HCV THERAPY ADVANCES NEW ANTIVIRALS IN CLINICAL PRACTICE Next Generation Regimens Joost PH Drenth Department of Gastroenterology and Hepatology, Radboudumc Nijmegen, The Netherlands AMSTERDAM, THE NETHERLANDS • 4 DECEMBER 2015 14.10h

What are the issues?

1. Where do we come from? 2. Were are we heading? 3. What are our goals? 4. What are our tools? 5. What we have solved already 6. What lies ahead?

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Where do we come from?

Where are we heading?

The voyage of HCV

Where are we heading?

Finish MD studies

Military Service HQ AFCENT

Clinical Investigator

PhD thesis defense

Departmental Head

Resident Internal medicine

Training completed Chair UEG cie

My personal voyage as a physician

Where are we heading?

Finish MD studies

Military Service HQ AFCENT

Clinical Investigator

PhD thesis defense

Departmental Head

Resident Internal medicine

Training completed Chair UEG cie

Elimination??

My personal voyage as a physician

What are our therapeutic goals?

• Sustained Viral Response (SVR): • aviremia 12 weeks after completion of antiviral therapy for HCV

infection • basis for FDA approval of drugs

• Assumption • virological cure ~ prevents development of cirrhosis and improves

survival • Observational studies: improvement in survival, lower HCC incidence

Gastroenterology. 2013 Jun;144(7):1450-1455 JAMA. 2012 Dec 26;308(24):2584-93.

http://www.ncbi.nlm.nih.gov/pubmed/23470616http://www.ncbi.nlm.nih.gov/pubmed/23268517

What are our therapeutic goals • But..

• SVR is a surrogate outcome • Not validated as primary outcome measure • Observational studies: high risk of bias • SVR bears no relation to quality of life • SVR in (de)compensated HCV cirrhosis: not always improvement • Child-Pugh score & MELD may increase after SVR

Saxena et al. AASLD 2015, Abstract #1825.

SMV/SOF ±RBV for 12-24 wks

What are our tools?

NS3/4a NS5A NS5B

Simeprevir Daclatasvir Sofosbuvir

Paritaprevir Ombitasvir Dasabuvir

Ledipasvir

What have we solved already

Higher SVR

Identification of molecular targets

Low risk of resistance

Acceptable route of administration

Acceptable safety profile

Pangenotypic efficacy

Drug drug interactions

Shortened treatment

Viszeralmedizin. 2015 Aug;31(4):290-6

http://www.ncbi.nlm.nih.gov/pubmed/26557839

Next generation tools ?

Velpatasvir Sofosbuvir

Grazoprevir Elbasvir

Grazoprevir MK-8408 MK-3682

ABT-439 ABT-530

NS3/4a: Grazoprevir NS5a: Elbasvir & MK-8408 NS5b: MK-3682

Grazoprevir Short treatment in non-cirrhotic naives

• Grazoprevir • Treatment-naïve, non-cirrhotic patients HCV GT1, 2 or 3 infection • 8 weeks combination with

• Elbasvir & MK-3682 (NS5b) • MK-3682 & MK-8408 (NS5a)

Gane AASLD 2015 LB-15

An 8-week regimen of grazoprevir/ MK-8408/MK-3682 (450 mg): high (>90%) SVR Safety: 1/240 (0.4%) patients ALT 8-fold >ULN at TW8

Grazoprevir short treatment in non-cirrhotic naives

Gane AASLD 2015 LB-15

Grazoprevir & Elbasvir • Phase 2/3 programme 6 RCT’s ~1600 pts, • Post Hoc Analysis • Child-Pugh A cirrhosis, ~93% GT 1 • Patients treated with Grazoprevir & Elbasvir • 12 weeks ; naïve (n=169) ; experienced (n=233)

Treatment naive Treatment experienced

12 weeks 12 weeks 16/18 weeks

SVR

Jacobson I, AASLD 2015, Abstract 42

Implications: Grazoprevir & Elbasvir

High efficacy across a broad spectrum of patients (incl cirrhotic patients) 8 week regime of grazoprevir/ MK-8408/MK-3682 (450 mg) is promising for

naïve noncirrotics Cirrhotics Longer therapy (16/18 vs. 12 weeks) may be more effective

Ribavirin addition May lead to higher efficacy in treatment experienced

Safety Rare (0.8%) elevation of ALT (without bilirubin increase)

Sofosbuvir & Velpatasvir

Sofosbuvir & Velpatasvir

• ASTRAL-1 • 706 patients HCV genotype 1, 2, 4, 5, or 6 • 81 sites EU, USA, Hong Kong (July –December 2014) • RCT 12 weeks:

• Sofosbuvir (400 mg) / Velpatasvir 100 mg (n=624) • Placebo (n=116)

