
80
60
VR
(%
)
100
80
60
7379
Poorly Responsive to IFN:< 1 log10 HCV RNA decline at Wk 4
Responsive to IFN:≥ 1 log10 HCV RNA decline at Wk 4
0/12
15/46
15/44
SV
PR48
40
20
0
0
33 34
BOC RGT BOC/PR48
17/67
80/110
90/114
SV
PR48
40
20
0
25
BOC RGT BOC/PR48
n/N =
Bacon BR, et al. N Engl J Med 2011;364:1207-1217.
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Bruce R. Bacon, MD, FACG
SVR in Poor IFN Responders Based on TW8 Response (Log Decline in VL Compared to BL VL) (BOC
Arms Combined)
91
7983
80
100
38
21
50
9
33
48
16
30
49
20
40
60
80
%
SV
R
0 0 00
RESPOND-2 SPRINT-2 CombinedStudies
<3 3-4 4-5 >5
016
38
628
1020
1011
028
223
2370
1531
2329
<3 3-4 4-5 >5 <3 3-4 4-5 >5
044
531
2998
2551
3340
Efficacy of boceprevir in prior null responders to peginterferon/ribavirin: the PROVIDE study*
100 PEG IFNα 2b : 1 5 µg/kg/week + ribavirin 600 1400 mg/day+
473840
60
80
100
Pat
ien
ts (
%)
PEG-IFNα-2b : 1,5 µg/kg/week + ribavirin 600-1400 mg/day+ boceprevir 800 mg day
16
0
20
n/N =
EOT20/43
SVR16/42
Relapse3/19
*Of 48 prior null responders from SPRINT-2 and RESPOND-2, 3 discontinued during the 4-week lead-in phase, 2 are ongoing treatment(1 entering TW3, 1 entering TW18 of BOC/PR) and 1 is in follow-up phase Relapse: an undetectable HCV RNA level at EOT, but with a detectable HCV RNA level during the follow-up period
Vierling J, et al. Hepatology 2011;54(Suppl. S1): Abstract 931
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Bruce R. Bacon, MD, FACG
Prior relapsers
Prior partial responders
Prior null responders
87100 Pbo/PR48
Telaprevir in Patients With Bridging Fibrosis or Cirrhosis
32
18 20
87 85 8477
56
3441 39
40
60
80Pooled T12/PR48
SV
R (
%)
137
18
06
0
1014
0
20
53/62n/N= 2/1512/38 145/167 10/180/53/17 36/47 16/380/91/5 11/32
No, minimal or portal fibrosis
CirrhosisStage
48/571/15 1/18 24/59 1/10 7/50
Bridgingfibrosis
No, minimal or portal fibrosis
CirrhosisBridgingfibrosis
No, minimal or portal fibrosis
CirrhosisBridgingfibrosis
http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf
SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used
Key for Waves of New Ggents:Direct-Acting Anti-Virals (DAAs) and Host-Targeting antiviral (HTAs)
First Wave Second Wave Third Wave
DAAs1st 2nd 3rd
Telaprevir Boceprevir
TMC435BI 201335BMS-790052PSI-7977
BI 201335/BI 207127BMS-790052/BMS-650032Mericitabine/MK-5172
Alisporivir/DEB 025 SCY635
HTAs
30
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Bruce R. Bacon, MD, FACG
HCV Pipeline by Mechanism of Action and Stage of Development
*Only represents a sample of agents in development for HCVSchlutter J. Nature. 2011;474(7350):S5-S7.© 2011 Nature Publishing Group.
Antiviral Efficacy of 2nd Wave NS3 PIs
4
5
0IU
/mL
)
3.8 3.94.2
4.6
1
2
3
HC
V R
NA
Dec
line
(lo
g10
3.3
1.8
0
1
Danoprevir200 mg TID
TMC435200 mg QD
BI-201335 240 mg QD
Vaniprevir700 mg BID
BMS-650032 400
mg BID
PHX1766 800 mg BID
Mea
n
Sarrazin C, Zeuzem S. Gastroenterology. 2010;138(2): 447-462. © 2010 by the AGA Institute.
