Pivotal “New England Journal of Medicine” papers 2014 ...regist2.virology-education.com/2014/4thHCVadv/03_Zeuzem.pdf · recommendation (Germany) Treatment-naive w/o cirrhosis

Pivotal “New England Journal of Medicine” papers 2014

Phase 3 Trial data

Stefan Zeuzem, MD University of Frankfurt

Germany

4th HCV Therapy Advances Meeting

Paris, December 12-13, 2014

Disclosures

• Consultancies: Abbvie, BMS, (Boehringer Ingelheim), Gilead, (Idenix), Janssen, Merck, Novartis, (Roche), Santaris, (Vertex)

• Honoraria for lectures: Abbvie, BMS, (Boehringer Ingelheim), Gilead, Janssen, Merck, (Roche)

Phase III Trials of IFN-free Regimens: Genotype 1

• Sofosbuvir + Ledipasvir ± RBV

• Ion-1: TN ± cirrhosis; 12 vs. 24 wks

• Ion-2: TE (incl. PI-failure), ± cirrhosis; 12 vs. 24 wks

• Ion-3: TN w/o cirrhosis; 8 vs. 12 wks

• Paritaprevir/r + Ombitasvir + Dasabuvir ± RBV

• Sapphire-I: TN w/o cirrhosis; 12 wks

• Sapphire-II: TE w/o cirrhosis; 12 wks

• Turquoise-II: TN and TE ± cirrhosis; 12 vs. 24 wks

• Pearl-II, -III, IV: ± RBV

ION-1: SOF/LDV ± RBV in GT1 tx-naive patients SV

R12

(%)

99,5 100,0 99,1 100,0 99,3 100,0 100,0 100,0 100,0 100,0 97,1 100,0

0

20

40

60

80

100

SOF/LDV12 weeks

SOV/LDV + RBV12 weeks

SOV/LDV24 weeks

SOF/LDV + RBV24 weeks

n N

141 142

143 143

143 143

211 212

66 66

211 211

67 67

212 214

66 68

Overall GT1a GT1b

141 141

215 215

71 71

SOF = 400 mg/day; LDV = 90 mg/day; RBV = 1000 or 1200 mg/day. Subgroup results do not include patients who withdrew consent or who were lost to follow-up. Error bars: 95% CI.

Afdhal N, et al. N Engl J Med. 2014;370:1889-98

Error bars represent 95% confidence intervals

100 100 99 100 97 100 97 100

0

20

40

60

80

100

Absence of Cirrhosis Cirrhosis

179/179 32/33 178/178 33/33 181/182 31/32 179/179 36/36

SV

R12

(%)

12 Weeks 24 Weeks

LDV/SOF + RBV LDV/SOF + RBV LDV/SOF LDV/SOF

ION-1: SVR12 by Presence of Cirrhosis


12 Weeks 24 Weeks

Patients, n (%) LDV/SOF

n=214 LDV/SOF+RBV

n=217 LDV/SOF

n=217 LDV/SOF+RBV

n=217 SVR12 211 (99) 211 (97) 212 (98) 215 (99) Breakthrough 0 0 1 (<1) 0 Relapse 1 (<1) 0 1 (<1) 0 Lost to Follow-Up 2 (<1) 4 (2) 2 (<1) 2 (<1) Withdrew Consent 0 2 (<1) 1 (<1) 0

Single on-treatment breakthrough was due to non-adherence

Two of 865 subjects (0.23%) had post-treatment relapse

– Both had NS5A-resistant variants at baseline and at relapse

16% of all subjects had NS5A RAVs at baseline, with 96% achieving SVR

ION-1: Reasons for Not Achieving SVR


ION-3: SOF/LDV ± RBV in GT1 tx-naive patients

SOF = 400 mg/day; LDV = 90 mg/day; RBV = 1000 or 1200 mg/day. * One patient achieved SVR12, but was not subgenotyped. Error bars: 95% CI.

