are all patients easy to treat? · pa rita p re v ir g ra zo p re v ir si m e p re v ir glecaprev...

DAAs for treating HCV:Are really all patients easy to treat?

Sanjay Bhagani

Royal Free Hospital/UCL

London

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WHO GLOBAL ELIMINATION STRATEGY:2015 BASELINE TOWARDS 2030

*

* Measurement of progress on HBV treatment target currently limited by the absence of data on the proportion of persons eligible and the absence of a functional cure

DAAs in 2017, and beyond…

OUR COMPANYJanssen to Discontinue Hepatitis C Development ProgramViral Hepatitis Research and Development to Focus on Addressing Significant Unmet Needs in Chronic Hepatitis BCORK, Ireland, September 11, 2017 - Janssen Sciences Ireland UC (Janssen), today announced a strategic

decision to discontinue further development of the investigational hepatitis C treatment regimen JNJ-4178, a combination of three direct acting antivirals - AL-335, odalasvir and simeprevir. The ongoing phase II studies with JNJ-4178 will be completed as planned, but there will be no additional development thereafter. This decision was made in light of the increasing availability of a number of highly effective therapies addressing the medical need in hepatitis C.

Merck Discontinues MK-3682B and MK-3682C Development Programs

SEPTEMBER 29, 2017

Company to Focus on Maximizing the Potential of ZEPATIER® (Elbasvir and Grazoprevir)KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced itsstrategic decision to discontinue the development of the investigational combination regimens MK-3682B (grazoprevir/ruzasvir/ uprifosbuvir) and MK-3682C (ruzasvir/uprifosbuvir) for the treatment of chronic hepatitis C virus (HCV) infection. This decision was madebased on a review of available Phase 2 efficacy data and in consideration of the evolving marketplace and the growing number of treatmentoptions available for patients with chronic HCV infection, including ZEPATIER® (elbasvir and grazoprevir).

Many barriers to treatment, but traditionally three groups of patients

that were ‘difficult to treat’

• Genotype 3 treatment-experienced

• Cirrhotics

• Patients with renal failure

• And since 2016 – patients with DAA failure

So what has changed in 2017/2018?

2017…next generation NS3/4 PIs

• Voxilaprevir (in combination with Sofosbuvir + Velpatasvir)

• Glecaprevir (in combination with Pibrentasvir)

Efficacy of current and upcoming NS3/4 PIs and NS5a inhibitors against G3a stable replicon

NS3/4 Protease Inhibitors EC50 (pM)

Paritaprevir Grazoprevir Simeprevir Glecaprevir (ABT-493)

Voxilaprevir (GS-9857)

19 3.5 472 1.6 6.1

NS5A Inhibitors

Ombitasvir Ledispasvir Daclatasvir Velpatasvir Elbasvir Ruzasvir (MK-8408)

0.019 168 0.53 0.02 0.14 0.002

Pibrentasvir (ABT-530)

0.002

NS5b Inhibitors

Sofosbuvir MK-3682

50 ??

8

*Endpoint was tested only after 12 weeks of G/P was determined non-inferior to 12 weeks of SOF + DCV

Foster G, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, 2017. Abst. GS-007.

ENDURANCE-3 Study: Objective and Study Design

SVR12

Arm BN = 115

Arm AN = 233

Weeks

SVR12

0 12

G/P

20

Treatment Period

(1)

no

n-i

nfe

rio

rity

24

Post-treatment Period

Arm CN = 157 G/P

SOF + DCV SVR12

2:1

Ran

do

miz

ed

(2)

no

n-i

nfe

rio

rity

• Arm C: 8-week treatment duration

• Per discussion with regulatory authorities after phase 2 treatment data became available, an 8 week treatment Arm of G/P was added to the study design• SVR12: Non-inferiority of 8 weeks of G/P compared to 12 weeks of G/P*

Foster G, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, 2017. Abst. GS-007.

