novel direct acting antivirals against...

Novel Direct Acting Antivirals against HCV

2nd Asian Conference on Hepatitis and HIV, Beijing, China

Jürgen Rockstroh, Department of Medicine I,

University of Bonn, Germany

Predictors of Mortality Among US HCV Infected Veterans

195,585 HCV Patients 202,739 HCV Negative Veterans

All cause mortality 43.9 per 1000

person-years

HCV Positive

All cause mortality 24 per 1000

person-years

Erqou S, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 453.

HCV Negative

Predictors of Mortality Among US HCV Infected Veterans: Results

Predictor Hazard ratio (95 % CI)

Decompensated Liver Disease 3.05 (2.97-3.14)

Anemia 2.03 (1.98-2.08)

Cancer 1.72 (1.67-1.77)

Chronic Kidney Disease 1.42 (1.38-1.46)

COPD 1.40 (1.35-1.44)

HCV Treatment 0.43 (0.41-0.46)

Erqou S, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 453.

Treatment of HCV disease is evolving

Patients achieving SVR (%)

100

80

60

40

20

0 24 48 78 Peg-IFN IFN +

ribavirin Peg-IFN + ribavirin Weeks

IFN monotherapy

All genotypes Genotype 1 Genotypes 2 or 3

6-19 11-19 10-22

18-39 35-43

61-79

33-36

76-82

42-46

*Range of values reported; lower bar represents lower value;

Manns MP, Foster GR, Rockstroh JK, et al: Nature Reviews Drug Discovery, 2008

Why do we need new treatments ?

• Improvement of SVR

• Reduction of adverse effects

• Reduction of treatment duration

• Reduction of cost

• Non-Responders to PEG-IFN plus Ribavirin

• Difficult to treat populations

BUT: SVR rates in difficult-to-treat populations !!!

*Range of values reported; bar represents higher value Carrat F et al. JAMA 2004; Torriani FJ et al. NEJM 2004; Brau N et al. J Viral Hepat 2006; Conjeevaram HS et al. Gastroenterology 2006; Jeffers LJ et al. Hepatology 2004; Harrison SA et al. Clin Gastroenterol Hepatol 2005; Horoldt B et al. Liver Int 2006; Berenguer M et al. Liver Transpl 2006

SVR rate (%)

Advanced fibrosis / cirrhosis

HIV coinfected

African Americans

Steatosis Liver transplant

17–29* 6–28*

44–62*

50

23

42 35

39 31

60

0

20

40

60

80

100 Genotypes 1 or 4 Genotypes 2, 3 or 5

The new DAAs……………..

Protease- Inhibitors Polymeraseinhibitors

NI NNI

NS5A-Inhibitors

TLR-Agonists Therapeutic Vaccine

Other IFNs PEG-IFN lambda

Entry-Inhibitors

Cyclophillin Inhibitors

Ribavirin

HCV Protease inhibitors

»Telaprevir (licensed in US and Europe) »Boceprevir (licensed in US and Europe) »TMC 435350 (Simeprevir) (phase III) »BI 201335 (Feldaprevir) (phase III)

New Standard Treatment Triple-Therapy Protease-Inhibitor + PEG-IFN & Ribavirin

Jacobson et al. NEJM 2011

Sust

aine

d vi

rolo

gic

resp

onse

Response guided

TVR 12 wks + PEG2a

+ Riba

75% 69%

44%

PEG2a + Riba

(48 wks)

Response guided

TVR 8 wks + PEG2a

+ Riba

Poordad et al. NEJM 2011

Response guided LI BOC

+ PEG2b + Riba

63% 66%

38%

PEG2b + Riba

(48 wks)

LI BOC + PEG2b

+ Riba (48 wks)

TVR TVR SOC BOC BOC SOC

Telaprevir ADVANCE

RGT, TVR 12 vs. 8 wks

Boceprevir SPRINT-2

Lead-in(LI), RGT vs. non-RGT

Treatment-naive HCV genotype 1 patients

New Standard Treatment Triple-Therapy Protease-Inhibitor + PEG-IFN & Ribavirin

0

20

40

60

80

100

Sust

aine

d vi

rolo

gic

resp

onse

15% 24%

REL

57%

31%

86%

TVR SOC

5%

P-NR NULL

Relapser (REL): negative at end-of-treatment but relapse thereafter Partial Non-Responder (P-NR): ≥2log wk12 but pos HCV RNA wk 24 Null-Responder (NULL): <2log wk 12

