SAVINO BRUNO, MD - AISF | Associazione Italiana per lo ... · AO Fatebenefratelli e Oftalmico, Milano. ... Simeprevir US Prescribing information Patients at Week 4 (%) ... 53/62 10/18

SAVINO BRUNO, MDDirector

Internal Medicine and Hepatology UnitAO Fatebenefratelli e Oftalmico, Milano

Market whereTelaprevir has not yet launched

Victrelis is still launching

ROMA12 febbraio 2014

January 29th 2014

Developed by a select panel of 20 thought leaders:

SOVALDI in various combinations is “Recommended” regimen for treatment of chronic HCV genotype 1, 2, 3, 4, 5 or 6 infection.

OLYSIO with peginterferon alfa and ribavirin (PR) is “Alternative” regimen in select patients (interferon‐eligible chronic HCV genotype 1 patients with either HCV genotype 1b or HCV genotype 1a infection in whom the Q80K polymorphism is not detected at baseline; treatment‐naïve chronic HCV genotype 4 patients who are eligible for interferon).

VICTRELIS with PR along with INCIVEK (telaprevir) with PR are “Not Recommended” for Chronic HCV genotype 1 patients.

PR are “Not Recommended” for Chronic HCV genotype 2, 3 or 4 patients.

ROMA12 febbraio 2014

•Treatment is assigned the highest priority for those patients with advanced

fibrosis (Metavir F3), those with compensated cirrhosis (Metavir F4), liver

transplant recipients, and patients with severe extrahepatic hepatitis C

•Based on available resources, treatment should be prioritized as necessary

so that patients at high risk for liver‐related complications and severe

extrahepatic hepatitis C complications are given high priority

11st August 2014 update

1.Natap.org

1.natap.org

Summary of Appraisal Committee’s key conclusions

1.3 Simeprevir, in combination with sofosbuvir (with or without ribavirin) is not recommended within its

marketing authorisation for treating genotype 1 or 4 chronic hepatitis C.

1.Nice.org

NICE National Institute for Health and Care Exellence

Risk of complications (degree of fibrosis and comorbidities) Efficacy, safety, duration, pill burden and dosing frequency of therapies Patient motivation/reluctanceAffordability

2014/15 Treatment Options: Right drug ‐ Right patient

Key Factors in Deciding to Treat patients with HCV infection

2014/15 Treatment OptionsRight drug ‐ Right patientHCV‐related disease:

a condition with a wide heterogeneity of clinical features

MILD TO MODERATE FIBROSIS stageF 2 Metavir, F2 to 3 Ishak, LSM: ≥ 6 KPa < 9.5 Kpa (possible overlap with either less or more severe stage), APRI: <

0.5 (possible overlap)ADVANCED FIBROSIS stage(F3 Metavir, F3 to 4 Ishak, LSM: ≥ 9.5 KPa < 12.5 Kpa (possible overlap wth either less or more severe stage), APRI:

>0.5 <1.5 (possible overlap) WELL COMPENSATED cirrhosis (early stage: 1)F4 Metavir, F5 to 6 Ishak) or LSM: ≥ 12.5 KPa#, usually no clinically significant portal hypertension*: HVPG ≥ 6, mmHg

< 10 mmHg, no esophageal varices, Child A5, MELD < 10. MARGINALLY COMPENSATED (more severe stage: 2)F4 Metavir, F5 to 6 Ishak or LSM: ≥ 12.5 KPa#, with moderate to severe portal hypertension§: HVPG ≥ 10/12 mmHg,

±esophageal varices , PLT ≤ 100000 /mm3, low albumin value, Child A5, A6 rarely B7, MELD ≥ 10, in Child A5 severe portal hypertension with still preserved liver function may co‐exist

DECOMPENSATED, Child B7 or more, MELD >15 and/orwaiting for OLT for ESLD

#Castera L. Gastroenterology 2012 *Garcia Tsao G. et al, Hepatology 2010§Qamar A. et al, Hepatology 2008 Boccaccio V, Bruno S. Liver International 2014 updated

2014 Treatment OptionsRight drug ‐ Right patientHCV‐related disease:









TVR: SVR in naive patients with mild to moderate fibrosis(ADVANCE, ILLUMINATE, OPTIMIZE)

SVR %

80 80 7978,8 80

0

10

20

30

40

50

60

70

80

90

100

n=630 n=580 213/2673/17 208/262 421/529

T12(bid)/PR

T12(q8h)/PR

All patients

F0–1 F2 F0–F2

SVR according to fibrosis score and historical response in F0‐F2 patients in REALIZE study

