BOCEPREVIR (BOC): EVIDENCE FROM TRIALS

Transcription

1 BOCEPREVIR (BOC): EVIDENCE FROM TRIALS ROME, FEBRUARY 22 nd -25 th, 212 Savino Bruno, MD Department of Internal Medicine A.O. Fatebenefratelli e Oftalmico Milan, Italy

2 Savino Bruno, MD Director of InternalMedicine, Gastroenterologyand Liver Units A.O. Fatebenefratelli e Oftalmico Milan, Italy Il sottoscritto dichiara di aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione Speaking Bureau and advisory Board MSD e che la presentazione contiene discussione di farmaciin studio o ad usooff-label Boceprevir

3 On-treatment response markers according to BOC use: the new lexicon BOC RVR Responsive Poorly responsive Early Late HCV RNA undetectable at wk 4 after Lead-in (LI) HCV RNA drop from baseline >1 log 1 after LI HCV RNA drop from baseline < 1 log 1 after LI HCV RNA undetectable at Wk 8 after BOC addition HCV RNA detectable at Wk 8 after BOC addiction * *LLD = 9 IU/ml, LLQ= 25 IU/ml

4 SPRINT-2 Treatment naive patients

5 SVR rates according to three different arms SVR % / / /363 BOC PR 48 BOC RGT PR Poordad F, et al. NEJM 211

6 SVR rates by week 4 response >1 log decline/undetectable <1 log decline undetectable SVR % PR 48 BOC RGT BOC PR 48 Poordad F, et al. NEJM 211

7 SVR rates by EARLY (week 8 HCV-RNA undetectable) and LATE (week 8 HCV-RNA detectable) response % Patients eligible for short therapy with PR /BOC due to HCV-RNA undetectable at week 8 SPRINT-2 Early Resp Late Resp SVR % Early Resp Late Resp Early Resp Late Resp BOC RGT BOC PR48 Poordad F, et al. NEJM 211

8 SVR rates according to IL-28B* SVR % /64 63/77 44/55 CC CT TT PR48 BOC RGT BOC44/PR48 PR48 BOC RGT BOC44/PR48 PR48 BOC RGT BOC44/PR /37 23/42 23/64 *6% of included patients Poordad F, et al. EASL 211

9 SVR rates according to Genotype (1a vs 1b) SVR % PR BOC RGT BOC/PR 48 Gen 1a Gen 1b

10 Anemia as predictor of SVR 1 9 SVR % PR BOC/PR Hb 1 g/dl Hb<1 g/dl Sulkowski M, et al. EASL 211

11 IL-28B CC Polymorphism as a Predictor of SVR (Multiple Stepwise Logistic Regression Model) Genotype: 1b/Other vs 1a Age 4 vs>4 IL28B Genotype: CC vs. Non-CC BOC/RGT vs PR48 BOC/PR48 vs PR48 P <.1 P =.2 P <.1 P <.1 P <.1 IL28 (CC vs non-cc) was also predictive of SVR in full model with limited covariates (OR = 4.5, p <.1) Baseline HCV-RNA: 4, vs. >4, Only 7-9% of patients had VL 4, P <.1 23 Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the figure. Factors entered but not retained in the model were, region, race, gender, weight, BMI, steatosis, platelets, ALT, statin use, and fibrosis

12 IL28B and fibrosis are no longer an important predictor of SVR when Lead-in Response is considered SPRINT-2 (effect) Odds Ratio (95% CI) p-value BOC/PR48 vs PR48 7. (4.1, 12.) <.1 BOC/RGT vs PR48 6. (3.5, 1.2) <.1 Baseline HCV-RNA: 4, vs. >4, IU/mL 5.8 (1.9, 17.5).2 Log decline in HCV-RNA at TW 4 (continuous variable) 2.6 (2.1, 3.) <.1 Genotype: 1b/others vs 1a 2.3 (1.5, 3.6) <.1 BMI: 25-3 kg/m 2 vs. >3 kg/m (1.4, 3.9).2 BMI: 25 kg/m 2 vs. >3 kg/m (1.1, 3.3).2 Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the table.

