Protease inhibitor based triple therapy in treatment experienced patients Universitätsklinikum Leipzig Thomas Berg Sektion Hepatologie Klinik und Poliklinik für Gastroenterologie und Rheumatologie Leber und Studienzentrum am Checkpoint, Berlin
Virologic response patterns on dual therapy with Peg Interferon plus ribavirin in HCV type 1 Baseline Treatment Null Nonresponder HCV RNA Partial responder Breakthrough Relapser HCV RNA undetectable Detection limit Sustained responder (SVR) < 15 IU/ml Time 6 Months 1. Strader D, et al. Hepatology 24; 39: 1147 2. Farci P, et al. PNAS 22; 99: 381
Innate immunity and HCV Interferon signaling and Mechanismens of Interferon nonresponsiveness Ineffective upregulation of ISGs Pre-activated IFN system IFN system not activated Induction of the endogenous IFN system in the liver is not only ineffective in clearing viral infection, but also prevents response to peg IFNa and ribavirin therapies Heim M. J Hepatol 213; 58: 564
Early virologic response patterns during HCV protease inhibitor monotherapy Telaprevir monotherapy Median Log HCV RNA 7 6 5 4 3 2 1 Placebo (n = 6) Breakthrough (n = 13) Plateau (n = 8) Continuous decline (n = 7) 2 4 6 8 1 12 14 16 18 1 Time (Days) Sarrazin C, et al. Gastroenterology 27
Individual response to Peg IFN/ribavirin: Implications for the use of Protease inhibitor (PI) based triple therapy 7 6 Peg IFN alpha RBV Null response (<1 log decline at week 4) Risk of a functional PI mono therapy Log HCV RNA 5 4 3 Partial reponse, plateau (>1 log Week 4, >2 log Week 12) High chance of achieving SVR with PI Triple 2 1 Relapser Detection limit Rapid response High chance of SVR, no need for PI? Potential Time to reduce treatment duration with PI
On treatment failure rates during triple therapy according to prior response pattern 6 Telaprevir 57% 6 Boceprevir On treatment virologic failure 5 4 3 2 1 18% 8% 1% naiv REL P NR NULL 5 4 3 2 1 42%* 2% 9% Naiv Rel/Part NULL BT or stopping rule tx wk 24 or. wk 12 BT or stopping rule TVR wk 4,6,8 >1 /1 IU/mL entire tx. <2log wk 12/HCV RNA pos. wk 24 Bacon et al., NEJM 211; Poordad et al., NEJM 211 * PROVIDE Study, Vierling AASLD 211 Jacobson et al., NEJM 211; Zeuzem et al., NEJM 211
Individual viral kinetics during triple therapy patients with prior null response to Peg IFNa/Ribavirin Vertex 17 Study; Null Response = <1log wk. 4 / <2log wk. 12) 8 7 Viral kinetics during PEG IFNa/Riba 8 7 Viral kinetics during retreatment with triple therapy PEG/Riba + Telaprevir (TVR) 6 6 Log 1 (HCV RNA) 5 4 3 2 Log 1 (HCV RNA) 5 4 3 2 1 LOQ LOD 1 LOQ LOD 1234 6 8 1121416 2 24 Weeks Shiffman et al., AASLD 28 LOQ = Limit of quantification; LOD = Limit of Detection 1234 6 8 1121416 2 24 TVR + Peg IFN + RBV TVR stop Peg IFN + RBV Weeks
SVR rates according to treatment experience Peg IFNa/RBV PI Triple (BOC or TVR) Treatment naïve 38 44% 63 75% Relapser 24 29% 75 88% Partial responder 7 15% 52 59% Null responder 5% 33 4% Bacon BR. et al. N Engl J Med 211; 364:127 1217. Bronowicki JP. et al. J Hepatol 212: 56: S6. Poordad F et al. N Engl J Med 211: 364: 1195 126 Sherman KE et al. N Engl J Med 211; 365: 114 124. Jacobson IM et al. N Engl J Med 211; 364 : 245 16. Zeuzem S. et al. N Engl J Med 211;364:2417 28
SVR rates according to treatment experience Peg IFNa/RBV PI Triple (BOC or TVR) Treatment naïve ~ 1.7 fold 38 44% 63 75% Relapser ~ 3 fold 24 29% 75 88% Partial responder ~ 4 fold 7 15% 52 59% Null responder ~ 6 fold 5% 33 4% Bacon BR. et al. N Engl J Med 211; 364:127 1217. Bronowicki JP. et al. J Hepatol 212: 56: S6. Poordad F et al. N Engl J Med 211: 364: 1195 126 Sherman KE et al. N Engl J Med 211; 365: 114 124. Jacobson IM et al. N Engl J Med 211; 364 : 245 16. Zeuzem S. et al. N Engl J Med 211;364:2417 28
