Presentation is loading. Please wait.

Presentation is loading. Please wait.

1 Sheng-Shun Yang, M.D., Ph.D. Division of Gastroenterology & Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung,

Similar presentations


Presentation on theme: "1 Sheng-Shun Yang, M.D., Ph.D. Division of Gastroenterology & Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung,"— Presentation transcript:

1 1 Sheng-Shun Yang, M.D., Ph.D. Division of Gastroenterology & Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 2013-11-28 Direct Acting Antivirals for Chronic Hepatitis C

2

3 C 型肝炎病毒感染之併發症 慢性 C 型肝炎是導致肝病重要的原因 [1] 慢性 C 型肝炎是導致肝病重要的原因 [1] –1/4 of the ~500,000 new HCC cases identified globally each year are attributable to HCV [2] 預估未來幾年, C 型肝炎相關的併發症增加兩倍 [3] 預估未來幾年, C 型肝炎相關的併發症增加兩倍 [3] C 型肝炎感染經常合併許多肝外疾病或症候 [4] C 型肝炎感染經常合併許多肝外疾病或症候 [4] –Mixed cryoglobulinemia vasculitis, lymphoproliferative disorders, diabetes (2-3 ↑ odds), renal disease, rheumatoid arthritis–like polyarthritis, sicca syndrome, depression, neurocognitive impairment 1. Lavanchy D. Clin Microbiol Infect 2011;17:107-115. 2. Montalto G, et al. Ann NY Acad Sci 2002;963: 13-20. 3. Milliman, Inc. Consequences of HCV: costs of a baby boomer epidemic, 2009. 4. Jacobson IM, et al. Clin Gastroenterol Hepatol 2010;8:1017-1029.

4   首要目標乃是根除此病毒   次要目標 Slow disease progression Minimize risk of liver cancer Improve liver damage Enhance quality of life Prevent transmission of virus Reduce extra-hepatic manifestations 治療 C 型肝炎的目標

5 Outline 國內當前標準療法 (standard of care) 國內當前標準療法 (standard of care) DAAs 新藥介紹 - 已上市 (Boceprevir & Telaprevir) - 即將上市 (Sofosbuvir & Simeprevir) - 研發中藥物

6 慢性 C 型肝炎治療里程碑 Sustained Virologic Response (%) 6% 13-19% 31-35% 38-43% 45-47% 54-63% 68-75% 1992 2001-2010 2011 SVR rates remain suboptimal in HCV genotype 1 Response-guided therapy (RGT): ~2004 IL28B genotypes: ~2009 Direct acting antivirals (DAAs): ~2011

7 治療 C 型肝炎之病毒動力學

8 SVR Is Durable & Beneficial “These patients should be considered as cured” 99.1% HCV RNA undetectable independent of population - Elevated ALT, persistently normal ALT, immunocompromised Independent of treatment by - IFN monotherapy, IFN/RBV, IFN/RBV/DAAs 34-61% reverse cirrhosis ~90% improve fibrosis Improved neurocognitive function, fatigue; reduces insulin resistance Reduces risk of HCC and improves liver & all-cause mortality Camma et al. Hepatology 2004;39(2):333-42; D’ Ambrosio et al. Hepatology 2012;56:532-43 Kraus MR, et al. Hepatology 2013;58:497-504; Brandman et al. Diabetes Care 2012;35(5):1090-4 Van der Maar, et al. JAMA 2012;308:2584-93.

9 ISDR in NS5A IL28B SNPs

10 宿主 IL28B 基因多型性  Genetic polymorphism near IL28B, which encodes for IFN lambda-3 –CC genotype 對當前標準療法有較佳的治療反應 ( 基因第一型病毒 ) Ge D, et al. Nature. 2009;461:399-401.

11 Modified from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. SVR, % IFN Monotherapy PegIFN + RBV (Taiwan) PegIFN + RBV (West) 24 wks48 wks78 wks All genotypes6-1911-1910-2218-39-- GT1 (48 wks)-- 75-8042-46 GT2/3 (24 wks)-- 85-9076-82 當前 C 型肝炎標準療法及療效

12 目前治療成效不錯 我們還需要 DAAs嗎? Multiple AEs from SOC Null/partial responders, relapsers Unwilling, intolerant, ineligible ‘Difficulty-to-treat’ (cirrhotics, HIV coinfected, post LT recurrent, renal transplant candidates & HCV infected post kidney transplantation)

13 部分地區或國家上市 DAAs Boceprevir (BOC) Telaprevir (TVR)

