How to use and whom to treat?congress-ph.ru/common/htdocs/upload/fm/gepatology/... · Hb 124 g/L...

Second generation PI

How to use and whom to treat?

Graham R Foster

Queen Marys University of London, London

Case study: treatment naive

Hb, haemoglobin; WBC, white blood cell count; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate

aminotransferase; AFP, alfa-fetoprotein; HBsAg, hepatitis B antigen; HIVAb, human immunodeficiency virus antibody; HCV,

hepatitis C virus; USS, ultrasound scan.

Test Result Test Result

Hb 124 g/L HBsAg neg

WBC 4.0 x 109 /L HIVAb neg

Platelets 245 x 109 /L HCV RNA 880,000

copies/mL

ALP 97 IU/L Fibroscan 5.7 kPa

ALT 67 IU/L Genotype information:

AST 45 IU/L G1b

AFP 2.0 ng/μL IL28B genotype CC

Bilirubin 9 μmol/L Ultrasound:

Albumin 43 g/L Unremarkable

A 34-year-old female was found to be HCV-positive, previous IVDU

She wants to have a second child

Laboratory investigations

IFN-based current and future options for

genotype 1 treatment-naïve patients

Cross comparison of studies cannot be carried out

SMV: simeprevir; FDV: faldaprevir; DCV: daclatasvir

SOF: sofosbuvir

74

66

80

73 72

65 64

90

20

60

100

40

80

SV

R (

%)

0

OPTIMIZE1 SPRINT-22 Pooled

QUEST1 & 23

COMMAND 15 STARTVerso1&24

274/

369

242/

366

419/

521

382/

521

378/

524

95/

147

94/

146

1. Buti M, Gastroenterology 2014;146:744–53

2. Boceprevir SmPC; 3. Jacobson I, et al. AASLD 2013. Poster 1122

4. Jensen DM, et al. AASLD 2013. Abstract 1088

5. Hézode, et al. AASLD 2012: Abstract 755;

6. Lawitz E, et al. N Engl J Med 2013;368:1878–

TVR/PR

(bid)

BOC/PR SMV/PR FDV

120mg/PR

FDV

240mg/PR

DCV

20mg/PR

DCV

60mg/PR SOF/PR

Neutrino6

295/

327

What can we expect with simeprevir?

Patients deciding on treatment want to know what are their

chances of responding

What are the factors that influence outcome?

Pooled QUEST 1&2 –

SVR in patients with mild disease

84 88 87

55 58 59

0

20

40

60

80

100

1.Jacobson I, et al. AASLD 2013. Poster 1122

2.Foster et al., EASL2014, Poster 1127

3. Adapted from Dore G, et al. APASL 2014. Poster

SV

R12 (

%)

317/378 106/192 191/217 64/110 179/202 61/103

SVR12 in METAVIR F0-F2 patients

Overall1 European patients2 Genotype subtype 1b3

SMV + PR PBO + PR

Pooled QUEST 1&2 –

SVR in patients with mild disease

84 88 87

55 58 59

0

20

40

60

80

100

1.Jacobson I, et al. AASLD 2013. Poster 1122

2.Foster et al., EASL2014, Poster 1127

3. Adapted from Dore G, et al. APASL 2014. Poster

SV

R12 (

%)

317/378 106/192 191/217 64/110 179/202 61/103

SVR rates were higher in the SMV/PR group compared

with PBO/PR irrespective of METAVIR score

SVR12 in METAVIR F0-F2 patients


SMV + PR PBO + PR

Pooled QUEST 1 & 2

SVR 12 in Genotype 1b meeting RGT

94 96 89 91

0

20

40

60

80

100

All genotype 1b patients METAVIR F0-F2

RGT criteria: HCV RNA <25 IU/mL, detectable/undetectable at Week 4

and <25IU/mL undetectable at Week 12 Dore G, et al. APASL 2014. Poster

Po

rtio

n o

f p

ati

en

ts (%

)

252/267 224/252 193/202 176/193

Genotype 1b

96% of patients with F0-F2 were eligible to shorten treatment duration to 24 weeks.