Relapsers Partial responders Null respondersSV

R %

Zeuzem S, et al. J Hepatol 2011

86

72

4132

18

6

0

10

20

30

40

50

60

70

80

90

100

144/167 10/38 34/47 3/17 24/59 1/18

CONCISE: SVR24 in non-cirrhotic IL28B CC treatment-naïve patients and relapsers achieving eRVR

Nelson DR, et al. HepDart 2013. Abstract 118

91/106 48/52

T12/PR12 T12/PR24

SVR by BOC in non‐cirrhotic patients

Naïve Relapser/PartialResponders

SVR %

9689

55

72

80

37

0

10

20

30

40

50

60

70

80

90

100

Early Responders (44%)

Late Responders (22%)

Naïve: 63% of patients on BOC‐PR‐RGT vs 38% on PR for 48 weeks achieved SVR (p<0.001)Treatment‐experienced: 59% of patients on BOC‐PR‐RGT vs 21% on PR for 48 weeks achieved SVR (p<0.001)

Null Responders

6/11 14/38

Poordad F, et al. Bacon BR, et al. NEJM 2011. Vierling JM, et al. J Hepatol 2014

86

54

6

0102030405060708090

100

F0‐F2

Undetectable

≥3 log10 decline and detectable<3 log10 decline anddetectable

Data on file

SVR (%

; 95%

CI)

5/78

SVR according to treatment week 8 virologic response* in F0‐F2

*Treatment‐naïve and previous treatment failures combined

Fibrosis Score* SVR [n/m (%)]TW8 <1000 IU/ml TW8 ≥1000 IU/ml

F0/F2 1075/1404 (76) 13/131 (10)

*Subjects in BOC arms from 5 clinical studies

SVR at a cutoff of 1,000 IU/mL at TW8 in the meta‐analysis of 5 clinical studies in mild to moderate fibrosis

Data on file

NEUTRINO: SVR12 by Sofosbuvir + P/R (12 weeks) According to Genotype and Fibrosis Level

Lawitz E, et al. NEJM 2013

SVR

12 (%

)

9280

100

80

60

40

20

0No

CirrhosisCirrhosis

252/273 43/54

SVR12 According to Fibrosis Level

SVR

12 (%

)

8996

100100

80

60

40

20

0GT 1 GT 4 GT 5,6

261/292 27/28 7/7

SVR12 According to Genotype

n/N =

p=0.0096

QUEST‐1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance

Jacobson I, et al. EASL 2013

18/31n/N = 5/17188/229 60/113

82

53 58

29

SMV + P/RP/R

100

80

60

40

20

0

SVR

12 (%

)

No Cirrhosis Cirrhosis

105/117 29/56105/147 36/74

71

49

90

52

100

60

20

0

SVR

12 (%

)

GT 1a GT 1b

80

40

Differences in SVR12 by Subgroup (95% CIs)GT 1a/other HCV

- With baseline Q80K vs Pbo- Without baseline Q80K vs Pbo

GT 1b HCV

28.2 (13.4-42.9)4.7 (-14.6 to 24.1)40.3 (25.8-54.8)42.1 (26.5-57.6)

1476086117

74747456

SMV (n) Pbo (n)

Favors Placebo Favors SMV-100 -50 0 50 100

56

92 95

8

76 79

23

53

66

0

10

20

30

40

50

60

70

80

90

100

SVR 24

(%)

Null respondersPartial responders

Simeprevir plus PegIFN and Ribavirin in treatment‐experienced F0‐F2 patients with HCV Genotype‐1 infection (the ASPIRE trial)

Zeuzem S, et al. Gastroenterology 2013

Relapsers

Placebo+PR

SMV 100 mg+PR*

SMV 150 mg+PR*

*duration groups pooled

N= 16 48 52 12 38 48 13 30 29

SMV + PR: Week 4 on-treatment response* predicts high SVR rates

HCV RNA < 25 IU/mL, detectable and undetectableIntent-to-treat population

FDA backgrounder for FDA advisory committee meeting October 25 2013; Simeprevir US Prescribing information

Patients at Week 4 (%)

247/260

474/521

12/260

35/521

201/247

409/474

5/12

7/35

Patients with SVR12 (%)

Relapser (PROMISE)Naïve (QUEST 1 & 2)

91–95% of patients had a Week 4 on-treatment response with a high probability of achieving SVR Patients with a Week 4 response ≥25 IU/mL are unlikely to achieve SVR

Discontinuation of treatment is recommended according to US prescribing information in these patients

detectable and undetectable










SVR according to fibrosis score and historical response in HCV G1 F3 patients in TVR trials (ADVANCE, ILLUMINATE, OPTIMIZE, REALIZE)