TVR SOC TVR SOC 0

20

40

60

80

100

7%

29%

REL

BOC SOC

P-NR NULL

BOC SOC

75%

52%

Bacon et al., NEJM 2011 *PROVIDE study, Vierling et al., AASLD 2011 Zeuzem et al., NEJM 2011

36%*

Treatment-experienced HCV genotype 1 patients

Telaprevir REALIZE

+/- Lead-in TVR 12 + PEG2a + Riba, 48 weeks

Boceprevir REPOND-2/PROVIDE

Lead-in (+/-RGT) BOC + PEG2b + Riba, 36/48 weeks

OPTIMIZE Study: Efficacy of TVR Dosed BID (1125mg) vs. q8h (750mg)

Buti M, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 798.

q8h

bid

CC and F0-F2

CC and F3-F4

Non-CC and F0-F2

Non-CC and F3-F4

N 79 75 29 28 183 192 79 74

SVR

12 (P

erce

ntag

e)

CUPIC: Virological response (ITT)

Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

TELAPREVIR BOCEPREVIR

0

10

20

30

40

50

60

70

80

90

100

49%

Patie

nts

with

und

etec

tabl

e H

CV

RN

A (P

erce

ntag

e)

79% 81%

56%

W4 W8 W12 W24 W48 W60 W16

77 % 68 %

146 295

234 295

239 295

227 295

200 295

165 295

118 295

0

10

20

30

40

50

60

70

80

90

100

16%

51%

62% 65% 67%

W4 W8 W12 W16 W24 W48 W60

31 190

97 190

118 190

124 190

128 190

108 190

57%

79 190

40% 41%

CUPIC: SVR12 According to Prior Treatment Response


61/116 43/135 8/28

Relapsers

Partial responders

Null responders

53%

32% 29%

P=0.004

P=0.001

P=0.03

TELAPREVIR TELAPREVIR

0

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

31 190

43/85 32/80 1/9

P=0.003

51%

40%

11%

BOCEPREVIR

Relapsers

Partial responders

Null responders

CUPIC: SVR12 Safety Findings Patients, n (% patients with at least one event) Telaprevir n=295 Boceprevir n=190

Serious adverse events (SAEs)* 535 in 160 patients (54.2%)

321 in 97 patients (51.0%)

Premature discontinuation / due to SAEs

139 (47.1%) / 63 (21.3%)

80 (42.1%)/ 27 (14.2%)

Death 7 (2.4 %) 3 (1.6%)

Infection (Grade 3/4) 27 (9.1 %) 8 (4.2%)

Hepatic decompensation (Grade ¾ ) 15 (5.1 %) 9 (4.7%)

Anemia (Grade ¾ : Hb < 8 g/dL) 38 (12.9 %) 19 (10%)

Rash (grade 3/SCAR) 16 (5.4 %)/ 2 (0.6 %) 2 (1.0%)/

EPO use / blood transfusion

168 (57 %) / 53 (18 %)

119 (62.6%) / 26 (13.7%)

GCSF use 8 (2.7 %) 13 (6.8%)

TPO use 6 (2 %) 3 (1.6%)


SAEs in patients SCAR: severe cutaneous adverse reaction

Introduction to Faldaprevir

»Faldaprevir (FDV; BI 201335) is a potent and selective inhibitor of HCV NS3/4A1

»FDV has antiviral activity against HCV genotypes (GT) 1, 2, 4, 5 and 6 in vitro1

»The pharmacokinetics of FDV allow oral, once-daily administration

» In Phase II FDV + pegylated interferon α2a and ribavirin (PegIFN/RBV) demonstrated: Significantly higher sustained virological response (SVR) versus placebo2