91% achieved SVR12

Met RGT criteria SVR in RGT +

Pooled QUEST 1 & 2: SVR 12 in Genotype 1b

94 96 89 91

0

20

40

60

80

100

All genotype 1b patients METAVIR F0-F2



Po

rtio

n o

f p

ati

en

ts (%

)

252/267 224/252 193/202 176/193

Genotype 1b

96% of patients with F0-F2 were eligible to shorten treatment duration to 24 weeks.

91% achieved SVR12


Pooled QUEST 1 & 2 –

SVR 12 in patients with severe disease (F4 meeting RGT)

91 86

92

83

0

20

40

60

80

100

All European patients METAVIR F4


and <25IU/mL undetectable at Week 12 Foster et al., EASL2014, Poster 1127

Po

rtio

n o

f p

ati

en

ts (

%)

252/276 231/252 12/14 10/12

European patients

86% of patients with F4 were eligible to shorten treatment duration to 24 weeks.

83% achieved SVR12



European patients (ITT) and IL-28

96

86

69

79

44

31

0

20

40

60

80

100

IL28B CC IL28B CT IL28B TT

Foster et al., EASL2014, Poster 1127

SV

R12 (

%)

72/75 33/42 143/166 37/84 24/35 5/16

higher SVR12 rates with SMV + PR compared with Pbo + PR, irrespective of IL28B

genotype

SVR12 by IL28B subgroup SMV + PR PBO + PR


SVR 12 by IL28B in patients meeting RGT

94 97

89

100

0

20

40

60

80

100

All genotype 1b IL28B CC



Po

rtio

n o

f p

ati

en

ts (

%)

252/267 224/252 65/67 65/65

Genotype 1b

97% of patients with IL28B CC were eligible to shorten treatment duration to 24

weeks. All of them achieved SVR12


Pooled QUEST 1 & 2 – SVR 12 by IL28B in

patients meeting RGT

91

83

92

76

0

20

40

60

80

100

All European patients IL28B TT


and <25IU/mL undetectable at Week 12 Foster et al., EASL2014, Poster 1127

Po

rtio

n o

f p

ati

en

ts (

%)

252/276 231/252 29/35 22/29

European patients

83% of patients with IL28B TT were eligible to shorten treatment duration to 24

weeks. 76% achieved SVR12


Pooled QUEST 1 & 2 – SVR12 by demographic

and baseline disease characteristics

79 82

67

82

74

85

78

92

48 53

36

51

41

52

40

77

0

20

40

60

80

100

Male Female Black Caucasian BMI ≥30 kg/m2

BMI <25kg/m2

HCV RNA>800,000

IU/mL

HCV RNA ≤800,000

IU/mL

SV

R12 (

%)

SMV + PR PBO + PR

Jacobson I, et al. AASLD 2013. Poster 1122

227/

288

72/

151 192/

233

60/

113

29/

43

5/

14

378/

464

124/

245

84/

113 29/

70

175/

207

53/

103

323/

417

78/

194

96/

104

54/

70

2 2

Significantly higher SVR rates were observed with SMV + PR compared to PR


Patients deciding on treatment want to know what are their

chances of responding

For this young European female the chance of an SVR is

>90% with simeprevir

Treatment regimen for naive and prior relapser

SMV + PR PR

0 12 24 Week

Russian SmPC Simeprevir *HCV genotype 1a patients, if testing is available, patients should be tested for the

presence of virus with the NS3 Q80K polymorphism before starting treatment

Stopping rules: discontinue SMV + PR if HCV RNA ≥ 25 IU/mL at treatment

Week 4, discontinue PR if ≥ 25 IU/mL at treatment Week 12 or week 24

Fixed treatment duration for treatment naïve and prior relpaser in GT 1*:

