Access to new HCV therapy and the place of

precision medicine

Graham Cooke

Imperial College, London

ECCMID, Amsterdam

11th April 2016

@grahamscooke

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Leading causes of death from infectious diseases

(GBD 2015 in preparation)

0

200

400

600

800

1000

1200

1400

1600

Viral Hepatitis TB HIV Malaria© ESCMID eLibrary

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So what does it tell us about viral hepatitis?

Vaccine Treatment

Hepatitis A Yes No

Hepatitis E Yes (Yes)

Hepatitis B Yes Yes

Hepatitis C No Yes

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• Treatment is particularly important as a

tool to control HCV

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Host DNA

It’s about cure = SVR

Host cell

Nucleus

HBVHIV HCV

cccDNAProviral DNA

Viral RNA

TREATMENT TREATMENT TREATMENT

Long-term

suppression of

viral replication

Long-term

suppression of viral

replication2,3

Viral Eradication =

Cure

Genotypes

important

1. Pawlotsky JM. J Hepatol 2006;44:S10-S13; 2. Siliciano JD, Siliciano RF. J

Antimicrob Chemother 2004;54:6-9;

3. Lucas GM. J Antimicrob Chemother 2005;55:413-416

cccDNA = covalently closed circular DNA© ESCMID eLibrary

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General: 18 studies

n=29,269

Avg. FU=4.6 years

No SVRSVR

Cirrhotic: 9 studies

n=2,734

Avg. FU=6.6 years

HIV/HCV: 5 studies

n=2,560

Avg. FU=5.1 years

Simmons et al CID 2015

Why do we want to achieve SVR? All-cause mortality

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Precision HCV Medicine before

“The Storm”

We already (variably) use precision/stratified

medicine

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Back in 2015: Virus? Q80K and simeprevir

100

80

60

40

20

0

SV

R12 (

%)

85

58

228/267

49/84

84

138/165

GT1b GT1a no Q80K

GT1a +Q80K

Q80K present in 34% of GT1a patients. No benefit of simeprevir if Q80K positive

53

70/133

4352

36/83

23/44

Simeprevir + P/R

P/R Standard care

n/N =

Jacobson I, et al. AASLD 2013. Abstract 1122.

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Host genetics? IFNλ3 (IL28) and IFNλ4

Prokunina-Olsson NG (2013)

Chr 19

PolyI:C

IFNL4

ΔG

ISGs

IL28B

Virhep-CBut?© ESCMID eLibrary

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HCV genotypes still matter for now

Messina et al Hepatology (2015)

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How relevant is this with new

treatments?

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1. Lindenbach BD & Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005;436:933-938

HCV lifecycle provides multiple targets for new drugs

Core

Virion assembly

Translation and polyproteinprocessing

RNA replication

Receptor bindingand endocytosis

Fusion anduncoating

(+) RNA

Transport and release

4A NS4B NS5AE2E1C p7 NS2 NS3 NS5B

NS3 protease

Serine protease domain

NS2–NS3 proteinase

Core Envelope RNA-dependent RNA polymerase

Nuc/Non-nuc

Polymerase Inhibitors

“-buvirs”

NS5a inhibitors

“-asvirs”

Protease inhibitors

“-previrs”

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Phase I

Phase II

Phase III

Phase IV

DAA combinations

NS5A inhibitors

Protease inhibitors

Polymerase inhibitors

Hepatitis C pipeline has been very busy: 2013

Franciscus, A. Hepatitis C Treatments in Current Clinical Development, 17 October 2012, available at:

http://www.hcvadvocate.org/hepatitis/hepC/HCVDrugs_2012.pdf

ABT072

(Abbott)

ABT333

(Abbott)

TMC647055

(Medivir/Tibotec)

TMC649128

(Medivir/Tibotec)

MK3291

(Merck)

ACH-2684

(Achillon)

ACH-2928

(Achillon)

ACH-3102

(Achillon)

AZD-7295

(AstraZeneca)

Clemizole

(Eiger BioPharmaceuticals)

IDX719

(Idenix) PPI-461

(Presidio)PPI-688

(Presidio)

ITX-5061

Entry Inhibitor

(iTherX) Telaprevir/VX-222

(Vertex)

ABT-450

(Abbott/Enanta)

ACH-1625

(Achillion)ALS-2200

(Alios/Vertex)

ANA598

(Anadys/Genentech)

BI 207127

(Boehringer)

BIT225

(Biotron)

BMS-650032

(BMS)

BMS-791325

(BMS)

Filibuvir

(Pfizer)

GS 9190

(Gilead)

GS-9256

(Gilead)

IDX184

(Idenix)

MK-5172

(Merck)

GS-938

(Gilead)

RG7128

(Gilead/Genentech)RG7227

(InterMune/Genentech)

