Novel DAAs combined with PEG/RIBAregist2.virology-education.com/2013/3HCVad/docs/02_Wedemeyer.pdfPR, peginterferon -2a + ribavirin; SVR12, sustained virological response (HCV RNA undetectable)

1

Novel DAAs combined with PEG/RIBA

Heiner Wedemeyer Hannover Medical School

Germany

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA

Disclosures

Honoraria for consulting or speaking (last 5 years): Abbott, Abvie, Biolex, BMS, Boehringer Ingelheim, Gilead, ITS,

JJ/Janssen, Medgenics, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV

Research grants: Abbott, BMS, Gilead, Merck, Novartis, Roche, Roche

Diagnostics, Siemens


Chronic Hepatitis C: Treatment Concepts 2014/15

PEG-IFNa + Ribavirin

PEG-IFNa + Ribavirin DAA

P-IFN+RBV DAA

DAA DAAs/RBV


Role of PEG-IFNa/RBV-based therapies in 2014/15 ?

PEG-IFNa + Ribavirin


P-IFN+RBV DAA

New IFN-combinations therapies: - Less side effects - Shorter therapies - Higher efficacy - less complicated (e.g. no RGT) - less expensive (???)


Direct Acting Antivirals Against HCV

Manns, von Hahn, Nat Rev Drug Discov 2013

NS5A Inhibitors

Protease Inhibitors Polymerase Inhibitors Nucs Non-Nucs “…previrs“

“…asvirs“

“…buvirs“


Direct Acting Antivirals Against HCV


NS5A Inhibitors


“…asvirs“

“…buvirs“

Sovaprevir

MK-5172 ABT-450/r

Danoprevir Asunaprevir

Faldaprevir

Simeprevir

Telaprevir Boceprevir

Ledipasvir Daclatasvir

ABT-267

…..

BMS-731225 Deleobuvir

VX-222

ABT-333

Filibuvir Setrobuvir

….

ABT-072

Mericitabine Sofosbuvir ALS-2200


Ledipasvir

ABT-267

…..

Mericitabine

Direct Acting Antivirals Against HCV Combination with PEG-IFNa/Ribavirin


NS5A Inhibitors


“…asvirs“

“…buvirs“

Sovaprevir

MK-5172 ABT-450/r

Danoprevir Asunaprevir

Faldaprevir

Simeprevir

Telaprevir Boceprevir

Daclatasvir

BMS-731225 Deleobuvir

VX-222

ABT-333

Filibuvir Setrobuvir

….

ABT-072

Sofosbuvir ALS-2200


Combination with new protease inhibitors - Simeprevir - Faldaprevir Combination with NS5A inhibitors - daclatasvir Combination with nucleotide polymerase inhibitors - sofosbuvir

Combination of novel DAAs with PEG-IFNa/RBV


Simeprevir + Faldaprevir

• Response-guided Therapy • Phase 3 trials completed • Overall SVR around 80% • >80% qualify for shortened therapy • SVR in patients with RVR (eRVR; ETS….) >80% • Stopping rules already at week 4 • Less side effects (no anemia!!) • HIV-coinfected patients show similar response rates



Simeprevir


QUEST- 1&2: Trial designs

• Patients were stratified by HCV subtype and IL28B genotype • Quest 2: 63% of patients were randomised to receive SMV or placebo + PegIFNα-2a or

2b/RBV; the remainder received PegIFNα-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)

12 24 48 Week 72 0

Post-therapy follow-up N=134 PR Placebo + PR

Post-therapy follow-up N=257 PR

Post-therapy follow-up SMV 150 mg

QD + PR PR

PR

Response-guided treatment

Manns et al oral presentation at EASL 2013


QUEST-1: Sustained virological response (SVR12)

Jacobson et al Poster 3232 - EASL 2013

*Controlling for stratification factors PR, peginterferon -2a + ribavirin; SVR12, sustained virological response (HCV RNA undetectable) 12 weeks after planned treatment end.

80

50

0102030405060708090

100

SMV 150 mg QD + PR Placebo + PR

Pro

porti

on o

f pat

ient

s (%

)

210/264 65/130

P<0.001*


81,3

50

0

20

40

60

80

100

%

%

QUEST-2: Proportion of patients achieving SVR12 P

ropo

rtion

of p

atie

nts

(%)

*Statistically significant difference between the SMV and placebo groups

209/257 67/134

p<0.001*

SMV/PR Placebo/PR

PR, PegIFN + ribavirin;SMV, simeprevir. *Based on the Cochran-Mantel-Haensze test controlling for type of PegIFN/ribavirin and stratification factors



