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Presented by. Jointly sponsored by the Duke University School of Medicine and The Chronic Liver Disease Foundation. Supported by:. Educational Objectives. - PowerPoint PPT PresentationTRANSCRIPT
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Supported by:Jointly sponsored by the Duke University School of Medicineand The Chronic Liver Disease Foundation
Presented by
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Educational Objectives• Describe the differences for each of the treatment
regimens newly approved or likely to be approved in 2014 in order to optimize patient outcomes.
• Identify the most important baseline characteristics when assessing benefit/risk of individual patients in order to make the decision to treat now or wait.
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Boceprevir and Telaprevir: Therapies Approved in 2011
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Generic Name Trade Name
boceprevirtelaprevir
Victrelis™Incivek™
First Direct Acting Antivirals (DAAs) with an Indication for the Treatment of GT 1 Chronic Hepatitis C
• Both compounds act by inhibiting HCV nonstructural NS3/4A protease and are referred to as direct acting antivirals
Telaprevir (INCIVEK™) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2013.Boceprevir (VICTRELIS™) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, September 2013.
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Limitations of Boceprevir and Telaprevir
• Telaprevir and boceprevir only approved for Genotype 1• Interferon and ribavirin backbone required• Twice per day dosing (BID) for telaprevir and three times per day (TID)
dosing for boceprevir• Response guided therapy (both) and lead-in (boceprevir) complicated• 24-48 week treatment • Limited efficacy in difficult to cure patients (e.g., patients with cirrhosis,
prior null responders, African-Americans)• Hematologic (both) and rash/dermatological (telaprevir) adverse events• Drug-drug interactions
Telaprevir (INCIVEK™) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2013.Boceprevir (VICTRELIS™) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, September 2013.
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• Protease inhibitors– Faldaprevir– Asunaprevir– ABT-450– MK-5172– Sovaprevir– ACH-2684
Many Direct Acting Antivirals in Development
• NS5A Inhibitors– Daclatasvir– Ledipasvir– ABT-267– GS-5816– ACH-3102– PPI-668– GSK2336805– Samatasvir– MK-8742
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• NS5B Nuc– VX-135– IDX20963– ACH-3422
Many Direct Acting Antivirals in Development
• NS5B Non-nuc– ABT-333– Deleobuvir– BMS 791325– PPI-383– GS 9669– TMC 647055
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Simeprevir (SMV) (protease inhibitor) +PEG-IFN/RBVAPPROVED REGIMEN FOR GT 1
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Simeprevir (SMV) (TMC 435)
• FDA approval: November 22, 2013• NS3/4A protease inhibitor • One capsule taken once daily with food• Must be used in combination with PEG/RBV• Approved for GT 1 infected subjects with
compensated liver disease (including cirrhosis)
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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SMV 150mg/PEG/RBV* PEG/RBV
PEG/RBVPost-Therapy Follow-Up
Post-Therapy Follow-Up
Response Guided Treatment
Placebo/PEG/RBV PEG/RBV PEG/RBV Post-Therapy Follow-Up
0 12 24 48 72Weeks
*PEG/RBV=Peginterferon/Ribavirin
QUEST 1, QUEST 2 and PROMISEStudy Designs
• Response Guided Therapy: if HCV RNA <25 International Units/mL at Week 4 and undetectable at Week 12, complete treatment at Week 24
• QUEST 1 and QUEST 2: GT 1, Treatment Naïve• PROMISE: GT 1, Prior Relapsers
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Overall GT 1a GT 1a Without Q80K
GT 1a With Q80K*
GT 1b0
20
40
60
80
100
8075
84
58
85
50 47 4352 53
SMV/PEG/RBVPEG/RBV
Patie
nts
Ach
ievi
ng S
VR12
(%)
419/521
132/264
191/254
62/131
138/165
36/83
49/84
23/44
228/267
70/133
SVR12 Rates in Treatment Naive Patients (QUEST 1 and QUEST 2 Combined)
*Observed prevalence of Q80K variants at baseline in US population in the Phase 2b/3 trials: 48% of GT 1a and 0% of GT 1b patientsSimeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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SVR12 Rates by METAVIR Fibrosis Score in Treatment Naive Patients With GT 1 Infection (Pooled Data QUEST 1 and QUEST 2)
F0-2 F3-40
20
40
60
80
10084
68
55
36
SMV/PEG/RBVPEG/RBV
Patie
nts
Ach
ievi
ng S
VR12
(%)
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
317/378
106/192
89/130
26/72
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Overall GT 1a GT 1a Without Q80K