14 限定基因第一型: 標準療法 (P/R) + C 肝病毒蛋白酶抑制劑 (PI) 使用於過去未曾治療過 (naïve) 的病患

15 Dosage and Administration  750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (not low fat; standard fat meal is 21 g, eg, 1/2 cup nuts or 2 oz cheddar cheese)  Must be administered with both pegIFN and RBV; telaprevir dose must not be reduced or interrupted Response-Guided Therapy  Treatment-naïve patients with compensated cirrhosis and eRVR may benefit from additional 36 wks of pegIFN + RBV (ie, to wk 48) No eRVR; PegIFN + RBV Telaprevir + pegIFN/RBV 用於基因第一型未曾治療過的病患 TVR + PegIFN + RBV Wks 48024124 eRVR; stop at Wk 24, f/u 24 wks PegIFN + RBV *Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. Telaprevir [package insert]. May 2011. Vertex/Johnson & Johnson's Incivo. HCV RNATVR + PegIFN/RBVPegIFN/RBVTotal Duration Undetectable* at wks 4 and 12First 12 wksAdditional 12 wks24 wks Detectable (but ≤ 1000 IU/mL) at wks 4 and/or 12First 12 wksAdditional 36 wks48 wks F/u 24 wks

16 Telaprevir + PR: 基因第一型未曾治療過的病患之持續病毒反應率 SVR 75 44 P <.001 SVR (%) 0 20 40 60 80 100 T12PR PR ADVANCE: TVR + PegIFN/RBV in Treatment-Naïve Genotype 1 271/363158/361n/N = Jacobson IM, et al. NEJM 2011;364:2405-2416.

17 Telaprevir + PR: 副作用  Higher rates of rash, anemia, and anorectal signs/symptoms in TVR arms vs control  Anorectal symptom management –Fiber, loperamide, hydrocortisone, and pramoxine topical cream Adverse Event, %TVR + PR RGT/48* (n = 1797) PR48 (n = 493) Rash5634 Anemia † 3617 Anorectal events297 Telaprevir package insert. May 2011. *Results from patients with 8 wks and 12 wks of TVR exposure pooled. Anemia rates from T12 groups estimated to be ~ 40%. † Anemia was managed with RBV dose modification; epoetin alfa was not permitted in clinical trials.

18 Boceprevir + PR 使用於基因第一型未曾治療過者 Dosage and Administration  800 mg (four 200-mg capsules) TID (every 7-9 hrs) with food (meal or light snack)  Must be administered with both pegIFN and RBV  Boceprevir dose must not be reduced or interrupted Response-Guided Therapy*  If undetectable at wks 8 and 24, continue 3-drug regimen to wk 28  If detectable at wk 8, but undetectable at wk 24, continue 3-drug regimen to wk 36, then administer pegIFN/RBV to wk 48  All cirrhotic patients should receive lead-in followed by pegIFN/RBV + boceprevir for 44 wks  Futility: stop all 3 drugs if wk 12 HCV RNA ≥ 100 IU/mL or wk 24 HCV RNA detectable  Wk 4 < 1 log HCV RNA reduction associated with greater risk of developing resistance and lower SVR rates: consider pegIFN/RBV + boceprevir for 44 wks after lead-in, no RGT F/u 24 wks Boceprevir + PegIFN  RBV Wks 48028124 PegIFN + RBV *Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. PegIFN + RBV 8 36 Boceprevir + PegIFN  RBV Boceprevir [package insert]. May 2011. Merck & Co’s Victrelis. 24 F/u 24 wks

19 Boceprevir + PR: 持續病毒反應率 P <.001 Nonblack Patients P =.04 P =.004 Black Patients 125/ 311 211/ 316 213/ 311 12/ 52 22/ 52 29/ 55 Poordad F, et al. NEJM 2011;364:1195-1206. SPRINT-2: BOC + PegIFN/RBV in Genotype 1 Treatment-Naïve Patients SVR (%) PR48 BOC RGT 100 80 60 40 20 0 BOC/PR48 40 67 68 SVR (%) PR48 BOC RGT 100 80 60 40 20 0 BOC/PR48 23 42 53 n/N =

20 Boceprevir + PR: 副作用  Significantly higher rates of anemia, neutropenia, and dysgeusia in boceprevir arms vs control Adverse Event, %Boceprevir + PR RGT/48 (n = 1225) PR48 (n = 467) Anemia*5030 Neutropenia2519 Dysgeusia3516 *Anemia was managed with RBV reduction and/or epoetin alfa (43% of boceprevir + PR and 24% PR). Boceprevir [package insert]. May 2011.

