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