graham cooke imperial college, london
TRANSCRIPT
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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