13 Impact of severe Fibrosison SVR SVR % F/1/2 F3/4 PR 48 BOC RGT BOC/PR48 Bruno S, et al. EASL 211

14 RESPOND-2 and PROVIDE Treatment experienced patients

15 SVR rates according to three different arms SVR % /161 95/162 17/8 BOC PR 48 BOC RGT PR Bacon BR, et al. NEJM 211

16 SVR rates in prior Relapser, Partial and Null Responders SVR % /28 53/145 16/42 Relapse Partial Null * Bacon BR, et al. NEJM 211 *Vierling J, et al. AASLD 211

17 SVR rates by EARLY (week 8 HCV-RNA undectable) and LATE (week 8 HCV-RNA detectable) response % Patients eligible for short therapy with PR /BOC due to HCV-RNA undetectable at week 8 Early Resp Late Resp RESPOND SVR % Early Resp Late Resp Early Resp Late Resp BOC RGT BOC PR48 Bacon BR, et al. NEJM 211

18 SVR rates according to IL-28B* SVR % CC CT TT PR 48 BOC RGT BOC PR 48 PR 48 BOC RGT BOC PR 48 PR 48 BOC RGT BOC PR 48 *6% of included patients Poordad F, et al. EASL 211

19 SVR rates according to Genotype (1a vs 1b) SVR % PR BOC RGT BOC/PR 48 Gen 1a Gen 1b

20 Anemia as predictor of SVR SVR % PR BOC/PR Hb 1 g/dl Hb<1 g/dl Sulkowski M, et al. EASL 211

21 IL-28B CC Polymorphism as a Predictor of SVR (Multiple Stepwise Logistic Regression Model) BMI: 25 kg/m2 vs >3 kg/m2 Previous Response: Relapser vs Nonresponder.4 P <.1 P <.1 IL28 (CC vs non-cc) was predictive of SVR in full model with limited covariates (OR = 2.2, p=.25) BOC/RGT vs PR48 P <.1 BOC/PR48 vs PR48 <.1 P <.1 Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the figure. Factors entered but not retained in the model were IL28 polymorphism, HCV 1 subtype, race, gender, age, weight, platelets, fibrosis, steatosis, previous treatment (peginterferon alfa-2a vs peginterferon alfa-2b), ALT, baseline viral load, statin use and region

22 IL28B is no longer an important predictor of SVR when Lead-in Response is considered RESPOND-2 (effect) Odds Ratio (95% CI) p-value BOC/PR48 vs PR (6. to 24.9) <.1 BOC/RGT vs PR (4.9 to 19.7) <.1 Previous Response: Relapser vs Nonresponder Log decline in HCV-RNA at TW 4 (continuous variable) 2.3 (1.4 to 3.8) (3. to 9.2) <.1 Model fit using historical treatment response (relapser vs non responder), week 4 response and baseline characteristics Week 4 response (>1 log vs < 1 log decrease in HCV-RNA from baseline) was stronger predictor of SVR than historical treatment response Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the table.

23 Impact of severe Fibrosison SVR SVR % PR 48 BOC RGT BOC/PR48 PR 48 BOC RGT BOC/PR48 F /1/2 F 3/4 Bruno S, et al. EASL 211

24 SVR rates according to fibrosis stages and historical response 1 Relapser Partial responder SVR % PR 48 BOC RGT BOC PR PR 48 BOC RGT BOC PR 48 9 PR 48 BOC RGT BOC PR 48 3 PR 48 BOC RGT F -2 F 3-4 F -2 F BOC PR 48 Bruno S, et al. EASL 211