GT 1a With Q80K GT 1b0
20
40
60
80
100
7970
78
47
86
3728 26 30
43
SMV/PEG/RBVPEG/RBV
Patie
nts
Ach
ievi
ng S
VR12
(%)
206/260
49/133
78/111
15/54
62/79
9/34
14/30
6/20
128/149
34/79
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
SVR12 Rates in Patients Who Relapsed AfterPrior IFN-Based Therapy (PROMISE)
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SVR12 Rates by METAVIR Fibrosis Score in Patients Who Relapsed After Prior IFN-Based Therapy (PROMISE)
F0-2 F3-40
20
40
60
80
100
8273
41
24
SMV/PEG/RBVPEG/RBV
Patie
nts
Ach
ievi
ng S
VR12
(%)
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
137/167
40/98
61/83
8/34
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Prior Relapser Prior Partial Responders Prior Null Responders0
20
40
60
80
100
7765
53
37
919
SMV/PEG/RBVPEG/RBV
Patie
nts
Ach
ievi
ng S
VR12
(%)
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
SVR24 Rates in Patients Who Failed PriorIFN-Based Therapy (ASPIRE)
20/26
10/27
15/23 2/23
9/17
3/16
12 weeks SMV/PEG/RBV followed by 36 weeks of PEG/RBV vs 48 weeks Placebo/PEG/RBV
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Simeprevir: Impact of the Q80K Polymorphism
• Efficacy of SMV/PEG/RBV is substantially reduced in patients infected with GT 1a with an NS3 Q80K polymorphism at baseline compared to patients without this polymorphism.
• Screening GT 1a patients for Q80K polymorphism at baseline is strongly recommended.
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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Simeprevir: Dosage and Administration
Triple TherapySMV/PEG/RBV*
Dual TherapyPEG/RBV
Total Treatment Duration*
Treatment-naive and prior relapse patients including those with cirrhosis
First 12 weeks Additional 12 weeks 24 weeks
Prior non-responder patients (including partial and null responders) including those with cirrhosis
First 12 weeks Additional 36 weeks 48 weeks
*Recommended duration of treatment if patient does not meet stopping rule.Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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• If PEG or RBV is discontinued for any reason, SMV must also be discontinued.
HCV-RNA Action
TW4,12 and 24: >25 IU/mL
TW4: Discontinue SMV/PEG/RBV
TW12: Discontinue PEG/RBV (SMV treatment complete at 12 weeks)
TW24: Discontinue PEG/RBV
Futility Rules
TW=treatment week, SMV=simeprevir, PEG=peginterferon, RBV=ribavirinSimeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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Higher SMV Concentrations Likely in Patientswith Hepatic Impairment
• SMV primarily metabolized by the liver• Phase 1 study conducted in HCV-uninfected subjects• Compared to subjects with normal hepatic function
– 2.4-fold higher concentrations in subjects with moderate hepatic impairment (Child-Pugh Class B)
– 5.2-fold higher concentrations in subjects with severe hepatic impairment (Child-Pugh Class C)
• Higher SMV exposures have been associated with increased frequency of adverse events
• No SMV dose recommendation givenSimeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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SMV Concentrations Based on Race
• Compared to Caucasians– Higher SMV concentrations in East Asians– Comparable SMV concentrations in Black/African Americans
• Higher SMV exposures have been associated with increased frequency of adverse events
• No SMV dose recommendation given for patients of East Asian ancestry
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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Drug: Drug Interaction Potential:SMV As An Inhibitor
• Potential for increased plasma concentrations of drugs that are substrates– CYP1A2– Intestinal CYP3A4 (not hepatic CYP3A4)– OATP1B1/3– P-gp transporters
• No adjustment required when co-administered with cyclosporine or tacrolimus
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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Drug: Drug Interaction Potential:SMV As A Substrate
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
• Co-administration of SMV with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended as this may lead to significantly lower or higher exposure of SMV, respectively
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Preferred Term or Grouped TermSMV/PEG/RBV
(First 12 Weeks)N=781
Placebo/PEG/RBV (First 12 Weeks)
N=397
Rash (including photosensitivity)** 28% 20%
Pruritus*** 22% 15%Nausea 22% 18%Myalgia 16% 13%
Dyspnea**** 12% 8%
Adverse Reactions (All Grades): ≥3% Higher Frequency Among Subjects Receiving 150 mg SMV/PEG/RBV vs Placebo/PEG/RBV*