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Bruce R. Bacon, MD, FACG
Goals for Hepatitis C Therapy
• Compared to PegIFN/RBV, new products should offer:offer:– Improved efficacy
– Efficacy in all patient types including previously treated patients, cirrhotic and black patients
– Orally effective regimen, IFN free
– Shorter treatment duration
– Improved side-effect profile
Selected Oral Directing Acting Antivirals for the Treatment of Chronic Hepatitis C, 2012
Compound Sponsor Activity
ABT 267 Abbott NS5A inhibitorABT-267 Abbott NS5A inhibitor
ABT-333 Abbott Non-nucleoside NS5B polymerase inhibitor
ABT-450 Abbott NS3/4A protease inhibitor
Faldaprevir Boehringer Ingelheim NS3/4A proteaseFaldaprevir(BI201335)
Boehringer Ingelheim NS3/4A protease inhibitor
BI207127 Boehringer Ingelheim Non-nucleoside NS5B polymerase inhibitor
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Bruce R. Bacon, MD, FACG
Selected Oral Directing Acting Antivirals for the Treatment of Chronic Hepatitis C, 2012 (cont)
Compound Sponsor ActivityAsunaprevir Bristol-Myers Squibb NS3 protease inhibitorp
(BMS-650032) y q p
Daclatasvir(BMS-790052)
Bristol-Myers Squibb NS5A replication complex inhibitor
BMS-791325 Bristol-Myers Squibb Non-nucleoside NS5B polymerase inhibitor
Sofosbuvir(GS 7977)
Gilead Uridine nucleotide analog NS5B(GS-7977) analog NS5B polymerase inhibitor
GS-5885 Gilead NS5A protein inhibitor
Not all-inclusive, but indicates drugs covered in this presentation
• Five arm study that evaluated different doses and durations in regimens with
SOUND-C2 Trial Update: BI 201335 + BI 207127 ± RBV
faldaprevir (PI) and BI207127 (non-nuc) with or without RBV
– Durations: 16, 28 or 40 weeks
– BID vs TID
• Randomization was stratified by genotype (1a vs 1b) and IL28B
– 9% of patients had cirrhosis
• SVR12 ranged between 52% to 69% in RBV-containing arms and 39% without RBV
SVR i i h ti i 54%*
Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A; *Soriano V et al, Abstract 84, AASLD 2012
– SVR in cirrhotics is 54%*
• IL28B CC, genotype 1b and female gender were favorably associated with SVR12
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Bruce R. Bacon, MD, FACG
SOUND-C2 Trial Update: Faldaprevir + BI 207127 ± RBV
Primary endpoint: SVR12 (ITT and per protocol)
100
40
60
80
SVR12(%)
66% 69% 69% 72%
44%59% 59%
52%
69%
39%
ITT
Per Protocol
Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.
0
20
BI 207127 Dosing TID TID TID BID TID
Duration (weeks) 16 28 40 28 28
RBV + + + + ‒
ELECTRON Trial
Objective• To evaluate sofosbuvir (SOF; formerly GS-7977), a uridine
nucleotide analog, plus ribavirin (RBV) in additional g, p ( )ELECTRON study arms:• SOF + RBV in treatment-naïve genotype 1 patients• SOF + RBV in null responder genotype 1 patients• SOF + RBV in treatment experienced (Prior null
response, breakthrough, or relapse) in genotype 2/3 patients
• To determine feasibility of shorter duration or reducedTo determine feasibility of shorter duration or reduced dose of RBV in treatment naive genotype 2/3 patients
• To evaluate the efficacy and safety of adding GS-5885, an NS5A inhibitor, to SOF + RBV in treatment naïve and null responder genotype 1 patients
Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307APress release. November 10, 2012. Gilead Sciences, Inc., Foster City, CA. Available at http://www.gilead.com/pr_1757156.