25 The paradigmoflead-inphase Potential biological and clinical usefulness of 4 week P/R lead-in period before the addition of BOC Achievement of steady-state drug levels (full biological actions) for Peginterferon/ribavirin Prevention of exposure to DAA agents in patients who cannot tolerate P/R therapy Accurate evaluation of real-time IFN responsiveness AssessmentofriskvsbenefitwhendecisiontoaddDAAisunclear NoroleinimprovingSVR

26 The paradigm of lead-in phase Undetectable Peg-interferon + Ribavirin for 4 weeks (Lead-in) before adding DAA HCV-RNA at week 4 RVR 1 log decay Responsive to IFN <1 log decay Poorly responsive to IFN

27 What is the role of lead-in period? Is lead-in period useful at identifying patients who can spare the addition of DAA? Is lead-in period useful at identifying patients at higher risk of developing resistance? May lead-in phase more accurately redefine the historical response in real-time?

28 SVR rates by HCV RNA undetectable (RVR) at TW 4 SVR % PR 48 BOC RGT BOC PR 48 Poordad F, et al. NEJM 211

29 What is the role of lead-in period? Is lead-in period useful at identifying patients who can spare the addition of DAA? Is lead-in period useful at identifying patients at higher risk of developing resistance? May lead-in phase more accurately redefine the historical response in real-time?

30 Resistance-Associated Variants (RAVs) SPRINT-2 RESPOND RAV % BOC RGT BOC PR BOC RGT 31 BOC PR48

31 Rate of resistant associated variants according to HCV-RNA decline at week 4 SPRINT-2 RESPOND RAV % <1 log >1 log decline decline RGT arm 6 <1 log >1 log decline decline Standard arm <1 log >1 log decline decline RGT arm 6 <1 log >1 log decline decline Standard arm Poordad F, et al. NEJM 211 Bacon BR, et al. NEJM 211

32 1 9 SVR and RAV rates according to TW4 response* SPRINT-2 % % SVR RAV SVR RAV SVR RAV SVR RAV 1 9 RESPOND * * < 1log decline >1 log decline < 1log decline >1 log decline

33 What is the role of lead-in period? Is lead-in period useful at identifying patients who can spare the addition of DAA? Is lead-in period useful at identifying patients at higher risk of developing resistance? May lead-in phase more accurately redefine the historical response in real-time?

34 SVR % SVR rates according to Historical response Partial responder PR 48 BOC RGT BOC PR TW 4 response 12 < 1 log decline PR 48 BOC RGT BOC PR 48 SVR % Relapser PR 48 BOC RGT BOC PR > 1 log decline PR 48 BOC RGT BOC PR 48 Bacon BR, et al. NEJM 211

35 RESPOND-2: SVR according to historical and TW4 response Historical response 18% Historical response % SVR % ,5 72 Partial Relapse ,5 72 Partial Relapse < 1 log decline at wk 4 > 1 log decline at wk 4

36 Poorly responsiveness to IFN patients

37 Predictors of SVR in Poor IFN Responders (SPRINT-2 and RESPOND-2 studies combined) Pre-treatment factors predictive of SVR Genotype 1b F/1/2 BL viral load <2,, IU/mL TW8 virologic response No patient with <3 log decline at TW8 achieved SVR Bacon BR, Bruno S, et al. AASLD 211

38 1 Combined Studies SVR in Patients with < or >1. log 1 Week 4 HCV-RNA Decline Patients With F3/F4 Score SVR % BOC/PR48 BOC RGT PR < 1 log decline > 1 log decline

39 ADVERSE EVENTS Adverse Event, % BOC+PR PR Treatment naive patients n=1225 n=467 1) Anemia 5 3 EPO use ) Dysgeusia ) Neutropenia Treatment experienced patients n=323 n=8 1) Anemia ) Dysgeusia Discontinuations due to adverse events, % Anemia 2 1 Poordad F, et al. NEJM 211