• Outcome SVR 99% • Regardless Cirrhosis/ Treatment history / Genotype

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N Engl J Med 2015 Nov 15

Sofosbuvir & Velpatasvir • ASTRAL-2

• HCV genotype 2 • 51 USA sites (Oct-Dec 2014)

• Sofosbuvir–Velpatasvir (n=134) vs • Sofosbuvir–Ribavirin (n=132)

• 12 weeks • SVR 99% vs. 94% (95% CI, 0.2 to 10.3; P = 0.02)

• ASTRAL-3 • HCV genotype 3 • 76 sites USA, Can, EU, Aus, NZ (July-Dec 2014)

• Sofosbuvir–Velpatasvir (12 weeks n=277) • Sofosbuvir–Ribavirin (24 weeks , n=275)

• SVR 95% vs. 80% (95% CI, 9.6 to 20.0; P

Sofosbuvir/Velpatasvir for HCV Patients With Decompensated Liver Disease ♦ ASTRAL-4 ♦ HCV GT 1-6 patients with CP B cirrhosis ♦ Randomized to once daily, oral, FDC

SOF 400 mg/VEL 100 mg ± RBV Week 0 12 24

SOF/VEL SVR12

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SOF/VEL+RBV SVR12

SOF/VEL

n=75

n=75

n=75

Overall GT 1 GT 3 GT 2, 4, 6

83 88

50

100 94 96 85 100 86 92

50

86

0

20

40

60

80

100

47% Improved 10% Worsened

Change in CPT Score -4 -5 -3 -2 -1 0 1 2 4 5

Implications: Sofosbuvir & Velpatasvir

• SOF/VEL for 12 weeks yields high SVR rates in patients with HCV GT 1-6

• SOF/VEL is superior to SOF/RBV for 12 wks in GT2

• SOF/VEL is superior to SOF/RBV for 24 weeks in GT3, but RBV is needed

• SOF/VEL for 12 weeks was well tolerated, with a safety profile similar to that of placebo treatment

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NS3/4A: ABT-493 NS5A: ABT-530

ABT-493 (NS3/4A) & ABT-530 (NS5A)

• ABT-493 & ABT-530 characteristics • Pangenotype activity • High barrier to resistance • ABT-493 boosts ABT-530 exposures • Once-daily oral dosing • Primary biliary excretion (not renally)

• Phase 2: 12 week programs, dose finding, w/o ribavirin

Surveyor-II

G1, Treatment Naïve and Peg/RBV Nulls, Non-cirrhotic G2 and G3 Treatment Naïve and Peg/RBV Nulls, Non-cirrhotic

AASLD 2015 LB-14, Oral 41, 248, 250,

Surveyor-I

ABT-493 (NS3/4A) & ABT-530 (NS5A)

SV

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2 0

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6 0

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2 4

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300mg 120mg

200mg 120mg

200mg 120mg RBV 1000-1200 mg

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% P

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ABT-493 200mg ABT-530 40mg

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Genotype 1 Genotype 2 Genotype 3

300mg 120mg

200mg 120mg

200mg 120mg RBV 1000-1200 mg

200mg 40mg

ABT-493 (PI) and ABT-530 (NS5Ai) Across genotypes and across dosages, without ribavirin: high SVR

AASLD 2015 Oral 41, 248, 250,

Implications: ABT-493 & ABT-450

• ABT-493 & ABT-450 for 12 weeks yields high SVR rates in patients with HCV GT 1,2,3

• QD Dosages 200 mg (ABT-493), 120 mg (ABT-450)

• Ribavirin does not add significant efficacy

• Most commonly-reported DAA-related adverse reactions (>10 %) fatigue, nausea and headache

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What is the future

Simplovir™ • pangenotypic • 100% SVR • no side effects • 1 week • 1 pill • cheap

HCV THERAPY ADVANCES�NEW ANTIVIRALS IN CLINICAL PRACTICEWhat are the issues?Where do we come from?Where are we heading?Where are we heading?Where are we heading?What are our therapeutic goals?What are our therapeutic goals�What are our tools?�What have we solved already�Next generation tools ?�NS3/4a: Grazoprevir�NS5a: Elbasvir & MK-8408�NS5b: MK-3682 � Grazoprevir�Short treatment in non-cirrhotic naivesGrazoprevir�short treatment in non-cirrhotic naivesGrazoprevir & ElbasvirImplications: Grazoprevir & ElbasvirSofosbuvir & Velpatasvir Sofosbuvir & VelpatasvirSofosbuvir & Velpatasvir�Sofosbuvir/Velpatasvir for HCV Patients With Decompensated Liver DiseaseImplications: Sofosbuvir & VelpatasvirNS3/4A: ABT-493�NS5A: ABT-530 ABT-493 (NS3/4A) & ABT-530 (NS5A)ABT-493 (NS3/4A) & ABT-530 (NS5A)Implications: ABT-493 & ABT-450 What is the future