Simeprevir (Olysio) Doç. Dr. Mustafa Kemal ÇELEN Dicle Üniversitesi Cappadocia

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Simeprevir (Olysio)

Doç. Dr. Mustafa Kemal ÇELEN Dicle Üniversitesi

Cappadocia-25.05.2014

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• Son 20 yıldır HCV tedavisinde etkin rol oynadı

• Mekanizması tam olarak anlaşılmadı

• Pegile formu ile tanıştık

• Lamda formu daha tolerable…

• Derken… interferonsuz seçenek ! 

• «Güle Güle» interferon mu?

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HEKİM PENCERESİ

?

%0 YAN ETKİ 



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1) Virus Girişi 2) Soyunma

3) Protein Sentezi

4) Ayrılma

5) RNA Replikasyonu

6) Paketleme

7) Olgunlaşma

8) Re-infeksiyon

Proteaz Inhibisyonu

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Simeprevirin Klinik Çalışmaları

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Tedavi naif GT1 hastalarında Simeprevir : QUEST-1

Placebo + PR SMV + PR

STOP if RGT +

Peg IFN 2a + RBV

Peg IFN 2a +RBV

0 12 24 48

Simeprevir: 150 mg QD (1 capsule) P: Peg IFN 2a 180 µg/wk

R: RBV 1000-1200 mg

RGT+: Response guided therapy criterion:

Primary endpoint: SVR12

N=264

N=130

Jacobson I et a. EASL 2013, Abstract 1425

Faz 3

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Simeprevir: QUEST 1 başlangıç dermografik verileri

SMV/PR N=264

Pbo/PR48 N=130

Female, % 44 43

Race, %

•White

•Black/African American

•Asian

87 10 2

94 3 2

Median age, y 48 48

Median BMI, kg/m2 27 27

IL28B CC, % IL28B non CC, %

29 71

29 72

Median HCV RNA, log10 IU/ml 6.5 6.4

HCV RNA > 800,000 IU/ml 83 74

Genotype 1a, % Genotype 1b, %

56 44

57 43 Metavir score, %

•F0-F1

•F2

•F3

•F4

45 25 18 12

39 31 18 13

Faz 3

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QUEST 1: SVR12 sonuçları

80

50 0 20 40 60 80 100

SVR12 (%)

Simeprevir/PR Pbo/PR48

210/264 65/130

P<0.001

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QUEST 1: fibroz derecesine göre SVR12 yanıtı

Jacobson I, et al. EASL 2013: Abstract 1425

83

78

60 58

26 29

152/183 54/90 36/46 6/23 18/31 5/17

SVR12 (%)

100

80

60

40

20

0

Simeprevir/PR Placebo/PR48

F0–F2 F3 F4

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QUEST 1: Genotip subtipine göre SVR12 yanıtı

71

90 49 52

0 20 40 60 80 100

Genotype 1a Genotype 1b

SVR12 (%)

Simeprevir/PR Pbo/PR48

105/147 36/74 105/117 29/56

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QUEST 1: İlk 12 haftada yan etki gelişimi

Parameter, % SMV/PR

N=264

Pbo/PR48 N=130

Grade 1 or 2 AE 72 65

Grade 3 or 4 AE 23 29

SAE 3 4

AE leading to SMV/Pbo discontinuation 3 3

Most common AEs (≥25% in SMV arm, preferred term)

Fatigue 40 38

Headache 31 37

Pruritus 21 11

Other AEs of interest (preferred term)

Increased bilirubin* 9 4

Rash (any type) 27 25

Photosensitivity conditions 3 1

Neutropenia 19 11

Anaemia 16 11

*Attributed to inhibition of OATP1B1/MRP2 transporter; not associated with elevations of AST, ALT or ALP

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QUEST-2

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GT 1 naif hastalarda simeprevir:

QUEST 2

Placebo + PR Peg IFN 2a/2b + RBV

0 12 24 48

SMV+PR

STOP if RGT +

Peg IFN 2a/2b + RBV

Peg IFN 2a/2b +RBV

Phase 3

Manns MP, et al. EASL 2013; Abstract 1413

N=257

N=134

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QUEST 2: SVR12 Sonuçları

81,3

50,0

0 20 40 60 80 100

SVR12 (%)

Simeprevir/PR Pbo/PR48

209/257 67/134

p<0.001

Manns MP, et al. EASL 2013; Abstract 1413

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PROMISE

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Promise: Tedavi deneyimli GT1 hastalarında Simeprevir etkinliği

Placebo + PR SMV + PR

STOP if RGT +

Peg IFN 2a + RBV

Peg IFN 2a +RBV

0 12 24 48

N=260

N=133

Faz 3

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Dermografik Özellikler

SMV/PR N=260

Pbo/PR48 N=133

Female, % 31 41

Race, %

•White 94 96

Median age, y 52 52

Median BMI, kg/m2 27 27

IL28B CC, % IL28B non CC, %

24 76

26 74

Median HCV RNA, log10 IU/ml 6.4 6.5

Genotype 1a, % Genotype 1b, %

42 57

41 59 Metavir score, %

•F0-F1

•F2

•F3

•F4

35 32 18 16

36 39 11 14

Lawitz E et a. DDW, Abstract

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Promise: Genotip subtipi ile SVR İlişkisi

18/257 43/134 30/236 21/288

70,3

85,9

27,8

43 0 20 40 60 80 100

1a 1b

Pr o p o rtio n o f p atie nts SV R12 ( %)

Simeprevir/PR Pbo/PR48

p<0.001 p<0.001

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SMV Promise: SVR 12 by IL28b Genotype

88,7

78,4

64,5 52,9

33,7

18,8

0 20 40 60 80 100

CC CT TT

Pr o p o rtio n o f p atie nts SV R12 ( %)

Simeprevir/PR Pbo/PR48

68/77 28/45 362/80 18/43 79/100 21/46

p<0.001 p<0.001

p<0.001

Lawitz E et a. DDW, Abstract ____

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Promise: SVR12 yanıtı ile metavir skoru ilişkisi

82,0

72,7 74,4

40,8

20 26,3

0 20 40 60 80 100

F0-F2 F3 F4

Pr o p o rtio n o f p atie nts SV R12 ( %)

Simeprevir/PR Pbo/PR48

68/77 28/45 362/80 18/43 79/100 21/46

p<0.001 p<0.001

p<0.001

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Simeprevir: Yan etki gelişimi

Parameter, % SMV/PR

N=260

Pbo/PR48 N=133

Grade 1 or 2 AE 75.4 71.4

Grade 3 or 4 AE 20.0 21.1

SAE 1.2 2.3

AE leading to SMV/Pbo discontinuation* 0.4 0

Most common AEs (≥25% in SMV arm)

Fatigue 31.9 42.1

Headache 31.9 36.1

Influenza-like illness 29.6 20.3

Other AEs of interest

Rash (any type) 18.5 14.3

Anaemia 10.8 6.0

Pruritus 23.5 16.5

Photosensitivity conditions 3.5 0

Increased Bilirubin 5.8 2.3

Neutropenia 14.6 16.5

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ATTAIN

Tedavi deneyimli GT1 HCV hastalarında

Simeprevir / telaprevir + PR tedavisinin etkinlik ve güvenlilik faz III çift kör, randomize çok

merkezli çalışması

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ATTAIN: Study design



Stratification by HCV genotype 1 subtype and prior treatment response



Virologic stopping rules: All study medications were stopped if:

– Weeks 4/12: HCV RNA >1000 IU/mL

– Weeks 24/36: Confirmed detectable HCV RNA

Prior non-responders (null and partial)

RBV :1000-1200mg/b.i.d per body weight (< 75 or ≥ 75 kg);

