Regimenes libres de Interferón - FLSIDA...W12 W24 W48 W72 Guidelines Peg+RBV * Pacientes con RNA VHC bajos y F0-F2 7 7 A real-time PCR-based assay with a LLD

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Regimenes libres de Interferón

Josep Mallolas/Cristina Tural Hospital Clínic/ Hospital Germans Trias I Pujol

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Regimen Comments

1. SOF + P/R (12 weeks) A1 Preferred IFN-containing option

2. SIM + P/R (SIM 12 weeks A/R 24 or 48 weeks) A1

Excluding GT1a with Q80K mutation

3. DCV + P/R (12 or 24 weeks) B1 Excluding GT1a

4. SOF + R (24 weeks) B2 If no other IFN-free option available

5. SOF + SIM [+R] (12 weeks) B1 Most attractive IFN-free combinations as of April 2014

6. SOF + DCV [+R] (12 weeks, naïve or 24 weeks, experienced) B1

2 *With drugs approved by EMA before end of 2014 1EASL Recommendations on Treatment of Hepatitis C,

April 2014. Available at http://www.easl.eu/

EASL HCV Guidelines 2014: Genotype 1

3

Regimen Comments 1. SOF + R (12 weeks, 16-20 weeks cirrhotic) A1 Best option

2. SOF + P/R (12 weeks) B1 For cirrhotic, especially treatment-resistant patients

3 *With drugs approved by EMA before end of 2014


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Regimen Comments

1. SOF + P/R (12 weeks) A2 Most efficacious and shorter duration

2. SOF + R (24 weeks) A2 Sub-optimal in treatment-experienced cirrhotics

3. SOF + DCV [+R] (12 weeks, naïve or 24 weeks, experienced) B1 Attractive IFN-free option



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Regimen Comments

1. SOF + A/R (12 weeks) B1 Most efficacious and easy IFN option

2. SIM + A/R (SIM 12 weeks A/R 24 or 48 weeks) B1

3. DCV + A/R (12 or 24 weeks) B1

4. SOF + R (24 weeks) C2 For IFN-intolerant or IFN-ineligible

5. SOF + SIM [+R] (12 weeks) B2 Most attractive options but lack data 6. SOF + DCV [+R] (12 weeks, naïve or

24 weeks, experienced) B2



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HCV-RNA neg

HCV-RNA pos

> 2 log drop

in HCV-RNA

< 2 log drop

in HCV-RNA

HCV-RNA neg

HCV-RNA pos

G2/3

G1/4

Stop

Stop

G2/3

G1/4

24 weeks therapy *

48 weeks therapy

72 weeks therapy

W4

W12

W24

W48

W72

Guidelines Peg+RBV

* Pacientes con RNA VHC bajos y F0-F2

7 7

A real-time PCR-based assay with a LLD <15 IU/ml A1

What method should be used to monitor efficacy?

How frequently should measurements occur

1.  SOF + A/R (12 weeks): at baseline, weeks 4 and 12, and 12 or 24 weeks after treatment A2

2.  SIM + A/R (SIM 12 weeks A/R 24 or 48 weeks): at baseline, weeks 4, 12, 24 and 48, and 12 or 24 weeks after treatment A2

3.  DCV + A/R (12 or 24 weeks): at baseline, week 4, 10 and 24, and 12 or 24 weeks after treatment A2

4.  IFN-free regimens (12 or 24 weeks): at baseline, week 2 (adherence), weeks 4, 12 or 24, and 12 or 24 weeks after treatment A2 1EASL Recommendations on Treatment of Hepatitis C,

April 2014. Available at http://www.easl.eu/

EASL HCV Guidelines 2014: How should patients be monitored ?

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Regimen GT1a

GT1b

GT2 GT3 GT4 GT5/

GT6

SOF + R + + + + + + SOF + P/R + + + + + + DCV + P/R + +

SIM +P/R + Except Q80K + +

SOF + DCV (+R) + + + + SOF + SIM (+R) + + +


SUMMARY OF DRUG COMBINATIONS

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Current and near future scenario in Interferon –free therapies

SOFOSBUVIR ( SOVALDI ) SIMEPREVIR ( OLYSIO )

DACLATASVIR ( DAKLINZA ) ABT-450/rtv +ABT-267 (ABT-450/rtv+ OMBITASVIR+DASABUVIR) +ABT-333 MK-5172+ MK-8742

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Situación Regulatoria y de Acceso

•  Desde Junio 2013 el acceso a Daclatasvir (DCV) es posible en España para pacientes con Hep C crónica con cualquier Genotipo, sin otras opciones terapéuticas y en riesgo vital o de descompensación inminente a través deun programa de Uso Compasivo.