Vaniprevir

(Merck)

VX-222

(Vertex)

VX-759

(Vertex)

Faldaprevir

(Boehringer)

asuneprevir

(BMS)

Sofosbuvir

(Gilead)

Simeprevir

(Medivir/Tibotec)

Boceprevir

(Merck)Telaprevir

(Vertex)

RG7128/RG7227

(Genentech)

GS-7977/TMC435

(Gilead/Tibotec)

GS-9256/GS-9190

(Gilead)

Boceprevir/Mericitabine

(Merck/Genentech)

BMS-790052/TMC435

(BMS/Tibotec)

BMS-790052/GS-7977

(BMS/Gilead)

BI 201335/BI 207127

(Boehringer)

ABT-450/ABT-333

(Abbot/Enanta)

ABT-450/ABT-267

(Abbot/Enanta)

ABT-450/ABT-072

(Abbot/Enanta)

ABT-450/ABT-267 and/or ABT-333

(Abbot/Enanta)

BMS-790052/BMS-650032

(BMS)

TMC435/TMC647055

(Medivir/Tibotec)

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Phase I

Phase II

Phase III

Phase IV

DAA combinations

NS5A inhibitors

Protease inhibitors

Polymerase inhibitors

Field is consolidating

ACH-2684

(Achillon)

ACH-3102

(Achillon)

PPI-461

(Presidio)

ITX-5061

Entry Inhibitor

(iTherX)

BIT225

(Biotron)

GS-9451

(Gilead)

VX-222

(Vertex)

Sofosbuvir

(Gilead)

Simeprevir

(Janssen)

A3D(

Daclatasvir/asunaprevir

(BMS)

ABT-493/530

Abbvie

(BMS/Tibotec)

Sofosbuvir/Velpatasvir

(Gilead)

Grazoprevir/Elb

(Merck)

Sofosbuvir/Ledipasvir

(Gilead)

GS9857

(Gilead)Sovaprevir

(Achillon)

VX-135

(Vertex)

Sofosbuvir/MK drugs

(Merck)

IDX21437/MK drugs

(Merck)

IDX21437

(Merck)

IDX21459

(Merck)

daclatasvir

(BMS)

c

Sofosbuvir/PPI-668

(Gilead/Presidio)

Alisporovir

(Novartis)

IDX 719

Sofosbuvir/5816/

GS-9256

(Gilead)

RG-101

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0

20

40

60

80

100

IFN

6 mo

IFN

12 mo

IFN+RBV

6 mo

IFN+RBV

12 mo

PEG

12 mo

PEG+RBV

12 mo

PI+PEG

+RBV

6-12 mo

LDV/SOF/RBV

AbbVie 3D

5172/8472

12 weeks

68-75

54-56

3942

34

16

6

90

1986 1998 20022001 2011 2013

SV

R R

ate

(%

)

*Year of data presentation at EASL 2014 and publication in NEJM

Adapted from Strader DB, et al. Hepatology 2004;39:1147-71. INCIVEK [PI]. Cambridge, MA: Vertex Pharmaceuticals; 2013. VICTRELIS [PI]. Whitehouse Station, NJ: Merck & Co; 2014. Jacobson I, et al. EASL 2013. Amsterdam. The Netherlands. Poster #1425. Manns M, et al. EASL 2013. Amsterdam. The Netherlands. Oral #1413. Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02; Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 ; Kowdley K, et al. N Engl J Med 2014; 2014 Apr 11

SMV+PEG

+RBV

6-12 mo

80-81

2014*

SOF+PEG

+RBV

3 mo

94-99

HCV Genotype 1 Treatment-Naïve Patients – improving SVRs

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Selected DAA Combinations in Late Development/ Approval

Nucleotide/

nucleoside

Non-nucleoside Protease Inh NS5a

Sofosbuvir

Sofosbuvir Ledipasvir

Sofosbuvir (GS-9857) Velpatasvir

Dasabuvir Paritaprevir/R Ombitasvir

ABT-493 ABT-530

(MK-3682) Grazoprevir Elbasvir

(MK-3682) Grazoprevir MK8408

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Outcomes in HIV very similar to monoinfection

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Role for precision medicine if very good outcomes?

Afdhal NEJM 2014

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Why not give everyone 12 weeks of next

generation therapy?

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Two big challenges

• Money

• Nature of the therapy

(adherence)

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Recent case

• 45 year old male ex- IDU

• Chronic HCV (mild disease)

• Pre-existing paranoid ideation

• Baseline HCV VL 6000000 IU/l, genotype 1a

• Started OMB/PAR/DAS/RIT/RBV

• Stopped treatment early at 3/52

• EOT +8 weeks remains HCV VL undetectable

Could we have known before treatment started

that 3/52 would be enough?

