Supported by:

1

Supported by:Jointly sponsored by the Duke University School of Medicineand The Chronic Liver Disease Foundation

Presented by

2

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.

3

Boceprevir and Telaprevir: Therapies Approved in 2011

4

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.

5

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.

6

• 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

7

• 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

8

Simeprevir (SMV) (protease inhibitor) +PEG-IFN/RBVAPPROVED REGIMEN FOR GT 1

9

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.

10

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

11

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.

12

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

(%)


317/378

106/192

89/130

26/72

13

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


SVR12 Rates in Patients Who Relapsed AfterPrior IFN-Based Therapy (PROMISE)

14

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

(%)


137/167

40/98

61/83

8/34

15

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

(%)


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

16

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.


17

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.

18

• 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.

19

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.

20

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


21

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


22

Drug: Drug Interaction Potential:SMV As A Substrate


• 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

23

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.

24

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*

25

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


26

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


27

Sofosbuvir (SOF)

APPROVED FOR GT 1, 2, 3 and 4

(REGIMENS DIFFER BY GENOTYPE AND PATIENT TYPE)

28

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.

29

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


30

SOF: Dosage and Administration

Patient Population* Treatment** Treatment Duration

GT 1 or 4 SOF + PEG/RBV 12 weeks

GT 2 SOF + RBV 12 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.

31

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


32

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


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

34

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.


35

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.

37

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)


38

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

39

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)


41

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.

42

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)


85/92

16/17

57/84

3/14

43

FUSION: Impact of Cirrhosis and Duration on SVR Rates (Prior Relapsers or Nonresponders)



102030405060708090

100 90

60

92

78

Genotype 2 Sofosbuvir + RBV 12 wksSofosbuvir + RBV 16 wks

SVR

12 (%

)


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.

45

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)


210/250

98/105

86/92

12/13

112/145

85/100

27/45

46

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?

47

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)

49

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

51

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 (%

)

52

Recap: Dosage and Administration

Patient Population* Treatment** Treatment Duration

GT 1 or 4 SOF + PEG/RBV 12 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



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)


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


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


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


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


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


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)


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


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


• 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


• 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


• 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


• 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


• 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 ✔

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