Understudied treatment populations: manage with care. Massimo Puoti Infectious Diseases Dept. AO Ospedale Niguarda Ca Granda Milan, Italy

Transcription

1 Understudied treatment populations: manage with care Massimo Puoti Infectious Diseases Dept. AO Ospedale Niguarda Ca Granda Milan, Italy

2 Understudied treatment populations Cirrhotics Data from registrative studies Data from Real Life Liver Transplant Data from explorative studies Patients on Haemodialysis Data IDU & prison inmates

3 Understudied treatment populations Cirrhotics Data from registrative studies Data from Real Life Liver Transplant Data from explorative studies Patients on Haemodialysis Data IDU & prison inmates

4 Prophesys: Decline in SVR rate with increasing fibrosis severity Patients achieving an SVR (%) n/n METAVIR score FIB-4 score F0 F1 F2 F3 F > > > >3.2 37/63 143/ / /495 26/142 42/62 143/ / /492 29/143 SVR = sustained virological response (HCV RNA <50 IU/mL) at 24 weeks after end of treatment Ferenci P, et al. APASL2012.

5 Mild hepatic impairment has no clinically significant effect on telaprevir pharmacokinetics n=10 healthy volunteers n=10 Child-Pugh A n=10 Child-Pugh B TVR 750mg SD TVR 750mg q8h TVR 750mg SD Day Day 6 TVR concentration (ng/ml) AUC 8h ratio estimate 54% AUC 8h ratio estimate 85% Time (hours) Healthy volunteers Child-Pugh A Child-Pugh B Adiwijaya B, et al. IWCPHT Abstract PK_1

6

7

8

9 RESPOND-2 (boceprevir): SVR by baseline fibrosis stage and prior response to Peg-IFN/RBV Prior relapsers Prior partial responders Prior null responders PR48 BOC RGT BOC44/PR48 SVR (%) Excluded from RESPOND-2 n/n= 12/38 59/79 58/77 2/10 11/22 15/18 2/23 18/38 23/42 0/5 3/10 6/13 Stage No, minimal or portal fibrosis (F0 F2) Bridging fibrosis / cirrhosis (F3/F4) No, minimal or portal fibrosis (F0 F2) Bridging fibrosis / cirrhosis (F3/F4) Bruno S, et al. J Hepatol 2011;54(Suppl. 1):S4

10 REALIZE: SVR by baseline fibrosis stage and prior response Prior relapsers Prior partial responders Prior null responders Pooled T12/PR48 Patients with SVR (%) Pbo/PR48 n/n= 145/ 12/ 53/ / 15 48/ 57 1/ 15 36/ 47 3/ 17 10/ 18 0/ 5 11/ 32 1/ 5 24/ 59 1/ 18 16/ 38 0/ 9 7/ 50 1/ 10 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31

11 REALIZE: AEs leading to study drug discontinuation in pooled TVR arms Cirrhotics (F4) N=139 Discontinuation of all study drugs during TVR treatment phase, n (%) Non-cirrhotics (F0 3) N=391 Any AE Rash* Anemia* Pruritus* 10 (7) 3 (2) 1 (<1) 1 (<1) 17 (4) 1 (<1) 3 (<1) 0 Discontinuation of TVR during TVR treatment phase, n (%) Any AE Rash* Anemia* Pruritus* 21 (15) 8 (6) 4 (3) 2 (1) 46 (12) 14 (4) 11 (3) 2 (<1) *Grouped SSC Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31

12 DAA in PNC-HCV Colombo M 1, Fernández I 2, Abdurakhmanov D 3, Abrão Ferreira PR 4, Strasser SI 5, Urbanek P 6, Moreno C 7, Streinu-Cercel A 8, Verheyen A 9, Iraqi W 10, DeMasi R 11, Hill A 12, Läuffer JM 13, Lonjon- Domanec I 10, Wedemeyer H 14 Treatment of Hepatitis C Genotype 1 Patients with Severe Fibrosis or Compensated Cirrhosis: The International Telaprevir Early Access Program AASLD G-1 HCV TPV/PR 12 wks + PR 36 wks HCV-RNA > (66%) 55% Cirrhotics G 1a (28%) Discontinuation: 8% Deaths: 3 (hepatic failure on PR)

