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

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

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]

– 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]

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.

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

Outline

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

慢性 C 型肝炎治療里程碑

0

20

40

60

80

100

IFN 6m IFN 12m IFN / RBV 6 m IFN / RBV 12m PEG-IFN 12m PEG-IFN / RBV 12m

PEG-IFN / RBV /DAA 12m

Su

stai

ne

d V

iro

log

ic R

esp

on

se (

%)

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

治療 C 型肝炎之病毒動力學

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;56:532-43Kraus MR, et al. Hepatology 2013;58:497-504; Brandman et al. Diabetes Care 2012;35(5):1090-4Van der Maar, et al. JAMA 2012;308:2584-93.

• 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;461:399-401.

Modified from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

SVR, %

IFN Monotherapy

PegIFNPegIFN+ RBV

(Taiwan)

PegIFN+ RBV(West)

24 wks 48 wks 78 wks

All genotypes 6-19 11-19 10-22 18-39 -- --

GT1 (48 wks) -- -- -- -- 75-80 42-46

GT2/3 (24 wks) -- -- -- -- 85-90 76-82

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 SOCNull/partial responders, relapsers

Unwilling, intolerant, ineligible‘Difficulty-to-treat’ (cirrhotics, HIV coinfected, post LT

recurrent, renal transplant candidates & HCV infected post kidney transplantation)

部分地區或國家上市 DAAs

Boceprevir (BOC)Telaprevir (TVR)

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

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 480 24124

eRVR; stop at Wk 24, f/u 24 wksPegIFN + 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 RNA TVR + PegIFN/RBV PegIFN/RBV TotalDuration

Undetectable* at wks 4 and 12 First 12 wks Additional 12 wks 24 wks

Detectable (but ≤ 1000 IU/mL) at wks 4 and/or 12 First 12 wks Additional 36 wks 48 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

75

44

P < .001

SV

R (

%)

0

20

40

60

80

100T12PRPR

ADVANCE: TVR + PegIFN/RBV in Treatment-Naïve Genotype 1

271/363 158/361n/N =

Jacobson IM, et al. NEJM 2011;364:2405-2416.

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)

Rash 56 34

Anemia† 36 17

Anorectal events 29 7

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.

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

Wks480 28124

PegIFN + RBV


PegIFN + RBV

8 36


Boceprevir [package insert]. May 2011. Merck & Co’s Victrelis.

24

F/u 24 wks

Boceprevir + PR: 持續病毒反應率

P < .001

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

SV

R (

%)

PR48 BOC RGT

100

80

60

40

20

0BOC/PR48

40

67 68

SV

R (

%)

PR48 BOC RGT

100

80

60

40

20

0BOC/PR48

23

4253

n/N = 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* 50 30

Neutropenia 25 19

Dysgeusia 35 16

*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

Wks480 24124

PegIFN + RBV

Telaprevir [package insert]. May 2011.

100

0

60

SV

R (

%)

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 Relapsers Previous Partial Responders

n/N =

Previous Null Responders

*P < .001 vs placebo/PR48.

REALIZE: TVR + PegIFN/RBV in Genotype 1 Previous Relapsers and Nonresponders

4/2729/49 26/48 2/3721/72 25/7516/68121/145 124/141

Zeuzem S, et al. NEJM 2011;364:2417-2428.

20

83*88*

24

59*54*

15

29*33*

5

T12/PR48 Pbo/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


Wks480 28124

PegIFN + RBV


PegIFN + RBV

8 36


Boceprevir [package insert]. May 2011.

24

BOC + PR: SVR by Historical Response (Partial Responders and Relapsers*)

*Partial responders had a decrease in plasma HCV RNA of at least 2 log10 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

SV

R (

%)

Partial Responder

100

80

60

40

20

0

7

Relapser

40

52

29

6975

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 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

SV

R12

(%

)

Overall Relapsers Partial Response Null Response

40 41

53 51

3240

29

11

Telaprevir + P/RBoceprevir + 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)

NS3/4AInhibitors

NS5AAInhibitors

NS5B Polymerase Inhibitors

First generation:TelaprevirBoceprevirFirst generation, second wave:SimeprevirFaldaprevir (BI 201335)AsunaprevirABT-450/rSovaprevir (ACH-1625)Second generation:MK-5172ACH-2684

Daclatasvir (BMS 790052)Ledipasvir (GS-5885)GS-5816ABT-267ACH-3102MK-8742PPI-668Samatasvir (IDX719)

NI:Sofosbuvir (GS-7977)VX-135NNI:Deleobuvir (BI 207127)BMS 791325GS-9669TMC 647055ABT-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 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 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 24 Wk 48Wk 12

QUEST-1: Virologic Response to Simeprevir + P/R Treatment

85% of pts in SMV arm met RGT criteria

Virologic Outcomes

24 Wks 48 Wks

Jacobson I, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122.