21 Triple Therapy 使用於基因第一型過去治療失敗者

22 Telaprevir + PR: 基因第一型過去治療失敗者 Dosage and Administration  750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (not low fat; standard fat meal is 21 g, eg, 1/2 cup nuts or 2 oz cheddar cheese)  Must be administered with both pegIFN and RBV  Telaprevir dose must not be reduced or interrupted Treatment duration  All previous partial responders or null responders receive 12 wks of triple therapy followed by 36 wks of pegIFN/RBV  Previous relapsers follow the same response-guided approach as treatment-naive patients F/u 24 wks TVR + PegIFN + RBV Wks 48 0 2412 4 PegIFN + RBV Telaprevir [package insert]. May 2011.

23 100 0 60 SVR (%) 80 40 Telaprevir 使用於過去治療失敗者的療效  Lead-in examined, but found to have no impact on response and not used in TVR label Previous RelapsersPrevious Partial Responders n/N = Previous Null Responders *P <.001 vs placebo/PR48. REALIZE: TVR + PegIFN/RBV in Genotype 1 Previous Relapsers and Nonresponders 4/2729/4926/482/3721/7225/7516/68121/145124/141 Zeuzem S, et al. NEJM 2011;364:2417-2428. 20 83* 88* 24 59* 54* 15 29* 33* 5 T12/PR48Pbo/PR48LI T12/PR48

24 Boceprevir + PR 用於基因第一型過去治療失敗之 無肝硬化患者 Dosage and Administration  800 mg (four 200-mg capsules) TID (every 7-9 hrs) with food (meal or light snack)  Must be administered with both pegIFN and RBV  Boceprevir dose must not be reduced or interrupted Partial Responders, Relapsers: Duration Based on Wks 8 and 24 HCV RNA*  If undetectable at both time points, continue 3-drug regimen to Wk 36  If detectable at Wk 8 but undetectable at Wk 24, continue 3-drug regimen to Wk 36, then administer pegIFN/RBV to Wk 48  All cirrhotic patients should receive lead-in then boceprevir + PR for 44 wks  Futility: stop all 3 drugs if Wk 12 HCV RNA ≥ 100 IU/mL or Wk 24 HCV RNA detectable  Wk 4 < 1 log HCV RNA reduction associated with greater risk of developing resistance associated variants and lower SVR rates: consider boceprevir + PR for 44 wks after lead-in, no RGT  If considered for treatment, previous null responders should receive lead-in then boceprevir + PR for 44 wks F/u 24 wks Boceprevir + PegIFN + RBV Wks 48028124 PegIFN + RBV *Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. PegIFN + RBV 8 36 Boceprevir + PegIFN + RBV Boceprevir [package insert]. May 2011. 24

25 BOC + PR: SVR by Historical Response (Partial Responders and Relapsers*) *Partial responders had a decrease in plasma HCV RNA of at least 2 log 10 by Wk 12 of previous therapy but with detectable HCV RNA throughout the course of therapy. Relapsers had undetectable HCV RNA at end of previous therapy without subsequent attainment of SVR. Bacon BR, et al. NEJM 2011;364:1207-1217. RESPOND-2: BOC + PegIFN/RBV in GT 1 Treatment-Experienced Patients 2/29 23/57 30/58 2/29 23/57 30/58 SVR (%) Partial Responder 100 80 60 40 20 0 7 Relapser 40 52 29 69 75 PR48 (n = 80) BOC RGT (n = 162) BOC/PR48 (n = 161) n/N =

26 CUPIC: Telaprevir or Boceprevir + P/R in GT 1 Treatment-Experienced Cirrhotics  French compassionate use program for early access to TVR and BOC before approval Fontaine H, et al. EASL 2013. Abstract 60. n/N = 118/ 295 79/ 190 61/ 116 43/ 85 43/ 135 32/ 80 8/ 28 1/9 100 80 60 40 20 0 SVR12 (%) OverallRelapsersPartial ResponseNull Response 40 41 53 51 32 40 29 11 Telaprevir + P/R Boceprevir + P/R Previous Response to P/R

27 與蛋白酶抑制劑交互反應的藥物  HCV PIs are CYP3A4 inhibitors –Approximately one half of drugs are metabolized by CYP3A4  List of drugs affected by CYP3A4 inhibitors is long –Consult package insert and review med lists frequently  Until the drug is specifically studied, magnitude of the impact of PI on its level is not known  Exercise caution with ALL coadministered medications

28 Telaprevir: Take Home  Administered with full-fat foods  For treatment-naïve and relapser patients –12 wks of TVR + pegIFN/RBV followed by RGT with pegIFN/RBV –Additional 12 wks if HCV RNA undetectable at Wks 4 and 12; otherwise, additional 36 wks –Recommended that all cirrhotics receive T12PR48  For partial and null responders –T12PR48  Futility rules for all patients: stop all therapy if HCV RNA > 1000 IU/mL at wk 4 or 12 or detectable at wk 24  TVR-associated adverse events: rash, anemia, anorectal symptoms