QUEST-2: RGT and SVR

91.4% (235/257) of patients met RGT criteria

and were eligible for 24

weeks of treatment

202/235

Pro

porti

on o

f pat

ient

s (%

)

86%

0

20

40

60

80

100 SVR12 in SMV/PR

8.6% (22/257) of patients did not meet RGT criteria – among them, 31.8% (7/22) achieved SVR12 PR, PegIFN + ribavirin; RGT, response-guided therapy; SMV, simeprevir. RGT criteria: HCV RNA

< 25 IU/mL detectable or undetectable at Week 4 and <25 IU/mL undetectable at Week 12

202/235



88.3%

77.5% 79%

62.2%

41.9%45.7%

0

20

40

60

80

100

PegIFNα-2b/RBV PegIFNα-2a/RBV, not randomised

QUEST-2: SVR12 by type of PegIFN

PegIFNα-2a/RBV

Statistically significantly higher SVR12 rates with SMV/PR compared with placebo/PR, irrespective of the type of PegIFN used

68/77 28/45 62/80 18/43 79/100 21/46

Pro

porti

on o

f pat

ient

s (%

)

p<0.001 p<0.001 p<0.001 SMV/PR Placebo/PR

PR, PegIFN + ribavirin; SMV, simeprevir. *Based on a logistic regression model with factors for treatment group, baseline HCV RNA, HCV geno/subtype, IL28B and type of PegIFN/RBV



Statistically significantly higher SVR12 rates with SMV/PR compared with placebo/PR, irrespective of HCV subtype

80.4% 82%

45.6%53.2%

0

20

40

60

80

100

QUEST-2: SVR12 by HCV subtype

1a 1b

PR, PegIFN + ribavirin; SMV, simeprevir. *Based on a logistic regression model with factors for treatment group, baseline HCV RNA, HCV geno-/subtype, IL28B and type of PegIFN/RBV

86/107 26/57 123/150 41/77

p<0.001 p<0.001 SMV/PR Placebo/PR

Pro

porti

on o

f pat

ient

s (%

)


Quest 1: 71% 1a vs. 93%1b


Faldaprevir


STARTVerso1+2: Faldaprevir in Treatment-naïve patients

Jensen et al., AASLD 2013


STARTVerso1+2: Faldaprevir in Treatment-naïve patients

SVR in Patients with ETS

Jensen et al., AASLD 2013


STARTVerso4: Faldaprevir in HCV/HIV co-infected patients

Rockstroh et al., EACS 2013



Randomisation and Allocation




SVR



Daclatasvir • Phase 3 program is ongoing („Command Studies“)

• EASL 2013: Study in Genotype 2-3 patients


■ Protocol-defined response (PDR): HCV RNA < LLOQTND or TD at Week 4 and < LLOQTND at Week 10 – DCV recipients without PDR discontinued DCV at Week 12 and received an additional 12 weeks of placebo +

peg-alfa/RBV

Primary efficacy endpoint: HCV RNA < LLOQTND 24 weeks post treatment (SVR24)

Adult treatment-naïve patients with HCV GT 2 or GT 3 infection

Randomization stratified by HCV genotype; modified intent-to-treat analysis

12 16 24 Study Week

0

16-week cohort (N = 50)

36-week follow-up

Placebo + peg-alfa/RBV

YES

NO 24-week follow-up

Control: 24 weeks (N = 51)

PDR ?

DCV + peg-alfa/RBV

12-week cohort (N = 50)

PDR ?

DCV + peg-alfa/RBV

36-week follow-up

24-week follow-up Placebo + peg-alfa/RBV

24-week follow-up Placebo + peg-alfa/RBV

YES

48

NO

Dore GJ, et al. EASL2013, Oral 1418. COMMAND GT 2/3

12-16 Weeks of Daclatasvir in Genoytpe 2/3 patients


Week 4 Week 12 End of Treatment

SVR12 SVR24a

DCV + peg-alfa/RBV, 12 weeks (N = 24)


Placebo + peg-alfa/RBV, 24 weeks (N = 24)

< LLOQTND < LLOQTD

HCV

RN

A Re

spon

se

(% o

f pat

ient

s)

aSVR24 observed values (excluding patients with missing post-treatment data): 95% (DCV 12 weeks), 100% (DCV 16 weeks), and 83% (placebo 24 weeks).

96 91

83

96 87 88

100 100 96

88 83

71

83 88

63

mITT analysis

12-16 Weeks of Daclatasvir in Genoytpe 2





Placebo + peg-alfa/RBV, 24 weeks (N = 27)

< LLOQTND < LLOQTD aSVR24 observed values (excluding patients with missing post-treatment data): 72% (DCV 12 weeks), 69% (DCV 16 weeks), and 70% (placebo 24 weeks).