ENDURANCE-3 Study: ResultsSVR12 by Intent-to-Treat (ITT) Analysis

*Conventional statistical methods were used in multiplicity comparison for determining non-inferiority

Non-inferiority:

• Lower bound of the confidence interval (CI) of the difference in SVR12 must be above -6%*• (1) -1.2% (95% CI -5.6 –

3.1)• (2) -0.4% (97.5% CI -5.4 –

4.6)

• Both G/P treatments met non-inferiority criteria for the primary endpoint

95 97 95

0

20

40

60

80

100

SVR

12

(%

Pat

ien

ts)

TreatmentDuration

G/P12 weeks

SOF + DCV12 weeks

G/P8 weeks

222233

111115

149157

(2) non-inferior

(1) non-inferior

Source: Wyles D, et al. Hepatology. 2017 Sep 19. [Epub ahead of print]

Glecaprevir-Pibrentasvir in HCV GT 3, with Cirrhosis and Prior Treatment

SURVEYOR-II (Part 3): Study Design

Drug Dosing: Glecaprevir-pibrentasvir (100/40 mg) fixed dose combination; three pills once daily

0 20Week 8Week 0 2812 16 24

GLE-PIB(n = 40)

SVR12

GLE-PIB(n = 22)

SVR12

GLE-PIB(n = 22)

SVR12

GLE-PIB(n = 47)

SVR12

GT 3, Treatment-Naive

With cirrhosis

GT3, Treatment-ExperiencedWithout cirrhosis

GT 3, Treatment-ExperiencedWithout cirrhosis

GT 3, Treatment-ExperiencedWith cirrhosis

Source: Wyles D, et al. Hepatology. 2017 Sep 19. [Epub ahead of print]

Glecaprevir-Pibrentasvir in HCV GT 3, with Cirrhosis and Prior Treatment

SURVEYOR-II (Part 3): Results

98

9195 96

0

20

40

60

80

100

TN, 12 Week(+) Cirrhosis

TE, 12 Weeks(-) Cirrhosis

TE, 16 Weeks(-) Cirrhosis

TE, 16 Weeks(+) Cirrhosis

Pati

en

ts w

ith

SV

R12 (

%)

Patients with HCV GT3 Treated with Glecaprevir-Pibrentasvir

39/40 20/22 45/4721/22

Abbreviations: TN = Treatment Naïve; TE = Treatment Experienced

Source: Jacobson IM, et al. Gastroenterology. 2017;153:113-22.

Sofosbuvir-Velpatasvir-Voxilaprevir in GT 3 and Cirrhosis POLARIS-3: Study Design

SOF/VEL/VOX SVR12GT 3

CirrhoticDAA Naïve

n = 110

SOF/VEL SVR12n = 109

Week 0 248 12 20

Abbreviations: SOF = sofosbuvir; VEL = velpatasvir; VOX = voxilaprevir

Drug Dosing

SOF-VEL-VOX (400/100/100 mg): fixed dose combination; one pill once daily

SOF-VEL (400/100 mg): fixed dose combination; one pill once daily


Sofosbuvir-Velpatasvir-Voxilaprevir in GT 3 and CirrhosisPOLARIS-3: Baseline Characteristics

Baseline CharacteristicSOF-VEL-VOX

8 weeks(n = 110)

SOF-VEL12 weeks(n = 109)

Age, mean (range) 54 (25-75) 55 (31-69)

Male, n (%) 74 (67) 100 (92)

White, n (%) 100 (91) 97 (89)

Cirrhosis Features

Platelets <100 x 103/L, n (%)

Mean Fibroscan (range), kPa

30 (29)

23 (13-75)

21 (19)

22 (13-75)

Body mass index, mean, kg/m2 (range) 28 (20-50) 27 (18-46)

Mean HCV RNA, log10 IU/mL (range) 6.0 (1.6-7.6) 6.3 (4.1-7.5)

IL28B CC, n (%) 41 (37) 52 (48)

Sofosbuvir-Velpatasvir-Voxilaprevir in GT 3 and CirrhosisPOLARIS-3: Results

POLARIS-3: SVR12 by Treatment Experience


96 9799

91

0

20

40

60

80

100

Treatment-Naïve Treatment-Experienced

Pati

en

ts (

%)

wit

h S

VR

12

SOF-VEL-VOX SOF-VEL

72/75 76/77 34/35 29/32

What about patients with renal impairment?