40 No Difference in SVR in Patients With Hb<1 g/dl with ESA or Dose Reduction of Ribavirin 1 SPRINT-2: BOC/PR SVR (%) Both RBV DR EPO Neither 3 44 Sulkowski M et al. EASL 211

41 DRUG-DRUG interation 1. Major metabolic pathway of BOC is aldokenoreductase (AKR) 2. Changes in exposure of sensitive CYP3A substrate drugs with concomitant BOC expected BOC inhibits CYP3A4 only 3. BOC was safely tolerated when taken with many commonly prescribed medications including methadone and antidepressants 4. No apparent differences in SVR in patients treated with BOC/PR and concomitant medications Poordad F et al. AASLD 211

42 Treating G1 patients with BOC Triple tx Overall SVR rates encouraging in both naives and treatment experienced patients including well-certified null-responders. Roughly half of all patients will be eligible for shortened course of therapy Successful treatment arrests progression of liver disease LI enables predictability of response, resistance, and individualized care *DUAL tx/ Defer tx * RVR after LI/IL28B CC at BL, Low rate of SVR in poorly IFN responsive patients with advanced fibrosis and cirrhosis (either naives or treatment experienced ones) Potential for better treatment options in future, eg, better response rates, fewer adverse events, shorter duration Risk of resistance if therapy fails; impact on future options?

43 Futility Rules Differ for Boceprevir Boceprevir If HCV RNA is 1 IU/mL at Wk 12, all 3 medications should be discontinued If HCV RNA is confirmed detectableat Wk 24, all 3 medications should be discontinued

44 Suggested algorithm in clinical practice of BOC treatment

45 Suggested algorithm in clinical practice of BOC treatment in either RVR or responsiveto IFN Lead-in TW 4 RNA RVR (Naives) 1 log decay No BOC Add BOC TW 8 RNA Neg Pos 24/48 wks based on BL viralload 28 (Naives)/36 wks(nr) 48 wks(cirrhosis) 48 wks

46 Suggested algorithm in clinical practice of BOC treatment in poorly responsive to IFN (both naive and treatment experienced patient) Lead-in TW 4 RNA Add BOC < 1 log decline Favourable baseline predictive factors Genotype 1b, F-2, LVL Unfavourable baseline predictive factors BothGenotypes, F3-4, HVL TW 8 RNA NEG or 3 log decay <3 log decay Stop 48 weeks Stop

47 Avoid False Start

48 BACK UP

49 SVR rates (%) in PATIENTS POORLY RESPONSIVENESS TO IFN according to GENOTYPE in F3-4 STAGE and baseline VL >2.. COMBINED SPRINT 2 AND RESPOND 2 STUDIES SVR % G1 a G1 b N=26 N=7 Bruno S, et al manuscript in progress

50 SVR rates (%) according to GENOTYPE, FIBROSIS STAGE and baseline VL in PATIENTS WITH POOR IFN RESPONSE (<1 log decline at TW4) COMBINED SPRINT 2 AND RESPOND 2 STUDIES Viral load Fibrosis G1a G1b HCV RNA (IU/ml) METAVIR % Patient number % Patient number 2.. F F >2.. F F

51 SVR rates (%) according to GENOTYPE, FIBROSIS STAGE and baseline VL in PATIENTS WITH POOR IFN RESPONSE (<1 log decline at TW4) COMBINED SPRINT 2 AND RESPOND 2 STUDIES Viral load/fibrosis G1a G1b HCV RNA 2. / METAVIR F (27paz) 65 (26 paz) HCV RNA 2. / METAVIR F (8) 1 (4) HCV RNA >2. / METAVIR F (13) 4 (58) HCV RNA >2. / METAVIR F (26) 14 (7)

52 Quarto Stato, Giuseppe Pellizza da Volpedo

53 IL28B is no longer an important predictor of SVR when Lead-in Response is considered RESPOND-2 (effect) Odds Ratio (95% CI) p-value BOC/PR48 vs PR (4.6 to 28.) <.1 BOC/RGT vs PR (3.3 to 18.9) <.1 Previous Response: Relapser vs Nonresponder 2.2 (1.2 to 4.3).1 Log decline in HCV-RNA at TW 4 (continuous variable) 1.8 (1.3 to 2.4) <.1 BMI: 25 kg/m 2 vs >3 kg/m (1.4 to 8.2).1 Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the table.