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Money

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The cost of sofosbuvir for Hepatitis C per person, 12 weeks treatment

$84,000

$67,000

$57,000

$1,000 $68-$1360

10

20

30

40

50

60

70

80

90

1 2 3 4 5

Tau

sen

de

USA Germany UK Egypt Minimum

Hill & Cooke (Science 2014)

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Cost and convenience

Economist 2014

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England : Run rates

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Costs

Hill et al CID 2014

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Hill et al CID 2014

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Overcoming the cost barriers to improve access

• More competition from manufacturers

• Value based pricing and other funding

structures

• NGO activity (activism)

• Access to generic treatments from outside

EU

• Making smarter use of the treatments we

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We will be overtreating most patients despite the costs

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A challenge common to many infectious diseases

This is true in

TB/TBM/MDR-TB (6-24/12)

Sepsis and bacterial infection (7-21d)

Hepatitis C (8-12/52)

Our evidence base for predicting who will be cured with shorter

duration of therapy is not often good enough to change

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Baseline stratification ; Viral load thresholds for Harvoni

Viral resistance testing for Graz/Elb

On treatment responses; data emerging

Treatment/Retreatment ; SYNERGY, C-SWIFT

We can do better: redefining stratification in IFN free era

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Treatment/Retreatment and Resistance?

- Key difference from the same challenges posed in other

infections (e.g. TB, sepsis)

- Merck’s C-SWIFT (ELB/GRAZ/SOF) studied durations down

to 4/52

Retreatment of failures presented in AASLD – 100% SVR

- NIH/Gilead Synergy Study also down to 4/52

Retreatment success of over 90% despite high rates of NS5a

emergence

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# P

ati

en

ts w

ith

Id

en

tifi

ed

RA

V

Baseline1st

RelapseRetreatment

Baseline

2nd

Relapse

Emergence of RAVs after short course Rx

0

5

10

15

20 K24R

M28T

Q30H

Q30K

Q30R

Q30T

L31I

L31M

L31V

S38F

Y93C

Y93H

Y93N

Q30L

Slide courtesy of Eleanor Wilson

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4-6 weeks A3D

Stratified by

Screening

HCV VL

Hepatitis C genotype 1a/1b

Mild disease (fibroscan). Mono- and co-infection

No drug-drug interactions with concomitant medications

(n=408)

Follow-up: day 3, 7, 14, 28: then every other week until 4 weeks post end of treatment; then 4-weekly until

12 weeks post end of treatment, then 24 weeks 24 post end of treatment.

Primary endpoint: Overall SVR12 (ie cure) at the end of first-line and any re-treatment (stratified randomisation)

SVR12 at the end of first-line (ribavirin comparison)

Secondary endpoints: SVR24; lack of initial virological response; viral load rebound (relapse) after becoming

undetectable; serious adverse events; grade 3 or 4 adverse events; adverse events of any

grade judged definitely/ probably related to the intervention; treatment-modifying toxicity of

any grade; grade 3 or 4 anaemia; emergence of resistance-associated Hepatitis C variants;

cost.

**not achieving SVR12= failure to suppress virus during treatment; relapse after

suppression either prior to or at week 12 after end of therapy.

8 weeks A3D

Fixed durationFactorial

random

-isation ± ribavirin± ribavirin

SVR12?** CUREYes

(n=359)

12 weeks SOF/LDV

+ ribavirin

No (n=49)

SVR12 CUREYes

(n=42)

STOPHCV1

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Where do we want to get to?

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Where do we want to get to?

We want to be able to offer all patients >90% chance of cure

with minimum duration of therapy

Leverage expertise in genetics (viral>host) and immunology

to support this in routine practice

Achieve this through further studies

- To evaluate other genotypes

- To validate rules for shortened treatment with goal

of >90%

Integrate with developments in informatics

European systems are better placed than anyone to do this

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IHME, Seattle

Mohsen Naghavi

Abraham Flaxman

Jeff Stanaway

Theo Vos

GBD Collaborators

WHO

Nathan Ford

Stefan Wiktor

Microhaart

Andrew Hill

MRC Clinical Trials@UCL

Sarah Walker

Sarah Pett

STOP HCV Consortium

Ellie Barnes

Will Irving

John Mclauchlan

Peter Vickerman

Natasha Martin

Peter Simmonds

Paul Klenerman

Graham Foster

MSF

Bhargavi Rao

Philipp du Cros

Jen Cohn

Isabelle Andrieux-Meyer

Thanks

Imperial College/ICHT

Borja Mora-Peris

Scott Mullaney

Ken Legg

Nur Johari

Bryony Wilkes

Janice Main

Mark Thursz

Ashley Brown

Simon Taylor-Robinson

Shahid Khan

Maud Lemoine

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