Evidenze II - HCV

Studio sui pazienti infetti da HCV trattati con Telaprevir

RBVpatients infetti (n = 81) con HCV TVR 750 mg ogni 8 ore + †24 settimane genotipo 1* PegIFN alfa-2a + RBV SVR (n = 82) follow-up (N = 334) TVR + †24 settimane SVRPegIFN alfa-2a follow-up (n = 78)*I pazienti hanno ricevuto una dose di carico di TVR 1250 mg o un placebo in base al braccio a cui sono stati †randomizzati. I pazienti devono raggiungere un'RNA di HCV non rilevabile alla settimana 4 (< 10 UI/mL) e all'ultimo test NEJM 2009 prima di interrompere la terapia a 12 o 24 settimane.

Telaprevir nei pazienti naive, genotipo 1 [2] PROVE 2[1] PROVE 1100 P = .004 P = .002 P = .12 P = .02080 6967 P = .20% 61 60 Rate, 60 4641 36 SVR 3540200 T12/PR12 T12/PR24 PR48PR48 T12/PR48 T12/P12 T12/PR12 T12/PR24 (n = 17) (n = 82) (n = 75) (n = 79) (n = 79) (n = 78) (n = 82) (n = 81)

1. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 2. Hézode C, et al. N Engl J Med. 2009;360:1839-1850.

Oggi

Genotipo Durata del trattamento Dose di Ribavirina

1 Peg-IFN+Riba 48 settimane 1000-1200 mg

2 Peg-IFN+Riba 24 settimane 800 mg

3 Peg-IFN+Riba 24 settimane

1. 800mg Peg-IFN+Riba 36 settimane 800-1000mg
2. Telapravir 12+ Peg+Riba 48 1000-1200 mg (24 week)
3. Peg-IFN+Riba 24 settimane* 800 mg
4. Peg-IFN+Riba 36 settimane 800-1000mg

Potential targets and approaches

Potential targets and approaches in the next 5 years

• Immuno-Specific Ribavirin modulators & New IFNs antivirals analogues therapeutic vaccines

Potential antiviral targets

Potential targets and approaches in the next 5 years

• Antiviral targets
• C E1 E2/NS1 NS2 NS3 NS4A NS4B NS5A NS5B ’5 ’3 Internal RNA Envelope Signal Serine protease/ RNA dependent ribosomal binding glyco- peptide helicase RNA polymerase entry site site proteins NEJM 2009 p<0.02 p<0.002 NEJM 2009 NEJM 2009 NEJM 2009 NEJM 2009 NEJM 2009 2011…

Genotype 1 AI

• Telapravir 12+ Peg+Riba 48 (24 week)

Genotype 2 24 weeks (AI)

Genotype 3 24 weeks (AI)

Genotype 3 and low viral load 12 weeks (BI)

24 weeks (BI)

Genotype 3 and high viral load or 48

weeks (BIII)EASL 2008: Focus on Investigational HCV Agents

PROVE 1: Telaprevir + PegIFN/RBV inTreatment-Naive HCV GT 1 Patients

Randomized, placebo-controlled, phase II trial

New molecules in development

(Roche) Phase II

Valopicitabine (Idenix) Phase II

Polymerase A-837093 (Abbott) preclinical

(Non-Nuc.) HCV-796 (ViroPharma/Wyeth) Phase II

Protease ITMN-191 (Intermune/Roche) Phase I

Telaprevir (Vertex/J&J) Phase II

SCH 503034 (Schering-Plough) Phase II

Robust antiviral effect of R1626

Treatment Follow-up

decrease 1 Placebo

500 mg bid

0 1500 mg bid

3000 mg bid

baseline -1)10 4500 mg bid

(log -2 Mean decrease = 1.2 log 10

RNA from -3 Mean decrease = 2.6 log 10

HCV -4 Mean decrease = 3.7 log 10

Mean -5 0 5 10 15 20 25 30

Study day– 8/9 BQL (<600 IU/mL) and 5/9 PCR negative (<50 IU/mL) at 4500 mg bid dose

Roberts S, et al. 57th AASLD 2006; Abstract LB2

PEG-INF alfa-2a plus VX-950: rapidviral load decline without viral rebound

Genotype 1, treatment- PEGASYS alone (n=4)

naive patients VX-950 alone 750 mg TID (n=8)

PEGASYS + VX-950 750 mg TID (n=8)

0from –1change )10(log –2RNA baseline –3 6 of 8 patients withundetectable

HCV –4 HCV RNA within14 days

Mean –5–6 5 10

1. Treatment day: 150
2. Reesink H, et al. 41st EASL 2006; Abstract 737
3. EASL 2008: Focus on Investigational HCV Agents

PROVE 1: Response Rates (ITT)

1 subject in the T12/PR24 arm did not meet RVR criterion, completed 48 weeks of treatment, and had an SVR, but was not counted as a responder in this analysis

*HCV RNA < 10 IU/mL.