*During the first 12 weeks of treatment (pooled phase 3 trials)**Grouped term ‘rash’ includes 26 preferred terms***Grouped term ‘pruritus’ includes the preferred terms ‘pruritus’ and ‘pruritus generalized’****Grouped term ‘dyspnea’ includes the preferred terms ‘dyspnea’ and ‘dyspnea generalized’Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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Laboratory Parameter WHO Toxicity GradeSMV/PEG/RBV
(First 12 Weeks)N=781
Placebo/PEG/RBV(First 12 Weeks)
N=397
Alkaline Phosphatase*
Grade 1 >1.25 to <2.50 x ULN*** 3% 1%
Grade 2 >2.50 to <5.00 x ULN <1% 0
Hyperbilirubinemia
Grade 1 >1.1 to <1.5 x ULN 27% 15%
Grade 2 >1.5 to <2.5 x ULN 18% 9%
Grade 3 >2.5 to <5.0 x ULN 4% 2%
Grade 4 >5.0 x ULN <1% 0
*During the first 12 weeks of treatment (pooled phase 3 trials)**No Grade 3 or 4 changes in alkaline phosphatase were observed. ***ULN=Upper Limit of NormalSimeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
Treatment-Emergent Lab Abnormalities (WHO Worst Toxicity Grades 1 to 4) Observed at a Higher Incidence in SMV-Treated Subjects*
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Laboratory Abnormalities
• Mild to moderate elevations in bilirubin
• Included elevation of both direct andindirect bilirubin
• Elevations occurred early after treatment initiation, peaked by Week 2 and were rapidly reversible upon cessation of SMV
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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Conclusions• Simeprevir + PEG/RBV is a newly approved HCV protease inhibitor
for GT 1-infected patients
• Total treatment duration (including patients with cirrhosis)– Treatment naive and prior relapsers: 24 weeks (12 weeks
SMV/PEG/RBV + 12 weeks PEG/RBV)
– Prior non-responder patients: 48 weeks (12 weeks SMV/PEG/RBV + 36 weeks PEG/RBV)
• Rash, pruritus, nausea, myalgia and dyspnea only adverse reactions reported at a >3% higher frequency in SMV/PEG/RBV patients compared to PEG/RBV patients
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
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Sofosbuvir (SOF)
APPROVED FOR GT 1, 2, 3 and 4
(REGIMENS DIFFER BY GENOTYPE AND PATIENT TYPE)
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Sofosbuvir (SOF) (GS-7977)
• FDA approval: December 6, 2013
• Nucleotide analog NS5B polymerase inhibitor
• One oral 400 mg tablet once daily with orwithout food
• Must be used in combination with RBV or in combination with PEG/RBV
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
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Sofosbuvir (SOF) (GS-7977)
• Approved for treatment of GT 1, 2, 3 and 4 including patients with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 coinfection
• Treatment regimen and duration dependent on both viral genotype and patient population
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
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SOF: Dosage and Administration
Patient Population* Treatment** Treatment Duration
GT 1 or 4 SOF + PEG/RBV 12 weeks
GT 2 SOF + RBV 12 weeks
GT 3 SOF + RBV 24 weeks
*HCV mono-infected and HCV/HIV-1 co-infected patients**If the other agents used in combination with SOF are permanently discontinued, SOF should also be discontinued.Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
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SOF: Dosage and Administration
• SOF + RBV for 24 weeks can be considered as a therapeutic option for chronic hepatitis C patients with GT 1 infection who are ineligible to receive an interferon-based regimen
• SOF + RBV is recommended up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
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Potential for Drug Interactions
• SOF rapidly converted to predominant circulating metabolite GS-331007 (>90% of drug related material systemic exposure)
• SOF is P-gp and breast cancer resistance protein (BCRP) substrate– Potent P-gp inducers in the intestine (rifampin, St. John’s wort)
may decrease SOF concentrations and should not be used with SOF
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
33Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
Drugs Without Clinically SignificantInteractions with SOF
• No adjustment required when co-administered with
– Cyclosporine or tacrolimus
– Methadone
– Darunavir/ritonavir, efavirenz, emtricitabine, raltegravir, rilpivirine or tenofovir disoproxil fumarate
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SOF Concentrations In Specific Populations
• Race has no clinically relevant effect on the exposure of SOF or the active metabolite.