54

55

56 Anemia as predictor of SVR SPRINT-2 RESPOND SVR (%) PR BOC/PR PR BOC/PR Hb 1 g/dl Hb<1 g/dl Hb 1 g/dl Hb<1 g/dl Sulkowski M et al, EASL 211

57 Next Stop

58 Early Interferon Response (Lead-In) Further Defines Likelihood of Success For Non-CC Patients SPRINT-2 and RESPOND-2 combined PR48 BOC RGT BOC/PR <1 log >1log <1log >1log <1log >1log CC CT TT Poordad, et al. Presented at the European Association for the Study of the Liver Annual Meeting; March 3 April 3, 211; Berlin, Germany. Abstract

59 %Patients with RAVs detected RAVs (All BOC treatment) 19% SPRINT-2 16% 1% 11% 87/468 24/232 Gen 1a RESPOND-2 Gen 1b RAVs (NON-SVR Patients Only 58% 48% SPRINT-2 Gen 1a 48% 42% 31/188 14/127 87/151 24/5 31/66 17/41 RESPOND-2 Gen 1b

60 SPRINT-2 RESPOND SVR% /177 51/126 16/179 89/ /237 85/117 11/46 6/34 5/94 44/66 61/96 43/61 1 PR BOC RGT BOC/PR 48 PR BOC RGT BOC/PR 48 Gen 1a Gen 1b Gen 1a Gen 1b

61 RESPOND-2: SVR by week 4 lead in response SVR (%) SVR (%) PR 48 BOC RGT BOC/PR48 PR 48 BOC RGT BOC/PR48 Poorly Responsive to IFN Responsive to IFN <1 log 1 viral load decline at treatment week 4 1 log 1 viral load decline at treatment week 4 Bacon R et al., NEJM 211

62 Boceprevir in treatment experienced patients: Sub-analysis according to prior response SVR % BOC PR 48 BOC RGT BOC PR 48 BOC RGT Relapse Partial

63 Boceprevir-response guided therapy guideline dosing regimen and duration of therapy Patient treatment status Naive to treatment with no cirrhosis Previous partial responder or relapser with no cirrhosis Patients with cirrhosis Week 1-4 (LI) Add at Week 5 Peg IFN and Ribavirin Peg IFN and Ribavirin Peg IFN and Ribavirin Boceprevir 8 mg 3 times daily Boceprevir 8 mg 3 times daily Boceprevir 8 mg 3 times daily Assessment HCV-RNA results Week 8 viral count Week 24 viral count Undetectable Undetectable Detectable Undetectable Undetectable Undetectable Detectable Undetectable Undetectable Undetectable Detectable Undetectable Treatment reccommendation Complete therapy with BPR up to treatment Week 28 Continue BPR up to treatment Week 36 then Give PR only from Week 37 to 48 Complete therapy with BPR up to treatment Week 36 Continue BPR up to treatment Week 36 then Give PR only from Week 37 to 48 Complete therapy with BPR up to treatment

64 SVR rate by EARLY (week 8 HCV-RNA negative) and LATE (week 8 HCV-RNA positive) response SPRINT-2 RESPOND SVR Early Resp Late Resp Early Resp Late Resp Early Resp Late Resp Early Resp Late Resp BOC RGT BOC PR48 BOC RGT BOC PR48 Poordad F, et al NEJM 211

65 Advancesin HCV treatment: Genotype1 towards the end the disease? SVR % IFN 24 IFN 48 IFN/RBV24 IFN/RBV 48 PEG/RBV 48 DAA RGT QUAD ? Since the year of FDA approval