210/264

n/N =

65/130 203/224 6/28

202/254

80

60

40

20

0

100

HC

V R

NA

Und

etec

tabl

e (%

)

Wk 4 SVR12

80

12

80

50

SMV + P/R P/R

80

60

40

20

0

SV

R12

(%

)

100 91

21

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 1122.

Differences in SVR12 by Subgroup (95% CIs)

GT 1a/other HCV With baseline Q80K vs Pbo Without baseline Q80K vs PboGT 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)

1476086117

74747456

SMV (n) Pbo (n)

Favors Placebo Favors SMV-100 -50 0 50 100

18/31n/N = 5/17188/229

60/113

82

5358

29

SMV + P/RP/R

100

80

60

40

20

0

SV

R1

2 (

%)

No Cirrhosis Cirrhosis

105/117 29/56105/147

36/74

71

49

90

52

100

60

20

0

SV

R1

2 (

%)

GT 1a GT 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

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 24 Wk 48Wk 12

Manns M, et al. EASL 2013 Abstract 1413.

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/RP/R

Overall 24 wks 48 wks

100

80

60

40

20

0

SV

R12

(%

)

81

50

86

32

209/257 67/134 202/235 7/22

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 2013. Abstract 1413.

86/107

26/57

123/150

41/77

189/231

61/119

11/17

6/15n/N =

GT 1a No Cirrhosis Cirrhosis

100

80

60

40

20

0

SV

R12

(%

)

80

46

82

65

SMV + P/RP/R

GT 1b

82

53 5140

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 72 65 70 73

Grade 3/4 AEs 23 29 26 24

Serious AEs 3 4 2 2

AEs leading to SMV/placebo discontinuation 3 3 2 1

AEs of interest

Pruritus 21 11 19 15

Rash (any type) 27 25 24 11

Anemia 16 11 14 16

Bilirubin increase 9 4 NR NR

Photosensitivity conditions 3 1 4 1

Jacobson I, et al. EASL 2013. Abstract 1425; Manns M, et al. EASL 2013. 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;368:1878-87.

P/R: pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day

HC

V R

NA

< L

LOQ

(%

) 99 9990100

80

60

40

20

0Wk 4 EOT SVR12

321/325 326/327 295/327n/N =

NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level

Lawitz E, et al. NEJM 2013;368:1878-87.

SV

R12

(%

)

92

80

100

80

60

40

20

0No

CirrhosisCirrhosis

252/273 43/54

SVR12 According to Fibrosis Level

SV

R12

(%

)

8996

100100

80

60

40

20

0GT 1 GT 4 GT 5,6

261/292 27/28 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 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 ≥ 106 IU/mL),

cirrhosis (yes vs no)

FISSION: Sofosbuvir/RBV Noninferior to P/R in Tx-Naïve GT 2/3 HCV Patients


P < .001

SVR12

On Treatment

249/250 158/236 242/244 207/224

Wk 4 Wk 24

HC

V R

NA

< L

LOQ

(%

)

188/190NA

Wk 12

170/253 162/243n/N =

Sofosbuvir + RBV PegIFN + RBV

100

80

60

40

20

0

99

67

99 9992

67 67

FISSION: SVR12 According to Genotype and Fibrosis Level


Genotype 2 Genotype 3

SV

R12

(%

)

No Cirrhosis No CirrhosisCirrhosis Cirrhosis

58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37n/N =

100

80

60

40

20

0

98

8291

62 6171

34 30

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


AEs Occurring in ≥ 15% in Either Arm, %

SOF/RBV(n = 256)

PegIFN/RBV(n = 243)