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Bruce R. Bacon, MD, FACG
ELECTRON Trial Update: Sofosbuvir + RBV vs.
Sofosbuvir + GS-5885 + RBV in Genotype 1 HCV
SOF + RBV SOF + GS-5885 + RBV
T t t N ll T t t N ll
Adverse Events, n (%)
Treatment-Naïve (n=25)
Null Responder
(n=10)
Treatment-Naïve (n=25)
Null Responder
(n=9)
SAEs* 1 (4) 0 2 (8) 0
AEs that led to discontinuation
0 0 1 (4) 0
≥Grade 2 AEs 10 (40) 3 (30) 12 (48) 2 (22)
A i 0 1 (10) 5 (20) 0
*SAEs considered unrelated to SOFStopped treatment at week 8 at time of partial colectomy for diverticular perforation
Gane EJ et al. Hepatology 2012;56(Suppl S1):306A-307A
Anemia 0 1 (10) 5 (20) 0
Headache 1 (4) 0 1 (4) 0
Depression 0 1 (10) 2 (8) 0
Ligament sprain 1 (4) 1 (10) 0 0
ELECTRON Trial Summary: Genotype 1 HCV
• SOF + RBV for 12 weeks provided SVR12 in 84% of treatment-naïve, but only in 10% of null responders
• Addition of GS-5885 increased efficacy of SOF + RBV
– 100% SVR4 in treatment-naïve patients
Gane EJ et al. Hepatology 2012;56(Suppl S1):306A-307A
– 3/3 SVR4 in null responders
– No additional safety/tolerability issues detected
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Bruce R. Bacon, MD, FACG
SOF in Combination with Low or Full Dose RBV in Difficult to Treat
Genotype 1 HCV Patients
Objective:Objective:
• To assess the safety, tolerability, and efficacy of SOF in combination with weight-based (full) or low dose ribavirin (RBV) for 24 weeks in HCV mono-infected, genotype 1, treatment-naive subjectsj
• SOF is a specific nucleotide analog HCV polymerase inhibitor
Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012
SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype
1 HCV PatientsTreatment Response: Full dose RBV (Part 1; N=10)
100 90% 90% 90% 90% 90%
40
60
80
100
ITTHCV RNA
<LLOQ(%)
Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012
0
20
Week 4 Week 12 ETR SVR4 SVR12
• mITT: 100% SVR12 (1 drop out at week 3)
ACG Regional Postgraduate Course - Los Angeles, CA Copyright 2013 American College of Gastroenterology
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Bruce R. Bacon, MD, FACG
SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype
1 HCV Patients
Conclusions:
• In this inner city population of HCV genotype 1 treatment-naïve patients, SOF + RBV administered for 24 weeks resulted in:
– Full dose RBV: SVR4 of 77%
– Low dose RBV: SVR4 of 56%
Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012
– Low dose RBV: SVR4 of 56%
• There were no safety signals or drug-related discontinuations in this study
All-Oral Combination of Daclatasvir Plus Sofosbuvir ± Ribavirin in
Treatment Naïve HCV GT 1, 2, or 3Objective:j
• To evaluate the efficacy and safety of daclatasvir (DCV; BMS-790052) plus sofosbuvir (SOF; GS-7977) with or without RBV
– 24 weeks in treatment-naïve patients infected with HCV GT1 (1a/1b), 2, or 3
12 weeks in treatment naïve patients infected with– 12 weeks in treatment-naïve patients infected with GT1 (1a/1b)
• DCV is an NS5A replication complex inhibitor; SOF is a nucleotide analogue NS5B polymerase inhibitor
Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012
ACG Regional Postgraduate Course - Los Angeles, CA Copyright 2013 American College of Gastroenterology
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Bruce R. Bacon, MD, FACG
Virologic Response is Maintained at PT Week 24 (GT 2 or 3; 24-Week
Treatment Groups)
120SOF LI + DCV DCV + SOF DCV + SOF + RBV
10094
88 88 88100 100 100 100 100100 100
86 8693
40
60
80
100
120
