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Futuros tratamientos de la hepatitis C
Maria Buti Hospital Universitario Valle Hebron and
Ciberehd del Instituto Carlos III Barcelona
Spain
IV Curso para Residentes “Diagnostico y Tratamiento de las Enfermedades Hepáticas”. Barcelona 2013
Future Treatment Aspirations: Overcoming the Barriers to Increase the Chance of Cure for More
Current HCV Care1 Future of HCV Care
North CS, et al. Gen Hosp Psych. 2012. Epub ahead of print
IFN Sparing Regimens
Simpler, shorter duration
Improved tolerability/ adherence
BroadlyEfficacious
Burden of Advanced Disease
Health-Care Costs
Increase Screening
Improved SVR
Preclinical
Phase I
Phase II
Phase III
Filed
Boceprevir Telaprevir
TMC-435
MK7009 ITMN191/R7227
BI201335
BMS650032
GS9256MK5172(MSD)
ABT450(ABT)
ACH2684
BMS 790052AZD-7295
BMS 824393PPI-1301
EDP-239GSK
IDX719MSD
IFN λAlisporivir
Nitazoxamide
Silibinine
Vitamine D
R7128
GS- 7977
BIJapan Tobacco
R0622Medivir
GLS9393
BiocrystBMS189
BMS791325 Filibuvir
GS9190
ANA598
BI201127
Vx222
ABT333ABT072
IDX 375
IDX 184
SCY-835
PPI-461
VBY-376
VX-985
VX-813
GS9451
RG7348
TMC 647055
A837093
VX-916VX-759
CelgosivirBavituximab
Lots of DAAs in Development
AVL-181AVL-192
ACH-2928
GS-5885
Nucleoside NS5B
Polymerase Inhibitors
Nucleotide NS5B Polymerase Inhibitors
Non Nuc NS5BPolymerase inhibitors
NS3/4A Protease inhibitors
NS5A inhibitors
DAA combinations
Others
Cyclophilin
IDX 077
IDX 079
ABT267
Adapted from Bourliere M, et al. Clin Res HepatolGastroenterol. 2011;35(suppl 2):S84-S95.
Farmacos combinados con PegIFN and Ribavirina Pendientes de Aprobacion en Octubre del 2013
Clase Farmaco Dosis Actividad
Analogo de los NucleotidosInhibidor de la
Sofosbuvir Diario Pangenotipic0[1,2]
Inhibidor Proteasa NS3A
Faldaprevir Diario GT 1, 4, 5, 6[3]
Inhibidor Proteasa NS3A
Simeprevir Diario GT 1, 2, 4, 5, 6[4]
1. Gane EJ, et al. N Engl J Med. 2013;368:34-44. 2. Herbst DA. Expert Opin Investig Drugs. 2013;22:527-36. 3. White PW, et al. Antimicrob Agents Chemother. 2010;54:4611-4618. 4. Moreno C, et al. J Hepatol. 2012;56:1247-1253.
Simeprevir+PR en Genotipo 1QUEST-2: SVR
Manns M, et al. EASL 2013. Abstract 1413. Reproduced with permission.
Brazo SMVDuracion TGR
91% of pts en el brazo de SMV con TGR
n/N =
SMV + P/RP/R
Todos 24 sem 48 sem
100
80
60
40
20
0
SVR1
2 (%
)
81
50
86
32
209/257 67/134 202/235 7/22
QUEST-1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance
Jacobson I, et al. EASL 2013. Abstract 1425. Reproduced with permission.
18/31n/N = 5/17188/229
60/113
82
5358
29
SMV + P/RP/R
100
80
60
40
20
0
SVR1
2 (%
)
No Cirrhosis Cirrhosis
105/117 29/56105/147
36/74
71
49
90
52
100
60
20
0
SVR1
2 (%
)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)
1476086
117
74747456
SMV (n) Pbo (n)
Favors Placebo Favors SMV-100 -50 0 50 100
STARTVerso1: SVR12 According to ETS, Genotype, and Fibrosis Level
• 23% of pts with GT 1a HCV had Q80K at baseline; not predictive of SVR12
Ferenci P, et al. EASL 2013. Abstract 1416. Reproduced with permission.
60/87
16/45
143/171
52/86
172/212
30/45
9/16
FDV 120 mg
n/N =
226/259
233/261
194/226
208/233
100
80
60
40
20
0
Patie
nts
(%)
Achieved ETS
SVR12 in ETS Pts
87 89 86 89 100
80
60
40
20
0
SVR1
2 (%
)
GT 1a GT 1b
69
36
84
60
FDV 240 mg Placebo
81
6756
< F3 ≥ F3 F4
ETS defined as HCV RNA < 25 IU/mL at Wk 4 and HCV RNA < 25 IU/mL, target not detected at Wk 8.
NEUTRINO: 12 Wks’ Sofosbuvir + P/R in Treatment-Naive GT 1/4/5/6 HCV Patients
• Open-label, single-arm study of sofosbuvir 400 mg QD + P/R for 12 wks in treatment-naive patients with GT 1/4/5/6 HCV– 17% had cirrhosis; 89% had GT 1, 9% had GT 4, < 1% had GT 5, 2% had GT 6 HCV
Lawitz E, et al. EASL 2013. Abstract 1411. Reproduced with permission.
