Patients - Chronic Liver Disease Foundation

Presented by
Jointly sponsored by the Duke University School of Medicine
and The Chronic Liver Disease Foundation
Supported by:
1
• 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.
2
3
Generic Name
Trade Name
boceprevir
telaprevir
Victrelis™
Incivek™
• 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.
4
• 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.
5
• Protease inhibitors
–
–
–
–
–
–
Faldaprevir
Asunaprevir
ABT-450
MK-5172
Sovaprevir
ACH-2684
• NS5A Inhibitors
–
–
–
–
–
–
–
–
–
Daclatasvir
Ledipasvir
ABT-267
GS-5816
ACH-3102
PPI-668
GSK2336805
Samatasvir
MK-8742
6
• NS5B Nuc
– VX-135
– IDX20963
– ACH-3422
• NS5B Non-nuc
–
–
–
–
–
–
ABT-333
Deleobuvir
BMS 791325
PPI-383
GS 9669
TMC 647055
7
APPROVED REGIMEN FOR GT 1
8
• 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.
9
Response Guided Treatment
0
SMV 150mg/
PEG/RBV*
PEG/RBV
PEG/RBV
Post-Therapy Follow-Up
Post-Therapy Follow-Up
Placebo/
PEG/RBV
PEG/RBV
PEG/RBV
Post-Therapy Follow-Up
12
24
Weeks
48
72
• 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
*PEG/RBV=Peginterferon/Ribavirin
10
Patients Achieving SVR12 (%)
100
80
SMV/PEG/RBV
85
84
80
58
60
PEG/RBV
75
50
47
53
52
43
40
20
0
419/
521
132/
264
Overall
191/
254
62/
131
GT 1a
138/
165
36/
83
49/
84
23/
44
GT 1a Without GT 1a With Q80K*
Q80K
228/
267
70/
133
GT 1b
*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 patients
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
11
Patients Achieving SVR12 (%)
100
SMV/PEG/RBV
84
80
PEG/RBV
68
55
60
36
40
20
0
317/
378
106/
192
F0-2
89/
130
26/
72
F3-4
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
12
Patients Achieving SVR12 (%)
100
SMV/PEG/RBV
86
80
79
PEG/RBV
78
70
60
47
43
37
40
28
30
26
20
0
206/
260
49/
133
Overall
78/
111
15/
54
GT 1a
62/
79
9/
34
GT 1a Without
Q80K
14/
30
6/
20
GT 1a With Q80K
128/
149
34/
79
GT 1b
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
13
Patients Achieving SVR12 (%)
100
SMV/PEG/RBV
82
80
PEG/RBV
73
60
41
40
24
20
0
137/
167
40/
98
F0-2
61/
83
8/
34
F3-4
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
14
Patients Achieving SVR12 (%)
SMV/PEG/RBV
100
80
PEG/RBV
77
65
60
53
37
40
20
0
20/
26
10/
27
Prior Relapser
15/
23
9
2/23
Prior Partial Responders
9/
17
19
3/
16
Prior Null Responders
12 weeks SMV/PEG/RBV followed by 36 weeks of PEG/RBV vs 48 weeks Placebo/PEG/RBV
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
15
• 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.
16
Triple Therapy
SMV/PEG/RBV*
Dual Therapy
PEG/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.
17
HCV-RNA
Action
TW4: Discontinue SMV/PEG/RBV
TW4,12 and 24:
>25 IU/mL
TW12: Discontinue PEG/RBV
(SMV treatment complete at 12 weeks)
TW24: Discontinue PEG/RBV
• If PEG or RBV is discontinued for any reason, SMV must
also be discontinued.
TW=treatment week, SMV=simeprevir, PEG=peginterferon, RBV=ribavirin
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
18
• 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 given
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
19
• 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.
20
• 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.
21
• 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
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
22
Preferred Term or Grouped Term
SMV/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%
*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.
23
WHO Toxicity Grade
SMV/PEG/RBV
(First 12 Weeks)
N=781
Placebo/PEG/RBV
(First 12 Weeks)
N=397
Grade 1
>1.25 to <2.50 x ULN***
3%
1%
Grade 2
>2.50 to <5.00 x ULN
<1%
0
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
Laboratory Parameter
Alkaline Phosphatase*
Hyperbilirubinemia
*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 Normal
Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.
24
• Mild to moderate elevations in bilirubin
• Included elevation of both direct and
indirect 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.
25
• 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.
26
APPROVED FOR GT 1, 2, 3 and 4
(REGIMENS DIFFER BY GENOTYPE
AND PATIENT TYPE)
27
• FDA approval: December 6, 2013
• Nucleotide analog NS5B polymerase inhibitor
• One oral 400 mg tablet once daily with or
without food
• Must be used in combination with RBV or in
combination with PEG/RBV
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
28
• 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.
29
Patient Population*
Treatment**
Treatment Duration
SOF + PEG/RBV
12 weeks
GT 2
SOF + RBV
12 weeks
GT 3
SOF + RBV
24 weeks
GT 1 or 4
*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.