•  DCV fue aprobado por la EMA el pasado 22 de Agosto 2014 con el nombre de Daklinza. Actualmente se encuentra en proceso de negociación de precio & reembolso en España.

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MECHANISM OF ACTION

•  Possible modes of action for NS5A inhibitors

–  Inhibitors could act at several stages of the viral life cycle

–  Block NS5A function(s) involved in active replication complexes

–  Disrupt higher order multimers of NS5A, and thereby inactivate a replication complex

–  Alter subcellular localisation of NS5A from endoplasmic reticulum to the surface of lipid droplets

Gao M. Curr Opin Virol. 2013;3:514–20

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PAN-GENOTYPIG COVERAGE

•  Potent NS5A inhibitor with pan-genotypic coverage (EC50: 9 to 146 pM in vitro)

1. Gao M, et al. Nature. 2010;465:96; 2. Fridell RA, et al. Hepatology. 2011;54:1924; 3. Fridell RA, et al. J Virol. 2011;85:7312; 4. Wang C, et al. Antimicrob Agents Chemother. 2013;57:611; 5. Wang C, et al. Antimicrob Agents Chemother. 2012;56:1588.

GT EC50

1a (H77) 50 ± 13 pM

1b (Con1) 9 ± 4 pM

2a (JFH) 71 ± 17 pM

3a 146 ± 34 pM

4a 12 ± 4 pM

5a 33 ± 10 pM 0

2000

4000

6000

8000

M28

T Q

30H

Q

30R

L3

1M

L31V

Y9

3C

L31V

Y9

3H

L31M

-Y93

H

F28S

L3

1M

C92

R

Y93H

A

30K

L3

1F

Y93H

R

30G

R

30H

R

30S

L30H

Y9

3H

Y93R

Fold

resi

stan

ce

GT 1a1 GT 45 GT 23 GT 1b2 GT 34

In vitro resistance profile In vitro potency1

* Data derived from hybrid replicons EC50 = Half maximal effective concentration

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Multiple daclatasvir doses: Rapid and potent HCV suppression in GT1a and GT1b patients

Nettles RE, et al. Hepatology. 2011;54:1956–65.

Mean change from baseline in log10 HCV RNA

n=4 for each dosing cohort

Time (Days)

1 mg

10 mg 30 mg

60 mg

30 mg BID

100 mg

log 1

0 HC

V R

NA

-6

-5

-4

-3

-2

-1

0

1

-1 1 2 3 4 5 7 9 11 14

placebo

GT1a

placebo

1 mg

30 mg BID

10 mg

100 mg

1mg 10mg 30mg 30mg BID 60mg 100mg

GT1b

Time (Days) -1 1 2 3 4 5 7 9 11 14

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DCV –CLINICAL PROGRAMME

COMMAND

HALLMARK

UNITY

ALLY

2011 2012 2013 2014 2015

FOURward

GT1 Naïve ethnicity (DCV+P/R Af -Am, Latino, Caucasian, n=230) GT1 Naïve HIV co-infection (DCV+P/R, n=300) GT4 Naïve (DCV+P/R, n=120)

GT1 Naïve (DCV+P/R v TVR+P/R, n=600)

GT1/4 QUAD NR (DCV+ASV+P/R, n=390)

GT1b DUAL DCV/ASV Naïve/NR/Intolerant (n=725)

GT1b DUAL DCV/ASV Japan (n=200)

GT1b DUAL DCV/ASV Asia Inel/Intol (n=150)

GT1/4 DCV 3DAA Naïve/NR (n=306)

GT1 DCV 3DAA FDC (non-cirrhotic, n=400)

GT1 DCV 3DAA FDC (cirrhotic, n=400)

GT1 DCV 3DAA FDC Naïve/Exp (n=160)

GT1 DCV 3DAA / DUAL Japan (n=276)

GT1-6 DCV+SOF cirrhosis / post-transplant (n=110)

GT1-6 DCV+SOF HIV co-infection (n=200)

GT3 DCV+SOF (n=150) GT1 (naïve non-cirrhotic) 3DAA+SOF (n=30)