Kowdley KV, et al. N Engl J Med. 2014;370:1879-88

SVR1

2 (%

)

94,0 93,1 95,4 93,0 92,4 94,8 97,7 95,5 97,7

0

20

40

60

80

100

SOF/LDV*8 weeks


SOV/LDV12 weeks

n N

159 171

159 172

163 172

202 215

42 43

201 216

42 44

206 216

43 44

Overall GT1a GT1b

8 Weeks 12 Weeks

Patients, n (%)

LDV/SOF n=215

LDV/SOF + RBV n=216

LDV/SOF n=216

SVR12 202 (94) 201 (93) 206 (95) Breakthrough 0 0 0 Relapse 11 (5) 9 (4) 3 (1) Lost to Follow-Up 1 (<1) 5 (2) 7 (3) Withdrew Consent 1 (<1) 1 (<1) 0

All virologic failures were due to relapse (n=23) – 9 subjects had baseline RAVs, 8 subjects with no RAVs, 6 subjects with new

RAVs 18% of subjects had baseline NS5A RAVs, and 90% achieved SVR12



Patients, n (%)

LDV/SOF 8 Weeks

n=215

LDV/SOF + RBV

8 Weeks n=216

LDV/SOF 12 Weeks

n=216

AEs 145 (67) 165 (76) 149 (69)

Grade 3‒4 AEs 2 (<1) 8 (4) 7 (3)

Death 0 0 0

Grade 3‒4 laboratory abnormality 7 (3) 18 (8) 16 (7)

Hemoglobin <10 g/dL 0 11 (5) 1 (<1)

Hemoglobin <8.5 g/dL 0 0 0

SAEs occurred in 4 (2%) of LDV/SOF 8 weeks, 1 (<1%) of LDV/SOF+RBV 8 weeks, and 5 (2%) of LDV/SOF 12 weeks Treatment D/C due to AEs occurred in 0 of LDV/SOF 8 weeks, 1 (<1%) of LDV/SOF+RBV 8 weeks, and 2 (1%) of LDV/SOF 12 weeks

ION-3: LDV/SOF ± RBV Safety Summary


Preferred term, n (%)

LDV/SOF 8 wk

n=215

LDV/SOF + RBV 8 wk

n=216

LDV/SOF 12 wk n=216

Overall 145 (67) 165 (76) 149 (69)

Fatigue 45 (21) 75 (35) 49 (23)

Headache 30 (14) 54 (25) 33 (15)

Nausea 15 (7) 38 (18) 24 (11)

Insomnia 11 (5) 26 (12) 15 (7)

Irritability 3 (1) 29 (13) 9 (4)

Diarrhea 15 (7) 13 (6) 9 (4)

Arthralgia 9 (4) 11 (5) 16 (7)

Constipation 9 (4) 13 (6) 8 (4)

Dizziness 6 (3) 13 (6) 9 (4)

Rash 3 (1) 19 (9) 5 (2)

Pruritus 2 (<1) 16 (7) 5 (2)

Cough 3 (1) 12 (6) 7 (3)

Anemia 2 (<1) 17 (8) 2 (<1)

Muscle Spasms 3 (1) 11 (5) 6 (3)

Dyspnea 0 11 (5) 1 (<1)

ION-3: Adverse Events (≥ 5% in Any Arm)


ION-2: SOF/LDV ± RBV in GT1 tx-experienced pts SV

R12

(%)

93,6 96,4 99,1 99,1 95,3 95,5 98,8 98,9 87,0 100 100 100

0

20

40

60

80

100

SOF/LDV12 weeks


SOV/LDV24 weeks

SOF/LDV + RBV24 weeks

n N

82 86

84 88

84 85

102 109

20 23

107 111

23 23

108 109

24 24

Overall GT1a GT1b

87 88

110 111

23 23

SOF = 400 mg/day; LDV = 90 mg/day; RBV = 1000 or 1200 mg/day. * One patient achieved SVR12, but was not subgenotyped. Error bars: 95% CI.



