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

Transkript

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

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3 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?

4 HEKİM PENCERESİ %0 YAN ETKİ?

5 2) Soyunma 1) Virus Girişi 3) Protein Sentezi Proteaz Inhibisyonu 4) Ayrılma 8) Re-infeksiyon 5) RNA Replikasyonu 6) Paketleme 7) Olgunlaşma

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8 Simeprevirin Klinik Çalışmaları

9 Faz 3 Tedavi naif GT1 hastalarında Simeprevir : QUEST-1 Simeprevir: 150 mg QD (1 capsule) P: Peg IFN 2a 180 µg/wk R: RBV mg RGT+: Response guided therapy criterion: Primary endpoint: SVR12 STOP if RGT + N=264 SMV + PR Peg IFN 2a +RBV Peg IFN 2a + RBV N=130 Placebo + PR Peg IFN 2a + RBV Jacobson I et a. EASL 2013, Abstract 1425

10 Faz 3 Simeprevir: QUEST 1 başlangıç dermografik verileri SMV/PR N=264 Pbo/PR48 N=130 Female, % Race, % White Black/African American Asian Median age, y Median BMI, kg/m IL28B CC, % IL28B non CC, % Median HCV RNA, log10 IU/ml HCV RNA > 800,000 IU/ml Genotype 1a, % Genotype 1b, % Metavir score, % F0-F1 F2 F3 F Jacobson I et a. EASL 2013, Abstract 1425

11 SVR12 (%) QUEST 1: SVR12 sonuçları 100 P< /264 65/130 Simeprevir/PR Pbo/PR48 Jacobson I et a. EASL 2013, Abstract 1425

12 SVR12 (%) QUEST 1: fibroz derecesine göre SVR12 yanıtı 100 Simeprevir/PR Placebo/PR /183 54/90 36/46 6/23 18/31 5/17 F0 F2 F3 F4 Jacobson I, et al. EASL 2013: Abstract 1425

13 SVR12 (%) QUEST 1: Genotip subtipine göre SVR12 yanıtı / /117 36/74 29/56 Genotype 1a Genotype 1b Simeprevir/PR Pbo/PR48 Jacobson I et a. EASL 2013, Abstract 1425

14 Parameter, % QUEST 1: İlk 12 haftada yan etki gelişimi SMV/PR N=264 Pbo/PR48 N=130 Grade 1 or 2 AE Grade 3 or 4 AE SAE 3 4 AE leading to SMV/Pbo discontinuation 3 3 Most common AEs ( 25% in SMV arm, preferred term) Fatigue Headache Pruritus Other AEs of interest (preferred term) Increased bilirubin* 9 4 Rash (any type) Photosensitivity conditions 3 1 Neutropenia Anaemia *Attributed to inhibition of OATP1B1/MRP2 transporter; not associated with elevations of AST, ALT or ALP Jacobson I et a. EASL 2013, Abstract 1425

15 QUEST-2

16 GT 1 naif hastalarda simeprevir: QUEST 2 Phase 3 STOP if RGT + N=257 SMV+PR Peg IFN 2a/2b +RBV Peg IFN 2a/2b + RBV N=134 Placebo + PR Peg IFN 2a/2b + RBV Manns MP, et al. EASL 2013; Abstract 1413

17 SVR12 (%) QUEST 2: SVR12 Sonuçları 100 p< , , /257 67/134 Simeprevir/PR Pbo/PR48 Manns MP, et al. EASL 2013; Abstract 1413

18 PROMISE

19 Faz 3 Promise: Tedavi deneyimli GT1 hastalarında Simeprevir etkinliği STOP if RGT + N=260 SMV + PR Peg IFN 2a +RBV Peg IFN 2a + RBV N=133 Placebo + PR Peg IFN 2a + RBV