HCV RNA plasma concentration determined using the Roche COBAS Taqman HCV/HPS v2.0 assay (lower limit of quantification [LLOQ] 25 IU/mL; lower limit of detection [LLOD], 15 IU/mL)

PR, peginterferon α-2a + ribavirin; QD, once daily; RBV, ribavirin; SMV, simeprevir; TID, three times daily; TVR, telaprevir SMV 150 mg QD +

PR PR

Arm 1 (n=379)

TVR 750 mg TID +

PR PR

Arm 2 (n=384)

0 4 12 24 36 48 60 72

Week

Follow-up SVR12

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ATTAIN: Patient disposition

ITT, intent to treat; PegIFN, peginterferon; PR, peginterferon α-2a + ribavirin;

RBV, ribavirin; SMV, simeprevir; TVR, telaprevir

Prior partial responders

(n=145)

Prior null responders

(n=234)

Prior partial responders

(n=146)

Prior null responders

(n=238)

SMV/PR (n=379) TVR/PR (n=384)

Received study treatment, ITT

(N=763) Randomised

(N=771)

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ATTAIN: SVR12 (ITT population)

*Weighted by stratification factors and the corresponding 95% CI based on the normal approximation. **Based on the asymptomatic distribution of the generalised CMH statistic controlling for stratification factors, using a non-inferiority margin of 12%. PR, peginterferon α-2a + ribavirin; SMV, simeprevir;

SVR12, sustained virologic response at 12 weeks after planned end of treatment; TVR, telaprevir

Difference in proportions (95% CI)*: -1.1 (-7.8;5.5) P-value for non-inferiority** <0.001

SMV/PR TVR/PR

53.6% 54.7%

0 20 40 60 80 100

SVR12 (%)

210/384

203/379

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43.6%

69.7%

46.2%

68.5%

0 20 40 60 80 100

Prior null responders Prior partial responders

SVR12 (%)

ATTAIN: SVR12 by prior treatment response (ITT population)

*Difference in proportions (SMV-TVR) weighted by stratification factors and the corresponding 95% confidence interval (CI) based on the normal approximation.

PR, peginterferon α-2a + ribavirin; SMV, simeprevir; SVR12, sustained virologic response at 12 weeks after planned end of treatment; TVR, telaprevir

102/234 110/238 101/145 100/146

Adjusted difference -2.8 95% CI: -11.3;5.8*

Adjusted difference 1.5 95% CI: -9.0;12.0*

SMV/PR TVR/PR

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ATTAIN: Yan etki

SMV/TVR + PR PR

SMV (n=379)

TVR (n=384)

SMV (n=379)

TVR (n=384) Most common AEs (≥25% in SMV/PR or TVR/PR arm), %

Kaşıntı 31.1 43.0 37.5 46.6

Yorgunluk 31.7 38.0 34.8 40.4

Başağrısı 25.1 28.9 26.9 31.5

Anemi 12.9 36.7 25.6 41.1

Bulantı 16.9 28.4 19.5 28.6

*Permanent stop of at least one drug; AE, adverse event; PR, peginterferon α-2a + ribavirin; SAE, serious AE; SMV, simeprevir; TVR, telaprevir

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ASPIRE

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Confidential – For internal use only (Incivo team)

ASPIRE (TMC435): G1, tedavi deneyimli

**TMC435* + PR TMC435* + PR**

PR

24 12

0 48 72

Follow-up

TMC12/PR48 100mg, n= 66 150mg, n= 66

**TMC435* +** PR

PR Follow-up

Follow-up

Follow-up PR

TMC24/PR48 100mg, n= 65 150mg, n= 68

TMC48/PR48 100mg, n= 66 150mg, n= 65

Control, n= 66

*TMC435 either 100 or 150mg QD; PR: 180µg peginterferon alfa 2a + 1000-1200mg ribavirin

Weeks

Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1

faz 2b

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Confidential – For internal use only (Incivo team)