• Total treatment duration is 24 weeks irrespective of fibrosis stage

Safety in treatment naive European patients

*Without regard to peginterferon and ribavirin

n (%)

First 12 weeks Entire treatment phase

SMV + PR

(n=276)

Pbo + PR

(n=142)

SMV + PR

(n=276)

Pbo + PR

(n=142)

At least 1 AE, n (%) 260 (94.2) 135 (95.1) 266 (96.4) 137 (96.5)

Grade 1 or 2, n (%) 191 (69.2) 98 (69.0) 179 (64.9) 90 (63.4)

Grade 4, n (%) 9 (3.3) 2 (1.4) 12 (4.3) 3 (2.1)

At least 1 SAE, n (%) 8 (2.9) 2 (1.4) 12 (4.3) 3 (2.1)

AEs leading to discontinuation

of SMV/ PBO*

6 (2.2) 1 (0.7) 6 (2.2) 1 (0.7)

AEs of special interest

Increased bilirubin 34 (12.3) 6 (4.2) 35 (12.7) 6 (4.2)

Rash (any type) 63 (22.8) 13 (9.2) 73 (26.4) 23 (16.2)

Pruritus 56 (20.3) 21 (14.8) 74 (26.8) 38 (26.8)

Photosensitivity conditions 9 (3.3) 0 (0.7) 9 (3.3) 1 (0.7)

Grade 3 or 4 laboratory parameters, n (%)

Haemoglobin 1 (0.4) 4 (2.8) 2 (0.7) 4 (2.8)

Bilirubin 9 (3.3) 1 (0.7) 9 (3.3) 1 (0.7)

Neutrophils 44 (16.0) 24 (16.9) 65 (23.6) 38 (26.8)

Foster et al., EASL2014, Poster 1127

Can we shorten treatment duration further?

Is 12 weeks enough?

Response-guided therapy of 12 or 24 weeks guided by HCV RNA measurements at treatment weeks

2, 4 and 8

– All patients: 12 weeks of triple therapy*; stop all therapy after Week 12 if HCV RNA <25 IU/mL

(detectable or undetectable) at Week 2 AND <25 IU/mL undetectable at Week 4 AND <25 IU/mL

undetectable at Week 8; otherwise continue treatment

*Unless a virologic stopping rule is met

PR: Peg-IFNα-2a 180 µg/wk + RBV 1000–1200 mg/day www.clinicaltrials.gov (NCT01846832)

Week 12 Week 24 Week 36 Week 48

SMV 150 mg qd + PR

Post-treatment follow up

Continue PR to

Week 24

Week 4

Post-treatment follow up

Treatment-naïve patients:

• GT 1 & 4

• F0–F2

• irrespective of Q80K, irrespective of IL28B

Case study: prior relapser

A 53-year-old male with chronic HCV

January 2009: patient was treated with PR but relapsed

Concomitant diseases: depression (well controlled by antidepressants);

BMI 28 kg/m2

HCV-RNA: 266,575 IU/mL; genotype 1b; IL28B-GT: CT

Fibrosis score: F4;

Albumin and prothrombin time normal; no clinical signs of

decompensated liver disease

i.v., intravenous; BMI, body mass index; US, ultrasound


Patients deciding on their second course of treatment want it

to be their last!

Who is going to be cured second time around?

First generation PIs in treatment experienced

patients

84

69

47

0

20

40

60

80

100

122/145 100/146

75

52

41

0

20

40

60

80

100

20/49 110/238 30/58 77/103

Telaprevir Boceprevir

Relapser Partial

responder

null

responder

Relapser Partial

responder

null

responder

REALIZE1 ATTAIN2 RESPOND 23 PROVIDE4

SV

R (

%)

SV

R (

%)

