Boceprevir e Telaprevir nel cirrotico e nel trapiantato

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1 Boceprevir e Telaprevir nel cirrotico e nel trapiantato Bruno Cacopardo Dipartimento di Biomedicina Clinica e Molecolare Università di Catania Paestum (Sa) maggio 2014 Relatore

2 May not need immediate treatment BUT Easier to treat High likelihood of response Greater need for treatment BUT Response to current IFNbased therapy may be impaired Mild disease Cirrhosis

3 CAUTELA

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5 GESTIONE DEL PAZIENTE CON CIRROSI (1) 1. particolarmente complessa a causa dei possibili effetti collaterali anche gravi (A1). 2. I pazienti con cirrosi epatica compensata costituiscono un gruppo di pazienti eterogeneo. Alcune variabili clinico laboratoristiche (conta piastrinica < /mmc e riduzione dei livelli di albuminemia) possono essere utilizzate per identificare i pazienti con malattia piu avanzata e a maggior rischio di sviluppare eventi avversi seri (B2). 3. Una fase iniziale di 4 settimane di duplice terapia con Peg IFN + RBV (inteso come test di tollerabilita) utile per identificare i soggetti con ridotta tolleranza alla terapia Peg IFN + RBV e potenzialmente non in grado di sostenere la triplice terapia (C1). 4. Il paziente cirrotico trattato con triplice terapia deve essere sottoposto a stretta sorveglianza clinica per il pronto riconoscimento degli effetti collaterali e la loro tempestiva gestione (A1). Oltre agli effetti collaterali tipici del trattamento con triplice (anemia, rash cutaneo, ecc.), particolare attenzione va posta al rischio infettivo e a quello di scompenso funzionale della cirrosi (A1). 24 Aprile 2013

6 Outcome, % Telaprevir (N = 292) Boceprevir (N = 205) Serious adverse event Premature discontinuation Hepatic decompensation 2 3 Death* 3 1 Infection (grade 3 or 4) 7 2 *Causes of death: septicemia, septic shock, pneumopathy (2), endocarditis, esophageal varices bleeding. Why are the results different from phase III trials? Higher risk in cirrhotic patients? Study population healthier in phase III trials? Is the population truly compensated cirrhosis? Hezode C, et al. AASLD Abstract 51.

7 CUPIC enrolled treatment-experienced patients with compensated cirrhosis and notable risk factors Patients achieved high SVR rates with TVR or BOC plus pegifn/rbv Patients with cirrhosis who present with significant risk factors require careful monitoring when treated with pegifn/rbv Albumin < 35 g/l Albumin 35 g/l Platelet Count 100,000/mm 3 Platelet Count > 100,000/mm 3 N Complications, n (%) 19 (51.4) 5 (16.1) SVR12, n (%) 10 (25.0) 9 (29.0) N Complications, n (%) 9 (12.2) 19 (6.2) SVR12, n (%) 27 (36.5) 168 (54.9) Fontaine H, et al. AFEF 2013

8 Patients (%) 100 Telaprevir P <.001 < 65 yrs 65 yrs 100 Boceprevir P = P < P = P =.032 P / / / / / / / / / / 44 89/ / 44 Hezode C, et al. AASLD Abstract 1845.

9 Percentage of patients (%) Discontinuation for F3: n=3 (1%) Discontinuation for F4: n=16 (5%) Colombo M et al AASLD 2013

10 Percentage of patients (%) Colombo M et al AASLD 2013 Table TSFAE01b

11 Neutropenia % Anemia % Thrombocytopenia % PEG-IFNalfa + RBV n BOC + PEG+ RBV n * 46* TEL + PEG + RBV n * 52* * P<0.01 vs PR Suddle et al. Hep Int 2014

12 SVR (%) Patients randomized 2:1 to either placebo or eltrombopag + pegifn alfa-2a (ENABLE-1) or placebo or eltrombopag + pegifn alfa-2b (ENABLE-2) Higher platelet counts in eltrombopag arms vs placebo by Wk 2 of treatment, enabling full dose of pegifn to be maintained ENABLE-1: 11,000/µL vs 79,000/µL ENABLE-2: 124,000/µL vs 89,500/µL Placebo Eltrombopag n/n = 14 32/ / ENABLE-1 Afdhal NH, et al. Gastroenterology. 2014;146: P =.0064 P = / / 506 ENABLE-2

13 Renal Impairment at Wk 12 in Pts With Normal Renal Function at Baseline (%) Observational study of 1185 patients with GFR data at baseline Results emphasize that renal function must be assessed during treatment P =.0753 P =.0188 Risk Factor for Renal Insufficiency P Value Age <.001 Hypertension <.001 Diabetes <.05 Cirrhosis > 7 CP < (1/109) PR 4.7 (10/211) BOC PR 6.6 (38/575) TVR PR Mauss S, et al. EASL Abstract 872.