29 Boceprevir: Take Home  Administer with meal or light snack  PegIFN/RBV x 4 wks, then add BOC for up to 44 wks of triple therapy  Key HCV RNA assessments at wks 4, 8, 12, 24  RGT based on wk 8 HCV RNA –Treatment-naïve patients may be eligible for 24 wks of triple therapy following lead-in –Treatment-experienced patients may be eligible for 32 wks of triple therapy following lead-in –Late or slow responders (ie, detectable at wk 8 but undetectable by wk 24) should receive 32 wks of triple therapy then 12 wks of pegIFN/RBV alone  Stop all therapy if HCV RNA ≥ 100 IU/mL at wk 12 or detectable at wk 24  All compensated cirrhotic patients should receive lead-in then BOC + PR for 44 wks –Same regimen should be used for null responders, if considered for treatment  BOC-associated adverse events: anemia, dysgeusia

30 即將上市 DAAs US FDA Advisory Committee, Oct 24-25, 2013 Unanimous recommendations to approve Simeprevir (SMV) Sofosbuvir (SOF)

31 DAAs Currently in Development (not all-inclusive) NS3/4A Inhibitors NS5AA Inhibitors NS5B Polymerase Inhibitors First generation: Telaprevir Boceprevir First generation, second wave: Simeprevir Faldaprevir (BI 201335) Asunaprevir ABT-450/r Sovaprevir (ACH-1625) Second generation: MK-5172 ACH-2684 Daclatasvir (BMS 790052) Ledipasvir (GS-5885) GS-5816 ABT-267 ACH-3102 MK-8742 PPI-668 Samatasvir (IDX719) NI: Sofosbuvir (GS-7977) VX-135 NNI: Deleobuvir (BI 207127) BMS 791325 GS-9669 TMC 647055 ABT-333

32 QUEST-1: Simeprevir + P/R RGT in Treatment- Naïve GT 1 HCV  Randomized, double-blind, placebo-controlled phase III trial –12% to 13% had cirrhosis, 56% to 57% had GT 1a HCV Jacobson IM, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122. Simeprevir 150 mg QD + P/R* (n = 264) Treatment-naive pts with GT 1 HCV (N = 394) Stratified by GT 1 subtype, IL28B genotype P/R *Response-guided therapy: Patients with HCV RNA < 25 IU/mL at Wk 4 and HCV RNA undetectable at Wk 12 received a total of 24 wks of therapy. Those not achieving this on-treatment response received 48 wks of therapy. P/R, peginterferon alfa-2a 180 µg/wk + ribavirin 1000-1200 mg/day. P/R Placebo + P/R (n = 130) Wk 24Wk 48Wk 12

33 QUEST-1: Virologic Response to Simeprevir + P/R Treatment 85% of pts in SMV arm met RGT criteria Virologic Outcomes 24 Wks48 Wks Jacobson I, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122. 210/ 264 n/ N = 65/ 130 203/2246/28 202/ 254 80 60 40 20 0 100 HCV RNA Undetectable (%) Wk 4 SVR12 80 12 80 50 SMV + P/RP/R 80 60 40 20 0 SVR12 (%) 100 91 21 SVR12 by RGT Group SMV Arm: Total Duration of RGT n/ N =

34 QUEST-1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance Jacobson I, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122. Differences in SVR12 by Subgroup (95% CIs) GT 1a/other HCV  With baseline Q80K vs Pbo  Without baseline Q80K vs Pbo GT 1b HCV 28.2 (13.4-42.9) 4.7 (-14.6 to 24.1) 40.3 (25.8-54.8) 42.1 (26.5-57.6) 147 60 86 117 74 56 SMV (n) Pbo (n) Favors Placebo Favors SMV -100-50050100 18/31n/N =5/17188/22960/113 82 53 58 29 SMV + P/R P/R 100 80 60 40 20 0 SVR12 (%) No CirrhosisCirrhosis 105/11729/56105/14736/74 71 49 90 52 100 60 20 0 SVR12 (%) GT 1aGT 1b 80 40

35 Treatment-naive pts with GT 1 HCV (N = 391) Simeprevir 150 mg QD + P/R † (n = 257) Randomized 2:1*; stratified by GT 1 subtype, IL28B genotype P/R *63% of patients in each arm were randomly assigned to receive pegIFN alfa-2a or pegIFN alfa-2b; the remainder were assigned pegIFN alfa-2a. † RGT: Patients with HCV RNA < 25 IU/mL at Wk 4 and HCV RNA undetectable at Wk 12 received a total of 24 wks of therapy. Those not achieving this on-treatment response received 48 wks of therapy. Placebo + P/R (n = 134) P/R QUEST-2: Simeprevir + P/R RGT in Treatment- Naïve GT 1 HCV  Phase III, randomized, double-blind, placebo-controlled trial  7% to 11% had cirrhosis, 58% had GT 1b HCV Wk 24Wk 48Wk 12 Manns M, et al. EASL 2013 Abstract 1413.