13 DAA in PNC-HCV ITT Colombo M 1, Fernández I 2, Abdurakhmanov D 3, Abrão Ferreira PR 4, Strasser SI 5, Urbanek P 6, Moreno C 7, Streinu-Cercel A 8, Verheyen A 9, Iraqi W 10, DeMasi R 11, Hill A 12, Läuffer JM 13, Lonjon- Domanec I 10, Wedemeyer H 14 Treatment of Hepatitis C Genotype 1 Patients with Severe Fibrosis or Compensated Cirrhosis: The International Telaprevir Early Access Program AASLD 2012 Time on treatment Week 4 Week 12 HCV RNA suppression <25 IU/mL Not detected <25 IU/mL Not detected Naïve (n=124) 86% 59% 88% 85% Relapser (n=171) 80% 63% 87% 85% Partial responder (n=94) 80% 52% 85% 77% Null responder (n=176) 68% 41% 76% 68% Viral breakthrough (n=28) 82% 68% 89% 86% Overall (n=609) 77% 54% 83% 79%

14 DAA in PNC-HCV Saxena V. 1, Catalli L 1, Wayne EM 1, Terrault N 1 Protease-Inhibitor (PI) Triple Therapy (TT) in Cirrhotics with Compensated and Mildly Decompensated Disease: Implications for Wait-Listed Patients Gastroenterology, University of California San Francisco, CA, United States. AASLD Cirrhotics PR + BOC (24%) PR + TPV (76%) On-treatment VR: 40% RVR associated with: Prev. Naive Prev. Relapser Low VL PI: no prediction

15 DAA in PNC-HCV G1 Cirrhosis awaiting LT Verna EC 1, Terry N 2, Lukose T 1, Mentore K 2, Olsen SK 1, Fox AN 1, Laurin J 2, Satoskar R 2, Dove LM 1, Shetty K 2, Brown RS 1 High Early Response Rates with Protease Inhibitor Triple Therapy in a Multicenter Cohort of HCV-Infected Patients Awaiting Liver Transplantation. 1Columbia University Medical Center, New York, 2Georgetown University Hopsital, Washington, DC, United States Triple therapy (PR + TPV or BOC) Mean duration 14 w Mean (range) initial UNOS MELD 9 (7-31) HCC 45% History of ascites or HE 20% N. Completed (4w) - (12 w) 90-70% Time from PI to <LOD 28 days Undetectable HCV-RNA W4 61% W12 86%

16 DAA in PNC-HCV G1 Cirrhosis awaiting LT Verna EC 1, Terry N 2, Lukose T 1, Mentore K 2, Olsen SK 1, Fox AN 1, Laurin J 2, Satoskar R 2, Dove LM 1, Shetty K 2, Brown RS 1 High Early Response Rates with Protease Inhibitor Triple Therapy in a Multicenter Cohort of HCV-Infected Patients Awaiting Liver Transplantation. 1Columbia University Medical Center, New York, NY, United States. 2Georgetown University Hopsital, Washington, DC, United States Triple therapy (PR + TPV or BOC) Time from PI to <LOD 28 days Breakthrough 0 1 NR Discontinuation 1 Rash 1 Neuritis 2 Decompensation (10%) 5 (25%)

17 Understudied treatment populations Cirrhotics Data from registrative studies Data from Real Life Liver Transplant Data from explorative studies Patients on Haemodialysis Data IDU & prison inmates

18 Outcome of HCV post-transplant Gane E LT 2008;14:S36-44.

19 Background: telaprevir increases exposure to immunosuppressants (CYP3A4 & P-gp substrates) Calcineurin Inhbitor Cyclosporine A Tacrolimus C max AUC t 1/2 1.3-fold increase 9.4-fold increase 4.6-fold increase 70-fold increase From hours From hours Significant immunosuppressant dose reductions and prolongation of the dosing intervals will be required Close monitoring of immunosuppressant blood levels, renal function and immunosuppressant related side effects are recommended when co-administered with telaprevir Garg V, et al. Hepatology 2011;54:20 7; Telaprevir EU SmPC