Week 4 Week 12 End of Treatment

SVR12 SVR24a

92 89

48

89 96

82

100 96

85

69 78

52

70 69 59

HCV

RN

A Re

spon

se

(% o

f pat

ient

s)

mITT analysis

12-16 Weeks of Daclatasvir in Genoytpe 3



Sofosbuvir

P-IFN+RBV DAA

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87

12 24

SVR12 HCV GT 1, 4, 5, 6 Treatment-naïve

N=327

0 Study Week

SOF 400 mg QD + PEG-alfa-2a 180 µg/week +

RBV 1000‒1200 mg/day

No response guided therapy

♦ Primary endpoint: SVR12

– Prespecified comparison to historical SVR control rate of 60%

– SVR24 was also assessed

♦ Expanded inclusion criteria

– Targeted 20% enrollment of patients with cirrhosis, no upper limit to age or BMI, opiate replacement therapy permitted, platelets ≥ 90,000/mm3, neutrophils ≥ 1500/mm3 or 1000/mm3 (Blacks)

SVR24

Follow-Up 3 Years

Sofosbuvir + PEG-IFNa + Ribavirin „The Neutrino Study“


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 (SD) 6.4 (+ 0.7) Cirrhosis, n (%) 54 (17)

Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87



♦ Study met primary endpoint of superiority over historical control rate of 60% (P<0.001) On treatment

299/327 321/325 326/327

Week 2 Week 4 Week 12/EOT

Patie

nts

with

HC

V R

NA

<LLO

Q (%

)

91

SVR 12/24

296/327

♦ Relapse accounted for all virologic failures ♦ No S282T mutations observed by population or deep sequencing (1% cutoff)

>




91 9096 100

0

20

40

60

80

100

Patie

nts

with

HC

V R

NA

<LLO

Q

(%)

Overall GT 1 GT 4 GT 5,6

296/327 262/292 27/28 7/7


Sofosbuvir + PEG-IFNa + Ribavirin Response by Genotype


91 93 99 96 100 100 9380

0

20

40

60

80

100

No cirrhosis Cirrhosis

On treatment

Patie

nts

with

HC

V R

NA

<LLO

Q (%

)

50/54 52/54 53/53

Week 2 Week 4 Week 12 SVR 12/24

43/54 249/273 269/271 267/267 253/273

*SVR12 GT1 = 81%

*


Sofosbuvir + PEG-IFNa + Ribavirin Response by Cirrhosis Status

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Patel K, et al. AASLD 2013. Washington, DC. #1093

SVR12 Rates by Biopsy Fibrosis Stage (n=232)

SVR12 Rates by FibroTest Stage (n=323)

16/16 124/137 34/38 32/41 76/78 26/29 75/76 46/54 68/86 63/65 23/26 66/67 41/49 64/81

SV

R12

(%)

76/78 101/105 46/54 68/86

97 96

8579

n =0

20

40

60

80

100

()

100

91 89

78

16/16 124/137 34/38 32/41n =0

20

40

60

80

100

F1–2

F3

F4

F0

100 91 89

78

97 96

85 79

Treating at earlier stages of fibrosis is associated with higher response

Sofosbuvir + PEG-IFNa + Ribavirin Response by Fibrosis Stage


S V R 1 2 R a t e , % ( 9 5 % C I ) O v e r a l l

H C V G T

1 ( 1 a , 1 b , 1 a / b ) 1 a 1 b 4 , 5 , 6

C i r r h o s i s N o Y e s

R a c e B l a c k N o n - b l a c k

H C V R N A l e v e l < 6 l o g 1 0 I U / m L ≥ 6 l o g 1 0 I U / m L

I L 2 8 B C C N o n - C C

S O F + P E G - I F N + R B V

S V R 1 2 R A T E , % ( 9 5 % C I )

6 0 7 0 8 0 9 0 1 0 0 Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87

Sofosbuvir + PEG-IFNa + Ribavirin response by pre-specified subgroups


Sofosbuvir + PEG-IFNa/RBV

in genotype 2/3


SOF + PegIFN + RBV 1000–1200 mg

Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4

SVR12

0 12 24 Study Week

GT 2/3 TE

N=47

Open-label, Phase 2 study of the efficacy of SOF + pegylated interferon (PegIFN) + RBV for 12 weeks in treatment-experienced patients with GT 2 or 3

Mean age (range), y 56 (39‒72) Male, n (%) 32 (68) White, n (%) 45 (96) Hispanic, n (%) 21 (45) Mean BMI (range), kg/m2 31 (21‒53) IL28B CC, n (%) 17 (36) HCV GT 3, n (%) 24 (51) Mean BL HCV RNA (range), log10 IU/mL 6 (4‒7) Cirrhosis, n (%) 26 (55) Prior relapse/breakthrough, n (%) 40 (85)