30
• 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 interferonbased 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.
31
• 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.
32
• No adjustment required when co-administered with
– Cyclosporine or tacrolimus
– Methadone
– Darunavir/ritonavir, efavirenz, emtricitabine, raltegravir, rilpivirine or
tenofovir disoproxil fumarate
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
33
• 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.
34
35
Week 0
12
Sofosbuvir/PEG/RBV, n=327
24
SVR12
• 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.
36
100
90
89
96
92
82
SRV12 (%)
80
60
40
20
0
295/
327
261/
292
206/
225
54/
66
27/
28
All Patients
GT 1
GT 1a
Genotype
GT 1b
GT 4
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
37
100
92
91
80
80
SVR12 (%)
87
71
60
40
20
0
252/
273
43/
54
47/
54
248/
273
37/
52
Multiple Factors*
*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.
38
39
100
95
78
80
SVR12 (%)
SOF + RBV
(12 wks)
67
67
63
56
60
PEG + RBV
(24 wks)
40
20
0
171/
256
162/
243
Overall
69/
73
52/
67
Genotype 2
102/
183
110/
176
Genotype 3
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
40
100
97
81
SVR12 (%)
80
SOF + RBV
(12 wks)
83
71
62
60
PEG + RBV
(24 wks)
61
40
34
20
13
38 13/
38
0
59/
61
44/
54
10/
12
8/
13
No Cirrhosis
Cirrhosis
Genotype 2
89/ 99/
145 139
30
11/
37
No Cirrhosis
Cirrhosis
Genotype 3
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
41
100
Genotype 2
94
92
Genotype 3
80
68
60
40
20
0
21
85/
92
57/
84
16/
17
No Cirrhosis
3/
14
Cirrhosis
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
42
100
90
80
70
60
50
40
30
20
10
0
90
Genotype 3
Sofosbuvir + RBV 12 wks
Sofosbuvir + RBV 16 wks
92
78
SVR12 (%)
SVR12 (%)
Genotype 2
60
26/
29
24/
26
No Cirrhosis
6/
10
7/
9
Cirrhosis
100
90
80
70
60
50
40
30
20
10
0
Sofosbuvir + RBV 12 wks
Sofosbuvir + RBV 16 wks
63
61
37
19
14/
38
25/
40
No Cirrhosis
5/
26
14/
23
Cirrhosis
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
43
Wk 0
Wk 12
Wk 24
SVR4, SVR12,
SVR24
Placebo*
(n = 85)
Sofosbuvir + Ribavirin
(n = 84)*
Sofosbuvir + Ribavirin
(n = 250)
*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.
44
100
93
93
92
85
84
All
77
80
Non-cirrhotics
60
60
Cirrhotics
40
20
0
210/
250
Overall
98/
105
86/
92
12/
13
Treatment Naïve
112/ 85/
145 100
27/
45
Treatment
Experienced
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
45
• 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?
46
Wk 0
GT 2/3
(N=47)
Wk 12
SOF + PEG/RBV
Wk 24
Wk 36
SVR12
• 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
Lawitz E, et al. Abstract #LB-4, AASLD 2013
47
100
83
83
10/12
10/12
Cirrhosis
No Cirrhosis
SVR12 (%)
80
60
40
20
0
Lawitz E, et al. Abstract #LB-4, AASLD 2013
48
49
Wk 0
GT 1
TN
Wk 24
Wk 36
SVR12
SOF + RBV, n=114
GT 2/3 TN
SOF + RBV, n=68
GT 2/3 TE
SOF + RBV, n=41
•
Wk 12
SVR12
SVR12
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
50
100
SVR12 (%)
80
92
88
76
60
40
20
87/1
14
23/
26
12/
13
GT 1/TN/24 wks
GT 2/TN/12 wks
GT 3/TE/24 wks
0
*GT 2 patients treated for 24 weeks and GT 3 patients treated for 12 weeks were not included
Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.
51
Treatment**
Treatment
Duration
SOF + PEG/RBV
12 weeks
GT 2
SOF + RBV
12 weeks
GT 3
SOF + RBV
24 weeks
Patient Population*
GT 1 or 4
*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.
52
INVESTIGATIONAL COMBO FOR GT 1
53
• Simeprevir and sofosbuvir are both approved by the
US 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
54
0
4
12
24
36
48
Week
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
Enrollment ratio 2:1:2:1
• 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
Jacobson IM, et al. Abstract #LB-3, AASLD 2013
55
100
12 week treatment
93
79
80
60
40
20
0
14/15
19/24
SMV/SOF
SMV/SOF/RBV
Patients Achieving
SVR12 (%)
Patients Achieving
SVR12 (%)
24 week treatment
100
92
96
80
60
40
20
0
13/14
26/27
SMV/SOF
SMV/SOF/RBV
Jacobson IM, et al. Abstract #LB-3, AASLD 2013
56
SVR4 (SMV/SOF)
SVR4 (SMV/SOF/RBV)
Patients Achieving
SVR12 (%)
12 week treatment
100
100
96
100
100
100
7/7
12/12
7/7
93
80
60
40
20
0
14/14
26/27
Total
Naïves
14/15
Nulls
Jacobson IM, et al. Abstract #LB-3, AASLD 2013
57
24 weeks
12 weeks
SMV + SOF +
RBV (n=54)
SMV + SOF
(n=31)
SMV + SOF +
RBV (n=54)
SMV + SOF
(n=28)
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%
0
Adverse Event, %
Fatigue
aNo
sun-protective measures were in place for this trial
Jacobson IM, et al. Abstract #LB-3, AASLD 2013
RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir
58
• 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
59
• 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?
