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 Sheng-Shun Yang, M.D., Ph.D. Division of Gastroenterology & Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Direct Acting Antivirals for Chronic Hepatitis C
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  慢性 C 型肝炎是導致肝病重要的原因  –1/4 of the ~500,000 new HCC cases identified globally each year are attributable to HCV  預估未來幾年， C 型肝炎相關的併發症增加兩倍  預估未來幾年， C 型肝炎相關的併發症增加兩倍  C 型肝炎感染經常合併許多肝外疾病或症候  C 型肝炎感染經常合併許多肝外疾病或症候  –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: Montalto G, et al. Ann NY Acad Sci 2002;963: Milliman, Inc. Consequences of HCV: costs of a baby boomer epidemic, Jacobson IM, et al. Clin Gastroenterol Hepatol 2010;8:
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
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: Kraus MR, et al. Hepatology 2013;58: ; Brandman et al. Diabetes Care 2012;35(5): Van der Maar, et al. JAMA 2012;308:
ISDR in NS5A IL28B SNPs
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:
Modified from Manns MP, et al. Nat Rev Drug Discov. 2007;6: SVR, % IFN Monotherapy PegIFN + RBV (Taiwan) PegIFN + RBV (West) 24 wks48 wks78 wks All genotypes GT1 (48 wks) GT2/3 (24 wks) 當前 C 型肝炎標準療法及療效
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)
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 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 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
Telaprevir + PR: 基因第一型未曾治療過的病患之持續病毒反應率 SVR P <.001 SVR (%) T12PR PR ADVANCE: TVR + PegIFN/RBV in Treatment-Naïve Genotype 1 271/363158/361n/N = Jacobson IM, et al. NEJM 2011;364:
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 *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.
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 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 Merck & Co’s Victrelis. 24 F/u 24 wks
Boceprevir + PR: 持續病毒反應率 P <.001 Nonblack Patients P =.04 P =.004 Black Patients 125/ / / / 52 22/ 52 29/ 55 Poordad F, et al. NEJM 2011;364: SPRINT-2: BOC + PegIFN/RBV in Genotype 1 Treatment-Naïve Patients SVR (%) PR48 BOC RGT BOC/PR SVR (%) PR48 BOC RGT BOC/PR n/N =
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.
Triple Therapy 使用於基因第一型過去治療失敗者
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 PegIFN + RBV Telaprevir [package insert]. May 2011.
SVR (%) 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: * 88* 24 59* 54* 15 29* 33* 5 T12/PR48Pbo/PR48LI T12/PR48
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 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
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: 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 Relapser PR48 (n = 80) BOC RGT (n = 162) BOC/PR48 (n = 161) n/N =
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 Abstract 60. n/N = 118/ / / / 85 43/ / 80 8/ 28 1/ SVR12 (%) OverallRelapsersPartial ResponseNull Response Telaprevir + P/R Boceprevir + P/R Previous Response to P/R
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
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
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
即將上市 DAAs US FDA Advisory Committee, Oct 24-25, 2013 Unanimous recommendations to approve Simeprevir (SMV) Sofosbuvir (SOF)
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 ) Asunaprevir ABT-450/r Sovaprevir (ACH-1625) Second generation: MK-5172 ACH-2684 Daclatasvir (BMS ) Ledipasvir (GS-5885) GS-5816 ABT-267 ACH-3102 MK-8742 PPI-668 Samatasvir (IDX719) NI: Sofosbuvir (GS-7977) VX-135 NNI: Deleobuvir (BI ) BMS GS-9669 TMC ABT-333
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 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 mg/day. P/R Placebo + P/R (n = 130) Wk 24Wk 48Wk 12
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 / 264 n/ N = 65/ /2246/28 202/ HCV RNA Undetectable (%) Wk 4 SVR SMV + P/RP/R SVR12 (%) SVR12 by RGT Group SMV Arm: Total Duration of RGT n/ N =
QUEST-1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance Jacobson I, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 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 ( ) 4.7 (-14.6 to 24.1) 40.3 ( ) 42.1 ( ) SMV (n) Pbo (n) Favors Placebo Favors SMV /31n/N =5/17188/22960/ SMV + P/R P/R SVR12 (%) No CirrhosisCirrhosis 105/11729/56105/14736/ SVR12 (%) GT 1aGT 1b 80 40
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.
