Simeprevir (Olysio)
Doç. Dr. Mustafa Kemal ÇELEN
Dicle Üniversitesi
Cappadocia-25.05.2014
•
•
•
•
•
•
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?
HEKİM PENCERESİ

%0 YAN ETKİ 
?
1) Virus Girişi
2) Soyunma
Proteaz Inhibisyonu
3) Protein Sentezi
4) Ayrılma
8) Re-infeksiyon
5) RNA Replikasyonu
6) Paketleme
7) Olgunlaşma
Simeprevirin Klinik Çalışmaları
Faz 3
Tedavi naif GT1 hastalarında Simeprevir : QUEST-1
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
STOP if RGT +
N=264
SMV + PR
Peg IFN 2a +RBV
Peg IFN 2a + RBV
N=130
Placebo + PR
0
Peg IFN 2a + RBV
12
24
48
Jacobson I et a. EASL 2013, Abstract 1425
Faz 3
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
Jacobson I et a. EASL 2013, Abstract 1425
QUEST 1: SVR12 sonuçları
P<0.001
100
SVR12 (%)
80
80
60
50
40
20
0
210/264
Simeprevir/PR
65/130
Pbo/PR48
Jacobson I et a. EASL 2013, Abstract 1425
QUEST 1: fibroz derecesine göre SVR12
yanıtı
Simeprevir/PR
100
Placebo/PR48
83
78
SVR12 (%)
80
60
60
58
40
29
26
20
152/183
54/90
36/46
6/23
18/31
5/17
0
F0–F2
F3
F4
Jacobson I, et al. EASL 2013: Abstract 1425
QUEST 1: Genotip subtipine göre
SVR12 yanıtı
100
SVR12 (%)
80
90
71
60
52
49
40
20
0
105/147
36/74
Genotype 1a
Simeprevir/PR
105/117
29/56
Genotype 1b
Pbo/PR48
Jacobson I et a. EASL 2013, Abstract 1425
QUEST 1: İlk 12 haftada
yan etki gelişimi
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
Fatigue
40
38
Headache
31
37
Pruritus
21
11
Increased bilirubin*
9
4
Rash (any type)
27
25
Photosensitivity conditions
3
1
Neutropenia
19
11
Anaemia
16
11
Parameter, %
Most common AEs (≥25% in SMV arm, preferred
term)
Other AEs of interest (preferred term)
*Attributed to inhibition of OATP1B1/MRP2 transporter; not associated with elevations of AST, ALT or ALP
Jacobson I et a. EASL 2013, Abstract 1425
QUEST-2
Phase 3
GT 1 naif hastalarda simeprevir:
QUEST 2
STOP if RGT +
N=257
Peg IFN 2a/2b
+RBV
SMV+PR
Peg IFN 2a/2b + RBV
Placebo + PR
N=134
0
Peg IFN 2a/2b + RBV
12
24
48
Manns MP, et al. EASL 2013; Abstract 1413
QUEST 2: SVR12 Sonuçları
p<0.001
100
81,3
SVR12 (%)
80
60
50,0
40
20
0
209/257
Simeprevir/PR
67/134
Pbo/PR48
Manns MP, et al. EASL 2013; Abstract 1413
PROMISE
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
0
Peg IFN 2a + RBV
12
24
48
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
Promise: Genotip subtipi ile SVR İlişkisi
Proportion of patients SVR12 (%)
100
p<0.001
p<0.001
85,9
80
70,3
60
43
40
27,8
20
18/257
43/134
30/236
21/288
0
1a
Simeprevir/PR
1b
Pbo/PR48
SMV Promise: SVR 12 by IL28b Genotype
Proportion of patients SVR12 (%)
100
p<0.001
p<0.001
p<0.001
88,7
78,4
80
64,5
60
52,9
40
33,7
18,8
20
68/77
28/45
362/80
18/43
79/100
21/46
0
CC
CT
Simeprevir/PR
TT
Pbo/PR48
Lawitz E et a. DDW, Abstract ____
Promise: SVR12 yanıtı ile metavir skoru
ilişkisi
Proportion of patients SVR12 (%)
100
p<0.001
p<0.001
p<0.001
82,0
80
74,4
72,7
60
40,8
40
26,3
20
20
68/77
28/45
362/80
18/43
79/100
21/46
0
F0-F2
F3
Simeprevir/PR
F4
Pbo/PR48
Lawitz E et a. DDW, Abstract ____
Simeprevir: Yan etki gelişimi
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
Fatigue
31.9
42.1
Headache
31.9
36.1
Influenza-like illness
29.6
20.3
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
Parameter, %
Most common AEs (≥25% in SMV arm)
Other AEs of interest
16.5
Lawitz E et a. DDW, Abstract ____
ATTAIN
Tedavi deneyimli GT1 HCV hastalarında
Simeprevir / telaprevir + PR tedavisinin etkinlik
ve güvenlilik faz III çift kör, randomize çok
merkezli çalışması
ATTAIN: Study design
SVR12
Prior non-responders
(null and partial)
0
4
12
24
36
48
60
Week
Follow-up
Arm 1
(n=379)
SMV 150 mg QD +
PR
PR
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 :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
72
ATTAIN: Patient disposition
Randomised
(N=771)
Received study
treatment, ITT
(N=763)
SMV/PR (n=379)
Prior partial
responders
(n=145)
TVR/PR (n=384)
Prior null
responders
(n=234)
ITT, intent to treat; PegIFN, peginterferon; PR, peginterferon α-2a + ribavirin;
RBV, ribavirin; SMV, simeprevir; TVR, telaprevir
Prior partial
responders
(n=146)
Prior null
responders