Relapsers Partial responders Null responders

SVR %

Zeuzem S, et al. J Hepatol 2011. Zeuzem S, et al. AASLD 2013

68,4

85

55

39

0

10

20

30

40

50

60

70

80

90

100

53/62 10/18 15/38

Naïve

169/247


SVR %

71,777,1

58,1

41,2

0

10

20

30

40

50

60

70

80

90

100

162/210 36/62 49/119

Naïve

91/127

International EAP TVR:ITT SVR by previous treatment response in 552 F3 patients

Colombo M, et al. J Hepatol 2014 in press

Overall SVR by F3

BOC PR PR

SVR %

54

26

0

20

40

60

80

100

F3

58/107 6/22

Vierling JM, Bruno S, et al. J Hepatol, 2014

85

34

0

10

20

30

40

50

60

70

80

90

SVR (%

, 95%

CI)

SVR according to treatment week 8 virologic response in F3 patients*

*Treatment-naïve and previous treatment failures combined

F3

40/47 16/4700/5

≥3 log HCV-RNA declineand detectable

<3 log HCV-RNA decline and detectable

Undetectable


≤1000 IU/ml (88%) >1000 IU/ml (12%)

SVR %

63

0

0

20

40

60

80

100

150/238


The importance of TW 8 HCV‐RNA decline in patients with advanced fibrosis/cirrhosis (F3 and F4 pooled) during BOC‐therapy

0/31

p<0.0001

SVR12 overall and according to prior response in 121 F3 patientsAll patients who received at least one dose of BOC included

61,3%

50,6%

37,9%

61,7% 61,3%

50%

0

10

20

30

40

50

60

70

Relapser Partial responder Null responder

Overall F3

29/47 45/89 19/31 58/153 21/4284/137

Bruno S, et al. JVH in press

SVR12 in 121 F3 according to treatment week 8 virologic responseAll patients who received at least one dose of BOC included

80,0%

20,0%

39,7%

60,3%

0

10

20

30

40

50

60

70

80

90

SVR No SVR

HCV-RNA Undetectable HCV-RNA Detectable

4455 11

55

2358 35

58

67%

33%

0%

100%

0102030405060708090

100

SVR No SVR

HCV-RNA < 1000 UI/mL HCV-RNA > 1000 UI/mL

6798

3398

1313

PPV=80,0%NPV=60.3%

PPV=67%NPV=100%


0

79

55

13

50 50

0

22

38

0

10

20

30

40

50

60

70

80

90

100

SVR 24

(%)


Simeprevir plus PegIFN and Ribavirin in treatment‐experienced F3 patients with HCV Genotype‐1 infection (the ASPIRE trial)


Relapsers

Placebo+PR

SMV 100 mg+PR*

SMV 150 mg+PR*


N= 4 19 11 8 16 10 1 9 8










SVR according to fibrosis score and historical response in HCV G1 F4 patients in TVR trials (ADVANCE, ILLUMINATE, OPTIMIZE, REALIZE)


SVR %

Zeuzem S, et al. AASLD 2013. Zeuzem S, et al. J Hepatol 2011

53,5

84

34

14

0

10

20

30

40

50

60

70

80

90

100

48/57 11/32 7/50

Naïve

99/185


SVR % 62,8 64,4

53,2

28,6

0

10

20

30

40

50

60

70

80

90

100

94/146 41/77 50/175

Naïve

59/94

International EAP TVR:ITT SVR by previous treatment response in 526 F4 patients

Colombo M, et al. J Hepatol 2014 in press

Overall SVR by F4

BOC PR PR

SVR %

55

17

0

20

40

60

80

100

F4

99/180 6/32


89

35

0102030405060708090

100

SV

R (

%, 9

5% C

I)SVR according to treatment week 8 virologic

response* in F4

*Treatment-naïve and previous treatment failures combined

40/47 65/73 28/7900/17

≥3 log HCV-RNA declineand detectable

<3 log HCV-RNA decline and detectable

Undetectable

Vierling JM, Bruno S, et al. J Hepatol 2014

≤1000 IU/ml (88%) >1000 IU/ml (12%)

SVR %

63

0

0

20

40

60

80

100

150/238


The importance of TW 8 HCV‐RNA decline in patients with advanced fibrosis/cirrhosis (F3 and F4 pooled) during BOC‐therapy

0/31

p<0.0001

EoTR, SVR12 and relapse rate overall and in 260 cirrhotic patientsAll patients who received at least one dose of BOC included

62%

49%

20%

65%

45%

25%

0

10

20

30

40

50

60

70

80

EoTR SVR12 Relapse

Overall F4

158/260 188/381 118/260 49/237 40/158237/381


61,3%

50,6%

37,9%

61,1%

44,8%

33.3%

0

10

20

30

40

50

60

70

Relapser Partial responder Null responder

Overall F4

55/90 45/89 26/58 58/153 37/11184/137

SVR12 overall and according to prior response in 260 cirrhotic patientsAll patients who received at least one dose of BOC included