1.INCIVO (telaprevir) EU SmPC 2.Reddy KR, et al. APASL 2014. Oral presentation

3.VICTRELIS (boceprevir) EU SmPC 4. Vierling J, et al. DDW 2013. Abstract 869c

Current and future IFN based options for

genotype 1 in treatment-experienced patients

79

70

44

70

58

33 33

0

20

40

60

80

100

SV

R (

%)

Cross comparison of studies cannot be carried out. ¶in Japanese patients only

1. Forns X, et al. Gastroenterology 2014;146:1669–1679

2. Reddy K, et al. APASL 2014; 3. Jacobson I, et al. AASLD 2013. Abstract 1100

4. Lawitz E, et al. EASL 2014. Abstract O165; 5. Suzuki F, et al. APASL 2012

Some data on

re-treatment

with SOF/PR,

but no Phase

II or III data

available 101/

145

102/

234

206/

260

69/

99

33/

57

48/

145 3/9

Relapsers

Partial

responders Nulls

Non

responders Relapsers

Partial

responders Nulls Nulls

SMV

150 mg*/PR

PROMISE1

SMV

150 mg*/PR

ATTAIN2

FDV* 240mg/PR (12 week arm)

STARTVerso-33

DCV

60 mg*/PR¶

COMMAND-25

SOF/PR

PROMISE – SVR by fibrosis stage in prior relapser

74

85 84

26 30

25

0

20

40

60

80

100


2.Forns et al., EASL2014

3.Gane et al., APASL2014

SV

R12 (

%)

29/39 5/19 23/27 3/10 16/19 2/8

SVR12 in METAVIR F4 patients


SMV + PR PBO + PR

PROMISE – SVR by fibrosis stage in prior relapser

74

85 84

26 30

25

0

20

40

60

80

100


2.Forns et al., EASL2014

3.Gane et al., APASL2014

SV

R12 (

%)

29/39 5/19 23/27 3/10 16/19 2/8

SVR rates were higher in the SMV/PR group compared

with PBO/PR irrespective of METAVIR score

SVR12 in METAVIR F4 patients


SMV + PR PBO + PR

PROMISE – SVR 12 by fibrosis stage in

Genotype 1b patients meeting RGT

95 95 89 89

0

20

40

60

80

100

All genotype 1b patients METAVIR F4


and <25IU/mL undetectable at Week 12 Gane E, et al. APASL 2014. Poster

Po

rtio

n o

f p

ati

en

ts (%

)

141/149 125/141 18/19 16/18

Genotype 1b

95% of patients with F4 were eligible to shorten treatment duration to 24 weeks.

89% achieved SVR12


Patients with on treatment response at week 4*

achieve high SVR

For prior treatment failures - if you have not got an

early response at week 4 you won’t do well with

simeprevir

BUT

If you do have an early response you have a very

high chance of response with simeprevir

*Early response at week 4: HCV RNA <25IU/ml Forns X, et al. AASLD 2014

89

78

64

53

34

19

0

20

40

60

80

100

CC CT TT

SMV + PR: PROMISE – SVR12 by IL28B genotype

P<0.001, based on a logistic regression model with factors for treatment

group, baseline HCV RNA, HCV 1 subtype and IL28B genotype Forns X, et al. Gastroenterology 2014;146:1669–1679

SV

R12 (

%)

137/167 40/98 32/44 3/15 29/39 5/19

Significantly higher SVR12 rates with SMV + PR compared with Pbo +

PR, irrespective of IL28B genotype

SMV + PR PBO + PR

76 75

90

6 2 0

0

20

40

60

80

100

CC CT TT

PROMISE – RVR by IL28B genotype in prior

relapsers

P<0.001, based on a logistic regression model with factors for treatment

group, baseline HCV RNA, HCV 1 subtype and IL28B genotype Forns X, et al. AASLD 2014

RV

R (

%)

47/62 2/33 125/167 2/81

28/31 0/16

RVR rates were significantly higher with SMV + PR vs Pbo + PR,

regardless of IL28B genotype

SMV + PR PBO + PR

SMV + PR: PROMISE – SVR12 by IL28B in

genotype 1b prior relapsers who met RGT

P<0.001, based on a logistic regression model with factors for treatment group, baseline HCV RNA,