(n=238)
ATTAIN: SVR12 (ITT population)
SMV/PR
100
SVR12 (%)
80
60
TVR/PR
Difference in proportions (95% CI)*: -1.1 (-7.8;5.5)
P-value for non-inferiority** <0.001
53.6%
54.7%
203/379
210/384
40
20
0
*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
ATTAIN: SVR12 by prior treatment response (ITT
population)
SMV/PR
100
SVR12 (%)
80
Adjusted difference -2.8
95% CI: -11.3;5.8*
TVR/PR
Adjusted difference 1.5
95% CI: -9.0;12.0*
69.7%
68.5%
101/145
100/146
60
43.6%
46.2%
40
20
102/234
110/238
0
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
ATTAIN: Yan etki
SMV/TVR + PR
SMV
(n=379)
TVR
(n=384)
PR
SMV
(n=379)
Most common AEs (≥25% in SMV/PR or TVR/PR arm), %
31.1
43.0
37.5
Kaşıntı
TVR
(n=384)
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
ASPIRE
faz 2b
Confidential – For internal use only (Incivo team)
ASPIRE (TMC435): G1, tedavi deneyimli
TMC12/PR48
TMC435* +
PR
PR
Follow-up
PR
TMC435* + PR
Follow-up
100mg, n= 66
150mg, n= 66
TMC24/PR48
100mg, n= 65
150mg, n= 68
TMC48/PR48
0
TMC435* + PR
Follow-up
100mg, n= 66
150mg, n= 65
PR
Follow-up
Control, n= 66
12
24
48
72
Weeks
*TMC435 either 100 or 150mg QD; PR: 180µg peginterferon alfa 2a + 1000-1200mg ribavirin
Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1
Phase 2b
Relapsers
100
Patients with SVR24 (%)
Confidential – For internal use only (Incivo team)
ASPIRE (TMC435): SVR24 by prior response
85
Partial
responders
Null
responders
85
80
75
57
60
46
40
51
37
19
20
9
n=27
n=79
n=79
n=23
n=68
n=69
n=16
n=50
n=51
0
PR48
TMC435 TMC435
100mg* 150mg*
PR48
PR48
PR48
TMC435 TMC435
100mg* 150mg*
PR48
PR48
PR48
TMC435 TMC435
100mg* 150mg*
PR48
PR48
10
10
*All TMC435 duration pooled
Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1
PILLAR
•
•
•
•
•
Tedavi naif sirotik olmayan hastalar
Genotip 1
Faz II
SMV+PR….SVR %75-86
PR…………..SVR %65
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…
HELIX-1
HELIX-1: Çalışma dizaynı
Tedavi naif GT1 ve 4 hastalarında Samatasvir (IDX719)+SIM+RB faz II çalışması
N=93
Weeks 1-12
20
25 mg IDX719
150 mg simeprevir
RBVa
20
50 mg IDX719
150 mg simeprevir
RBVa
33b
100 mg IDX719
150 mg simeprevir
RBVa
20
150 mg IDX719
150 mg simeprevir
RBVa
EOT to SVR24
Off-treatment Follow-up
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.
designed to have N=40(20 subjects with and 20 subjects without ribavirin). Following DSMB review, the RBV -free group was capped at 13
3
subjects and RBV added at first dose to all subjects.
b Originally
Lawtiz E,et al EASL 2014 Poster 1222
8
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.
Lawtiz E,et al EASL 2014 Poster 1222
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
OPTIMIST
Optimal Treatment with a
simeprevir and sofosbuvir
Therapy
OPTIMIST 1
Tedavi naif ve deneyimli GT1 sirotik olmayan HCV hastalarında gerçekleştirilen çok merkezli , açık uçlu ve
randomize Faz III çalışması.
N=300
Wks
Stratified by IL28B and HCV genosubtype
Baseline
Arm 1
N=150
4
12
8
4
8
SMV 150 mg qd + SOF
PR
400 mg qd
16
12
20
------------------- ---Post Tx Follow up-------------------
Primary objective: %80 SVR
SVR24
36
24
-------------------Post Tx Follow up-------------------
SMV 150 mg qd + SOF 400 mg qd
Baseline
Arm 2
N=150
SVR12
timepoint
32
OPTIMIST 2
Tedavi naif ve deneyimli GT1 sirotik HCV hastalarında gerçekleştirilen çok merkezli , tek kollu Faz III
çalışması.
N=200
Baseline
4
8
Wks
Single
Arm
SVR12
timepoint
Stratified by IL28B and HCV genosubtype
SMV 150 mg qd + SOF 400 mg qd
Primary objective: SVR %60
PR
12
16
24
-------------------Post Tx Follow up-------------------
SVR24
36
COSMOS- Cohort 1
• Çok merkezli, açık etiketli, faz II çalışması
Sonuç Olarak…
%20 iskonto… 218,799
• PR kombinasyonlarında%40
yanıtiskonto…
Telaprevir164,099
kombinayonuna
ancak
yan etki daha
22,120
USD + 45,157benzer
TL %60
iskonto…
109,333
düşük
Abi bunu yuvarlak
• İnterferonsuz ve/veya PR’siz
tedaviler
mevcut
hesap
düz…yapalım….
X3
• Yan etki profili düşük
• Yanıtsız ve sirotik hastalarda yüksek başarı
• Ve en önemlizi U C U Z…..(ama artık hayal
değil !)
273,499 TL
Download

Simeprevir (Olysio)