Impact of Renal Impairment on DAA Pharmacokinetics

Change in exposure compared to healthy subjects with normal renal function

Mild impairment(eGFR = 60–89

mL/min/1.73m2)

Moderateimpairment(eGFR = 30–59

mL/min/1.73m2)

Severeimpairment(eGFR = <30

mL/min/1.73m2)

Ombitasvir ↔ ↔ ↔

Paritaprevir ↑ ≤20% ↑ ≤37% ↑ ≤50%

Dasabuvir ↑ ≤20% ↑ ≤37% ↑ ≤50%

Ledipasvir NA NA Change not clinically relevant

SofosbuvirGS-331007

↑ 61%*

↑ 55%*

↑ 107%†

↑ 88%†

↑ 171%

↑ 451%

Simeprevir NA NA ↑ 62%

Daclatasvir‡ ↑ 18%‡ ↑ 39%‡ ↑ 51%‡

Grazoprevir NA NA ↑ 65%

Elbasvir NA NA ↑ 86%

Khatri A, et al. Hepatology 2014; 60(Suppl):320A;Harvoni, (July 2016) Olysio (August 2016) , and Daklinza(October 2016) Summaries of Product Characteristics Yeh WW, et al. Hepatology 2014; 60(Suppl4):1940 (poster presentation)..

EASL 2016: IFN-Free Treatment Options in CKD Stage 4-5

Combination regimen GT1 GT2 GT3 GT4 GT5-6

SOF + RBV No Suboptimal Suboptimal No No

SOF/LDV ± RBV Caution No No Caution Caution

SOF/VEL ± RBV Caution Caution Caution Caution Caution

OBV/PTV/r + DSV (3D) ± RBV Yes No No No No

OBV/PTV/r (2D) ± RBV No No No Yes No

GZR/EBR ± RBV Yes No No Yes No

SOF + DCV ± RBV Caution Caution Caution Caution Caution

SOF + SIM ± RBV Suboptimal No No Caution No

EASL HCV Treatment Recommendations. J Hepatol. 2017;66(1):153-194

What about Glecaprevir/Pibrentasvir?

Change in exposure compared to healthy subjects with normal renal function

Mild impairment(eGFR = 60–89

mL/min/1.73m2)

Moderateimpairment(eGFR = 30–59

mL/min/1.73m2)

Severeimpairment(eGFR = <30

mL/min/1.73m2)

Glecaprevir ↑ <56% ↑ <56% ↑ 86%

Pibrentasvir ↑ <56% ↑ <56% ↑ 54%

Glecaprevir/Pibrentasvir in Patientswith CKD

Pol S. et al , Integrated analyses G/P phase2/3 studies EASL 2017

Glecaprevir/Pibrentasvir in Patients with CKD

Pol S. et al , intergrated analyses G/P phase 2/3 studies, EASL 2017

Renal Impairment

• GZR/EBR (G1 and 4)

• GLE/PBR – pan-genotypic

• Studies underway to formally evaluate (phase 2)

– SOF/VEL

– SOF/VEL/VOX

Suboptimal Efficacy of DAAs in Decompensated Cirrhosis.