14 Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly increased (p<0.001) for both protease Inhibitors: cautious clinical monitoring should focus also on renal function Virlogeux V et al J Vir Hep 2014

15 Saxena et al Aliment Pharmacol Ther 2014

16 EFFICACIA

17 SVR (%) SVR (%) 100 F0-2 F3/ n/ N = 123/ PR 213/ 319 BOC RGT 211/ 313 BOC n/ N = 9/ 24 14/ PR BOC RGT 22/ 42 BOC 48 Poordad F, et al. N Engl J Med. 2011;364:

18 SVR (%) SVR (%) ADVANCE 1 ILLUMINATE 2 No, minimal or portal fibrosis Bridging fibrosis or cirrhosis No, minimal or portal fibrosis Bridging fibrosis or cirrhosis PR48 T12PR PR48 T12PR T12PR ITT T12PR ITT 18 n/n= 134/ /290 24/73 45/73 294/391 94/ Jacobson IM, et al. N Engl J Med 2011;364: ; 2. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A

19 SVR (%) REALIZE: TVR + PegIFN/RBV in GT1 Previous Relapsers and Nonresponders Previous Relapsers Previous Partial Responders Previous Null Responders Pooled T12/PR48 Pbo/PR n/n = 0 144/ No, Minimal, or Portal Fibrosis 1/ 12/ 53/ 2/ 48/ 2/ 34/ 3/ 10/ / 1/ 24/ 18 15/ 7/ / /9 50 Bridging Fibrosis Cirrhosis Zeuzem S, et al. EASL Abstract No, Minimal, or Portal Fibrosis Bridging Fibrosis Stage Cirrhosis 41 6 No, Minimal, or Portal Fibrosis 39 Bridging Fibrosis / 10 Cirrhosis

20 TEL. SVR12 BOC SVR Relapsers Partial Null 0 Hezode C et al. Gastroenterol 2014

21 SVR (%) F0-4 F4 F3/4 F4 F0-4 F4 F3/4 F Telaprevir Boceprevir Relapsers *Cross-comparison of studies cannot be carried out Null Responders 1. Zeuzem S, et al. N Engl J Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364: Fontaine H, et al. EASL Abstract Fontaine H, et al. AFEF Abstract Vierling JM, et al. DDW Abstract 869c.

22 Saxena et al Aliment Pharmacol Ther 2014

23 % BOC TEL Naive Null Partial Relapse Backus et al Aliment Pharmacol Ther 2014

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27 Biggins SW, Terrault NA. Infect Dis Clin N Am 2006; 20:155

28 Everson et al. Hepatology 2013

29 Everson et al. Hepatology 2013

30 Berenguer M. J Hepatol 2008;49:274-87

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32 % SVR 24 RBV dose red. EPO Eltrombopag Kwo et al. Clin Transplant 2014

33 Prospective multicenter cohort study of 79 pts from 17 European transplant centers Active, chronic GT1 HCV HCV recurrence: F1 or cholestatic hepatitis Pts treated with 1 of 3 regimens (planned duration, 48 wks) P/R lead-in for 4 wks, followed by BOC 800 mg TID + P/R (n = 35) P/R lead-in for 4 wks, followed by TVR 750 mg TID + P/R (n = 19) TVR 750 mg TID + P/R (n = 25) Coilly A, et al. AASLD Abstract 216. Characteristic BOC + P/R (n = 35) TVR + P/R (n = 44) Mean MELD score (SD) 11.0 (4.5) 11.2 (6.8) METAVIR stage, % F F FCH, % 6 16 GT1b HCV, % IL28B CC genotype, % 23 6 Mean HCV RNA, log 10 IU/mL (SD) Previous P/R post-lt, % 6.69 (0.68) 6.54 (0.73) Naive Nonresponse Relapse Breakthrough Mean time from LT, yrs (SD) 5.5 (6.0) 4.3 (4.0)

34 Patients (%) Virologic Outcomes TVR + P/R BOC + P/R 41 Coilly A, et al. AASLD Abstract 216. Reproduced with permission N = EOT SVR12 RBV dose reduction + EPO: 94% Required transfusion: 49% Required GCSF: 19% SAEs, % BOC + P/R (n = 35) TVR + P/R (n = 44) Rehospitalization Acute kidney injury 3 14 Biopsy-proven acute 17 9 rejection Infections FCH only factor independently associated with infection (P =.04) Death 8 7 Fold Increase in CNI at PI Completion BOC + P/R (n = 35) TVR + P/R (n = 44) Tacrolimus Cyclosporine

35 Response (%) Ongoing multicenter, single-arm study Median time since LT: 4.3 yr CTP 7 and MELD 17 40% with cirrhosis 52% severe adverse events (60% anemia, 25% infections,15% rejection Virologic Response Rates Week 4 EOT* SVR12 Charlton MR, et al. EASL 2014.

36 . Twice-Daily Telaprevir in Combination with Peginterferon Alfa- 2a/Ribavirin in Genotype 1 HCV post-transplant patients : Interim Week 12 Safety and Efficacy Results REFRESH STUDY AEs are manageable when T/PR is used with TAC or CsA Anemia was more common than in non-liver transplant patients No moderate, severe, or serious rash reported No rejections, autoimmune hepatitis, or deaths have been reported to date Grade 2 or 3 creatinine toxicity was observed in 12/46 patients. Brown KA et al AASLD 2013