• No SOF dose adjustment is recommended for patients with mild, moderate and severe hepatic impairment.
• Renal impairment– No dose adjustment is required for patients with mild to moderate renal
impairment– Safety and efficacy has not been established in patients with severe renal
impairment or end stage renal disease.
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
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Sofosbuvir:GT 1 and GT 4 Data
36
SVR12Sofosbuvir/PEG/RBV, n=327
Week 0 12 24
NEUTRINO: Study Design
• Open label– SOF+PEG+RBV for 12 weeks (no response-guided therapy)
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
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All Patients GT 1 GT 1a GT 1b GT 40
20
40
60
80
100 90 89 9282
96
Genotype
SRV1
2 (%
)
206/225
295/327
261/292
54/66
27/28
SVR12 Rates in Treatment-Naive GT 1 and GT 4 Patients (NEUTRINO)
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
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Multiple Factors*0
20
40
60
80
100 9287
7180
91
SVR
12 (%
)SVR Rates in Selected Subgroups (NEUTRINO)
*Patients with GT 1, METAVIR F3/F4, IL28B non-CC, HCV RNA >800,000 IU/mL (factors traditionally associated with a lower response to interferon-based treatment.Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
BlackNon-Black
No Cirrhosis
Cirrhosis
252/273
47/54
248/273
37/52
43/54
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Sofosbuvir:GT 2 and GT 3 Data
40
Overall Genotype 2 Genotype 30
102030405060708090
100
67
95
56
67
78
63
SOF + RBV (12 wks)PEG + RBV (24 wks)
SVR
12 (%
)
69/73
52/67
102/183
110/176
171/256
162/243
SVR12 Rates in GT 2 and GT 3 Treatment Naive Patients (FISSION)
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
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No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis0
20
40
60
80
100 97
83
61
34
81
6271
30
SOF + RBV (12 wks)PEG + RBV (24 wks)
SVR
12 (%
)
59/61
1338
Genotype 2
44/54
10/12
8/13
89/145
99/139
13/38
11/37
Impact of Cirrhosis on SVR12 Rates in Treatment-Naive Patients (FISSION)
Genotype 3Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
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No Cirrhosis Cirrhosis0
20
40
60
80
100 92 94
68
21
Genotype 2Genotype 3
SOF + RBV for 12 Weeks: Impact of Cirrhosis on SVR12 Rates in Interferon-Intolerant, Ineligible or Unwilling Adults (POSITRON)
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
85/92
16/17
57/84
3/14
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FUSION: Impact of Cirrhosis and Duration on SVR Rates (Prior Relapsers or Nonresponders)
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
No Cirrhosis Cirrhosis0
102030405060708090
100 90
60
92
78
Genotype 2 Sofosbuvir + RBV 12 wksSofosbuvir + RBV 16 wks
SVR
12 (%
)
No Cirrhosis Cirrhosis0
102030405060708090
100
37
19
63 61
Genotype 3 Sofosbuvir + RBV 12 wksSofosbuvir + RBV 16 wks
SVR1
2 (%
)
6/10
5/26
26/29
7/9
24/26
14/38
14/23
25/40
44
Wk 0 Wk 24 SVR4, SVR12, SVR24
Placebo*(n = 85)
Sofosbuvir + Ribavirin (n = 250)
Sofosbuvir + Ribavirin(n = 84)*
Wk 12
VALENCE: Evaluating Impact of Duration on SVR With SOF/RBV (GT 2 and GT 3)
*Protocol amended to eliminate placebo arm. 12-wk arm predominantly GT2 patients (N = 73); 11 GT3 patients completed 12 wks SOF + RBV prior to amendment to extend treatment duration. Zeuzem S, et al. AASLD 2013. Abstract 1085.