1 Terrault et al AASLD 2015, 2 Petersen et al EASL 2016, 3 Foster et al J Hepatology 2016, 4 Fernández-Carrillo et al EASL 2016,Gambato and Canini et al, EASL 2016 Barcelona (SAT-210)

10

0

80

60

40

20

0

8083

123/14

7329/40

9

112/14

4

78

UK3Europe2 Spain4

140/17

0

U.S1

81

G 1-6

SOF/NS5

ARBV

G 1-6

SOF/NS5ARB

V

SOF/DCVRBV

G 3

SOF/DCV

RBV

G1-6

Different

DAA

regimens

SV

R12

(%

)

LSM≥21kPa LSM<21kPa

Median time to cure was significantly longer in

patients with FS≥21 kPa (Fig. A) compared to

those with FS<21 kPa (Fig. B)

<LLQ<LLQ

Time (days)

Early HCV kinetics to individualize DAA

treatment duration in advanced

cirrhosis

Al Marzooqi & Feld. Liver International 2015

PK parameters and hepatic impairment – Glecaprevir and

Voxilaprevir

Change in exposure compared to healthy subjects with normal hepatic function

Child-Pugh A Child-Pugh B Child-Pugh C

Glecaprevir ↑ 33% ↑100% ↑ 1100%

Voxilaprevir ↑ 73% ↑ 299% ↑ 500%

Real World VA Study: Study Population

Evaluable population (EP)*

n=2,436

Per protocol population (PP)**

n=2,257

On-treatment HCV RNA or SVR data unavailable (n=494)

Treated for >17 weeks (n=32)

RBV added >1 month after treatment initiation (n=23)

Received EBR/GZR < 11 weeks of treatment (n=179)

* Per Protocol (PP) denominator limited to patients who completed treatment course** Evaluable population (EP) denominator – all patients with SVR outcomes available

HCV-infected Patients initiated EBR/GZR from Feb 1-Aug 1, 2016,≥ 18 years, positive HCV RNA, ≥1 inpatient or outpatient visit within

1 year prior to treatment (n=2,985)

Kramer J, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, 2017. Abst. PS-095.

CharacteristicsEBR/GZR Regimens

N = 2,436

Age, mean (S.D) 63.5 (5.9)

Male, n (%) 2350 (96.5)

Race/ethnicity, n (%)

African American 1400 (57.5)

White 824 (33.8)

Hispanic 81 (3.3)

Other 35 (1.4)

Genotype, n (%)

GT1 (all)** 2324 (95.4)

GT1a 844 (36.3)

GT1b 1428 (61.5)

GT2, GT3 6 (0.3)

GT4 64 (2.6)

BVL >800,000 IU/ml, n (%)* 1560 (67.9)

Real World VA Study: Patient Characteristics (EP)

CharacteristicsEBR/GZR Regimens

N = 2,436

Comorbidities, n (%)

Cirrhosis 808 (33.2)

CKD (stage 3-5) 800 (32.8)

Depression 1394 (57.2)

Diabetes 1295 (53.2)

History of drug abuse† 1313 (53.9)

History of alcohol abuse† 1473 (60.5)

HIV 74 (3.0)

Prior Treatment, n (%)

Treatment naïve 1988 (81.6)

Previous treatment

Prior PEG+/- RBV 316 (13.0)

Prior BOC/TEL 6 (0.3)

Prior SOF/SIM+SOF 9 (0.4)

Prior LDV/SOF 82 (3.4)

Prior PrOD 35 (1.4)


Real World VA Study: Results - Overall SRV

97,0% 95,6%

0%

20%

40%

60%

80%

100%

Per Protocol population Evaluable population

2,1902,257

2,3282,436


Real World VA Study: SVR (EP) in Cirrhosis, CKD, and HIV Subgroups

95,6% 95,5% 95,2% 96,7% 96,3% 95,5% 98,6%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Nocirrhosis

Cirrhosis eGRF >=60ml

Stage 3CKD

Stage 4-5CKD

No HIV Had HIV

Cirrhosis Status CKD Stages HIV Co-infection Status

15561628

772808

15331611

380393

392407

22552362

7374


• Study evaluated treatment regimen selections by genotype between October 2015 and October 2016

• Impact of advent of SOF/VEL in June 2016

Utilization of SOF/VEL in G2–6 HCV:

Real-World Experience from the TRIO Network

pre-SOF+VEL (n=366)

post-SOF+VEL (n=485)

pre-SOF+VEL (n=168)


SOF+VEL±RBVDCV+SOF±RBVEBR/GZR±RBV

SOF+RBVLDV/SOF±RBVOther

G4-6 Regimen Starts

G3Regimen Starts

DCV+SOF±RBV 18%

SOF+RBV 77%

SOF+VEL ±RBV 81%

SOF+RBV 11%

DCV+SOF±RBV 7%

SOF+RBV 77%

LDV/SOF±RBV 50%

SOF+VEL ±RBV 36%

EBR/GZR±RBV 14%

EBR/GZR±RBV 7%

pre-SOF+VEL (n=371)


SOF+VEL ±RBV 74%

DCV+SOF ±RBV 86%

SOF+RBV 12%

SOF+RBV 2%

DCV+SOF ±RBV 22%

G2 Regimen Starts

Curry M, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, 2017. Abst. PS-102.

9488

95 94 9697 95 97 95 97

0

20

40

60

80

100

All TE TN F4 F0–3

SOF+RBV SOF/VEL±RBV

SVR

12

, PP

(%

)

238/252

91/94

30/34

21/22

208/218

70/72

48/51

21/22

188/196

70/72

TRIO Study:Patient Disposition and SVR12 (GT2-3)

Genotype 2

Genotype 3

96 93 97 93 9697 9298 93

100

0

20

40

60

80

100

All TE TN F4 F0–3

DCV+SOF±RBV SOF/VEL±RBV

266/276

66/68

52/56

214/220

214/220

55/56

67/72

14/15

196/201

52/52

SVR

12

, PP

(%

)

Curry M, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, 2017. Abst. PS-102.

So what do we do with the small numbers with DAA failures?

Rescue treatment for DAA-failures

- NS5B & NS3 RASs disappear within weeks and months

- NS5A RASs seem to persist

- Rescue treatment with the same regimen has limited efficacy

• Addition of Ribavirin (failure to 1st gen. NS5A Inh. and re-treatment with 2nd gen. NS5A Inhibitor VEL)

• Extension to 24 weeks (if cirrhosis is present)

• Addition of Sofosbuvir (high barrier to resistance)

• Protease-Inhibitor NS5A Inhibitor

• NS5A Inhibitor Protease-Inhibitor

EASL Clinical Practice Guidelines on Hepatitis C, J Hepatol 2017

SVR1216 weeksN = 47

12 weeksN = 44

Weeks

SVR12

0 12 24

G/P

20

Treatment Period

1:1

Ran

do

miz

ed

G/P

16 28Patients with cirrhosis: 50% enrollment maximumNS5A-naïve patients: 40% enrollment maximum

Poordad F, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, 2017. Abst. PS-156.MAGELLAN-1, Part 2: Registrational Study

MAGELLAN-1, Part 2 Study: Objective and Study Design

• Objective• Determine the efficacy and safety of G/P for 12 or 16 weeks in patients with chronic HCV GT1,

4, 5 or 6 infection and prior DAA failure, including those with compensated cirrhosis

Characteristic , n (%)G/P

12 weeksN = 44

G/P 16 weeks

N = 47

Previous DAA regimen class*

NS3/4A PI only (NS5A inhibitor-naïve) 14 (32) 13 (28)

NS5A inhibitor only (PI-naïve) 16 (36) 18 (38)

NS3/4A PI + NS5A inhibitor 14 (32) 16 (34)

Prior DAA treatment response

On-treatment failure 14 (32) 13 (28)

Virologic relapse 30 (68) 34 (72)

Presence of key baseline substitutions†

None 13 (30) 13 (30)

NS3 only 2 (5) 4 (9)

NS5A only 24 (55) 23 (52)

NS3 + NS5A 5 (11) 4 (9)

Poordad F, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, 2017. Abst. PS-156.