P/R: pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day
HCV
RN
A <
LLO
Q (%
)
99 9990100
80
60
40
20
0Wk 4 EOT SVR12
321/325 326/327 295/327n/N =
NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level
Lawitz E, et al. EASL 2013. Abstract 1411. Reproduced with permission.
SVR1
2 (%
)
92
80
100
80
60
40
20
0No
CirrhosisCirrhosis
252/273 43/54
SVR12 According to Fibrosis Level
SVR1
2 (%
)
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 =
Summary of Safety Findings From Phase III Trials
• Greatly improved Hb profile with simeprevir and faldaprevir vs boceprevir/telaprevir with no significant increase over pegIFN/RBV[5-7]
• Simeprevir[5,6]
– Generally well tolerated; no added safety signals with triple therapy
• Faldaprevir[7]
• Generally well tolerated (clinically benign and transient bilirubin increases with 240 mg dose; higher incidence of gastrointestinal events and rash)
• Sofosbuvir[1-4]
– Generally well tolerated; low rates of grade 3/4 AEs, serious AEs, and treatment discontinuation due to AEs; improved profile with SOF/RBV vs pegIFN/RBV
1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. 5. Jacobson I, et al. EASL 2013. Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract 1416.
Summary of Resistance Findings From Phase III Trials
• Sofosbuvir[1-4]
– No S282T mutations identified; other NS5B genetic variants not associated with change in phenotypic susceptibility
• Simeprevir[5,6]
– Baseline Q80K polymorphism present in 41% of patients with GT 1a HCV and associated with lower SVR12 rate in QUEST-1[5]
– Emergent NS3 protease mutations in > 90% of patients without SVR (GT 1a: R155K alone, with mutations at positions 80 and/or 168; GT 1b: most common mutation D168V, Q80R + D168E)[5,6]
• Faldaprevir[7]
– Baseline Q80K present in 23% of patients with GT 1a HCV but not associated with SVR12 rate
1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. 5. Jacobson I, et al. EASL 2013. Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract 1416.
E1C E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B
Viral targets Host targets
HCV Drugs in Development in All Oral Regimens
**On clinical hold, Idenix press release; **On clinical hold, Novartis press release
NS3 NS5A NS5B Cyclophilin A
PHASE IIIABT-450/r ABT-267
Non-nucleoside analogueABT-333
* 8 patients with SVR12 have not returned for >24 weeks and are counted as virologic failures for SVR24; 3 patients relapsed between SVR12 and SVR24.
Trea
tmen
t-na
ïve ABT-450 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333
ABT-450 ABT-267 RBV
NABT-450 ABT-267 ABT-333 RBV
Wk 0 Wk 8 Wk 12 Wk 24
80
79
79
79
80
41
Regimen/Duration
Nul
l Re
spon
der ABT-450 ABT-267 RBV
ABT-450 ABT-267 ABT-333 RBV
45
45
43 ABT-450 ABT-267 ABT-333 RBV
SVR12
%SVR24*
%Breakthrough/
Relapse
89 88 0 / 10
85 83 1 / 4
91 89 1 / 8
90 87 1 / 5
99 96 0 / 1
93 90 0 / 2
89 89 0 / 5
93 93 3 / 0
98 95 1 / 0
AVIATOR Study: ABT-450/r, ABT-267, ABT-333 +/- RBV in Non-Cirrhotic, Naïve and Null Responders
Kowdley K, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 3.
N = 571
AVIATOR: Safety
Grade 3 event, n
Pooled(N =247)
Treatment-Naïve (N =159)
Null Responders(N = 88)
ALT >5x – 20x ULN 1 1 0
AST >5x – 20x ULN 0 0 0
Alkaline Phosphatase >3x – 20x ULN 0 0 0
Total bilirubin > 3x – 10xULN 6 4 2
Hemoglobin < 8.0 – 6.5 g/dL 0 0 0
Grade 4 event, nALT > 20x ULN 0 0 0
AST > 20x ULN 0 0 0
Alkaline Phosphatase > 20x ULN 0 0 0
Total bilirubin > 10x ULN 0 0 0
Hemoglobin < 6.5 g/dL 0 0 0
Kowdley K, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 3.