REALIZE (Telaprevir): SVR by HCV subtype and prior response to prior Peg IFN/RBV therapy Prior relapsers Prior partial responders Prior null responders 1b Pbo/PR48 Pooled T12/PR48 1a SVR (%) n/n= 1/34 119/142 6/31 123/14 3/16 26/55 1/1 27/4 1/17 24/88 1/2 22/59 HCV subtype 1a 1b 1a 1b 1a 1b Zeuzem S, et al. EASL 211. Abstract 2371
REALIZE (Telaprevir): SVR by baseline fibrosis stage and prior response to prior Peg IFN/RBV therapy Prior relapsers Prior partial responders Prior null responders Pbo/PR48 Pooled T12/PR48 SVR (%) n/n= 12/38 144/167 2/15 53/62 2/15 48/57 3/17 34/47 /5 1/18 1/5 11/32 1/18 24/59 /9 15/38 1/1 7/5 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 Zeuzem S, et al. EASL 211. Abstract 2371
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 2/1 11/22 15/18 2/23 18/38 23/42 /5 3/1 6/13 Stage No, minimal or portal fibrosis (F F2) Bridging fibrosis / cirrhosis (F3/F4) No, minimal or portal fibrosis (F F2) Bridging fibrosis / cirrhosis (F3/F4) Bruno S, et al. J Hepatol 211;54(Suppl. 1):S4
Regimens in genotype 1 HCV infected prior relapsers without cirrhosis Telaprevir Telaprevir + Peg IFN + RBV Peg IFN alfa + RBV Stop treatment at Week 24 if undetectable at Week 4 and 12 Peg IFN alfa + RBV if detectable at Week 4 or 12 Boceprevir Peg/RBV lead in Boceprevir + Peg IFN + RBV Peg IFN + RBV 4 8 12 24 28 36 48 Weeks Telaprevir EU SmPC; Boceprevir EU SmPC
CONCISE Interim Analysis: 12 week telaprevir (TVR) triple Treatment naïve or prior relapse HCV type 1 patients; IL28B CC (no cirrhosis) RVR (< 25 IU/mL, not detected Stop (N=57) (n=128) Telaprevir + Peg IFN + RBV Peg IFN + RBV (N=28) 12 24 36 48 Weeks Nelson DR et al. J Hepatol 213 (Suppl) S37; #881 (EASL 213, poster)
CONCISE Interim Analysis: 12 week telaprevir (TVR) triple Treatment naïve or prior relapse HCV type 1 patients; IL28B CC (no cirrhosis) RVR (< 25 IU/mL, not detected Stop SVR4 96% (N=57) SVR12 89% (n=128) Telaprevir + Peg IFN + RBV Peg IFN + RBV (N=28) 12 24 36 48 Weeks Nelson DR et al. J Hepatol 213 (Suppl) S37; #881 (EASL 213, poster)
Dosing duration in patients with partial or null response and/or with compensated cirrhosis TVR + Peg IFN + RBV Peg IFN + RBV >1 IU/mL: Stop all drugs >1 IU/mL: Stop all drugs Detectable: Stop Peg IFN/RBV Peg IFN + RBV BOC+ Peg IFN + RBV Cirrhosis and null response BOC+ Peg IFN + RBV Partial response Peg IFN + RBV 1 IU/mL: Stop all drugs Detectable: Stop all drugs 4 12 24 36 48 Telaprevir EU SmPC; Boceprevir EU SmPC
Should we wait for better treatment options in treatment experienced patients (especially patients with null response?)
Peg IFNacontaining regimens Future HCV treatment strategies Phase III Treatment naive 2nd Gen. PI Triple Faldaprvir, Simeprevir NUC Triple Sofosbuvir HCV type 1 and 4 6 Next wave of triple/quadruple regimens Asunaprevir (PI) MK5172 (PI) MK79 (PI) Daclatasvir (NS5A) GS8558 (NS5A) Daclatasvir + Asunaprevir GS5885 + GS9451 213 214 215 216 217 Phase III Next wave of all oral regimens Interferon free regimens NUC + RBV Sofosbuvir HCV type 2 and 3 ABT 45/r (PI/r)+ABT 267 (NS5A)+ABT 333 (NNUC)+RBV Faldaprevir (PI) + BI 27127 (NNUC) + RBV Daclatasvir (NS5A) + Sofosbuvir (NUC) ±RBV GS5885 (NS5A) + Sofosbuvir (NUC) + RBV GS9669 (Non NUC) + Sofosbuvir (NUC) RBV Asunaprevir (PI) + Daclatasvir (NS5A) + BMS791325 PI = Protease Inhibitor, NUC = nucleosidic polymerase (NS5B) inhibitor, NS5A = NS5A Inhibitor, PI/r ritonavir boosted PI, RBV = Ribavirin
Can we better characterize nonresponder patients who are likely to respond?