P/R = Peginterferon + ribavirin; NR = null-responder

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Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection: Study AI444-040

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DCV + SOF ± RBV study design

•  Objective: Assess the efficacy and safety of DCV + SOF ± RBV in treatment-naïve GT1, 2, or 3 patients and GT1 TVR or BOC failures

•  Primary endpoint: SVR12 following 12 or 24 weeks of treatment

Sulkowski MS, et al. N Engl J Med. 2014;370:211–21.

n=41

n=15

n=14 C: DCV + SOF

E: DCV + SOF + RBV Follow-up

n=41

n=15

A: 7-d lead-in SOF, then DCV + SOF Follow-up

Follow-up

Follow-up

Follow-up

G: DCV + SOF

H: DCV + SOF + RBV

Week 24 SVR12

Week 12 SVR12

Chronic HCV GT2/3 naïve

(n=44)

n=16 Follow-up

D: DCV + SOF Follow-up

F: DCV + SOF + RBV Follow-up

n=14

B: 7-d lead-in SOF, then DCV + SOF

n=14

Follow-up

Week 24 SVR12

I: DCV + SOF Follow-up

J: DCV + SOF + RBV Follow-up

n=21

n=20

Chronic HCV GT1, TVR or BOC

failure (n=41)

7dLI

7dLI

7-d lead-in (7dLI): groups A and B received 7 days of SOF monotherapy prior to DCV + SOF

Chronic HCV GT1 naïve

(n=126)

LI = lead-in

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100% 100% 100% 100% 95%

0

20

40

60

80

100 a

A LI SOF,

DCV + SOF

H DCV

+ SOF + RBV

J DCV

+ SOF + RBV

C DCV

+ SOF

E DCV

+ SOF + RBV

G DCV

+ SOF

I DCV + SOF

24 weeks treatment

naïve

HC

V R

NA

<LLO

Q

patie

nts,

%

Patients achieving SVR12

SVR12 primary endpoint (mITT) for GT1 patients


15 15

14 14

41 41

39 41

15 15

12 weeks treatment

naïve

100% 95%

21 21

19 20

24 weeks PI failures

b

GT1a - 98% (129/132) GT1b - 100% (35/35)

•  aOne patient with missing data at post treatment week 12, who achieved SVR24, and 1 patient was lost to follow-up after achieving SVR4

•  bOne patient with missing data at post treatment week 12, who achieved SVR24

mITT = modified intent-to-treat

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D DCV

+ SOF

F DCV

+ SOF + RBV

HC

V R

NA

<LLO

Q

patie

nts,

%

88% 100%

86%

0

20

40

60

80

100

Patients achieving SVR12

SVR12 primary endpoint (mITT) for GT2/3 patients

Sulkowski et al. N Engl J Med. 2014;370:211–21.

12 14

14 14

B LI SOF,

DCV + SOF

24 weeks treatment naïve

a

HC

V R

NA

<LLO

Q

patie

nts,

%

92% 89%

0

20

40

60

80

100

24 26

16 18

GT2 DCV + SOF ±

RBV

24 weeks treatment naïve

GT 2 and 3 combined GT 2 and 3 analysed separately

•  aOne patient with missing data at post-treatment week 12, who achieved SVR24, and 1 patient was lost to follow-up

GT3 DCV + SOF ±

RBV

14 16

a

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Adverse events


Treatment-naïve patients Prior TVR or BOC failures

Treatment duration 24 weeks 12 weeks 24 weeks Patients with event, n

(%) A and B Lead-In SOF,

DCV + SOF

(n=31)

C and D DCV + SOF

(n=28)

E and F DCV + SOF

+ RBV

(n=29)

G DCV + SOF

(n=41)

H DCV + SOF

+ RBV

(n=41)

I DCV + SOF

(n=21)

J DCV + SOF

+ RBV

(n=20)

Any AE 25 (81) 26 (93) 26 (90) 38 (93) 38 (93) 16 (76) 20 (100)

AE occurring in ≥25% in any groupa

Fatigue Headache Nausea

9 (29) 5 (16) 5 (16)

14 (50) 8 (29) 9 (32)

9 (31) 11 (38) 9 (31)

16 (39) 14 (34) 8 (20)

15 (37) 9 (22) 8 (20)

6 (29) 7 (33)

0

9 (45) 7 (35) 2 (10)

Discontinuation due to AEb

0 1 (4) 1 (3) 0 0 0 0

SAEc 2 (6) 4 (14) 2 (7) 1 (2) 0 0 1 (5)

aAll events listed were mild or moderate in intensity. bFibromyalgia in 1 patient and stroke in 1 patient; both had a sustained virologic response. c1 case each of gastroenteritis, colitis, stroke, acute renal failure from dehydration that resolved with administration of fluids, forearm fracture, anxiety and pleuritic pain, exacerbation of psoriasis, and hypokalemia; Five events of overdose (extra study medication doses), classified as SAEs, are not included in the table; no clinically significant effects were reported from any of the overdoses.