P Value

Fatigue 36 55 < .0001

Headache 25 44 < .0001

Nausea 18 29 .0057

Insomnia 12 29 < .0001

Rash 9 17 .0052

Diarrhea 9 17 .0075

Irritability 10 17 .0328

Decreased appetite 7 18 .0001

Myalgia 8 17 .0060

Pruritus 7 17 .0009

Influenzalike symptoms 3 18 < .0001

Chills 3 18 < .0001

FUSION: Sofosbuvir + RBV for 12 or 16 Wks in Tx-Experienced GT 2/3 HCV Pts


– 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)


(n = 103)


(n = 98)

Wk 16Wk 12

Placebo

Stratified by HCV GT (2 vs 3),

cirrhosis (yes vs no)

FUSION: Overall Efficacy Outcomes of Sofosbuvir + RBV in GT 2/3


97/100 93/95 100/100 95/95

Wk 4 End of Treatment

HC

V R

NA

< L

LOQ

(%

)

SVR12

50/100 69/95n/N =

Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks

100

80

60

40

20

0

97 98 100 100

50

73

FUSION: SVR12 With Sofosbuvir + RBV by Genotype and Fibrosis Level


6/10 5/26

SV

R12

(%

)

25/26 7/923/23 14/38 14/2325/40

No Cirrhosis

Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks

No CirrhosisCirrhosis Cirrhosis

Genotype 2 Genotype 3

19

6163

37

n/N =

100

80

60

40

20

0

96 100

60

78

100

80

60

40

20

0

SV

R12

(%

)

POSITRON: Sofosbuvir + RBV for 12 Wks in GT 2/3 IFN-Unwilling/Intolerant/Ineligible


Jacobson I, et al. EASL 2013. Abstract 61.

IFN unwilling, intolerant, or

ineligible pts with GT 2/3 HCV (N = 278)


(n = 207)

Placebo(n = 71)

Wk 12Stratified 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 2013. Abstract 61.

202/204

202/202

Wk 4 EOT

HC

V R

NA

< L

LOQ

(%

)

SVR12

161/207n/N =

Overall Outcomes

GT 2 GT 3

SV

R12

(%

)85/92 16/17 57/84 3/14

No cirrhosis

Cirrhosis

100

80

60

40

20

0

99 100

78

100

80

60

40

20

0

92 94

68

21

Topline Summary of Sofosbuvir Trials

Trial Patient Population n Regimen Duration, Wks SVR12, %

NEUTRINO[1]

Tx-naive GT 1 292 SOF + P/R 12 89

Tx-naive GT 4 28 SOF + P/R 12 96

Tx-naive GT 5/6 7 SOF + P/R 12 100

FISSION[2]Tx-naive GT 2 70 SOF + RBV 12 97

Tx-naive GT 3 183 SOF + RBV 12 56

FUSION[3]

Tx-experienced GT 2 36 SOF + RBV 12 86




POSITRON[4]IFN-UII GT 2 109 SOF + RBV 12 93

IFN-UII GT 3 98 SOF + RBV 12 61

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.

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 24 Wk 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

STARTVerso1: SVR12 According to ETS, Genotype, and Fibrosis Level

23% of pts with GT 1a HCV had Q80K at baseline; not predictive of SVR12


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

Pat

ient

s (%

)

Achieved ETS

SVR12 in ETS Pts

87 89 86 89 100

80

60

40

20

0

SV

R12

(%

)

GT 1a GT 1b

69

36

84

60

FDV 240 mg Placebo

81

67

56

< F3 ≥ F3 F4

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


Safety Outcome, % FDV 120 mg + PR(n = 259)

FDV 240 mg + PR(n = 261)

PR(n = 132)

Serious AE 7 7 6

AEs leading to discontinuation of all drugs 4 5 4

AEs leading to discontinuation of FDV or placebo 1 3 0

Grade 2-4 AEs* 52 55 48

Anemia 13 12 11

Gastrointestinal events 7 12 3

Rash 8 9 6

Jaundice 2 3 0

Photosensitivity 0 1 0

Grade 3/4 laboratory abnormalities*

Total bilirubin 12 53 1

Rash 32 33 22

Grade 2-4 rash* 8 9 6

*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[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.

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.