HCV RNA<LLOQ
(% patients)
Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012
0
20
Week 4 EOT SVR4 SVR12 SVR24
16 14 14 16 14 14 16 14 14 16 14 14 16 14 14
All-Oral Combination of DaclatasvirPlus Sofosbuvir ± Ribavirin in
Treatment Naïve HCV GT 1, 2, or 3
Conclusions:
• DCV + SOF with or without RBV achieved SVR in ≥93% of patients with HCV genotype 1, 2, or 3
• HCV genotype 2 or 3 (N=44)
– 24-week duration: SVR24=93% of patients
• HCV genotype 1 (N=126)
Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012
g yp ( )
– 12-week duration: SVR4=96%
– 24-week duration: SVR24=98%
ACG Regional Postgraduate Course - Los Angeles, CA Copyright 2013 American College of Gastroenterology
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Bruce R. Bacon, MD, FACG
ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV
Objectivej
• To assess efficacy and safety of several interferon free regimens of ABT-450/r with ABT-267 and/or ABT-333 ±ribavirin (RBV)
– ABT-450 is an HCV NS3/4 protease inhibitor that is co-administered with ritonavir (ABT-450/r) and dosed once dailyonce daily
– ABT-267 is an NS5A inhibitor that is dosed once daily
– ABT-333 is a non-nucleoside polymerase inhibitor dosed twice daily
Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012
ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null
Responders with Genotype 1 HCV
87.5% 85.4% 89.9% 87.3%97.5%
88.9% 93.3%100SVR12 Rates (ITT) for 8- and 12-week Arms
85.4%
20
40
60
80
ITTSVR12
(%)
n=80 n=79 n=79 n=79 n=45 n=45n=41
Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012
0ABT-450
ABT-333RBV
ABT-450ABT-267
RBV
ABT-450ABT-267ABT-333
ABT-450ABT-267ABT-333
RBV
ABT-450ABT-267ABT-333
RBV
ABT-450ABT-267
RBV
ABT-450ABT-267ABT-333
RBV
8 wks 12 wks 12 wks
Treatment Naïve Prior Null Responder
n 80
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Bruce R. Bacon, MD, FACG
ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null
Responders with Genotype 1 HCVConclusionsCo c us o s
• The 12-week 3 DAA + RBV regimens showed the greatest efficacy in both treatment-naive and null responder populations
• All DAA combinations studied were well tolerated through 8 - 12 weeks of treatment
Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012
• Phase 3 studies with the 3 DAA combination (with and without RBV) recently initiated
What’s In the Future? – Multiple DAAs?
Multiple DAAs + IFN Backbone + RBV• 2nd generation PIs• Nucleoside polymerase inhibitors• NS5A inhibitors• Nonnucleoside polymerase inhibitors (NNIs)
• Considerations:Considerations:– 2 DAA programs– Consider replacing RBV– RGT
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Bruce R. Bacon, MD, FACG
What’s In the Future? – IFN Free?
Polymerase BackbonePolymerase Backbone
• Highest resistance barrier
• Pan-genotypic
• Second generation PI / NS5A / NNI / RBV
• Cyclophilin inhibitor
• 3- or 4-drug regimens
• SVR?
Antiviral activity in all HCV genotypesAntiviral activity in all HCV genotypes No selection of resistanceNo selection of resistance
HCV — The Revolution Has Begun
All-oral combination regimenAll-oral combination regimen Short treatment durationShort treatment duration
QD (or BID) dosingQD (or BID) dosing Excellent safety and tolerabilityExcellent safety and tolerability
Applicable in difficult-to-treat populations: Transplant Coinfection End-stage renal disease, etc.
Applicable in difficult-to-treat populations: Transplant Coinfection End-stage renal disease, etc.
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