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Regimen •  DCV 30 mg QD (low dose)† +

SMV 150 mg QD ± RBV 1000–1200 mg/d

•  GT 1b: Patients who complete 12 weeks re-randomized to stop or continue treatment to Week 24

•  GT 1a: 24 weeks of treatment

Patients N=168

•  Treatment-naive or prior null responders with GT 1b infection –  Cirrhotic patients included (n = 26)

•  Exploratory cohort of 21 patients with GT 1a

Countries USA, Argentina, France,

Germany, Hungary, Spain

Status Completed

†DCV dose based on PK data in healthy volunteers showing a 2-fold increase in DCV (60 mg) exposure when dosed in combination with SMV (150 mg). SMV, simeprevir. Ongoing collaboration with Janssen Research & Development, LLC. www.clinicaltrials.gov NCT01628692; Zeuzem et al. CROI 2014, oral 28LB.

LEAGUE-‐1 (AI444-‐062): phase 2, randomized, open-‐label study of DCV + SMV ± RBV

Week 48 Week 24 Week 12

DCV + SMV + RBV

DCV + SMV + RBV

Week 0

DCV + SMV + RBV

DCV + SMV

Ran

dom

ize

1:1

DCV + SMV

DCV + SMV + RBV

Re-randomization of Week 12 completers

Naive: 53

Null: 23

N

Naive: 51

Null: 20

Null:

9

GT 1b

GT 1a (exploratory)

Naive: 12

Follow-up

Primary endpoint: SVR12

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LEAGUE-‐1: SVR12

aObserved SVR12 includes all patients with HCV RNA data at posttreatment Week 12. bAll patients who received ≥ 1 dose of study medication; patients with missing data at posttreatment week 12 were considered failures.

SMV, simeprevir.

Zeuzem et al. CROI 2014, oral 28LB.

GT 1b:

•  Comparable SVR in treatment-naive patients and prior null responders

•  15 virologic breakthroughs •  6 posttreatment relapses

GT 1a:

•  Treatment-naive: SVR12 67% (8/12)b

•  Null responders: offered addition of peginterferon due to high virologic breakthrough

–  All 9 patients analyzed as non-SVR

DCV + SMV

DCV + SMV + RBV

GT 1b SVR12 (observed)a

Naive Null

90 79 83

95

0

20

40

60

80

100

Pat

ient

s w

ith S

VR

12, %

SVR12, % (mITT)b 85

75 95 65

𝟒𝟓/𝟓𝟎   𝟑𝟖/𝟒𝟔   𝟏𝟓/𝟏𝟗   𝟏𝟗/𝟐𝟎  

24

24 week follow-up

24 week follow-up

24 week follow-up

Programa ALLY ( Fase III)

*Estimated enrolment; 1. http://clinicaltrials.gov/show/NCT02032875; 2.http://clinicaltrials.gov/show/NCT02032888. 3. http://clinicaltrials.gov/show/NCT02032901.

24 week follow-up (n = 60) Group 1: DCV + SOF +RBV (pre-transplant pts)

(n = 50) Group 2: DCV + SOF + RBV (post-transplant pts)

Week 12 ALLY 11 AI444-215 (n = 110)*

Peri-transplant patients

(including cirrhotics)

(GT1, 2, 3, 4, 5, 6)

(n = 50) Group 2: DCV + SOF (tx-naive)

(n = 50) Group 3: DCV + SOF (tx-experienced)

24 week follow-up (n = 100) Group 1: DCV + SOF (tx-naive)

Week 12

ALLY 22 AI444-216 (n = 200)* HIV/HCV

co-infected patients

24 week follow-up

Week 8

(n = 50) Group 2: DCV + SOF (tx experienced)

24 week follow-up (n = 100) Group 1: DCV + SOF (tx naive)