93 96 100 98 94 97 98 100

0

20

40

60

80

100

Failed PegIFN+RBV Failed Protease Inhibitor + PegIFN+RBV

SV

R12

(%)

40/43 62/66 45/47 62/64 58/58 49/50 58/59 51/51

12 Weeks 24 Weeks


ION-2: SVR12 in PegIFN+RBV vs. PI+PegIFN+RBV Failures



95 100 99 99 86 82 100 100

0

20

40

60

80

100

Absence of Cirrhosis Cirrhosis

SV

R12

(%)

83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22

12 Weeks 24 Weeks


ION-2: SVR12 - Absence of Cirrhosis vs. Cirrhosis


12 Weeks 24 Weeks

Patients, n (%) LDV/SOF

n=109 LDV/SOF+RBV

n=111 LDV/SOF

n=109 LDV/SOF+RBV

n=111 SVR12 102 (94) 107 (96) 108 (99) 110 (99) Breakthrough 0 0 0 1 (<1) Relapse 7 (6) 4 (4) 0 0 Lost to Follow-Up 0 0 0 0 Withdrew Consent 0 0 1* (<1) 0

* One patient withdrew consent after the post-treatment Week 4 visit, at which HCV RNA < 25 IU/mL

Single on-treatment breakthrough was due to documented non-adherence 11 subjects had virologic failure were due to relapse

– 6 subjects had baseline RAVs, 5 subjects with no RAVs 14% of subjects had NS5A RAVs at baseline, with 89% achieving SVR



Ledipasvir / Sofosbuvir FDC label (GT 1)

Patient population

US Label

EU Label Practical

recommendation (Germany)

Treatment-naive w/o cirrhosis

12 wks 8 wks (> 6 MIU/mL HCV RNA)

12 wks 8 wks may be considered in TN pts

8 wks (low VL) 12 wks (> 6 MIU/mL HCV RNA)

Treatment-naive with cirrhosis

12 wks 24 wks* 12 wks + RBV

Treatment-experienced w/o cirrhosis

12 wks 12 wks 24 wks should be considered for TE pts with uncertain subsequent tx options

12 wks

Treatment-experienced with cirrhosis

24 wks 24 wks* 12 wks + RBV

Decompensated cirrhosis

--- 24 weeks + RBV 24 wks ± RBV

*12 weeks may be considered for pts deemed at low risk for clinical progression and who have subsequent tx options

Phase III Trials of IFN-free Regimens: Genotype 1

• Sofosbuvir + Ledipasvir ± RBV

• Ion-1: TN ± cirrhosis; 12 vs. 24 wks

• Ion-2: TE (incl. PI-failure), ± cirrhosis; 12 vs. 24 wks

• Ion-3: TN w/o cirrhosis; 8 vs. 12 wks

• Paritaprevir/r + Ombitasvir + Dasabuvir ± RBV

• Sapphire-I: TN w/o cirrhosis; 12 wks

• Sapphire-II: TE w/o cirrhosis; 12 wks

• Turquoise-II: TN and TE ± cirrhosis; 12 vs. 24 wks

• Pearl-II, -III, IV: ± RBV

SAPPHIRE-I: HCV GT1 treatment-naive patients

Feld JJ, et al. N Engl J Med. 2014;370:1594-603

SVR1

2 (%

)

96,2 95,3 98,0

0

20

40

60

80

100

Overall GT1a GT1b

n N

455 473

307 322

148 151

Treatment-naive

Error bars: 95% CI.

3D + RBV x 12 wks

3D: co-formulated Paritaprevir/ritonavir/ombitasvir, 150 mg/100 mg/25 mg qd; dasabuvir, 250 mg bid

RBV: 1000-1200 mg/d

SAPPHIRE-I: Breakthrough and Relapse Rates

Event, n/N (%)

3D + RBV (N=473)

SVR12 455/473 (96.2)

Virologic failure

Breakthrough 1/473 (0.2)

Relapse 7/463 (1.5)

Prematurely discontinued study drug* 7/473 (1.5)

Lost to follow-up after completion of treatment 3/473 (0.6)

*Patients (n=7) who prematurely discontinued without breakthrough; 2 due to adverse events, 5 withdrew consent/ lost to follow-up.


SAPPHIRE-I: AEs Occurring in >10% of Patients

Event, n (%)

3D + RBV (N=473)

Placebo (N=158)

P Value

Any AE 414 (87.5) 116 (73.4) <0.05 Fatigue 164 (34.7) 45 (28.5) NS Headache 156 (33.0) 42 (26.6) NS Nausea 112 (23.7) 21 (13.3) <0.05 Pruritus 80 (16.9) 6 (3.8) <0.05 Insomnia 66 (14.0) 12 (7.6) <0.05 Diarrhea 65 (13.7) 11 (7.0) <0.05 Asthenia 57 (12.1) 6 (3.8) <0.05 Rash 51 (10.8) 9 (5.7) NS

Adverse events (AEs) were generally mild.