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Overall Treatment Naïve Treatment Experienced0
20
40
60
80
10084
93
77
9385
92
60
AllNon-cirrhoticsCirrhotics
SVR12 Rates in GT 3 Patients: SOF + RBV for 24 weeks (VALENCE)
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
210/250
98/105
86/92
12/13
112/145
85/100
27/45
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Group Discussion
• Patient– GT 3-infected with cirrhosis who is prior nonresponder
to PEG/RBV
• Approved regimen: 24 weeks SOF + RBV– SVR rate ~60%– Would you treat?
• Other options?
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LONESTAR-2: Study Design
• Study population– HCV GT 2 or 3– Failed treatment with pegylated interferon and ribavirin– Approximately 50% with compensated cirrhosis– HIV and HBV coinfected patients excluded
SOF + PEG/RBV SVR12GT 2/3(N=47)
Wk 0 Wk 12 Wk 24 Wk 36
Lawitz E, et al. Abstract #LB-4, AASLD 2013
48
Cirrhosis No Cirrhosis0
102030405060708090
10083 83
SVR
12 (%
)
10/12 10/12
Lawitz E, et al. Abstract #LB-4, AASLD 2013
SVR12 Rates in GT 3 Patients: SOF + PEG/RBV for 12 weeks (LONESTAR-2)
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Sofosbuvir:HCV/HIV-1 Coinfection Data
50
Wk 0 Wk 12 Wk 24 Wk 36
SOF + RBV, n=114 GT 1 TN SVR12
SOF + RBV, n=41GT 2/3 TE SVR12
SOF + RBV, n=68 GT 2/3 TN SVR12
PHOTON-1: Study Design
• Broad inclusion criteria– Cirrhosis permitted with no platelet cutoff– Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females)
• Wide range of ART regimens allowed – Undetectable HIV RNA for >8 weeks on stable ART regimen
• Baseline CD4 count– ART treated: CD4 T-cell count >200 cells/mm3– ART untreated: CD4 T-cell count >500 cells/mm3
Sulkowski MS, et al. Abstract #212, AASLD 2013
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GT 1/TN/24 wks GT 2/TN/12 wks GT 3/TE/24 wks0
102030405060708090
100
76
88 92
87/114
23/26
12/13
SVR12 Rates in HCV/HIV-1 Coinfected Patients Treated with SOF + RBV*
*GT 2 patients treated for 24 weeks and GT 3 patients treated for 12 weeks were not includedSofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
SVR
12 (%
)
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Recap: Dosage and Administration
Patient Population* Treatment** Treatment Duration
GT 1 or 4 SOF + PEG/RBV 12 weeks
GT 2 SOF + RBV 12 weeks
GT 3 SOF + RBV 24 weeks
*HCV mono-infected and HCV/HIV-1 co-infected patients**If the other agents used in combination with SOF are permanently discontinued, SOF should also be discontinued.Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
53
Simeprevir + Sofosbuvir + RBV
INVESTIGATIONAL COMBO FOR GT 1
54
Background
• Simeprevir and sofosbuvir are both approved by theUS FDA
– GT 1: Approved labeling is for use of either agent with PEG/RBV backbone
– Neither package insert/label contains information regarding using the 2 newly approved agents concomitantly