20 Background: boceprevir increases exposure to immunosuppressants (CYP3A4 & P-gp substrates) Calcineurin Inhbitor Cyclosporine A Tacrolimus C max AUC t 1/2 2-fold increase 10-fold increase 2.6-fold increase 17-fold increase From hours From hours Boceprevir co-administration significantly increased blood concentrations of cyclosporine and tacrolimus Therapeutic medicine monitoring is recommended when administering boceprevir with CYP3A4/5 substrates that have a narrow therapeutic window (e.g., tacrolimus, cyclosporine) Individual patients may require additional titration of their immunosuppressant dosage when boceprevir is started or stopped to ensure clinically effective blood levels Hulskotte EGJ, et al. Global Antivir J 2011;7(Suppl. 1):110; Boceprevir EU SmPC

21 Triple Therapy post LT Pooled analysis 8 AASLD abstracts 1 paper 204 post LTx patients Triple treatment 81% Telaprevir 19% Boceprevir Disease stage & previous treatment > 50% with F3-F4 or FCH > 50% experienced Immunosuppression: Cya 62% Tac 32% Syrolimus 6% 48 weeks of therapy Burton J et al. AASLD 2012 #211, Pungpapong S et al. AASLD 2012 #10; Coilly A et al AASLD 2012 #9; Aqel B et al AASLD 2012 # 706; Mantry PS et al. AASLD 2012, # 712; Koning L et al. AASLD 2012 #209; Nar S et al AASLD 2012 #720; Kuo PY et al. AASLD 2012 #719; Werner CR et al Liver Transpl 2012

22 Burton J et al. AASLD 2012 #211, Pungpapong S et al. AASLD 2012 #10; Coilly A et al AASLD 2012 #9; Aqel B et al AASLD 2012 # 706; Mantry PS et al. AASLD 2012, # 712; Koning L et al. AASLD 2012 #209; Nar S et al AASLD 2012 #720; Kuo PY et al. AASLD 2012 #719; Werner CR et al Liver Transpl 2012 Triple therapy post LT 30% stopped 2/3 Futility 1/3 AE 3% Death 20% Breakthrough & Relapse 70/165

23 Triple therapy post LT - Safety Can the patient wait for future therapy Fibrosis Renal function Creatinine clearance > 50 ml/min Watch for AKI Anemia Lowe Ribavirin starting dose 90% of patients required growth factors Transfusion are common Use Lead In regardless of PI Assess Tolerability Adjust PEG IFN & RBV dose Minimize risk of PI discontinuation

24 Triple Therapy post LT Drug-Drug Interactions Stop or switch all non essential meds w/ddi Anti-hypertensive HMG-CoA reductase inhibitors Psych Meds Cya is the easiest Not all patients can be switched Medical instability FCH Renal dysfunction If not managed can risk of rejection Steroids & Syrolimus have unstudied DDI Mycophenolate no DDI

25 DDI with CNI and mtor change over time Triple therapy post LT Drug Drug Interactions Telaprevir most profound effect 1 st 6 weeks: 0-2 lowest dose 2-6 frequent monitoring increased dose >6 Increased stability dosing > 12 Coming off Koning et al. found decreased dose over time with Boceprevir Reasons: Liver failure improvement in FCH Alterations in Absorption Metabolism O Leary et al AASLD 2012 # 707 Koning et al. AASLD 2012 #209

26 Can they wait for the future? FCH geno 1b PEG + RBV w12 HCVRNA 3200 UI/mL Bilirubin 37 mg/dl Re LT FCH PEG + RBV + DACLATASVIR 24 wks + 4 wks PEG + RBV SVR FCH geno 1b Sofosbuvir + Daclatasvir HCVRNA undetectable w4 Ascites resolved w8 24 w SVR Fontana R et al Liv Transpl 2012; Fontana R et al. AASLD 2012 #694