SAPPHIRE-I: Laboratory Abnormalities

No cases consistent with Hy’s law

Elevations in total bilirubin were mainly transient and predominantly indirect bilirubin

1 patient received EPO; no patient was transfused

Ribavirin dose was modified due to AE(s) in 26 (5.5%) 3D + RBV recipients

Event, n (%)

3D + RBV (N=469)

ALT >5X ULN 4 (0.9) AST >5X ULN 3 (0.6) Alkaline phosphatase >5X ULN 0 Total bilirubin >3X ULN 13 (2.8) Hemoglobin <10-8.0 g/dL 27 (5.8) <8.0-6.5 g/dL 0 <6.5 g/dL 0


SAPPHIRE-II: HCV GT1 tx-experienced patients

Zeuzem S, et al. N Engl J Med. 2014;370:1604-141

SVR1

2 (%

)

96,3 96,0 96,7

0

20

40

60

80

100

Overall* GT1a GT1b

n N

286 297

166 173

119 123

Treatment-experienced

* One patient achieved SVR12, but was unable to be subgenotyped. Error bars: 95% CI.

3D + RBV x 12 wks


RBV: 1000-1200 mg/d

SAPPHIRE-II: HCV GT1 tx-experienced patients

SVR1

2 (%

)

95,3 100,0 95,2

0

20

40

60

80

100

Priorrelapse

Priorpartial

response

Priornull

response

n N

82 86

65 65

139 146

Treatment-experienced

Error bars: 95% CI. Zeuzem S, et al. N Engl J Med. 2014;370:1604-141

3D + RBV x 12 wks


RBV: 1000-1200 mg/d

SAPPHIRE-II: SVR12 and Reasons for Non-Response

No patient had breakthrough and 2.4% of patients had a relapse

All relapses occurred 2-8 weeks post-treatment

All Patients (N=297)

Prior Relapsers

(N=86)

Prior Partial Responders

(N=65)

Prior Null Responders

(N=146) SVR12, n/N (%) 286/297

(96.3) 82/86 (95.3)

65/65 (100)

139/146 (95.2)

Virologic failure, n

Breakthrough 0 0 0 0

Relapse 7 1 0 6

Prematurely discontinued study drug,* n

4 3 0 1

*Patients (n=4) who prematurely discontinued without breakthrough; 3 due to adverse events, 1 withdrew consent during week 11

Zeuzem S, et al. N Engl J Med. 2014;370:1604-141

PEARL-II and -III: Paritaprevir/r + Ombitasvir + Dasabuvir ± RBV

Ferenci P, et al. N Engl J Med. 2014;370:1983-92 Andreone P, et al. Gastroenterology. 2014;147:359-365

GT1b naive, 12 weeks (PEARL-III)

99,5 99.0

0

20

40

60

80

100

RBV No RBV

GT1b experienced, 12 weeks (PEARL-II)

96,6 100

0

20

40

60

80

100

RBV No RBV

207 209

85 88

SVR1

2 (%

)

209 210

91 91

Co-formulated paritaprevir/ritonavir/ombitasvir, 150 mg/100 mg/25 mg qd; dasabuvir, 250 mg bid RBV: 1000-1200 mg/d

PEARL-IV: Paritaprevir/r + Ombitasvir + Dasabuvir ± RBV for 12 weeks in GT1a treatment-naive patients

Ferenci P, et al. N Engl J Med. 2014;370:1983-92

SVR1

2 (%

)

97.0 90,2

0

20

40

60

80

100

RBV No RBV

97 100

185 205

Co-formulated paritaprevir/ ritonavir/ombitasvir, 150 mg/100 mg/25 mg qd; dasabuvir, 250 mg bid RBV: 1000-1200 mg/d

TURQUOISE-II: SVR12 rates in HCV GT1 treatment-naive and experienced cirrhotic patients