Favourable safety and tolerability profile versus placebo2

»Three Phase III trials of FDV + PegIFN/RBV in HCV GT-1 are complete A further Phase III trial of FDV + PegIFN/RBV in HIV co-infection is ongoing FDV is also being investigated in Phase III interferon-free trials

HCV, hepatitis C virus 1. White PW, et al. Antimicrob Agents Chemother 2010;54:4611–4618; 2. Sulkowski et al Hepatology 2013 Jan 28 (epub)

STARTVerso1: Treatment-naïve patients

• Patients enrolled from Europe and Japan • Eligibility: Treatment naive, GT1 infection, no HBV or HIV coinfection, adult, platelets

>90,000 cells/mm3 • Criteria for response guided therapy

– Early Treatment Success (ETS): HCV RNA <25 IU/mL at Week 4 and undetectable at Week 81 – Patients with ETS in active treatment arms were eligible to stop all treatment at Week 24

• Primary endpoint: SVR 12 weeks after completion of all treatment

PegIFN/RBV Placebo + PR Observation Period

Day 1 Week 12 Week 24 Week 48 Week 72

Faldaprevir 240 mg QD + PR

Observation Period

Placebo + PR

PegIFN/RBV Observation Period

ETS

No ETS

Arm 2 (n=261)

Arm 3

(n=262)

Arm 1

(n=133)

Observation Period

Faldaprevir 120 mg QD + PR

PegIFN/RBV Observation Period

ETS

No ETS Faldaprevir 120 mg QD + PR

Placebo + PR

Ferenci P, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1416. 1 Roche COBAS® Taqman HCV/HPS assay

STARTVerso1: Primary Endpoint SVR12 (ITT)

(∆ = 28.6; 95% CI, 19.0–38.2; p <0.0001)

(∆ = 26.7; 95% CI, 17.1–36.3; p <0.0001)

SVR12 rates adjusted for race and genotype ITT, intention-to treat

204/259 210/261 69/132

SVR

12 (%

)

Ferenci P, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1416.

QUEST-1: Trial Design for GT1, Treatment Naïve Patients

» RGT in simeprevir arm: if HCV RNA <25 IU/mL at week 4 and undetectable at Week 12, complete treatment at Week 24

» Stopping rules: if HCV RNA > 1000 IU/mL Week 4. stop SMV/placebo; if HCV RNA <2log10 IU/mL reduction at Week 12, or confirmed >25 IU/mL at Week 24 or 36, stop all treatment

PR, peginterferon a-2a 180µg/wk + ribavirin 1000-1200mg/day; QD, once daily..

SMV 150mg QD+PR PR

PR

Post-Therapy Follow-Up Post-Therapy Follow-Up

Response Guided Treatment

N=264

Placebo + PR PR PR Post-Therapy Follow-Up N=130

0 12 24 48 72 Weeks

Jacobson I, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1425.

QUEST-2: Trial Design for GT1, Treatment Naïve Patients

» Patients were stratified by HCV subtype and IL28B genotype » 63% of patients were randomized to receive SMV or placebo + PeglFNα-2a/RBV » Response-Guided Therapy (RGT) criteria: HCV RNA <25 IU/mL detectable

or undetectable at Week 4 and <25 IU/mL undetectable at Week 12 » Primary Endpoint: SVR12 (determined 12 weeks after planned end of

treatment)

HCV RNA was assessed using Roche COBAS Taqman HCV/HPS v2.0 assay

SMV 150mg QD+PR PR

PR

Post-Therapy Follow-Up Post-Therapy Follow-Up

Response Guided Treatment

N=257

Placebo + PR PR PR Post-Therapy Follow-Up N=134

0 12 24 48 72 Weeks

Manns M, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1413.

QUEST-1 and QUEST-2: Simeprevir (PI) + Peg-IFN + RBV in Treatment-naive GT1

n/N = 211/ 264

208/ 257

67/ 134

65/ 130

85-91% qualified for shortened therapy

Manns M, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1413. Jacobson I, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1425.

»Toxicity: Rash, Pruritis, Anaemia

»Resistence

»Pharmacokinetic profile

»Compliance

»Cost

»Benefit for non-responders ???