Note: Value must also be more extreme than the baseline value
3 DAAs + RBV
E1C E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B
Viral targets Host targets
HCV Drugs in Development in All Oral Regimens
**On clinical hold, Idenix press release; **On clinical hold, Novartis press release
NS3 NS5A NS5B Cyclophilin A
Faldaprevirnon-nucleoside analogueBI-207127,
SOUND-C2: SVR12 by HCV GT-1 subtype and IL28B genotype
Zeuzem et al., J Hepatol 2012;56(Suppl.2):S45 (Abstract 101)
Series10
20
40
60
80
100
75
32
9184
1a non-CC1a CC 1b non-CC1b CC
6/8 7/22 10/11 31/37
SVR1
2 (%
)
Faldaprevir 120 mg QD, deleobuvir 600 mg BID and RBV for 28 weeks:
Adverse Events and discontinuationsNumber (%) of patients
TID16W(n=81)
TID28W(n=80)
TID40W(n=77)
BID28W(n=78)
TID28W, no RBV(n=46)
D/C due to AEs 4 ( 4.9) 10 ( 12.5) 19 ( 24.7) 6 ( 7.7) 5 ( 10.9)
Photosensitivity AEs Moderate 4 (5) 3 (4) 6 (8) 0 0 Severe 0 1 (1) 2 (3) 0 0 Jaundice AEs Moderate 2 (3) 6 (8) 3 (4) 2 (3) 0 Severe 0 0 0 0 0 Rash AEs Moderate 2 (3) 2 (3) 2 (3) 0 4 (9) Severe 1 (1) 0 1 (1) 0 0Vomiting AEs Moderate 4 (5) 10 (13) 3 (4) 3 (4) 2 (4) ALT/GPT
Grade 3 1 (1) 0 0 2 (3) 0BilirubinGrade 3 33 (41) 15 (19) 20 (26) 20 (26) 6 (13)Grade 4 4 (5) 10 (13) 5 (6) 10 (13) 0
E1C E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B
Viral targets Host targets
HCV Drugs in Development in All Oral Regimens
**On clinical hold, Idenix press release; **On clinical hold, Novartis press release
NS3 NS5A NS5B Cyclophilin A
Ledipasvir (GS-5885)
Nucleos(t)ide Analogue
Sofosbuvir
Non-NucsGS-9669
ELECTRON Study: Sofosbuvir + Ledipasvir (NS5A )or GS-9669 (NonN NS5B) + RBV: 12 week Regimens in GT1
non cirrhotic
SOF + RBV SOF + LDV + RBV SOF + GS-9669 + RBV
Naïve(n=25)
Null(n=10)
Naïve(n=25)
Null(n=9)
Naïve(n=25)
Null(n=10)
Week 1 8/25 (32) 1/10 (10) 11/25 (44) 0/9 (0) 3/25 (12) 0/10 (0)
Week 2 17/25 (68) 7/10 (70) 22/25 (88) 4/9 (44) 15/25 (60) 2/10 (20)
Week 4 25/25 (100) 10/10 (100) 25/25 (100) 8/9 (89) 23/25 (92) 10/10 (100)
EOT 25/25 (100) 10/10 (100) 25/25 (100) 9/9 (100) 25/25 (100) 10/10 (100)
SVR4 22/25 (88) 1/10 (10) 25/25 (100) 9/9 (100) 23/25 (92) 10/10 (100)
SVR12 21/25 (84) 1/10 (10) 25/25 (100)† 9/9 (100) 23/25 (92) 3/3
Patients with HCV RNA <LOD* over time, n/N (%)
Gane E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 14.
* Analyzed by TaqMan® HCV Test 2.0 with limit of detection (LOD) of 15 IU/mL.† Includes 1 patient who stopped all treatment due to a serious adverse event (AE) at Week 8; this patient subsequently achieved SVR12.EOT, end of treatment; SVR4, sustained virologic response 4 weeks after EOT.
No cirrhosis Cirrhosis No cirrhosis Cirrhosis0
20
40
60
80
100 9891
61
34
82
62
71
30
SOF + RBVPEG + RBV
SVR1
2 (%
)
5859
4454
1011
813 89
14599
139
1338
1137
Genotype 2 Genotype 3E. Gane et al, Abstract 5. EASL, April 2013; Lawitz et al., N Engl J Med 2013. DOI: 10.1056/NEJMoa1214853
FISSION study SOF+RBV 12 wksSVR12 results by Genotype and Fibrosis
96 100
6078
0
20
40
60
80
100
37
63
19
61
0
20
40
60
80
100
6/10 5/26
FUSION Study: Treatment-experienced, Genotype 2 or 3 Patients SVR12 by HCV Genotype/Cirrhosis
SVR1
2 (P
erce
ntag
e)
25/26 7/923/23 14/38 14/2325/40No cirrhosis
SOF + RBV 12 weeks SOF + RBV 16 weeks
No cirrhosisCirrhosis Cirrhosis
GT 2 GT 3
Nelson D, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 6.
GT3= 62%, Relapse 75%
POSITRON Study: Interferon Ineligible/Intolerant Genotype 2 or 3 Patients
SVR12 by Cirrhosis Status
Series10
20
40
60
80
100 92 94
68
21
GT 2 GT 3
SVR1
2 (P
erce
ntag
e)
85/92 16/17 57/84 3/14
No cirrhosis Cirrhosis
Jacobson I, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 61.
Futuro Tratamiento hepatitis C
Tratamiento oral
Actividad antiviral en todos los genotipos
Duracion más corta
Problablemente sin ribavirina
Seguridad y Eficacia excelente
No Resistencias
Amplia Aplicabilidad: Coinfeccion, Cirrosis descompensada Trasplantados, Enfermedad renal terminal