HCV 1 subtype and IL28B genotype

RGT criteria: HCV RNA <25 IU/mL, detectable/undetectable at Week 4 and <25IU/mL undetectable at Week 12 Gane et al. APASL 2014

SV

R12 (

%)

All genotype1b patients achieved high SVR rates irrespective of their

IL28B genotype

95 97 94 95 89

97 90

68

0

20

40

60

80

100

All genotype1b

CC CT TT

141/

149

125/

141

32/

33

31/

32

90/

96

81/

90

19/

20

13/

19

Patients who met

RGT

SVR12 of patients

who met RGT

Safety in treatment experienced European patients

*Also included photosensitivity events Forns et al., EASL2014

First 12 weeks Entire treatment phase

SMV/PR

(N=184)

PBO/PR

(N=90)

SMV/PR

(N=184)

PBO/PR

(N=90)

Grade 3 / 4 AEs, % 17.9 / 1.6 17.8 / 2.2 22.8 / 3.3 26.7 / 4.4

Any SAE, % 1.7 1.2 5.6 9.2

Most frequently occurring AEs, %

Fatigue 31.5 35.6 32.1 36.7

Headache 30.4 31.1 31.5 31.1

Pruritus 26.6 20.0 32.1 33.3

Pyrexia 26.1 25.6 29.3 27.8

Influenza-like illness 29.9 20.0 29.9 20.0

AEs of clinical interest, %

Rash (any type)* 16.3 6.7 20.7 15.6

Photosensitivity conditions (any type) 4.3 0 4.3 0

Treatment regimen in Russia for naive and prior

relapser1

Treatment-naive and prior relapser,

F0-F4 SMV + PR PR

0 12 24 Week

Russian SmPC Simeprevir

1.Including HCV/HIV co-infected patients

*HCV genotype 1a patients, if testing is available, patients should be tested for the presence of virus with the

NS3 Q80K polymorphism before starting treatment

Stopping rules: discontinue SMV + PR if HCV RNA ≥ 25 IU/mL at treatment

Week 4, discontinue PR if ≥ 25 IU/mL at treatment Week 12 or week 24

Fixed treatment duration for treatment naïve and prior relpaser with SMV +

PR in genotype 1* irrespective of fibrosis stage

Treatment regimen for partial and null responder1

1includes HIV/HCV coinfected patients.

*HCV genotype 1a patients, if testing is available, patients should be tested for the presence of virus with the

NS3 Q80K polymorphism before starting treatment

0 12 24 48 Weeks

Prior partial and null responders

F0−F4

4

If HCV RNA ≥25 IU/mL,

discontinue SMV + PR If HCV RNA ≥25 IU/mL,

discontinue PR

SMV + PR PR

Stopping rules

Recommended combination and treatment duration with SMV + PR

in genotype 1*

Russian SmPC Simeprevir

Partial and Null responder will be treated for a total duration of 48 weeks

Simeprevir in Treatment Experienced Patients

A good choice with good predictability criteria

What about the alternatives?

IFN free regimens for genotype 1 treatment-

experienced patients

10

96 98

82

94-96 99

87 95

0

20

40

60

80

100

120

Cross comparison of studies cannot be carried out

*METAVIR score derived from fibrotest (classified according to manufacturers website)

Patients with F4 were required to have no evidence of cirrhosis based upon a biopsy

¶ GT1b patients only

1.Gane et al., N Engl J Med 2013;368:34-44

2.Lawitz et al., EASL2014. LB O165

3. Sulkowski MS, et al. N Engl J Med 2014;370:211–21

4. Manns M et al. EASL 2014. Abstract O166

5.Afdhal N, et al. N Engl J Med. 2014; 370:1483–1493

6.Poordad F, et al. N Engl J Med 2014 [Epub ahead of print]