27 Triple therapy post OLT Summary Triple therapy is being used in very selected LT patients Response Rates: Pooled analysis 204 w 12 70% HCVRNA Safety concerns: 3% Deaths Anemia: > 90% growth factors and transfusions Renal function critical AKI Lead in can be helpful DDI Minimize # before starting CNI or mtor may need to be adjusted throughout

28 Unlicensed DAA post LT Emerging data Author Citation DAA Duration/r esult Fontana R Fontana R Ouwerkerk Mathias Liv Transpl 2012 AASLD 2012 # 694 AASLD 2012 # 80 AASLD 2012 #1869 Sofosbuvir + Daclatasvir Dacalatasvi r + P/R Simeprevir Sofosbuvir 24 weeks/svr 24 w + 4/SVR Subjects Impact on Cya 1 FCH pt None Impact on Tac 1 FCH pt none Healthy Volunteers n. 28 Healthy volunteers n. 40 No clinical impact No clinical impact No clinical impact No clinical impact

29 Cirrhotics Understudied treatment Data from registrative studies Data from Real Life Liver Transplant Data from explorative studies Patients on Haemodialysis Data IDU & prison inmates populations

30 Rationale for anti HCV Tx in CKD HCV-infected kidney transplant recipients have reduced long-term patient and graft survivals compared to uninfected controls. Positive anti-hcv serologic status after kidney transplantation is implicated in the pathogenesis of acute glomerulopathy, de novo graft HCV-associate nephropathy, and a higher incidence of chronic allograft nephropathy For HCV-infected patients with CKD who are kidney transplant candidates, antiviral therapy is recommended KDIGO Clinical Practice Guidelines for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidn Intern

31 Severe renal impairment had a limited effect on telaprevir pharmacokinetics 24 volunteers received single dose telaprevir 750mg in two groups Normal renal function (CrCl >80 ml/min, n=12) Severe renal impairment (CrCl <30 ml/min, n=12) TVR concentration (ng/ml ± SD) AUC ratio estimate 121% Time (hours) Healthy volunteers Severe renal impairment n=11 for AUC in renal impairment cohort van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1):S492

32

33 Understudied treatment populations Cirrhotics Data from registrative studies Data from Real Life Liver Transplant Data from explorative studies Patients on Haemodialysis Data IDU & prison inmates

34 DAVIS STUDY 543 drug addicts (mean age 35.3 years, 85.1% males) enrolled from 25 Services for Substance Dependence, scattered all over the country, evaluated for anti-hcv, HCV-RNA, HCV genotype, HBV markers, anti-hdv and anti-hiv during the period April-November Anti-HCV 63.9%. HCV-RNA % of anti-hcv positive. HBsAg 2.8% : 6.7% HBeAg+ 20% anti HDV Vaccinated 30% HBV susceptibles 42.3% HIV positivity 3.1%,

35 Prevalenza anti HCV in nuovi utenti: tassi in decremento

36 DAVIS STUDY : patients characteristics Prevalence of HCV genotype 4: three times higher than that observed in 1996 in a study performed in Central Italy

37 DAVIS STUDY: HCV awareness and anti HCV treatment in drugs users in Italy The majority (87.0%) of anti-hcv positive subjects knew about their hepatic condition. Only 67 out of 347 anti-hcv positive subjects (19.3%) had undergone specific antiviral treatment.

38 Methadone & Telaprevir Effect of Protein Displacement Trends for protein displacement: PK: Total concentrations, Free fraction (%), Free concentrations Clinical: Often described as of minor clinical consequence C135 study: Methadone vs telaprevir Total methadone concentration Bound Unbound No change in concentration (but fraction +26%) Total R-methadone reduced by 31%... Bound Unbound But free R-methadone concentration maintained with no impact on drug craving Methadone alone Methadone + TVR PK: Pharmacokinetics

39 Understudied treatment population: Key Messages Well compensated patients eligible according to SPC: good results safety different from CUPIC Decompensated cirrhosis only in the transplant setting results still preliminary Post LT : according to pre-defined protocols Renal failure: strong rationale studies are needed DU: strong rationale studies are needed 39