No response guided therapy

36

Sofosbuvir + PEG-IFNa + Ribavirin Genotype 2/3


* The 1 cirrhotic patient who did not achieve SVR prematurely discontinued therapy without <LLOQ

22/23

96

0

20

40

60

80

100

SVR1

2 (%

)

Overall

9/9

100

Non-cirrhotic Cirrhotic

GT2

13/14*

93

37

Sofosbuvir + PEG-IFNa + Ribavirin Genotype 2



*2 relapses; 2 lost to follow-up


20/24*

83

0

20

40

60

80

100

SVR1

2 (%

)

Overall

10/12

83

Non-cirrhotic Cirrhotic

GT3

10/12

83

38

Sofosbuvir + PEG-IFNa + Ribavirin Genotype 3



Safety of DAAs + PEG-IFNa/RBV


Kidney

Heart

Brain

Liver

Direct Toxicity of

Drugs

Pancreas

Bone Marrow


QUEST-2: Incidence of AEs

Patients, % SMV/PR (N=257)

Placebo/PR (N=134)

Grade 1 or 2 AE 70.0 73.1 Grade 3 or 4 AE 25.7 23.9 Serious AE 2.3 1.5 AE leading to discontinuation of SMV* 1.6 0.7 Most common AEs (≥25% in SMV arm)

Headache 37.0 33.6 Pyrexia 30.4 35.8 Fatigue 34.6 38.8 Influenza-like illness 25.7 25.4

Other AEs of interest Rash (any type) 23.7 11.2 Anaemia 13.6 15.7 Pruritus 18.7 14.9 Photosensitivity conditions 3.9 0.7

*Without regard to PegIFN and ribavarin. AE, adverse event; PR, PegIFN + ribavirin; SMV, simeprevir

Data for the first 12 weeks of treatment are shown The majority of rash AEs in the SMV/PR group (97.0%) were grade 1 or 2



QUEST-2: Changes in laboratory parameters

Bilirubin

0

Entire treatment phase – bilirubin (µmol/L)

Weeks

30

Mea

n va

lues

(±SE

)

20

10

0 4 8 24 36 48 20 16 12 2

131 132 111 87 80 110 124 130 134 Placebo

262 251 238 8 7 242 248 248 257 TMC435

No. of subjects

Haemoglobin

0

Entire treatment phase – haemoglobin (µmol/L)

Weeks

200

Mea

n va

lues

(±SE

)

180

160

140

120

100 4 8 24 36 48 20 16 12 2

131 131 110 88 81 111 121 130 134 Placebo

252 251 237 8 7 242 247 247 257 TMC435

No. of subjects

Placebo/PR SMV/PR



SOF+PEG-IFN+RBV N=327

Overall safety

AEs, n (%) 310 (95)

Grade 3‒4 AEs, n (%) 48 (15)

Serious AEs, n (%) 4 (1)

Treatment D/C due to AEs, n (%) 5 (< 2)

Hematologic abnormalities

Grade 3-4 laboratory abnormality, n (%) 159 (49)

Hemoglobin < 10 g/dL, n (%) 74 (23)

Hemoglobin < 8.5 g/dL, n (%) 8 (2)

Absolute neutrophil count < 750/mm3, n (%) 66 (20)

Platelets < 50,000/mm3, n (%) 1 (< 1) ♦ SOF was well tolerated without any additive effects to the expected safety

profile of PEG-IFN+RBV ♦ Most common AEs were fatigue (59%), headache (36%), nausea (34%), and

insomnia (25%) ♦ A total of 5/327 (1.5%) of patients D/C due to an AE


Sofosbuvir + PEG-IFNa + Ribavirin Safety


Liver

Direct Toxicity of

Drugs


Direct Toxicity of

Drugs

Liver Disease

“Immune-mediated mechanisms”

Drug-Drug Interactions

Bilirubin Increases

other infections other drugs

Fatty Liver Disease


Direct Toxicity of

Drugs

Liver Disease

“Immune-mediated mechanisms”

Drug-Drug Interactions

Bilirubin Increases

other infections other drugs

Fatty Liver Disease


Role of PEG-IFNa in Future Treatment of Hepatitis C

Shortening of Therapy – Cost Saving (?)

Increasing Efficacy in Genotype 3


Novel DAAs combined with PEG/RIBAregist2.virology-education.com/2013/3HCVad/docs/02_Wedemeyer.pdfPR, peginterferon -2a + ribavirin; SVR12, sustained virological response (HCV RNA undetectable)

Documents