SV

R (

%)

SOF/SMV

±RBV

12 wks

SOF/DCV±RBV

24 wks

1/10

ELECTRON1

40/41

SOF + LDV

±RBV

12 wks

3D + RBV

12 wks

3D + RBV

24 wks

Null responder Treatment

experienced

TURQUOISE-II6

SOF

+ RBV

12 wks

100% cirrhotics No cirrhotics

21/22

COSMOS2 A14440403

PI

experienced

168

/205

Partial/ Null

responder¶

Hallmark

Dual4

59/

62

65/

75

DCV +ASV

24 wks

Null responder

No cirrhotics*

SOF + LDV

±RBV

24 wks

209

/220

218

/220

ION-25

100% cirrhotics 31% cirrhotics 15-17% cirrhotics

COSMOS: SVR12 in naïve and prior null responder with F3/F4

Cohort 2; intent-to-treat population

Lawitz E, et al. EASL 2014. Oral presentation O165

EU SmPC Simeprevir

SMV + SOF + RBV SMV + SOF

SMV + SOF + RBV SMV + SOF

SMV + SOF ± RBV

24 weeks

100

SV

R1

2 (

%)

12 weeks

80

60

40

20

0

100

80

60

40

20

0

93 100

93 93 100

80

60

40

20

0 82/87

Overall

28/30 16/16 25/27 13/14

94

SMV + SOF ± RBV for 12 weeks is approved by EMA

Improved HCV treatments continue to be developed

but when can we expect these treatments?

Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec

Telaprevir

Boceprevir

Interferon Free

Triple therapy

Faldaprevir*

(G1)

Sofosbuvir

(G1,4,5,6)

Sofosbuvir

+

RBV

G2/3 +

Asunaprevir*

Daclatasvir*

±

BMS-325*

Daclatasvir*

(G1, 2, 3, 4)

Sofosbuvir+

Ledipasvir

FDC*

Ombitasvir*

Dasabuvir*

+

ABT-450*/r

RBV

+

±

2011 2012 2013 2014 2015

IFN

-fre

e

IFN

-ba

se

d

Simeprevir

(G1, 4)

EMA approvals

RBV

±

Protease inhibitor

Nuc inhibitors

NS5A

NS5B inhibitor

Nuc: nucleotide polymerase inhibitor; NS5A: hepatitis C virus non-structural protein 5a protease inhibitor

*Not yet approved in Europe

Sofosbuvir

Simeprevir

+

RBV

±

G1/4

Development of SMV in IFN-free based regimens in

HCV genotype 1 patients

Clinicaltrials.gov

Ongoing/future IFN-free studies with SMV

Genotype 1b, Post-OLT, treatment-naïve

and null responder

SATURN: SMV + DCV + RBV

(NCT01938625)

Treatment-naïve, HCV GT 1b/4/6 and

treatment-naïve/exp HCV GT1a/b

HELIX 1&2: SMV +

samatasvir ± TMC647055/r ±

RBV (NCT01852604)

Treatment-naïve and treatment

experienced, 8 vs 12 weeks, non F4

OPTIMIST 1

SMV + SOF (NCT02114177)

Treatment-naïve and experienced

12 weeks, including F4

OPTIMIST 2

SMV + SOF (NCT02114151)

Phase II

Pha

se I

II

Conclusion

Second generation PIs demonstrate high SVR rates with an

improved safety profile

– The European subpopulation and GT 1b patients achieve even

higher SVR rates

– SMV was generally well tolerated in the European HCV

genotype 1 patient population and most AEs were Grade 1 or 2

Treatment naïve and prior relapser will be treated with a

simplified fixed treatment duration of 24 weeks with a once

daily regimen of SMV+PR irrespective of their fibrosis stage

How to use and whom to treat?congress-ph.ru/common/htdocs/upload/fm/gepatology/... · Hb 124 g/L...

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