Poordad F, et al. N Engl J Med. 2014;370:1973-82

0

20

40

60

80

100 88.6

12-week arm

24-week arm

98.5 94.2 100

GT 1a GT 1b

3D + RBV

SVR1

2, %

Pat

ient

s

124/140 67/68 114/121 51/51

3D: co-formulated paritaprevir/ ritonavir/ombitasvir, 150 mg/100 mg/25 mg qd; dasabuvir, 250 mg bid

RBV: 1000-1200 mg/d

TURQUOISE-II: SVR12 Rates by Prior Treatment Response in HCV Subtype 1a

0

20

40

60

80

10092.2

12-week arm

24-week arm

92.9

Naïve Prior Relapse Response

3D + RBV

SVR1

2, %

Pat

ient

s

59/64 14/15 52/56 13/13

93.3 100 100 100 80.0 92.9

11/11 40/50 10/10 39/42

Prior Partial Response

Prior Null Response

HCV Subtype 1a Poordad F, et al. N Engl J Med. 2014;370:1973-82


RBV: 1000-1200 mg/d

TURQUOISE-II: SVR12 Rates by Prior Treatment Response in HCV Subtype 1b

0

20

40

60

80

100100

12-week arm

24-week arm

100

Naïve Prior Relapse Response

3D + RBV

SVR1

2, %

Pat

ient

s

22/22 25/25 18/18 20/20

100 100 85.7 100 100 100

6/7 14/14 3/3 10/10

Prior Partial Response

Prior Null Response

HCV Subtype 1b Poordad F, et al. N Engl J Med. 2014;370:1973-82


RBV: 1000-1200 mg/d

TURQUOISE-II: SVR12 Rates by Surrogates of Portal Hypertension and Hepatic Function

0

20

40

60

80

100 88.9

12-week arm

24-week arm

97.0

<100 ≥ 100

3D + RBV

SVR1

2, %

Pat

ient

s

40/45 151/163 32/33 133/139

92.6 95.7 84.0 88.9 92.9 96.8

21/25 170/183 16/18 149/154

<35 ≥35 Baseline Platelet Count

(x109/L) Baseline Serum Albumin

Count (g/L)



RBV: 1000-1200 mg/d

TURQUOISE-II: Patients Not Achieving SVR12

Event, n/N (%)

12-Week Arm

24-Week Arm

Patients not achieving SVR12 17/208 (8.2) 7/172 (4.1)

Premature discontinuation 4/208 (1.9) 3/172 (1.7)

Adverse event, n 4 1

Withdrew consent/other, n 0 2

Virologic failure

Breakthrough 1/208 (0.5) 3/172 (1.7)

Relapse through PTW12 12/203 (5.9)* 1/164 (0.6)**

Virologic failure occurred in 17/380 patients (4.5%) 15 of these patients had at least 1 resistance-associated variant at the time of virologic failure

• D168V (NS3) and Q30R (NS5A) seen most frequently in GT1a-infected patients

The significance and persistence of these variants are under investigation

*7/12 were GT1a null responders. **Significant difference.


TURQUOISE-II: Chemical and Hematologic Abnormalities

ALT elevation • Asymptomatic, transient, and improved or resolved with ongoing

study drug dosing Bilirubin elevation

• Transient, predominantly indirect, no discontinuations due to hyperbilirubinemia

Hemoglobin decrease • Managed with reduction of ribavirin dose in 34 patients (8.9%)

12-Week Arm (N=208)

24-Week Arm (N=172)

ALT >5x ULN (%) 2.9 0 Total bilirubin >3x ULN (%) 13.5 5.2 Hemoglobin (%) <10 g/dL 7.2 11.0 <8.0 g/dL 1.4 0.6

ULN: upper limit of normal.