60
• 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?
61
INVESTIGATIONAL COMBO FOR GT 1
62
Prior TVR/BOC
Failures,
GT 1a/1b
(N = 41)
n = 21
DCV once daily + SOF once daily
Follow-up
n = 20
DCV once daily + SOF once daily + RBV
Follow-up
• Patients
SVR12
Week 24
SVR4
– 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
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
63
HCV RNA < LLOQ
(% patients)
100
100
91
95
100 100
100 100
100
95*
DCV+SOF
80
80
DCV+SOF
+RBV
60
40
20
0
N=
21
20
Week 2
21
20
Week 4
21
20
EOT
21
20
SVR4
21
20
SVR12
• 21/41 patients have reached follow up week 24; all have achieved SVR24
*1 patient missing at follow up week 12: HCV RNA was undetectable at follow up week 4 and follow up week 24
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
64
INVESTIGATIONAL COMBO FOR GT 1
65
COHORT 2
(n=40)
PI Failures
(50%
cirrhosis)
Randomized
1:1
Treatment
COHORT 1 Naive
(n=60)
(No
cirrhosis)
Randomized
1:1:1
Wk 0
Wk 8
Wk 12
Wk 20
Wk 24
SOF/LDV
SVR12
SOF/LDV + RBV
SVR12
SOF/LDV
SVR12
SOF/LDV
SVR12
SOF/LDV + RBV
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
66
PI Failures
n=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
• All patients were required to have experienced virologic failure
– Patients who stopped prior therapy due to an AE were excluded
Lawitz E, et al. Abstract #215, AASLD 2013
67
Patients (%)
100
100
95
95
95
100
80
60
40
20
0
RBV
Duration (week)
19/20
21/21
18/19
18/19
21/21
─
8
+
─
12
─
12
+
8
Treatment Naïve
(No Cirrhosis)
12
PI Failures
(50% Cirrhosis)
Lawitz E, et al. Abstract #215, AASLD 2013
68
• 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?
69
SVR12 (%)
100
97.7
97.2
93.6
96.4
99.1
209/
214
211/
217
102/
109
107/
111
-RBV
+RBV
-RBV
+RBV
108/
109
-RBV
99.1
94
93.1
95.4
110/
111
202/
215
201/
216
206/
216
+RBV
-RBV
+RBV
-RBV
80
60
40
20
0
12 weeks
GT 1 TreatmentNaïve (15.7% cirrhotics)
Gilead press release, December 18, 2013.
12 weeks
24 weeks
GT 1 TreatmentExperienced (20% cirrhotics)
8 weeks
12 weeks
GT 1 TreatmentNaïve (No cirrhotics)
70
INVESTIGATIONAL COMBO FOR GT 1
71
Primary endpoint: SVR12
N = 80
DCV 30 mg BID +
ASV 200 mg BID +
BMS-791325 75 mg BID
N = 86
DCV 30 mg BID +
ASV 200 mg BID +
BMS-791325 150 mg BID
Week 0
12-week follow-up
12
Additional
follow-up
to SVR48
24
• 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
72
Response, % of patients
100
88.8
89.5
92.2
91.7
80
DCV+ASV+'3
25 75 mg
DCV+ASV+'3
25 150 mg
60
40
20
71/
77
0
mITT*
77/
84
Observed**
*Modified Intent to Treat (mITT): missing, breakthrough, relapse or addition of PEG/RBV=failure
**Observed: breakthrough, relapse, or addition of PEG/RBV=failure
Everson GT, et al. Abstract #LB-1, AASLD 2013
73
INVESTIGATIONAL COMBO FOR GT 1
74
• 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.
75
• 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)
AbbVie press releases, November 18, 2013 and December 10, 2013.
76
Patients (%)
100
90
80
70
60
50
40
30
20
10
0
96
96
95
96
98
97
455/
473
286/
297
307/
322
166/
173
148/
151
119/
123
TN
TE
Overall
TN
TE
GT1a
TN
TE
GT1b
TN=treatment-naive; TE=treatment-experienced
AbbVie press releases, November 18, 2013 and December 10, 2013.
77
• 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.
78
79
• 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) ✔
80
• 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
✔
81
• 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 ✔
82
• 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✓
83
• 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 ✔
84
• 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 ✔
85

Download Report