36 QUEST-2: Virologic Response to Simeprevir + P/R Treatment Manns M, et al. EASL 2013. Abstract 1413. SMV Arm: Total Duration of RGT 91% of pts in SMV arm met RGT criteria n/N = SMV + P/R P/R Overall 24 wks48 wks 100 80 60 40 20 0 SVR12 (%) 81 50 86 32 209/25767/134202/2357/22

37 QUEST-2: SVR12 by Subtype and Fibrosis Level  Higher rates of SVR12 with SMV, irrespective of HCV genotype or cirrhosis  Baseline Q80K mutation not a predictor of response (unlike in QUEST-1) Manns M, et al. EASL 2013. Abstract 1413. 86/ 107 26/ 57 123/ 150 41/ 77 189/ 231 61/ 119 11/ 17 6/ 15 n/N = GT 1aNo CirrhosisCirrhosis 100 80 60 40 20 0 SVR12 (%) 80 46 82 65 SMV + P/R P/R GT 1b 82 53 51 40

38 Summary of Simeprevir  RGT met in 85-91% of patients; 86-91% had SVR  Q80K polymorphism in G1a affected SVR in QUEST-1 and in pooled analysis  Safety profiles similar between groups through first 12 wks of treatment –No increase in anemia with SMV; slightly higher rash or photosensitivity –Mild, transient bilirubin increases with SMV; other liver parameters did not change AEs During First 12 Wks, % QUEST-1 [1] QUEST-2 [2] SMV + PR (n = 264) PR (n = 130) SMV + PR (n = 257) PR (n = 134) Grade 1/2 AEs 72657073 Grade 3/4 AEs 23292624 Serious AEs 3422 AEs leading to SMV/placebo discontinuation 3321 AEs of interest  Pruritus 21111915  Rash (any type) 27252411  Anemia 16111416  Bilirubin increase 94NR  Photosensitivity conditions 3141 Jacobson I, et al. EASL 2013. Abstract 1425; Manns M, et al. EASL 2013. Abstract 1413.

39 NEUTRINO: Sofosbuvir + P/R for 12 Wks in Treatment-Naïve GT 1/4/5/6 HCV Patients  Open-label, single-arm study of sofosbuvir 400 mg QD + P/R for 12 wks in treatment-naive patients with GT 1/4/5/6 HCV –17% had cirrhosis; 89% had GT 1, 9% had GT 4, < 1% had GT 5, 2% had GT 6 HCV Lawitz E, et al. NEJM 2013;368:1878-87. P/R: pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day HCV RNA < LLOQ (%) 99 90 100 80 60 40 20 0 Wk 4EOTSVR12 321/325326/327 295/327 n/N =

40 NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level Lawitz E, et al. NEJM 2013;368:1878-87. SVR12 (%) 92 80 100 80 60 40 20 0 No Cirrhosis Cirrhosis 252/27343/54 SVR12 According to Fibrosis Level SVR12 (%) 89 96 100 80 60 40 20 0 GT 1GT 4GT 5,6 261/29227/28 7/7 SVR12 According to Genotype n/N =

41 FISSION: Sofosbuvir/RBV vs PegIFN/RBV in Treatment-Naïve GT 2/3 HCV Patients  Randomized, controlled, open-label phase III noninferiority trial –20% to 21% had cirrhosis; 72% had GT 3 HCV Gane E, et al. EASL 2013. Abstract 5. Treatment-naive patients with GT 2/3 HCV (N = 499) Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day (n = 256) PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day (n = 243) Wk 24Wk 12 Stratified by HCV GT (2 vs 3), HCV RNA (< vs ≥ 10 6 IU/mL), cirrhosis (yes vs no)

42 FISSION: Sofosbuvir/RBV Noninferior to P/R in Tx-Naïve GT 2/3 HCV Patients Gane E, et al. EASL 2013. Abstract 5. P <.001 SVR12 On Treatment 249/250158/236242/244207/224 Wk 4Wk 24 HCV RNA < LLOQ (%) 188/190NA Wk 12 170/253162/243n/N = Sofosbuvir + RBV PegIFN + RBV 100 80 60 40 20 0 99 67 99 92 67

43 FISSION: SVR12 According to Genotype and Fibrosis Level Gane E, et al. EASL 2013. Abstract 5. Genotype 2Genotype 3 SVR12 (%) No Cirrhosis Cirrhosis 58/5944/5410/118/1389/14599/13913/3811/37n/N = 100 80 60 40 20 0 98 82 91 62 61 71 34 30 Sofosbuvir + RBV PegIFN + RBV