100 100 97,1 97,1 97,1

0

20

40

60

80

100

RVR EOTR SVR4 SVR12 SVR24

• Due to interactions between calcineurin inhibitors (CNIs) and study regimen, modified dosing was advised

– Tacrolimus: 0.5 mg QW or 0.2 mg every 3 days; cyclosporine: 1/5 the daily pre-study dose QD

• No acute or chronic rejection • 1 d/c due to AEs; 2x SAEs • 5 patients (14.7%) received EPO

SVR rates in liver transplant recipients with recurrent HCV G1 infection receiving ABT-450/r/ombitasvir + dasabuvir + RBV

• No lab abnormalities, except 2 x elevated bilirubin at a single time point

• No virologic breakthrough • One pt had virologic relapse (post-treatment day 3)

Kwo et al., NEJM 2014

• High RVR and SVR rates in F0–2 patients • Well-tolerated • CNI dosing was manageable using PK guidance

established in prior DDI study in volunteers • Antiviral therapy may benefit patients before

acceleration of fibrosis

3D + RBV (N=34) SVR12 SVR24

Day 0 Week 24 To Week 72 CORAL-1: Efficacy results

Patie

nts (

%)

34/34 34/34 33/34 33/34 33/34

Baseline demographics 3D + RBV (N=34) Median time since transplantation 39.5 months Male (%) 79.4 Mean age (years) 59.6 Fibrosis stage F0/F1/F2 (%) 17.6/38.2/44.1 IL28B non-CC 76.5 HCV subtype G1a/G1b (%) 85.3/14.7 Mean HCV RNA (log10 IU/mL) 6.6 Immunosuppression TAC/CSA (%) 85.3/14.7 Mean CrCl (mL/min) 90.5 Mean ALT (U/L) 78.9 Mean AST (U/L) 63.9 Mean GGT (U/L) 170.3

(Week 4) (Week 24)

Putative Label of Paritaprevir/r + Ombitasvir + Dasabuvir ± Ribavirin

Patient population Recommended schedule

Treatment-naive w/o cirrhosis HCV-1a for 12 weeks with RBV HCV-1b for 12 weeks w/o RBV

Treatment-naive with cirrhosis

12 weeks with RBV

Treatment-experienced w/o cirrhosis

HCV-1a for 12 weeks with RBV HCV-1b for 12 weeks w/o RBV (?)

Treatment-experienced with cirrhosis

12 weeks with RBV 24 weeks in HCV-1a prior NR

Other Studies in Patients Infected with HCV-1

SVR12 rates for daclatasvir (DCV) + SOF ± RBV in GT 1

Sulkowski MS, et al. N Engl J Med 2014;370:211–21

Prop

ortio

n of

pat

ient

s (%

)

*DCV 60 mg once daily, SOF 400 mg once daily ± RBV 1000/1200 mg/day

GT 1 (82% GT 1a), Rx-naïve N=82: DCV + SOF ± RBV for 12 weeks*

GT1 (80% GT 1a), prior PI non-responder N=41: DCV + SOF ± RBV for 24 weeks*

100 95

0

20

40

60

80

100

Category 1 Category 2

41/41 39/41

DCV + SOF DCV + SOF DCV + SOF + RBV DCV + SOF + RBV

Prop

ortio

n of

pat

ient

s (%

)

100 95

0

20

40

60

80

100

21/21 19/20

Lawitz E, et al. Lancet 2014 ITT: intent-to-treat;

SMV: simeprevir; VF: virological failure

7% 7% 7%

0

20

40

60

80

100

SMV/SOF±RBV SMV/SOF + RBV SMV/SOF + RBV SMV/SOF SMV/SOF 24 weeks 12 weeks Overall

SVR12 Non-VF* Relapse

93% 100% 93% 93% 94%

2/30 1/14 2/27 3/87 2/87

28/30 16/16 13/14 25/27 82/87

3% 2%

COSMOS Cohort 2: SVR12 – primary endpoint (ITT population)

*Patients who did not achieve SVR12 for reasons other than virological failure

Prop

ortio

n of

pat

ient

s (%

)

COSMOS Cohort 2: SVR12 by GT 1 subtype and baseline NS3 Q80K polymorphism*

*Excluding patients who discontinued for non-virological reasons

GT 1b GT 1a without Q80K 100 100

93 88

95

GT 1a with Q80K 100 100

88

100 96

SMV/SOF±RBV

Prop

ortio

n of

pat

ient

s (%

)