†Only subjects who met the RVR criterion and stopped at 12 or 24 total weeks of treatment.

McHutchison J, et al. EASL 2008. Abstract 4. clinicaloptions.com/hep

EASL 2008: Focus on Investigational HCV Agents

PROVE 1: AEs Associated With TVR

Gastrointestinal events, skin events (rash, pruritus), and anemia more frequent in TVR treatment arms

- Moderate and severe rash more frequent

in TVR-based treatment arms– Incidence and severity of other AEs similar vs peginterferon alfa-2a and ribavirin alone

Cumulative discontinuation due to AEs by Week 12 – TVR treatment arms: 18%

Peginterferon alfa-2a and ribavirin only: 4%

Hemoglobin levels lower in TVR arms for first 12 Weeks

McHutchison J, et al. EASL 2008. Abstract 4. clinicaloptions.com/hep

Epatite cronica da HCV

Goals della terapia

• Eradicazione o marcata riduzione della replicazione virale
• Normalizzazione o miglioramento delle lesioni istologiche
• Riduzione dello sviluppo di cirrosi e di HCC
• Miglioramento della sopravvivenza

Evidenza di successo terapeutico:

• Negativizzazione della viremia
• Normalizzazione delle transaminasi

Definition of Response to treatment

DURING THERAPY

• NR = Non Response
• HCV-RNA pos.(3 mo)

END OF FOLLOW UP(6 or 12 mo. after discontinuation)

• ALT normal SR = Complete Sustained Response
• HCV-RNA neg.
• ALT increased or normal R = Relapse
• HCV-RNA positive

Parametri “on treatment” di risposta

infection and RVR could be treated for 12-16 weeks• patients with genotype 1 infection, low baseline viremia and RVR could be treated for 24 weeks

Meta-analysis of interferon therapy for chronic hepatitis C

6 MU x 6 mo 3 MU x 6 mo

s.response 60 62 n.s.

40 53% 20 28 180 Complete response Sustained response

6 MU x 12 mo 3 MU x 12 mo

<0.005 response p<0.001

60 69 40 54 46% 20 280 Poynard et al., 1995

IFN alpha+Ribavirin

Sustained response in naive patients

αα IFNα -2b 3MU+ Ribavirin

IFNα -2b 3MU for 48 weeks (1-1.2 g/die) for 48 weeks

pts % pts %

Poynard, 98 278 19.0 277 42.6

McHutchinson 98 225 12.8 227 38.3

Total 503 16.3 504 40.6

αPegIFN 2a in patients with chronic hepatitis C

Sustained response in naive patients

αPegInterferon 2a for 48 weeks α-IFN 2a 3MU tiw for 48 weeks

39 40 35 26 30 19 25 20 15 7 10 50 Zeuzem 2000 Heathcote 2000

*n° pts: 267 264 87 88

* All patients with histological evidence of cirrhosis

αPegIFN 2b in patients with chronic hepatitis

Sustained response in naive patients:

• α µPegInterferon 2b (1.5 g/kg) for 48 weeks
• α µPegInterferon 2b (1.0µg/kg) for 48 weeks
• α µPegInterferon 2b (0.5µg/kg) for 48 weeks
• α-IFN 2b 3MU tiw for 48 weeks

30 252320 18% 12100n° pts: 304 297 315 303 Lindsay 2001

αPegIFN 2b+Ribavirin in patients with chronic hepatitis C:

• Sustained response in naive patients
• α µPegInterferon 2b (1.5 g\kg)+Ribavirin for 48 weeks
• α → µPegInterferon 2b (1.5→0.5 g\kg)+Ribavirin for 48 weeks
• α-IFN 2b 3MU tiw+Ribavirin for 48 weeks

60 54 47 475040% 3020100n° pts: 511 514 505 Manns 2001

αPegIFN 2a+Ribavirin in patients with chronic hepatitis C:

• Sustained response in naive patients
• α µPegInterferon 2a (180µg)+Ribavirin for 48 weeks
• α-IFN 2b 3MU tiw+Ribavirin for 48 weeks
• α µPegInterferon 2a (180µg) for 48 weeks

566050 4440% 293020100n° pts: 453 444 224 Fried, 2002

Factors

associated with a sustained response

Hepatitis C virus genotype Age < 40 years

other than 1 Lean or normal body

Low Viral load weigth

Low number and genetic Female gender

diversity of viral strains Insufficienza renale cronica

Absence of cirrhosis γ

Low -GT level

Short duration of disease

Norm