SVR12 in 260 F4 according to treatment week 8 virologic responseAll patients who received at least one dose of BOC included

68,3%

31,7%28,1%

71,9%

0

10

20

30

40

50

60

70

80

SVR No SVR

HCV-RNA Undetectable HCV-RNA Detectable

71104 33

104

38135 97

135

51,7%48,3%

9,1%

90,9%

0102030405060708090

100

SVR No SVR

HCV-RNA < 1000 UI/mL HCV-RNA > 1000 UI/mL

106204

992043

33

3033

PPV=68,3% - NPV=71,9% PPV=51,7%-NPV=90,9%


CUPIC SVR12 rates and safety (ANRS CO20‐CUPIC)

Undetectable HCV RNA (ITT) n (%)

BOCn = 212

TVR n = 299

SVR12 (Total) 91(43) 155 (52)

SVR12 in relapsers 55/102 (54) 92/124 (74)

SVR12 in partial responders 36/94 (38) 54/135 (40)

SVR12 in null responders 0/10 (0) 6/31 (19)SAE 44.3% 53.8%Death 1.4% 2.7%Infections 3.8% 9.7%Hepatic decompensation 4.2% 4.7%Anemia <8g/dl or blood tx 9%/11.8% 12.7%/18%

Fontaine H, et al. AFEF 2013

Risk factors for SAE Platelets count

> 100,000/mm3

Platelets count

≤ 100,000/mm3

Albumin 35 g/LSAE : 6.2 %

SVR : 54.9%(306)

SAE: 12.2 %SVR : 36.5%

(74)

Albumin <35 g/LSAE: 16.1 %SVR: 29%

(31)

SAE: 51.4 %SVR: 27%

(37)

Risk-benefit(SAE / SVR 12)

Missing data in 63 patients

( number of patients )

SVR >> SAE SVR > SAE

SVR > SAE SAE >> SVR

9%Hezode C, et al. Gastroenterology 2014

0102030405060708090

100

125/198 30/101

RVR NORVR

63%

40%

P < 0.001

TELAPREVIR

0102030405060708090

100

62/99 29/113

HCV RNADecline≥ 1log

W4

RVRW8

63%

26%

BOCEPREVIR

Fontaine H , France, AFEF 2013,

SVR12 according to on‐treatment response

HCV RNADecline< 1log

W4

NO RVRW8

HCV RNADecline< 3log

W8

58/81 33/131

72%

25%

4/636%

P < 0.001P < 0.001

0

70 73

0

15

82

0

46

31

0

10

20

30

40

50

60

70

80

90

100

SVR 24

(%)


Simeprevir plus PegIFN and Ribavirin in treatment‐experienced cirrhotic (F4) patients with HCV Genotype‐1 infection (the ASPIRE

trial)


Relapsers

Placebo+PR

SMV 100 mg+PR*

SMV 150 mg+PR*


N= 6 10 15 2 13 11 2 11 13

YES

Is there still a role of IFN‐based triple therapy with first generation PI in patientswith mild to moderate fibrosis and comorbities (NULLS EXCLUDED)

Overall SVR rates quite good,

Short duration of treatment in the vast majority ofpatients

Safety profile manageable

Approved futility rules useful and externally validated

NOPatient’ s reluctance

SMV or SOF+IFN soon available

*SOC may be considered in naives LVL RVR after lead in

YES









BASED ON FIRST GENERATION PIs COST

YES









BASED ON FIRST GENERATION PIs COST

YES

Is there still a role of IFN‐based triple therapy with first generation PI in patientswith advanced fibrosis (F3) and “early” stage (F4) compensated , NULLS F2

included

NOOverall SVR rates using early futility not that bad

Safety profile quite manageable

Approval of all-oral combination soon available

Patient’s reluctance

TREAT

Treating vs Deferring IFN‐based triple therapy in marginally compensated Cirrhotic patients withmoderate to severe portal hypertension

Urgency of treatment well established

Short-term prognosis worrying

Efficacy, safety, duration of therapy, pill burden and dosing frequency unacceptable

Approval of all-oral combination soon available

EA program or compassionate use soon available

DEFER

Thank you for your attention!

The opinions expressed here represent the opinion of the author. All products mentioned in the presentation should be applied according to

the Product Labels.

Documents

SAVINO BRUNO, MD - AISF | Associazione Italiana per lo ... · AO Fatebenefratelli e Oftalmico, Milano. ... Simeprevir US Prescribing information Patients at Week 4 (%) ... 53/62 10/18