• COSMOS is a Phase IIa, randomized, open-label study investigating simeprevir + sofosbuvir +/- ribavirin
55
SMV + SOF + RBV Post-treatment follow-up
0 4 12 24 36 48
Arm 1
Week
SMV + SOF
SMV + SOF + RBV
SMV + SOF
Post-treatment follow-up
Post-treatment follow-up
Post-treatment follow-up
Arm 2
Arm 3
Arm 4
Enrollment ratio 2:1:2:1
Jacobson IM, et al. Abstract #LB-3, AASLD 2013
• Cohort 1: Prior null responders (METAVIR F0-F2)– Final SVR12 for all arms
• Cohort 2: Treatment-naïve and prior null responders (METAVIR F3-F4)– Interim SVR4 for Arms 3 and 4
COSMOS: Study Design
56
Cohort 1: SVR12 in Null Responders (F0-2)
Jacobson IM, et al. Abstract #LB-3, AASLD 2013
SMV/SOF SMV/SOF/RBV0
20
40
60
80
100 9379
24 week treatment
Patie
nts
Ach
ievi
ng
SVR1
2 (%
)
14/15 19/24
SMV/SOF SMV/SOF/RBV0
20
40
60
80
100 92 96
12 week treatment
Patie
nts
Ach
ievi
ng
SVR1
2 (%
)
13/14 26/27
57
Cohort 2: Naive and prior null responders (F3-4); Interim Analysis, SVR4
Jacobson IM, et al. Abstract #LB-3, AASLD 2013
Total Naïves Nulls0
20
40
60
80
100100 100 10096 100
93
12 week treatmentSVR4 (SMV/SOF)SVR4 (SMV/SOF/RBV)
Patie
nts
Ach
ievi
ng
SVR
12 (%
)
7/7 12/12 7/7 14/1526/2714/14
58
24 weeks 12 weeks
Adverse Event, % SMV + SOF + RBV (n=54)
SMV + SOF (n=31)
SMV + SOF + RBV (n=54)
SMV + SOF (n=28)
Fatigue 37% 32.3% 24.1% 25%
Headache 20.4% 22.6% 16.7% 21.4%
Nausea 11.1% 12.9% 14.8% 21.4%
Insomnia 16.7% 6.5% 9.3% 14.3%
Rash 13.0% 9.7% 14.8% 3.6%
Pruritus 16.7% 3.2% 9.3% 10.7%
Photosensitivity/sunburna 3.7% 3.2% 5.6% 7.1%
Anemia 20.4% 3.2% 11.1% 0aNo sun-protective measures were in place for this trial RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvirJacobson IM, et al. Abstract #LB-3, AASLD 2013
Most Common AEs: Cohorts 1 and 2 Combined
59
Conclusion
• Treatment with SMV + SOF ± RBV results in:
– High SVR12 rates in HCV GT 1 null responder patients
– High SVR4 rates in naive and null responder patients with METAVIR F3-F4
• Addition of RBV to SMV + SOF may not be needed to achieve high rates of SVR in this patient population
• 12 weeks of treatment may confer similar SVR rates compared with 24 weeks of treatment
• SMV + SOF ± RBV was generally well tolerated Jacobson IM, et al. Abstract #LB-3, AASLD 2013
60
Group Discussion
• Do you anticipate using simeprevir + sofosbuvir in combination based on Phase 2 data even though both have only been approved for use with PEG/RBV backbone?– If so, in which patient populations?– Would you include RBV?– Safety concerns?– Concerns regarding patient reimbursement?
61
Group Discussion
• What options are currently available for GT 1 patients who previously failed boceprevir or telaprevir containing regimens due to resistance?– Simeprevir/PEG/RBV for 24 weeks if relapser?
48 weeks?
– Sofosbuvir/PEG/RBV for 12 weeks?
• What may be on the horizon?