Week 12

ALLY 33 AI444-218 (n = 150)*

GT3 patients

Or transplant 24 week follow-up Therapy up to 12 weeks

3 months-12 years post-transplant

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Ficha Técnica DAKLINZA:

Regímenes recomendados y duración del tratamiento Genotipo del VHC y

población de pacientes* Tratamiento Duración

Genotipo 1 o 4 sin cirrosis Daclatasvir + sofosbuvir

12 semanas Considerar la extensión del tratamiento a 24 semanas en

pacientes con tratamiento previo incluidos aquellos basados en un inhibidor de la proteasa NS3/4A (ver secciones

4.4 y 5.1)

Genotipo 1 o 4 con cirrosis compensada

Daclatasvir + sofosbuvir

24 semanas Se puede considerar una reducción de la duración del

tratamiento a 12 semanas en pacientes previamente no tratados con cirrosis y factores pronóstico positivos

como genotipo IL28B CC y/o baja carga viral basal. Considerar la adición de ribavirina en pacientes con

enfermedad hepática muy avanzada o con otros factores pronóstico negativos como el fracaso a un tratamiento

anterior. Genotipo 3 con cirrosis

compensada y/o tratamiento previo

Daclatasvir + sofosbuvir + ribavirina 24 semanas

Genotipo 4 Daclatasvir + peginterferón alfa + ribavirina

24 semanas de Daclatasvir en combinación con 24-48 semanas de peginterferón alfa y ribavirina.

Si el paciente tiene ARN del VHC indetectable en las semanas 4 y 12 de tratamiento, se deben continuar los 3 componentes del régimen hasta una duración total de 24 semanas.Si el paciente alcanza ARN del VHC indetectable, pero no en las semanas 4 y 12 de tratamiento, se debe discontinuar Daclatasvir a las 24 semanas y continuar con peginterferón alfa y ribavirina hasta una duración total de 48 semanas.

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DCV + SOF: Key summary

1.  Multi-genotype IFN-/RBV/-RTV-free regimen 2.  Overall, 99%* cure rates across genotypes1

3.  100%* cure rates in patients with advanced liver disease (F3/F4)1 4.  100%* cure rates in PI-Failure patients1

5.  Ongoing Phase 3 clinical program (ALLY 1-3) in pre-/post- liver transplant, HIV/HCV coinfection, and GT 3 patients

6.  Well-tolerated with only <1% of patients discontinuing therapy due to adverse events1

7.  Low potential for drug-to-drug interactions with SOF combination making it suitable for patients with high unmet needs2

1. Sulkowski MS, et al. N Engl J Med. 2014;370:211–21. 2. 2014 AI444-040 NEJM Q&A document.

RTV = ritonavir *Excludes SOF lead in arm Cure rate : long-term follow-up studies shown that an SVR corresponds to a definitive cure of HCV infection In more than 99% of cases with interferon-based regimens

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Phase III Approved Phase II

SUSTIVA® and ATRIPLA® HIV

REYATAZ®

HIV

BARACLUDE®

HBV

SUSTIVA®

Paediatric

BMS-663068 HIV attachment inhibitor

ZERIT®

HIV

VIDEX®

HIV Daclatasvir HCV NS5A inhibitor

BMS-791325 HCV NS5B inhibitor

Asunaprevir HCV NS3 inhibitor

HIV

HCV

HBV

Exploratory

BMS-955176 HIV maturation inhibitor

Anti-PD-L1

Atazanavir/Cobicistat

BMS virology key pipeline compounds

Virology

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HCV: Using daclatasvir in multiple combinations

SMV = Simeprevir Schaefer EA and Chung RT. Gastroenterology. 2012;142:1340–1350 Figure adapted with permission from Asselah and Marcellin Liver Int. 2011;31(Suppl 1):68

Daclatasvir, IFN-free regimens

NS5A inhibition + NS3/4 protease inhibition •  DCV + ASV •  DCV + SMV

NS5A inhibition + NS5B polymerase inhibition •  DCV + SOF •  DCV + VX-135

NS5A inhibition + NS3/4 protease inhibition + non-nucleoside NS5B polymerase inhibition •  DCV + ASV + BMS-791325

Documents

Regimenes libres de Interferón - FLSIDA...W12 W24 W48 W72 Guidelines Peg+RBV * Pacientes con RNA VHC bajos y F0-F2 7 7 A real-time PCR-based assay with a LLD