44 FISSION: Better Tolerability Profile With Sofosbuvir/RBV vs PegIFN/RBV  Grade ≥ 3 AEs: 7% with SOF/RBV vs 19% for pegIFN/RBV  Discontinuations due to AEs: 1% for SOF/RBV vs 11% for pegIFN/RBV Gane E, et al. EASL 2013. Abstract 5. AEs Occurring in ≥ 15% in Either Arm, % SOF/RBV (n = 256) PegIFN/RBV (n = 243) P Value Fatigue3655 <.0001 Headache2544 <.0001 Nausea1829.0057 Insomnia1229 <.0001 Rash917.0052 Diarrhea917.0075 Irritability1017.0328 Decreased appetite718.0001 Myalgia817.0060 Pruritus717.0009 Influenzalike symptoms318 <.0001 Chills318 <.0001

45 FUSION: Sofosbuvir + RBV for 12 or 16 Wks in Tx-Experienced GT 2/3 HCV Pts  Randomized, double-blind, placebo-controlled phase III trial –62% to 64% had GT 3 HCV, 33% to 35% had cirrhosis, 75% to 76% were previous relapsers Nelson D, et al. EASL 2013. Abstract 6. Treatment- experienced pts with GT 2/3 HCV (N = 201) Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day (n = 103) Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day (n = 98) Wk 16 Wk 12 Placebo Stratified by HCV GT (2 vs 3), cirrhosis (yes vs no)

46 FUSION: Overall Efficacy Outcomes of Sofosbuvir + RBV in GT 2/3 Nelson D, et al. EASL 2013. Abstract 6. 97/10093/95100/10095/95 Wk 4End of Treatment HCV RNA < LLOQ (%) SVR12 50/10069/95 n/N = Sofosbuvir + RBV 12 wksSofosbuvir + RBV 16 wks 100 80 60 40 20 0 97 98 100 50 73

47 FUSION: SVR12 With Sofosbuvir + RBV by Genotype and Fibrosis Level Nelson D, et al. EASL 2013. Abstract 6. 6/105/26 SVR12 (%) 25/267/923/2314/3814/2325/40 No Cirrhosis Sofosbuvir + RBV 12 wksSofosbuvir + RBV 16 wks No CirrhosisCirrhosis Genotype 2 Genotype 3 19 61 63 37 n/N = 100 80 60 40 20 0 96 100 60 78 100 80 60 40 20 0 SVR12 (%)

48 POSITRON: Sofosbuvir + RBV for 12 Wks in GT 2/3 IFN-Unwilling/Intolerant/Ineligible  Randomized, double-blind, placebo-controlled phase III trial Jacobson I, et al. EASL 2013. Abstract 61. IFN unwilling, intolerant, or ineligible pts with GT 2/3 HCV (N = 278) Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day (n = 207) Placebo (n = 71) Wk 12 Stratified by cirrhosis (yes vs no)

49 POSITRON: Virologic Response in GT 2/3 IFN- Unwilling/Intolerant/Ineligible  SVR12 0% for placebo Jacobson I, et al. EASL 2013. Abstract 61. 202/ 204 202/ 202 Wk 4EOT HCV RNA < LLOQ (%) SVR12 161/ 207 n/N = Overall Outcomes GT 2GT 3 SVR12 (%) 85/9216/1757/843/14 No cirrhosis Cirrhosis 100 80 60 40 20 0 99 100 78 100 80 60 40 20 0 9294 68 21

50 Topline Summary of Sofosbuvir Trials TrialPatient PopulationnRegimenDuration, WksSVR12, % NEUTRINO [1] Tx-naive GT 1292SOF + P/R1289 Tx-naive GT 428SOF + P/R1296 Tx-naive GT 5/67SOF + P/R12100 FISSION [2] Tx-naive GT 270SOF + RBV1297 Tx-naive GT 3183SOF + RBV1256 FUSION [3] Tx-experienced GT 2 36SOF + RBV1286 Tx-experienced GT 3 64SOF + RBV1230 Tx-experienced GT 2 32SOF + RBV1694 Tx-experienced GT 3 63SOF + RBV1662 POSITRON [4] IFN-UII GT 2109SOF + RBV1293 IFN-UII GT 398SOF + RBV1261 1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Gane E, et al. EASL 2013. Abstract 5. 3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61.