62
Daclatasvir (DCV) (NS5A inhibitor) + Sofosbuvir + RBV
INVESTIGATIONAL COMBO FOR GT 1
63
• Patients– GT 1, non-cirrhotic– Prior nonresponse, relapse, or breakthrough during treatment with
PEG/RBV+TVR or BOC– Patients who discontinued TVR or BOC due to an adverse event
were excluded
Week 24
Prior TVR/BOC Failures, GT 1a/1b(N = 41)
n = 21
Follow-upn = 20
DCV once daily + SOF once daily
DCV once daily + SOF once daily + RBV
Follow-up
SVR4
SVR12
Study Design: 24 Week Treatment
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
64
Virologic Response
*1 patient missing at follow up week 12: HCV RNA was undetectable at follow up week 4 and follow up week 24M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
• 21/41 patients have reached follow up week 24; all have achieved SVR24
0
20
40
60
80
100 91100 100 100 100
80
95 100 100 95*DCV+SOFDCV+SOF+RBV
HCV
RNA
< LL
OQ
(%
pat
ient
s)
EOT Week 2 SVR4N =
Week 421 20 SVR12
21 20
21 20
21 20
21 20
65
Ledipasvir (LDV) (NS5A inhibitor) + Sofosbuvir (Fixed Dose Combination) ± RBV
INVESTIGATIONAL COMBO FOR GT 1
66
Study Design: 8 and 12 Week Treatments
Ran
dom
ized
1:
1
SOF/LDV
SOF/LDV
SOF/LDV + RBV
SOF/LDV
Treatment Naive
(No
cirrhosis)
PI Failures
(50% cirrhosis) SOF/LDV + RBV
COHORT 1(n=60)
COHORT 2(n=40)
Wk 0 Wk 8 Wk 12
Ran
dom
ized
1:
1:1
Wk 24Wk 20
SVR12
SVR12
SVR12
SVR12
SVR12
• Single center study of GT 1 patients• Broad inclusion criteria
– No upper limit to age or BMI– Platelets ≥50,000/mm3
Lawitz E, et al. Abstract #215, AASLD 2013
67
PI Failuresn=40
Prior treatment with boceprevir 22/40 (55)
Prior treatment with telaprevir 18/40 (45)
Cirrhosis, n (%) 22/40 (55)
Mean platelet count, x 103/µL 107
Mean albumin, g/dL 3.8
Lawitz E, et al. Abstract #215, AASLD 2013
Demographics of Patients Who Previously Failed PI Therapy
• All patients were required to have experienced virologic failure– Patients who stopped prior therapy due to an AE were excluded
68
Series10
20
40
60
80
100 95100 95 95 100
Patie
nts
(%)
Treatment Naïve(No Cirrhosis)
PI Failures(50% Cirrhosis)
─ ─ ─+ +8 12 128 12
19/20 21/21 18/19 18/19 21/21
RBVDuration (week)
LONESTAR: SVR12 Results
Lawitz E, et al. Abstract #215, AASLD 2013
69
Group Discussion
• Based on Phase 2 data, would you retreat BOC or TVR failures with SMV+SOF?
– If so, would there be certain patient characteristics that would affect your decision?
– Do you believe RBV is necessary?
70
Series10
20
40
60
80
100 97.7 97.2 93.6 96.4 99.1 99.1 94 93.1 95.4
SVR
12 (%
)
209/214
Gilead press release, December 18, 2013.
SOF/LDV FDC: SVR12 Results (ION-1, ION-2 and ION-3)
GT 1 Treatment-Experienced (20% cirrhotics)
GT 1 Treatment-Naïve (No cirrhotics)
GT 1 Treatment-Naïve (15.7% cirrhotics)
-RBV -RBV -RBV -RBV -RBV+RBV +RBV +RBV +RBV
12 weeks 12 weeks 12 weeks24 weeks 8 weeks
211/217
102/109
107/111
108/109
110/111
202/215
201/216
206/216
71
Daclatasvir (DCV) (NS5A inhibitor) + Asunaprevir (ASV) (protease inhibitor)+ BMS-791325 (non-nuc)
INVESTIGATIONAL COMBO FOR GT 1
72
DCV 30 mg BID + ASV 200 mg BID + BMS-791325 75 mg BIDDCV 30 mg BID + ASV 200 mg BID + BMS-791325 150 mg BID
12-week follow-upAdditional follow-up to SVR48
0 12 24
N = 80
N = 86
Week
Primary endpoint: SVR12
Study Design: 12 Week Regimen
• Treatment-naive patients stratified by GT 1a/1b and presence of biopsy-confirmed cirrhosis (82% GT1a and 9% cirrhotics)
Everson GT, et al. Abstract #LB-1, AASLD 2013
73
*Modified Intent to Treat (mITT): missing, breakthrough, relapse or addition of PEG/RBV=failure**Observed: breakthrough, relapse, or addition of PEG/RBV=failureEverson GT, et al. Abstract #LB-1, AASLD 2013
SVR12 Rates: “Modified Intent to Treat” and “Observed”
mITT* Observed**0
20
40
60
80
100 88.8 92.289.5 91.7 DCV+ASV+'325 75 mg
DCV+ASV+'325 150 mg
Res
pons
e, %
of p
atie
nts
71/77
77/84
74
ABT-450/r (PI with ritonavir) + ABT-267 (NS5A inhibitor) + ABT-333 (non nuc) + RBV
INVESTIGATIONAL COMBO FOR GT 1
75
SAPPHIRE-I and SAPPHIRE-II:Study Overviews
• Phase 3, global, multi-center, randomized, double-blind, placebo-controlled studies
• 12 week treatment• “3D” regimen– Fixed-dose combination of ABT-450/ritonavir
co-formulated with ABT-267: Once daily– ABT-333: Twice daily– RBV: Twice daily
AbbVie press releases, November 18, 2013 and December 10, 2013.