Factors influencing antiviral response to direct antiviral acting agents (DAA) Genetics i.e. IL28B HCV Subtype (Viral load) Fibrosis stage Cirrhosis DAA Response Treatment Adherence (side effects) GGT Cholesterol Peg IFN/RBV Response
Virologic breakthough in protease inhibitor (PI) based Triple Therapy: Different Profiles Rapid breakthrough Early breakthrough Late breakthrough PI Triple PI Triple PI Triple Dual HCV RNA Detection limit 4 4 12 4 12 Treatment duration (Weeks) Dual = Peg IFNa plus Ribavirin
Virologic breakthough in protease inhibitor (PI) based Triple Therapy: Different Profiles Typical phenotypes Rapid breakthrough Early breakthrough Late breakthrough HCV RNA PI Triple PI Triple PI Triple Dual Prior null response Prior partial response Liver cirrhosis Adherence? HCV subtype 1a IL28B non CC Detection limit 4 4 12 4 12 Treatment duration (Weeks) Dual = Peg IFNa plus Ribavirin
Can we use the lead in phase to better predict treatment outcome in the individual?
RESPOND 2 (boceprevir): SVR according to IFN response at week 4 lead in 1 Poorly responsive to IFN (<1 log 1 HCV RNA decline at TW4) 1 Responsive to IFN ( 1 log 1 HCV RNA decline at TW4) 8 8 79 73 SVR (%) 6 4 34 33 SVR (%) 6 4 25 2 15 44 15 46 12 2 9 114 8 11 17 67 BOC + 48 wk Peg IFNα 2b/RBV RGT BOC + Peg IFNα 2b/RBV Placebo + 48 wk Peg IFNα 2b/RBV BOC + 48 wk Peg IFNα 2b/RBV RGT BOC + Peg IFNα 2b/RBV Placebo + 48 wk Peg IFNα 2b/RBV Bacon BR, et al. N Engl J Med. 211;364:127 1217
Predictors for Boceprevir Triple response in patients with < 1 log HCV RNA decline during lead in Pooled data from Sprint 2 and Respond 2 SVR Rates 1 HCV Subtype 1 Fibrosis stage 1 HCV RNA 8 8 8 6 49 6 6 54 4 2 24 4 2 38 17 4 2 26 1a 1b F/1/2 F3/4 < 2Mio IU/ml > 2 Mio IU/ml Bacon B et al, AASLD 211, #33 (oral)
Telaprevir based triple therapy in patients with nonresponse or relapse: Evaluation of the lead in concept Previous relapse Previous partial or nonresponse Zeuzem S et al. N Engl J Med 211; 364: 2417
Predictors for Boceprevir Triple response in patients with < 1 log HCV RNA decline during lead in 1 8 Pooled data from Sprint 2 and Respond 2 SVR Rates according to week 8 virologic response (i.e. week 4 on triple therapy) 83 SVR rates % 6 4 3 49 2 16 <3 3-4 4-5 >5 undetectable HCV RNA log decline at week 8 (week 4 on BOC) Bacon B et al, AASLD 211, #33 (oral)
SVR among telaprevir treated Patients with RVR and ervr, according to Previous Response (N=465) SVR for patients achieving RVR SVR for patients achieving ervr Patients (%) n/n= 183/21 38/56 28/42 183/193 38/55 27/38 Prior relapsers Prior partial responders Prior null responders Prior relapsers Prior partial responders Prior null responders Berg T et al. AASLD 211, #32
Role of Ribavirin?
Ribavirin reduces in vivo the mrna levels of a large number of ISGs (particularly those found up regulated in nonresponders to Peg IFNa/RBV) (Testoni et al, 211) RBV epigenetic reprogramming properties could synergize with anti HCV DAAs potent antiviral activity to restore the host innate immunity responses Testoni B et al. J Hepatol 213 (Suppl) S5, #11 (oral, EASL 213)
Ribavirin dose reduction during TVR Triple and early virologic response patterns (Treatment experienced pts with advanced fibrosis, N=25, HCV type 1) Ribavirin dose reduction W W4 W4 W12 No cevr 59% 83% 88% cevr in Nulls 44% 75% ND cevr in Hb < 12 g/dl vs. > 12 g/dl on treatment: 86% vs. 66% *EVR = early virologic response at week 12 Janczewska E et al. J Hepatol 213 (Suppl) S342; #816 (poster, EASL 213)
Conclusions Treatment experience per se is no unfavorable factor for treatment outcome using PI based triple regimens Highest chance for cure in patients with relapse and good partial response Highest chance for on treatment failure in null responders with HCV subtype 1a Cirrhosis High viral load Low LDL levels The individual value of lead in phase viral kinetics in order to predict who is going to respond to DAA regimens is questionable Regardless of the individual predictors, if RVR, chance for cure is high