NS3 PIs included: PTV, SMV, ASV, TVR, or BOC; NS5A inhibitors included: DCV, LDV, or OBV*Sofosbuvir (NS5B inhibitor) could be included in any prior treatment regimen†Only 44 patients had sequencing data available in each arm; percentages are based on N = 44; substitutions detected by next generation sequencing using 15% detection thresholdat positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 92, and 93 in NS5A

MAGELLAN-1, Part 2 Study:Clinical Characteristics (Cont’d)

Poordad F, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, 2017. Abst. PS-156.

MAGELLAN-1, Part 2 Study: ResultsSVR12 by DAA Class in Prior Therapy

Overall SVR12:

• 12-week: 89% (39/44)

• 1 OTVF; 4 relapse

• 16-week: 91% (43/47)

• 1 OTVF; 0 relapse

Prior Treatment History

• PI: TVR, SMV, BOC

• NS5A: LDV, DCV

• NS5A+PI: OBV and PTV, or other combinations

• OTVF, on-treatment virologic failure

100 88 79 100 94 81

0

20

40

60

80

100

SVR

12

(%

Pat

ien

ts)

Prior DAA PI NS5A PI+ PI NS5A PI+

Class only only NS5A only

only NS5A

Regimen G/P: 12 weeks G/P: 16 weeks

1414

1416

1114

1313

1718

1316

Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46.

Sofosbuvir-Velpatasvir-Voxilaprevir in NS5A-Experienced GT 1-6

POLARIS-1: Study Design

Sofosbuvir-Velpatasvir-

VoxilaprevirSVR12

Drug Dosing

Sofosbuvir-Velpatasvir-Voxilaprevir (400/100/100 mg): fixed dose combination; one pill once daily

Placebo: one pill once daily

GT 1-6 with NS5A

inhibitor experience*

n = 415

N=263

Placebo SVR12N=152

Week 0 12

• GT 1 patients randomized 2:1 ratio (active:placebo). Stratified by presence of cirrhosis (target ≥30%).

• Genotypes 2-6 were assigned to active arm (and not randomized).

• Placebo recipients were eligible for deferred treatment with sofosbuvir-velpatasvir-voxilaprevir

24


Sofosbuvir-Velpatasvir-Voxilaprevir in NS5A-Experienced GT 1-6

POLARIS-1: Prior NS5A Treatment

51

27

1113

0

10

20

30

40

50

60

Ledipasvir Daclatasvir Ombitasvir Other

Pati

en

ts (

%)

Prior NS5A Treatment

133/263 70/263 30/263 33/263

Sofosbuvir-Velpatasvir-Voxilaprevir in DAA-Experienced GT 1-6POLARIS-4: Results

POLARIS-4: Overall SVR by Baseline RAS


94100 100 100 100

89 90 9194

50

0

20

40

60

80

100

No RAS Any RAS NS3 Only NS5A Only NS3 + NS5A

Pati

en

ts (

%)

wit

h S

VR

12

SOF-VEL-VOX SOF-VEL

32/3440/40

N=22 patients had NS5B RASs – all went on to achieve SVR12.

No treatment-emergent RASs noted in the viral relapser on SOF/VEL/VOX. In SOF/VEL group, 10/15 developed Y93H or Y93C.

29/3239/3963/7083/8367/7584/89 2/44/4

So, are there really any more ‘difficult to treat patients’?

Conclusions• The licensing of G/P and Sof/Vel and Sof/Vel/Vox has been a real

‘game changer’– Effective management of G3 patients– Shorter duration of therapy (8 weeks)– Effective treatment for ESRD patients– Options for DAA-experienced patients

• Two groups of patients still need attention– Patients with advanced liver disease AND renal impairment– Patients with multiple DAA exposures/multiple mutations

• To achieve the WHO target of ‘HCV elimination’– Wider access to DAAs– Diagnosing the undiagnosed– Simplified pre-, peri- and post-treatment assessments– Short duration therapies

are all patients easy to treat? · pa rita p re v ir g ra zo p re v ir si m e p re v ir glecaprev...

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