1 Supported by: Jointly sponsored by the Duke University School
of Medicine and The Chronic Liver Disease Foundation Presented
by
Slide 2
2 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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3
Slide 4
4 Generic NameTrade 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.
Slide 5
5 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.
9 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.
15 Simeprevir (OLYSIO) Prescribing Information. Janssen
Therapeutics, Titusville, NJ. November, 2013. 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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16 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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17 Triple Therapy SMV/PEG/RBV* Dual Therapy PEG/RBV Total
Treatment Duration* Treatment-naive and prior relapse patients
including those with cirrhosis First 12 weeksAdditional 12 weeks24
weeks Prior non-responder patients (including partial and null
responders) including those with cirrhosis First 12 weeksAdditional
36 weeks48 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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18 If PEG or RBV is discontinued for any reason, SMV must also
be discontinued. HCV-RNAAction 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 TW=treatment week,
SMV=simeprevir, PEG=peginterferon, RBV=ribavirin Simeprevir
(OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville,
NJ. November, 2013.
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19 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.
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20 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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21 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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22 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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23 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% Nausea22%18%
Myalgia16%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.
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24 Laboratory ParameterWHO Toxicity Grade SMV/PEG/RBV (First 12
Weeks) N=781 Placebo/PEG/RBV (First 12 Weeks) N=397 Alkaline
Phosphatase* Grade 1>1.25 to 2.50 to 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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27 APPROVED FOR GT 1, 2, 3 and 4 (REGIMENS DIFFER BY GENOTYPE
AND PATIENT TYPE)
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28 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.
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29 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.
Slide 30
30 Patient Population*Treatment**Treatment Duration GT 1 or
4SOF + PEG/RBV12 weeks GT 2SOF + RBV12 weeks GT 3SOF + RBV24 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.
Slide 31
31 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.
Slide 32
32 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. Johns wort)
may decrease SOF concentrations and should not be used with SOF
Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc.
December, 2013.
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33 Sofosbuvir (SOVALDI) Prescribing Information. Gilead
Sciences, Inc. December, 2013. No adjustment required when
co-administered with Cyclosporine or tacrolimus Methadone
Darunavir/ritonavir, efavirenz, emtricitabine, raltegravir,
rilpivirine or tenofovir disoproxil fumarate
Slide 34
34 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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35
Slide 36
36 SVR12Sofosbuvir/PEG/RBV, n=327 Week 0 12 24 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.
46 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?
Slide 47
47 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 SVR12 GT 2/3 (N=47) Wk 0Wk 12 Wk 24 Wk 36 Lawitz E, et
al. Abstract #LB-4, AASLD 2013
Slide 48
48 10/12 Lawitz E, et al. Abstract #LB-4, AASLD 2013
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49
Slide 50
50 Wk 0Wk 12Wk 24Wk 36 SOF + RBV, n=114 GT 1 TN SVR12 SOF +
RBV, n=41 GT 2/3 TE SVR12 SOF + RBV, n=68 GT 2/3 TN 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
Slide 51
51 87/1 14 23/ 26 12/ 13 *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. SVR12 (%)
Slide 52
52 Patient Population*Treatment** Treatment Duration GT 1 or
4SOF + PEG/RBV12 weeks GT 2SOF + RBV12 weeks GT 3SOF + RBV24 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.
Slide 53
53 INVESTIGATIONAL COMBO FOR GT 1
Slide 54
54 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
Slide 55
55 SMV + SOF + RBVPost-treatment follow-up 0412243648 Arm 1
Week SMV + SOF SMV + SOF + RBV SMV + SOF 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-nave and prior
null responders (METAVIR F3-F4) Interim SVR4 for Arms 3 and 4
58 24 weeks12 weeks Adverse Event, % SMV + SOF + RBV (n=54) SMV
+ SOF (n=31) SMV + SOF + RBV (n=54) SMV + SOF (n=28)
Fatigue37%32.3%24.1%25% Headache20.4%22.6%16.7%21.4%
Nausea11.1%12.9%14.8%21.4% Insomnia16.7%6.5%9.3%14.3%
Rash13.0%9.7%14.8%3.6% Pruritus16.7%3.2%9.3%10.7%
Photosensitivity/sunburn a 3.7%3.2%5.6%7.1% Anemia20.4%3.2%11.1%0 a
No sun-protective measures were in place for this trial RBV,
ribavirin; SMV, simeprevir; SOF, sofosbuvir Jacobson IM, et al.
Abstract #LB-3, AASLD 2013
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59 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
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60 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?
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61 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?
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62 INVESTIGATIONAL COMBO FOR GT 1
Slide 63
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-up n =
20 DCV once daily + SOF once daily DCV once daily + SOF once daily
+ RBV Follow-up SVR 4 SVR 12 M.S. Sulkowski et al, Abstract 1417.
EASL, April 2013
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64 *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 21/41 patients
have reached follow up week 24; all have achieved SVR24 EOT Week
2SVR4 N = Week 4 21 20 SVR12 21 20
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65 INVESTIGATIONAL COMBO FOR GT 1
Slide 66
66 Randomized 1:1 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 8Wk 12 Randomized 1:1:1 Wk 24Wk 20
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
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67 PI Failures n=40 Prior treatment with boceprevir22/40 (55)
Prior treatment with telaprevir18/40 (45) Cirrhosis, n (%)22/40
(55) Mean platelet count, x 10 3 /L107 Mean albumin, g/dL3.8 Lawitz
E, et al. Abstract #215, AASLD 2013 All patients were required to
have experienced virologic failure Patients who stopped prior
therapy due to an AE were excluded
Slide 68
68 Treatment Nave (No Cirrhosis) PI Failures (50% Cirrhosis) ++
812 8 19/2021/2118/19 21/21 RBV Duration (week) Lawitz E, et al.
Abstract #215, AASLD 2013
Slide 69
69 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?
72 DCV 30 mg BID + ASV 200 mg BID + BMS-791325 75 mg BID DCV 30
mg BID + ASV 200 mg BID + BMS-791325 150 mg BID 12-week follow-up
Additional follow-up to SVR 48 0 1224 N = 80 N = 86 Week Primary
endpoint: SVR 12 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
Slide 73
73 *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 71/ 77 77/ 84
Slide 74
74 INVESTIGATIONAL COMBO FOR GT 1
Slide 75
75 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.
Slide 76
76 AbbVie press releases, November 18, 2013 and December 10,
2013. 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)
Slide 77
77 TN=treatment-naive; TE=treatment-experienced AbbVie press
releases, November 18, 2013 and December 10, 2013. 286/ 297 166/
173 119/ 123 455/ 473 307/ 322 148/ 151 TNTETNTETNTE
OverallGT1aGT1b
Slide 78
78 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.
Slide 79
79
Slide 80
80 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)
Slide 81
81 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
Slide 82
82 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
Slide 83
83 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
Slide 84
84 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
Slide 85
85 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