QUEST-2: Virologic Response to Simeprevir + P/R Treatment Manns M, et al. EASL Abstract 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 SVR12 (%) /25767/134202/2357/22
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 Abstract / / / / / / / 17 6/ 15 n/N = GT 1aNo CirrhosisCirrhosis SVR12 (%) SMV + P/R P/R GT 1b
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  QUEST-2  SMV + PR (n = 264) PR (n = 130) SMV + PR (n = 257) PR (n = 134) Grade 1/2 AEs Grade 3/4 AEs Serious AEs 3422 AEs leading to SMV/placebo discontinuation 3321 AEs of interest Pruritus Rash (any type) Anemia Bilirubin increase 94NR Photosensitivity conditions 3141 Jacobson I, et al. EASL Abstract 1425; Manns M, et al. EASL Abstract 1413.
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: P/R: pegIFN alfa-2a 180 µg/wk + RBV mg/day HCV RNA < LLOQ (%) Wk 4EOTSVR12 321/325326/ /327 n/N =
NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level Lawitz E, et al. NEJM 2013;368: SVR12 (%) No Cirrhosis Cirrhosis 252/27343/54 SVR12 According to Fibrosis Level SVR12 (%) GT 1GT 4GT 5,6 261/29227/28 7/7 SVR12 According to Genotype n/N =
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 Abstract 5. Treatment-naive patients with GT 2/3 HCV (N = 499) Sofosbuvir 400 mg QD + RBV 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)
FISSION: Sofosbuvir/RBV Noninferior to P/R in Tx-Naïve GT 2/3 HCV Patients Gane E, et al. EASL Abstract 5. P <.001 SVR12 On Treatment 249/250158/236242/244207/224 Wk 4Wk 24 HCV RNA < LLOQ (%) 188/190NA Wk /253162/243n/N = Sofosbuvir + RBV PegIFN + RBV
FISSION: SVR12 According to Genotype and Fibrosis Level Gane E, et al. EASL Abstract 5. Genotype 2Genotype 3 SVR12 (%) No Cirrhosis Cirrhosis 58/5944/5410/118/1389/14599/13913/3811/37n/N = Sofosbuvir + RBV PegIFN + RBV
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 Abstract 5. AEs Occurring in ≥ 15% in Either Arm, % SOF/RBV (n = 256) PegIFN/RBV (n = 243) P Value Fatigue3655 <.0001 Headache2544 <.0001 Nausea Insomnia1229 <.0001 Rash Diarrhea Irritability Decreased appetite Myalgia Pruritus Influenzalike symptoms318 <.0001 Chills318 <.0001
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 Abstract 6. Treatment- experienced pts with GT 2/3 HCV (N = 201) Sofosbuvir 400 mg QD + RBV mg/day (n = 103) Sofosbuvir 400 mg QD + RBV mg/day (n = 98) Wk 16 Wk 12 Placebo Stratified by HCV GT (2 vs 3), cirrhosis (yes vs no)
FUSION: Overall Efficacy Outcomes of Sofosbuvir + RBV in GT 2/3 Nelson D, et al. EASL 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
FUSION: SVR12 With Sofosbuvir + RBV by Genotype and Fibrosis Level Nelson D, et al. EASL 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 n/N = SVR12 (%)
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 Abstract 61. IFN unwilling, intolerant, or ineligible pts with GT 2/3 HCV (N = 278) Sofosbuvir 400 mg QD + RBV mg/day (n = 207) Placebo (n = 71) Wk 12 Stratified by cirrhosis (yes vs no)
POSITRON: Virologic Response in GT 2/3 IFN- Unwilling/Intolerant/Ineligible SVR12 0% for placebo Jacobson I, et al. EASL Abstract / / 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
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 Abstract 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
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 Abstract / 87 16/ / / / / 45 9/ 16 FDV 120 mg n/ N = 226/ / / / Patients (%) Achieved ETS SVR12 in ETS Pts SVR12 (%) GT 1aGT 1b FDV 240 mgPlacebo < 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.
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 Abstract 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* Anemia Gastrointestinal events7123 Rash896 Jaundice230 Photosensitivity010 Grade 3/4 laboratory abnormalities* Total bilirubin12531 Rash Grade 2-4 rash*896 *AEs graded according to Division of AIDS grading system.
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  –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: Nelson D, et al. EASL Abstract Nelson D, et al. EASL Abstract Jacobson I, et al. EASL Abstract Jacobson I, et al. EASL Abstract Manns M, et al. EASL Abstract Ferenci P, et al. EASL Abstract 1416.
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  –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  –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: Nelson D, et al. EASL Abstract Nelson D, et al. EASL Abstract Jacobson I, et al. EASL Abstract Jacobson I, et al. EASL Abstract Manns M, et al. EASL Abstract Ferenci P, et al. EASL Abstract 1416.
Summary of DAAs Clinical Trials- Up to
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 AI 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
Quadruple DAA with Peg-IFN + RBV Therapy for Untreated and Treated HCV Patients StudyPatientsTreatmentDrug classSVR (%) ZENITH G1, naïveTVR, VX-22PI, NNPI83-90 AI 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