20 Dermografik Özellikler SMV/PR N=260 Pbo/PR48 N=133 Female, % Race, % White Median age, y Median BMI, kg/m IL28B CC, % IL28B non CC, % Median HCV RNA, log10 IU/ml Genotype 1a, % Genotype 1b, % Metavir score, % F0-F1 F2 F3 F Lawitz E et a. DDW, Abstract

21 Proportion of patients SVR12 (%) Promise: Genotip subtipi ile SVR İlişkisi 100 p< ,9 p< , , /257 30/236 43/134 21/288 1a Simeprevir/PR Pbo/PR48 1b

22 Proportion of patients SVR12 (%) SMV Promise: SVR 12 by IL28b Genotype ,7 p<0.001 p<0.001 p< ,4 64, , , CC CT TT Simeprevir/PR Pbo/PR48 18,8 68/77 28/45 362/80 18/43 79/100 21/46 Lawitz E et a. DDW, Abstract

23 Proportion of patients SVR12 (%) Promise: SVR12 yanıtı ile metavir skoru ilişkisi 100 p<0.001 p<0.001 p< ,0 72,7 74, ,8 F0-F2 F3 F4 Simeprevir/PR 20 Pbo/PR48 26,3 68/77 28/45 362/80 18/43 79/100 21/46 Lawitz E et a. DDW, Abstract

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25 Simeprevir: Yan etki gelişimi Parameter, % SMV/PR N=260 Pbo/PR48 N=133 Grade 1 or 2 AE Grade 3 or 4 AE SAE AE leading to SMV/Pbo discontinuation* Most common AEs ( 25% in SMV arm) Fatigue Headache Influenza-like illness Other AEs of interest Rash (any type) Anaemia Pruritus Photosensitivity conditions Increased Bilirubin Neutropenia Lawitz E et a. DDW, Abstract

26 ATTAIN Tedavi deneyimli GT1 HCV hastalarında Simeprevir / telaprevir + PR tedavisinin etkinlik ve güvenlilik faz III çift kör, randomize çok merkezli çalışması

27 ATTAIN: Study design Prior non-responders (null and partial) Week SVR Arm 1 (n=379) SMV 150 mg QD + PR PR Follow-up Arm 2 (n=384) TVR 750 mg TID + PR PR 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 RBV : mg/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

28 ATTAIN: Patient disposition Randomised (N=771) Received study treatment, ITT (N=763) SMV/PR (n=379) TVR/PR (n=384) Prior partial responders (n=145) Prior null responders (n=234) Prior partial responders (n=146) Prior null responders (n=238) ITT, intent to treat; PegIFN, peginterferon; PR, peginterferon α-2a + ribavirin; RBV, ribavirin; SMV, simeprevir; TVR, telaprevir

29 SVR12 (%) ATTAIN: SVR12 (ITT population) 100 SMV/PR TVR/PR 80 Difference in proportions (95% CI)*: -1.1 (-7.8;5.5) P-value for non-inferiority** < % 54.7% / /384 *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

30 SVR12 (%) ATTAIN: SVR12 by prior treatment response (ITT population) 100 SMV/PR TVR/PR 80 Adjusted difference % CI: -11.3;5.8* 69.7% Adjusted difference % CI: -9.0;12.0* 68.5% % 46.2% / / / /146 Prior null responders Prior partial responders *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

31 ATTAIN: Yan etki SMV/TVR + PR SMV (n=379) TVR (n=384) Most common AEs ( 25% in SMV/PR or TVR/PR arm), % SMV (n=379) PR TVR (n=384) Kaşıntı Yorgunluk Başağrısı Anemi Bulantı *Permanent stop of at least one drug; AE, adverse event; PR, peginterferon α-2a + ribavirin; SAE, serious AE; SMV, simeprevir; TVR, telaprevir