51 Placebo + P/R (n = 133) Wk 12 *RGT: At Wk 12, patients with ETS continued P/R to Wk 24; patients without ETS continued triple therapy to Wk 24 followed by P/R to Wk 48. † RGT: At Wk 24, patients with ETS stopped treatment; patients without ETS continued P/R to Wk 48. ETS defined as HCV RNA < 25 IU/mL at Wk 4 and HCV RNA < 25 IU/mL, target not detected at Wk 8. Wk 24Wk 48 P/R Ferenci P, et al. EASL 2013. Abstract 1416. STARTVerso1: Faldaprevir + P/R RGT in Treatment-Naïve in GT 1 HCV  Final results of phase III STARTVerso1 trial –78% were white, 81% Europe, 19% Japan; 66% had GT 1b HCV; 39% had IL28B CC; 6% were cirrhotic Treatment-naive patients with GT 1 HCV (N = 656) Faldaprevir 120 mg QD + P/R* (n = 261) Faldaprevir 240 mg QD + P/R (n = 262) Placebo + P/R † Faldaprevir + P/R P/R Placebo + P/R P/R

52 STARTVerso1: SVR12 According to ETS, Genotype, and Fibrosis Level  23% of pts with GT 1a HCV had Q80K at baseline; not predictive of SVR12 Ferenci P, et al. EASL 2013. Abstract 1416. 60/ 87 16/ 45 143/ 171 52/ 86 172/ 212 30/ 45 9/ 16 FDV 120 mg n/ N = 226/ 259 233/ 261 194/ 226 208/ 233 100 80 60 40 20 0 Patients (%) Achieved ETS SVR12 in ETS Pts 87 89 86 89 100 80 60 40 20 0 SVR12 (%) GT 1aGT 1b 69 36 84 60 FDV 240 mgPlacebo 81 67 56 < F3≥ F3F4 ETS defined as HCV RNA < 25 IU/mL at Wk 4 and HCV RNA < 25 IU/mL, target not detected at Wk 8.

53 Summary of Safety Data with Faldaprevir  FDV + PR relatively safe and well tolerated –Most frequent AEs: gastrointestinal events, rash, and jaundice  Transient, dose-dependent bilirubin increases, primarily in FDV 240-mg arm –Not associated with concomitant increases in other liver parameters Ferenci P, et al. EASL 2013. Abstract 1416. Safety Outcome, % FDV 120 mg + PR (n = 259) FDV 240 mg + PR (n = 261) PR (n = 132) Serious AE776 AEs leading to discontinuation of all drugs454 AEs leading to discontinuation of FDV or placebo130 Grade 2-4 AEs*525548  Anemia131211  Gastrointestinal events7123  Rash896  Jaundice230  Photosensitivity010 Grade 3/4 laboratory abnormalities*  Total bilirubin12531 Rash323322  Grade 2-4 rash*896 *AEs graded according to Division of AIDS grading system.

54 Summary of Safety Findings From Phase III Trials  Sofosbuvir [1-4] –Generally well tolerated; low rates of grade 3/4 AEs, serious AEs, and treatment discontinuation due to AEs; improved profile with SOF/RBV vs pegIFN/RBV  Greatly improved Hb profile with simeprevir and faldaprevir vs boceprevir/telaprevir with no significant increase over pegIFN/RBV [5-7]  Simeprevir [5,6] –Generally well tolerated; no added safety signals with triple therapy  Faldaprevir [7] –Generally well tolerated (clinically benign and transient bilirubin increases with 240 mg dose; higher incidence of gastrointestinal events and rash) 1. Lawitz E, et al. NEJM 2013;368:1878-87. 2. Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. 5. Jacobson I, et al. EASL 2013. Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract 1416.

55 Summary of Resistance Findings From Phase III Trials  Sofosbuvir [1-4] –No S282T mutations identified; other NS5B genetic variants not associated with change in phenotypic susceptibility  Simeprevir [5,6] –Baseline Q80K polymorphism present in 41% of patients with GT 1a HCV and associated with lower SVR12 rate in QUEST-1 [5] –Emergent NS3 protease mutations in > 90% of patients without SVR (GT 1a: R155K alone, with mutations at positions 80 and/or 168; GT 1b: most common mutation D168V, Q80R + D168E) [5,6]  Faldaprevir [7] –Baseline Q80K present in 23% of patients with GT 1a HCV but not associated with SVR12 rate 1. Lawitz E, et al. NEJM 2013;368:1878-87. 2. Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. 5. Jacobson I, et al. EASL 2013. Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract 1416.