Summary of DAAs Clinical Trials-

Up to 2013-10

Triple DAA with Peg-IFN + RBV Therapy for Untreated and Treated HCV Patients

Study Patients Treatment Drug class SVR (%)

PILLAR G1, naïve SMV vs. Placebo PI 86 vs. 65

SILEN-C1 G1, naïve FDV vs. Placebo PI 83 vs. 56

ATLAS G1, naïve DNVr vs. Placebo PI 83 vs. 43

MATTERHORN G1, partial DNVr PI 56

NEXT-1 G1, naïve Narlaprevir vs. placebo PI 85 vs. 28

MK-7009 G1, naive VNR vs. placebo PI 61-84 vs. 63

ABT-450 G1, naive ABT450r vs. placebo PI 88 vs. 9

AI447016 G1, naive ASV vs. placebo PI 92 vs. 46

COMMAND-1 G1, naive DCV vs. placebo NS5A 83 vs. 25

D-LITE G1, naive DCV NS5A 76

PROTON G1, naive SOF vs. placebo NI 91 vs. 58

ATOMIC G1, naive SOF NI 97

NEUTRINO G1, naïve SOF NI 90

ELECTRON G2/3, naïve SOF NI 100

JUMP-C G1, naïve MCB vs. placebo NI 58 vs. 36

ESSENTIAL G1. naïve ALV CI 76 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


ZENITH G1, naïve TVR, VX-22 PI, NNPI 83-90

AI447017 G1, null ASV, DCV PI, NS5A 95

GILEAD G1, naïve GS-9256, tegobuvir PI, NNPI 98

MATTERHORN G1 partial DNVr, MCB PI, NI 86

G1, null DNVr, MCB PI, NI 84


IFN Free Therapy for Untreated and Treated HCV Patients


Triple DAA G1, naïve ASV, DCV, BMS-791325 PI, NS5A, NNPI 94

Lok G1, null ASV, DCV PI, NS5A 36

Co-Pilot G1, naïve ABT450r, ABT333, RBV PI, NNPI, RBV 95

G1, NR ABT450r, ABT333, RBV PI, NNPI, RBV 47

Pilot G1, naïve ABT-450r, ABT072, RBV PI, NNPI, RBV 91

AVIIATOR G1, naïve ABT450r, ABT267, ABT333, RBV PI, NS5A, NNPI, RBV 97

G1, null ABT450t, ABT267, ABT333, RBV PI, NS5A, NNPI, RBV 36

INFORM G1, naïve DNVr, MCB PI, NI Discontinued

G1, naïve DNVr, MCB, RBV PI, NI, RBV 41

MATTERHORN G1b, partial DNVr, MCB, RBV PI, NS5A, RBV 39

G1b, null DNVr, MCB, RBV PI, NI, RBV 55

SOUND-C2 G1a, naïve Faldaprevir, BI207127, RBV PI, NNPI, RBV 43

G1b, naïve Faldaprevir, BI207127, RBV PI, NNPI, RBV 83

G1, cirrhosis Faldaprevir, BI207127, RBV PI, NNPI, RBV 54-57

VITAL-1 G2/3, naïve ALV, RBV CI, RBV 88


IFN Free Therapy for Untreated and Treated HCV Patients


AI444-04 G1, naïve DCV, SOF NS5A, NI 100

G1, naïve DCV, SOF, RBV NS5A, NI, RBV 100

G2/3, naïve DCV, SOF NS5A, NI 88-100

G2/3, naïve DCV, SOF, RBV NA5A, NI, RBV 86

ELECTRON G1, naïve SOF, RBV NI, RBV 88, 84

G1, naïve GS5885, RBV NS5A, RBV 100

G2/3, naïve SOF, RBV NI, RBV 100

G1, null SOF, RBV NI, RBV 10, 10

G1, null GS5885, SOF, RBV NS5A, NI, RBV 100

G2/3, experienced SOF, RBV NI, RBV 80, 68

FISSION G2/3, naïve SOF, RBV NI, RBV 67

FUSION G2/3, experienced SOF, RBV NI, RBV 50, 73

POSITRON G2/3, ineligible, intolerant, unwilling SOF, RBV NI, RBV 78

Gilead-QUAD G1, naïve GS9451, GS5885, GS9190, RBV PI, NS5A, NNPI, RBV 100


Documents

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