LIMITATIONS OF HCV PIs

Polymerase Inhibitors

• Nucleoside analogues

– Require conversion to active triphosphate form – Cause chain termination

• Non-nucleosides – Active at noncatalytic sites – Do not require triphosphate conversion

NEUTRINO Study: Design

»Open label SOF 400 mg QD + Peg-IFN-alfa-2a 180 µg/week + RBV 1000‒1200 mg/day for 12 weeks (no response-guided therapy)

»Treatment-naïve, genotype 1, 4, 5, and 6 HCV-infected patients Targeted 20% enrollment of patients with cirrhosis

»Expanded inclusion criteria No upper limit to age or BMI Opiate replacement therapy permitted Platelets ≥90,000/mm3, neutrophils ≥1500/mm3 or 1000/mm3 (blacks)

SVR12 SOF + Peg-IFN + RBV, n=327

Week 0 12 24

Lawitz E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1411.

NEUTRINO Study: Demographics

SOF + Peg-IFN + RBV N=327

Mean age, y (range) 52 (19‒70)

Male, n (%) 209 (64)

Black, n (%) 54 (17)

Hispanic, n (%) 46 (14)

Mean BMI, kg/m2 (range) 29 (18‒56)

IL28B CC, n (%) 95 (29)

GT 1, n (%) 292 (89)

GT 4/5/6, n (%) 35 (11)

Mean baseline HCV RNA, log10 IU/mL (range) 6.4 (2.1‒7.6)

Cirrhosis, n (%) 54 (17)


NEUTRINO Study: SVR12 by HCV Genotype

Patie

nts

with

HC

V R

NA

<LLO

Q

(%)

Overall GT 1 GT 4

Error bars represent 95% confidence intervals.

GT 5,6

295/327 261/292 27/28 7/7


NEUTRINO Study: Virologic Response by Cirrhosis Status

Post-treatment On treatment

Patie

nts

with

HC

V R

NA

<LLO

Q (%

)

50/54 52/54 53/53

Week 2 Week 4 Week 12 Week 12

43/54 249/273 269/271 267/267 252/273



Week 0 12 24 36

FISSION Study: Treatment Naïve, Genotype 2 or 3 Patients

SOF + RBV n=256

Peg-IFN + RBV n=243

Mean age, y (range) 48 (20‒72) 48 (19‒77)

Male, n (%) 171 (67) 156 (64)

White, n (%) 223 (87) 212 (87)

IL28B CC, n (%) 108 (43) 106 (44)

GT 3, n (%) 183 (72) 176 (72)

Mean HCV RNA, log10 IU/mL (range) 6.0 (3.2‒8.3) 6.0 (3.2‒7.6)

Cirrhosis, n (%) 50 (20) 50 (21)

SOF + RBV*, n=256 SVR12

Peg-IFN + RBV* (SOC), n=243 SVR12

*RBV dose 1000-1200 mg/day for SOF + RBV and 800 mg/day for Peg-IFN + RBV

Gane E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 5.

98 82

91

62

61 71

34 30

0

20

40

60

80

100

SOF + RBV Peg-IFN + RBV

GT 2 GT 3

SVR

12 (P

erce

ntag

e)

No cirrhosis No cirrhosis Cirrhosis Cirrhosis

FISSION: SVR12 by Genotype and Cirrhosis

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



ELECTRON: Sofosbuvir + Ledipasvir or GS-9669: 12 week Regimens in GT1

SOF + RBV SOF + LDV + RBV SOF + GS-9669 + RBV

Naïve (n=25)

Null (n=10)

Naïve (n=25)

Null (n=9)

Naïve (n=25)

Null (n=10)

Week 1 8/25 (32) 1/10 (10) 11/25 (44) 0/9 (0) 3/25 (12) 0/10 (0)

Week 2 17/25 (68) 7/10 (70) 22/25 (88) 4/9 (44) 15/25 (60) 2/10 (20)

Week 4 25/25 (100) 10/10 (100) 25/25 (100) 8/9 (89) 23/25 (92) 10/10 (100)