SMV/SOF + RBV SMV/SOF + RBV SMV/SOF SMV/SOF

24 weeks 12 weeks Overall

6/6 11/11 11/11 4/4 7/7 4/4 5/5 13/14 7/8 3/3 7/8 3/3 18/18 38/40 25/26

100

80

40

20

0

60

100 100 100 100 100

Lawitz E, et al. Lancet 2014

SMV/SOF + RBV

100 100 94

100 98 100 100 91

86 95

0

20

40

60

80

100

SMV/SOF±RBV SMV/SOF + RBV SMV/SOF SMV/SOF 24 weeks 12 weeks Overall

16/16 12/12 6/6 9/9 15/16 10/11 7/7 6/7 44/45 37/39

F3 fibrosis F4 fibrosis

COSMOS Cohort 2: SVR12 by METAVIR score*

*Excluding patients who discontinued for non-virological reasons

Lawitz E, et al., Lancet 2014

Prop

ortio

n of

pat

ient

s (%

)

HALLMARK-DUAL: SVR12 With Daclatasvir + Asunaprevir in GT1b HCV

• Breakthrough: 9 (4%) treatment naive, 26 (13%) nonresponders, 20 (9%) IFN ineligible/intolerant • Relapse: 5 (3%) treatment naive, 7 (4%) nonresponders, 12 (6%) IFN ineligible/intolerant • 28 of 73 patients with NS5A-L31 and/or Y93 variants at baseline achieved SVR12

Manns M, et al. Lancet 2014; Jul 26 epub ahead of print

SVR12, % (n/N) Daclatasvir (60 mg qd) + Asunaprevir (100 mg bid) x 24 weeks

Treatment naive 90 (182/203)

Null responders 82 (98/119)

Partial responders 81 (68/84)

All IFN ineligible/intolerant 82 (192/235)

Advanced fibrosis/cirrhosis with thrombocytopenia

73 (56/77)

HALLMARK-DUAL: Adverse Events

*1 patient with confirmed Gilbert’s syndrome met laboratory but not clinical criteria for potential drug-induced liver injury. Patient had grade 3 increased hepatic enzymes and grade 4 ALT abnormality. Patient completed treatment and achieved SVR12. †Most commonly ALT/AST elevations that resolved off treatment (7 patients, 6 of 7 achieved SVR12).

• Serious AEs* occurred in 6% treatment-naive pts, 5% nonresponders and 7% IFN ineligible-intolerant pts

• AE leading to discontinuation† in 3%, 1% and 1%, respectively

• Grade 3/4 hemoglobin < 90 g/L in 0, 0.5% and 0, respectively

• Grade 3/4 ALT > 5 x ULN in 3%, 2% and 2%, respectively • Grade 3/4 AST > 5 x ULN in 3%, 1% and 1%, respectively • Grade 3/4 total bilirubin > 2.5 x ULN in 0.5%, 0 and 1%,

respectively

Manns M, et al. Lancet 2014; Jul 26 epub ahead of print

Other Studies in Patients Infected with HCV-2 or 3

Overall Treatment Naive Treatment Experienced

SVR

4 (%

)

n/N = 2/ 2

30/ 33

12/ 13

85/ 100

100

80

60

40

20

0

93 97 84

93 100 91 92 85

68/ 73

210/ 250

29/ 30

86/ 92

No Cirrhosis Cirrhosis

7/ 8

27/ 45

88

60

No Cirrhosis Cirrhosis Overall

12 Wks SOF + RBV in GT2 24 Wks SOF + RBV in GT3

Zeuzem S, et al., NEJM 2014

VALENCE Efficacy : SVR12

Conclusions • Two IFN-free regimen will be / are approved for HCV

genotype 1 infected patients in IV/2014 – I/2015 • Response to previous (IFN-based) therapy will be

less relevant • Cirrhosis (more granular differentiated) and

potentially baseline HCV RNA are expected to remain as baseline predictors for SVR

• Main differentiation between regimens • SVR and safety in patients with advanced disease • Drug-drug interactions

• Treatment options for cirrhotic patients, patients with renal impairment and those infected with HCV-3 need further refinement

Documents

Pivotal “New England Journal of Medicine” papers 2014 ...regist2.virology-education.com/2014/4thHCVadv/03_Zeuzem.pdf · recommendation (Germany) Treatment-naive w/o cirrhosis