32 ASPIRE

33 Confidential For internal use only (Incivo team) ASPIRE (TMC435): G1, tedavi deneyimli faz 2b TMC435* + PR PR Follow-up TMC12/PR48 100mg, n= mg, n= 66 TMC435* + PR PR Follow-up TMC24/PR48 100mg, n= mg, n= 68 TMC435* + PR Follow-up TMC48/PR48 100mg, n= mg, n= 65 PR Follow-up Control, n= Weeks *TMC435 either 100 or 150mg QD; PR: 180µg peginterferon alfa 2a mg ribavirin Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1

34 Confidential For internal use only (Incivo team) Patients with SVR24 (%) ASPIRE (TMC435): SVR24 by prior response Phase 2b 100 Relapsers Partial responders Null responders *All TMC435 duration pooled 9 n=27 n=79 n=79 n=23 n=68 n=69 n=16 n=50 n=51 PR48 TMC435 TMC435 PR48 TMC435 TMC435 PR48 TMC435 TMC mg* PR48 150mg* PR48 100mg* PR48 150mg* PR48 100mg* PR48 150mg* PR Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1

35 PILLAR Tedavi naif sirotik olmayan hastalar Genotip 1 Faz II SMV+PR.SVR %75-86 PR..SVR %65

36 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

37 HELIX-1

38 HELIX-1: Çalışma dizaynı Tedavi naif GT1 ve 4 hastalarında Samatasvir (IDX719)+SIM+RB faz II çalışması N=93 Weeks 1-12 EOT to SVR mg IDX mg simeprevir RBV a 50 mg IDX mg simeprevir RBV a 33 b 100 mg IDX mg simeprevir RBV a mg IDX mg simeprevir RBV a 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. Off-treatment Follow-up 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. 3 Lawtiz E,et al EASL 2014 Poster

39 HELIX-1 : Sonuçları Erken sonuçlara göre samatasvir dozu ile ilişkili SVR4 % oranında saptanmıştır. (25, 50,100,150 mg QD achieved 80, 75, 83,47% SVR4 respectively) Samatasvir 100 mg QD. Lawtiz E,et al EASL 2014 Poster 1222

40 HELIX-1: Özet Ciddi AE gelişmedi Samatasvir: İyi tolere edilmekte Anemi RBV ile ilişkili Simeprevir kullanımına bağlı artan Bilirübin düzeyi. Simeprevir: Güvenli bir profil Lawtiz E,et al EASL 2014 Poster 1222

41 OPTIMIST Optimal Treatment with a simeprevir and sofosbuvir Therapy

42 OPTIMIST 1 Tedavi naif ve deneyimli GT1 sirotik olmayan HCV hastalarında gerçekleştirilen çok merkezli, açık uçlu ve randomize Faz III çalışması. N=300 Stratified by IL28B and HCV genosubtype Wks Baseline SVR12 timepoint SVR Arm 1 N=150 SMV 150 mg qd + SOF 400 mg qd Post Tx Follow up Baseline Arm 2 N=150 SMV 150 mg qd + SOF 400 mg qd PR Post Tx Follow up Primary objective: %80 SVR

43 OPTIMIST 2 Tedavi naif ve deneyimli GT1 sirotik HCV hastalarında gerçekleştirilen çok merkezli, tek kollu Faz III çalışması. N=200 Stratified by IL28B and HCV genosubtype SVR12 timepoint SVR24 Wks Baseline Single Arm SMV 150 mg qd + SOF 400 mg qd Post Tx Follow up Primary objective: SVR %60 PR

44 COSMOS- Cohort 1

45 Çok merkezli, açık etiketli, faz II çalışması

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50 Sonuç Olarak PR kombinasyonlarında yanıt Telaprevir 22,120 kombinayonuna USD + 45,157 benzer TL ancak yan etki daha düşük İnterferonsuz ve/veya PR siz tedaviler mevcut Yan etki profili düşük %20 iskonto 218,799 %40 iskonto 164,099 %60 iskonto 109,333 Abi bunu yuvarlak hesap düz yapalım. X 3 Yanıtsız ve sirotik hastalarda yüksek başarı 273,499 TL Ve en önemlizi U C U Z..(ama artık hayal değil!)