EOT 25/25 (100) 10/10 (100) 25/25 (100) 9/9 (100) 25/25 (100) 10/10 (100)

SVR4 22/25 (88) 1/10 (10) 25/25 (100) 9/9 (100) 23/25 (92) 10/10 (100)

SVR12 21/25 (84) 1/10 (10) 25/25 (100)† 9/9 (100) 23/25 (92) 3/3

Patients with HCV RNA <LOD* over time, n/N (%)


* Analyzed by TaqMan® HCV Test 2.0 with limit of detection (LOD) of 15 IU/mL. † Includes 1 patient who stopped all treatment due to a serious adverse event (AE) at Week 8; this patient subsequently achieved SVR12. EOT, end of treatment; SVR4, sustained virologic response 4 weeks after EOT.

* 8 patients with SVR12 have not returned for >24 weeks and are counted as virologic failures for SVR24; 3 patients relapsed between SVR12 and SVR24.

Trea

tmen

t-naï

ve ABT-450 ABT-333 RBV

ABT-450 ABT-267 ABT-333 RBV


ABT-450 ABT-267 ABT-333

ABT-450 ABT-267 RBV

N ABT-450 ABT-267 ABT-333 RBV

Wk 0 Wk 8 Wk 12 Wk 24

80

79

79

79

80

41

Regimen/Duration

Nul

l R

espo

nder

ABT-450 ABT-267 RBV


45

45

43 ABT-450 ABT-267 ABT-333 RBV

SVR12 %

SVR24* %

Breakthrough/Relapse

89 88 0 / 10

85 83 1 / 4

91 89 1 / 8

90 87 1 / 5

99 96 0 / 1

93 90 0 / 2

89 89 0 / 5

93 93 3 / 0

98 95 1 / 0

AVIATOR Study: ABT-450/r, ABT-267, ABT-333 +/- RBV in Non-Cirrhotic, Naïve and Null Responders

Kowdley K, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 3.

N = 571

Daclatasvir Plus Sofosbuvir ± RBV in GT1 who Previously Failed Telaprevir or Boceprevir

41 adult HCV GT1-infected patients who had virologic non-response, relapse, or breakthrough during prior treatment with TVR or BOC + pegIFN/RBV were treated with:

– Daclatasvir (DCV): 60 mg QD NS5A replication complex inhibitor

– Sofosbuvir (SOF): 400 mg QD NS5B nucleotide inhibitor

with or without RBV for 24 weeks of therapy

Key Safety Findings: No patients discontinued due

to adverse events (AEs) Most common AEs (≥30% total)

were fatigue and headache No Grade 3/4 hematologic or

hepatic laboratory abnormalities

DCV + SOF

DCV + SOF + RBV 12-week Follow-up

12-week Follow-up Additiona

l follow-up to SVR48

0 12

24 SVR12

Weeks

Primary endpoint: SVR12

(n=21)

(n=20)

SVR4

Sulkowski M, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1417.

Key Demographics:

83% (34/41) GT1a

Mean baseline HCV RNA

6.3 log10 IU/mL

98% (40/41) IL-28B “non-CC”

0

20

40

60

80

100

EOT

HCV

RNA

< LL

OQ

(Pe

rcen

tage

of p

atie

nts)

Week 2 SVR4

N =

Week 4

21 20

SVR12

100 100 100 100

21 20 21 20 21 20 21 20

DCV + SOF

100

91

80

95 100 95*

DCV + SOF in Telaprevir or Bocepevir PR failures: SVR

Sulkowski M, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1417.

* 1 patient missing at post-treatment (PT) Week 12: HCV RNA was undetectable at PT Week 4 and at PT Week 24 21/41 patients have reached PT Week 24; all have achieved SVR24

DCV + SOF + RBV Missing

»Triple therapy (PEG-IFN + RIBA + DAA) for GT1

»Slightly higher SVR in naive genotype 1 patients

»Shorter duration of treatment: 24 weeks

»2nd wave Pis promise better tolerability

»Simplified administration

»Additional Cost

What do the new DAAs promise for the near future ?

novel direct acting antivirals against...

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