76AbbVie press releases, November 18, 2013 and December 10, 2013.
SAPPHIRE-I and SAPPHIRE-II: Patient Populations
• SAPPHIRE-I– N=631
– GT 1, non-cirrhotic
– Treatment-naive
• SAPPHIRE-II– N=394
– GT 1, non-cirrhotic
– Prior PEG/RBV treatment failures (49% prior null responders)
77
TN=treatment-naive; TE=treatment-experiencedAbbVie press releases, November 18, 2013 and December 10, 2013.
SVR12 Rates (SAPPHIRE-I and SAPPHIRE-II)
0
102030405060708090
100 96 95 9896 96 97
Patie
nts
(%)
286/297
166/173
119/123
455/473
307/322
148/151
TN TE TN TE TN TEOverall GT1a GT1b
78
Safety (SAPPHIRE-I and SAPPHIRE-II)
• Most commonly reported adverse events in both the 3D and placebo arms– Headache
– Fatigue
– Nausea
AbbVie press releases, November 18, 2013 and December 10, 2013.
79
Where Are We In 2014?
80
Have All Limitations of First Generation DAAs Been Addressed?
• Telaprevir and boceprevir only approved for GT 1
– SOF approved for GT 1, 2, 3 and 4 ✔
• Interferon and ribavirin backbone required
– GT 1 and GT 4: IFN/RBV still required ✖
– GT 2 and GT 3: IFN free (SOF+RBV) ✔
81
Have All Limitations of First Generation DAAs Been Addressed?
• Twice per day dosing (BID) for telaprevir and three times per day (TID) dosing for boceprevir
– SOF and SMV both once daily dosing ✔
• Response guided therapy (both) and lead-in (boceprevir) complicated
– SOF and SMV do not require response guided therapy or lead-in ✔
82
Have All Limitations of First Generation DAAs Been Addressed?
• 24-48 week treatment
– GT 1: SOF+PEG/RBV for 12 weeks ✔
– GT 1: SMV+PEG/RBV for 24-48 weeks ✖
– GT 2: SOF+RBV for 12 weeks ✔
– GT 3: SOF+RBV for 24 weeks ✓– GT 4: SOF+PEG/RBV for 12 weeks ✔
83
Have All Limitations of First Generation DAAs Been Addressed?
• Limited efficacy in difficult to cure patients (e.g., patients with cirrhosis, prior null responders, African-Americans)– GT 1: SMV and SOF demonstrate improved efficacy in difficult to
treat populations ✔
– GT 2: SOF+RBV strong efficacy ✔
– GT 3: SOF+RBV less efficacious in null responders with cirrhosis✓
84
Have All Limitations of First Generation DAAs Been Addressed?
• Hematologic (both) and rash/dermatological (telaprevir) adverse events
– No hematologic signal with SMV or SOF monotherapy ✔
– GT 1: SMV and SOF both require PEG/RBV backbone and hematologic adverse events comparable to PEG/RBV control arm ✔
– GT 2 and 3: Interferon free regimens have no hematologic signal beyond anemia associated with RBV ✔
85
Have All Limitations of First Generation DAAs Been Addressed?
• Drug-drug interactions
– SMV has DDIs with many of the same drug classes as boceprevir and telaprevir ✖
– SMV use with cyclosporine or tacrolimus does not require dose adjustments ✔
– SOF does not have any significant drug:drug interactions ✔