56 Summary of DAAs Clinical Trials- Up to 2013-10

57 Triple DAA with Peg-IFN + RBV Therapy for Untreated and Treated HCV Patients StudyPatientsTreatmentDrug classSVR (%) PILLAR G1, naïveSMV vs. PlaceboPI86 vs. 65 SILEN-C1 G1, naïveFDV vs. PlaceboPI83 vs. 56 ATLAS G1, naïveDNVr vs. PlaceboPI83 vs. 43 MATTERHORN G1, partialDNVrPI56 NEXT-1 G1, naïveNarlaprevir vs. placeboPI85 vs. 28 MK-7009 G1, naiveVNR vs. placeboPI61-84 vs. 63 ABT-450 G1, naiveABT450r vs. placeboPI88 vs. 9 AI447016 G1, naiveASV vs. placeboPI92 vs. 46 COMMAND-1 G1, naiveDCV vs. placeboNS5A83 vs. 25 D-LITE G1, naiveDCVNS5A76 PROTON G1, naiveSOF vs. placeboNI91 vs. 58 ATOMIC G1, naiveSOFNI97 NEUTRINO G1, naïveSOFNI90 ELECTRON G2/3, naïveSOFNI100 JUMP-C G1, naïveMCB vs. placeboNI58 vs. 36 ESSENTIAL G1. naïveALVCI76 vs. 55 Dabbouseh NM, et al. Nat Rev Gastroenterol Hepatol 2013;10:268-76

58 Quadruple DAA with Peg-IFN + RBV Therapy for Untreated and Treated HCV Patients StudyPatientsTreatmentDrug classSVR (%) ZENITH G1, naïveTVR, VX-22PI, NNPI83-90 AI447017 G1, nullASV, DCVPI, NS5A95 GILEAD G1, naïveGS-9256, tegobuvirPI, NNPI98 MATTERHORN G1 partialDNVr, MCBPI, NI86 G1, nullDNVr, MCBPI, NI84 Dabbouseh NM, et al. Nat Rev Gastroenterol Hepatol 2013;10:268-76

59 IFN Free Therapy for Untreated and Treated HCV Patients StudyPatientsTreatmentDrug classSVR (%) Triple DAA G1, naïveASV, DCV, BMS-791325PI, NS5A, NNPI94 Lok G1, nullASV, DCVPI, NS5A36 Co-Pilot G1, naïveABT450r, ABT333, RBVPI, NNPI, RBV95 G1, NRABT450r, ABT333, RBVPI, NNPI, RBV47 Pilot G1, naïveABT-450r, ABT072, RBVPI, NNPI, RBV91 AVIIATOR G1, naïveABT450r, ABT267, ABT333, RBVPI, NS5A, NNPI, RBV97 G1, nullABT450t, ABT267, ABT333, RBVPI, NS5A, NNPI, RBV36 INFORM G1, naïveDNVr, MCBPI, NIDiscontinued G1, naïveDNVr, MCB, RBVPI, NI, RBV41 MATTERHORN G1b, partialDNVr, MCB, RBVPI, NS5A, RBV39 G1b, nullDNVr, MCB, RBVPI, NI, RBV55 SOUND-C2 G1a, naïveFaldaprevir, BI207127, RBVPI, NNPI, RBV43 G1b, naïveFaldaprevir, BI207127, RBVPI, NNPI, RBV83 G1, cirrhosisFaldaprevir, BI207127, RBVPI, NNPI, RBV54-57 VITAL-1 G2/3, naïveALV, RBVCI, RBV88 Dabbouseh NM, et al. Nat Rev Gastroenterol Hepatol 2013;10:268-76

60 IFN Free Therapy for Untreated and Treated HCV Patients StudyPatientsTreatmentDrug classSVR (%) AI444-04 G1, naïveDCV, SOFNS5A, NI100 G1, naïveDCV, SOF, RBVNS5A, NI, RBV100 G2/3, naïveDCV, SOFNS5A, NI88-100 G2/3, naïveDCV, SOF, RBVNA5A, NI, RBV86 ELECTRON G1, naïveSOF, RBVNI, RBV88, 84 G1, naïveGS5885, RBVNS5A, RBV100 G2/3, naïveSOF, RBVNI, RBV100 G1, nullSOF, RBVNI, RBV10, 10 G1, nullGS5885, SOF, RBVNS5A, NI, RBV100 G2/3, experiencedSOF, RBVNI, RBV80, 68 FISSION G2/3, naïveSOF, RBVNI, RBV67 FUSION G2/3, experiencedSOF, RBVNI, RBV50, 73 POSITRON G2/3, ineligible, intolerant, unwilling SOF, RBVNI, RBV78 Gilead-QUAD G1, naïveGS9451, GS5885, GS9190, RBVPI, NS5A, NNPI, RBV100 Dabbouseh NM, et al. Nat Rev Gastroenterol Hepatol 2013;10:268-76


Download ppt "1 Sheng-Shun Yang, M.D., Ph.D. Division of Gastroenterology & Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung,"

Similar presentations


Ads by Google