66 Next stop Very potent DAA therapy will make predictors of treatment outcome useless Eg: PSI-7977 (NS5B NI) + RBV +/-PegIFN - G1 SVR = 91% (98% per protocol) - G2/3 SVR = 1% Lawitz E, AASLD, 211 Gane EJ, AASLD, 211

67 Response markers associated with SVR in the era of DAA Baseline IL28B Fibrosis/Cirrhosis stage Viral load Genotype Statins in Boceprevir (BOC) Race On treatment Lead-in Early-late response at week 8 in BOC

68 SVR rates in prior Relapser and Partial responder SVR % /28 53/145 Relapse Partial

69 % PROVIDE Study (SVR rates in prior NULL responders) /43 16/42 3/19 EOT SVR Relapse

70 Boceprevir in treatment naïvepatients: SVR rates by week 4 response >1 log decline/undetectable <1 log decline undetectable SVR % PR 48 BOC RGT BOC PR /197 (69%) 275/197 (25%) 69/197 (7%) Poordad F, et al. NEJM 211

71 2. SVR rates according to fibrosis/cirrhosis 1% 9% N=78 8% 7% 68 SVR % 6% 5% 4% 3% 2% 1% % B+PR 36/48 RGT B+PR 48 PR 48 Bruno S, et al. EASL 211

72 SVR rates according to poorly response or response Poorly Responsive at wk 4 Responsive at wk SVR % PR 48 BOC RGT BOC PR PR 48 BOC RGT BOC PR 48 Bacon et al, NEJM, 211

73 RESPOND-2: SVR according to historical and TW4 response SVR (%) SVR (%) PR48 Partial responders BOC RGT BOC/PR48 <1 log 1 HCV RNA reduction at Week _ 15 _ 15 _ 12 PR48 46 BOC RGT 44 BOC/PR48 SVR (%) 1 SVR (%) PR48 25 Relapsers BOC RGT BOC/PR _ 8 _ 9 _ PR48 BOC RGT BOC/PR48 1 log 1 HCV RNA reduction at Week 4 Bacon BR., et al. N Engl J Med 211; 364:

74 SVR rates according to Viral load SVR % , IU/mL >8, IU/mL /53 197/313 41/54 192/314 BOC PR 48 BOC RGT

75 RESPOND-2: SVR according to historical and TW4 response Historical response Historical response SVR % ,5 72 Partial Relapse ,5 72 Partial Relapse < 1 log decline at wk 4 > 1 log decline at wk 4

76 Real-Time Interferon Response (TW 4): RESPOND-2 STUDY SVR Rates According to Virologic Response by Wk 4 1 IFN responsiveness at TW Poor <1 log 1 HCV-RNA decline Patients (%) Good 1 log 1 HCV-RNA decline 2 18 Historical Partial responders Relapsers Overall, 26% of previous partial responders and relapsers are poorly IFN responsiveness Esteban R et al., EASL 211

77 SVR rates by week 4 response >1 log decline/undetectable <1 log decline undetectable SVR % PR 48 BOC RGT BOC PR /197 (69%) 275/197 (25%) 69/197 (7%) Poordad F, et al. NEJM 211

78 DRUG-DRUG Interactions Drug Class Alfha 1-adrenoreceptor antagonist Anticonvulsants Ergot derivatives GI motility agents Herbal products HMG CoA reductase inhibitors Oral contraceptives Neuroleptic PDE5 inhibitor Sedative/hypnotics Controindicated with BOC Alfuzosin Carbamazepine, phenobarbital, phenytoin Dihydroergotamine, ergonovine, ergotamine, methylergo novine Cisapride Hypericum perforatum Lovastatin, simvastatin Drospirenone Pimozide Sildenafil or tadalafil when used for treatment of pulmonary arterial hypertension Triazolam, midazolam Poordad F, et al., AASLD 211