ASPIRE (TMC435): SVR24 by prior response

37

85 85

9

57

75

19

46 51

0 20 40 60 80 100

Pa tients w ith SVR2 4 (% )

TMC435 100mg*

PR48

10 10 TMC435

150mg*

PR48

TMC435 100mg*

PR48 TMC435

150mg*

PR48 TMC435

100mg*

PR48

PR48 PR48 PR48 TMC435

150mg*

PR48

n=27 n=79 n=79 n=23 n=68 n=69 n=16 n=50 n=51

Relapsers Partial

responders

Null responders

*All TMC435 duration pooled Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1

Phase 2b

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PILLAR

• Tedavi naif sirotik olmayan hastalar

• Genotip 1

• Faz II

• SMV+PR….SVR %75-86

• PR…………..SVR %65

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CONCERTO-1

• Japonya’da tedavi naif 183 genotip 1, faz III

• simeprevir+PR tedavisi 12 hafta/ 36 hafta PR

• Placebo+PR tedavisi 12 hafta/ 36 hafta PR

• Simeprevir kombinasyon grubunda yanıt %92

• Tedavi deneyimli hasta grubunda devam eden

CONCERTO-2 ve CONCERTO-3, SMV kolu daha

etkin…

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HELIX-1

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3 8

HELIX-1: Çalışma dizaynı

N=93 Weeks 1-12 EOT to SVR24

20

25 mg IDX719 150 mg simeprevir

RBV^a

Off-treatment Follow-up 20

RBV^a

33^b

RBV^a

20

RBV^a

Lawtiz E,et al EASL 2014 Poster 1222

Samatasvir (IDX719, an NS5A inhibitor)

Treatment was discontinued at week 4 if HCV RNA > 25 IU/mL was detected

a Ribavirin (RBV) dosing weight-based, according to product label.

b Originally designed to have N=40(20 subjects with and 20 subjects without ribavirin). Following DSMB review, the RBV -free group was capped at 13 subjects and RBV added at first dose to all subjects.

Tedavi naif GT1 ve 4 hastalarında Samatasvir (IDX719)+SIM+RB faz II çalışması

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HELIX-1 : Sonuçları

• Erken sonuçlara göre samatasvir dozu ile ilişkili SVR4 % 47-83 oranında saptanmıştır.

(25, 50,100,150 mg QD achieved 80, 75, 83,47% SVR4 respectively)

• Samatasvir 100 mg QD.

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HELIX-1: Özet

– Ciddi AE gelişmedi – Samatasvir:

• İyi tolere edilmekte

• Anemi RBV ile ilişkili

• Simeprevir kullanımına bağlı artan Bilirübin düzeyi.

– Simeprevir:

• Güvenli bir profil

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OPTIMIST

Optimal Treatment with a simeprevir and sofosbuvir

Therapy

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4 12

Wks

Arm 1 N=150

N=300 Stratified by IL28B and HCV genosubtype

SMV 150 mg qd + SOF 400 mg qd ---Post Tx Follow up---

PR 8

SMV 150 mg qd + SOF 400 mg qd

Arm 2 N=150

Primary objective: %80 SVR

16 36

SVR24 Baseline 24

SVR12 timepoint

Baseline 4 8 12 20 32

--- ---Post Tx Follow up---

OPTIMIST 1

Tedavi naif ve deneyimli GT1 sirotik olmayan HCV hastalarında gerçekleştirilen çok merkezli , açık uçlu ve randomize Faz III çalışması.

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4 12

Wks Single Arm

N=200 Stratified by IL28B and HCV genosubtype

SMV 150 mg qd + SOF 400 mg qd ---Post Tx Follow up---

PR 8

Primary objective: SVR %60

16 36

SVR24 Baseline 24

SVR12 timepoint

OPTIMIST 2

Tedavi naif ve deneyimli GT1 sirotik HCV hastalarında gerçekleştirilen çok merkezli , tek kollu Faz III çalışması.