Daclatasvir&asunaprevir Sep13

Horizon Scanning Centre
September 2013
Daclatasvir and asunaprevir for

hepatitis C infection
SUMMARY
This briefing is
based on
information
available at the time
of research and a
limited literature
search. It is not
intended to be a
definitive statement
on the safety,
efficacy or
effectiveness of the
health technology
covered and should
not be used for
commercial
purposes or
commissioning
without additional
information.
NIHR HSC ID: 6864 & 6865
Daclatasvir and asunaprevir are intended for use in the treatment of patients
with chronic hepatitis C virus (HCV) infections genotype 1 and 4. If licensed
daclatasvir and asunaprevir will offer an additional treatment option for
patients with HCV genotypes 1 and 4, including those who have failed first
line treatment with peginterferon (PEG-IFN) and ribavirin (RBV). Daclatasvir
is a small molecule HCV non-structural 5A (NS5A) replication complex
inhibitor and asunaprevir is an oral selective inhibitor of the HCV NS3
protease
The true incidence of HCV infection is difficult to establish, however recent
estimates suggest that there are around 216,000 individuals chronically
infected with HCV in the UK, with around 90% being genotype 1 and
genotype 3. In 2011, there were 187 deaths registered in England and
Wales 1. The virus is acquired primarily through percutaneous exposure to
contaminated blood. Most acute infections with HCV are asymptomatic with
only 20% experiencing an overt hepatitis. Approximately 80% of people who
are infected go on to develop chronic HCV which may result in inflammatory
liver disease with the progressive development of hepatic fibrosis and
cirrhosis. Chronic HCV is categorised as mild, moderate or severe
depending on the extent of liver damage. The progression from infection to
cirrhosis is variable in time but on average takes 40 years. About 30% of
those who are infected with HCV develop cirrhosis within 2030 years.
The choice of therapy for HCV is influenced by genotype. Patients with
genotype 1 are treated with dual and triple combination therapy for a duration
influenced by pre-treatment factors (including cirrhosis) or response to
therapy. Patients with genotype 2 or 3 are usually treated with 24 weeks of
PEG-IFN-2 and RBV, whilst genotype 4 patients are treated with 48 weeks
of PEG-IFN-2 and RBV. All patients with chronic HCV (irrespective of the
stage of the disease) are considered for therapy, with the aim of preventing
the development of compensated and decompensated liver disease, and
hepatocellular carcinoma. Daclatasvir and asunaprevir are currently in a
number of trials comparing their effects on sustained viral response against
placebo PEG-IFN-2 and RBV alone.
This briefing presents independent research funded by the National Institute

for Health Research (NIHR). The views expressed are those of the author
and not necessarily those of the NHS, the NIHR or the Department of Health.
NIHR Horizon Scanning Centre, University of Birmingham
Email: nihrhsc@contacts.bham.ac.uk
Web: http://www.hsc.nihr.ac.uk
NIHR Horizon Scanning Centre

TARGET GROUP
Daclatasvir and asunaprevir for patients with hepatitis C virus (HCV) genotype 1b, who
are treatment nave or are ineligible, intolerant or have failed previous therapy with
peginterferon (PEG-IFN) and ribavirin (RBV) .
Daclatasvir and asunaprevir in combination with PEG-IFN and RBV, for patients with
HCV genotype 1 or 4 who have failed previous therapy with PEG-IFN and RBV.
Daclatasvir in combination with PEG-IFN and RBV, for patients with HCV genotype 4
who are treatment nave.
Daclatasvir in combination with PEG-IFN and RBV, for patients with HCV genotype 1b
who are treatment nave.
TECHNOLOGY
DESCRIPTION
Daclatasvir (BMS-790052) is a small molecule HCV non-structural 5A (NS5A) replication
complex inhibitor. It has been shown to block two distinct stages of the viral lifecycle, namely
viral RNA synthesis and virion assembly/secretion 2. Asunaprevir (BMS-650032) is an oral
selective inhibitor of the HCV NS3 protease. In the phase III trials, daclatasvir was
administered at 60mg once daily and asunaprevir at 100mg, 200mg or 400mg twice daily,
both for 24 weeks 3.
INNOVATION and/or ADVANTAGES

If licensed daclatasvir and asunaprevir will offer an additional treatment option for patients
with HCV genotypes 1 and 4, including those who have failed first line treatment with PEGIFN and RBV.
DEVELOPER
Bristol-Myers Squibb.
AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.
PATIENT GROUP
BACKGROUND
HCV is a member of the flaviviridae family of spherical, enveloped, positive-strand RNA
viruses. There are six different HCV genotypes; genotype 2 and 3 are the most common in
the UK and responsible for 50% of cases, closely followed by genotype 1 which is
responsible for 45% of cases, and the most resistant to treatment 4,5. The virus is acquired
primarily through percutaneous exposure to contaminated blood 6. Most acute infections with
HCV are asymptomatic with only 20% experiencing an overt hepatitis3. Approximately 80%
of people who are infected go on to develop chronic HCV4 which may result in inflammatory
liver disease with the progressive development of hepatic fibrosis and cirrhosis 7. Chronic
HCV is categorised as mild, moderate or severe depending on the extent of liver damage.

The progression from infection to cirrhosis is variable in time but on average takes 40 years4.
About 30% of those who are infected with HCV develop cirrhosis within 2030 years 8,9.
Patients with detectable levels of HCV DNA have an increased risk of hepatic and
extrahepatic disease 10. There are also a number of other factors known to increase the rate
of progression such as age, male sex, excessive alcohol consumption and HIV co-infection5.
NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to:
The Blood Borne Virus Action Plan for Wales 2009-2014. 2008.
Hepatitis C Action Plan for England. 2004.
CLINICAL NEED and BURDEN OF DISEASE

The true incidence of HCV infection is difficult to establish, however recent estimates
suggest that there are around 216,000 individuals chronically infected with HCV in the UK 11,
with around 90% infected with HCV genotype 1 or genotype 310. Chronic HCV was the
primary cause of 2,404 admissions to hospitals in England in 2011-12 resulting in 3,332 bed
days 12 (ICD-10 B17.1, B18.2). In 2011, there were 187 deaths registered in England and
Wales 13. HCV is the major cause of liver transplantation in Europe 14; in 2011 there were 102
first registrations for liver transplant as a result of post-HCV cirrhosis in England8.
PATIENT PATHWAY
RELEVANT GUIDANCE
NICE Guidance
NICE technology appraisal in development. Hepatitis C (children and young people)

peginterferon alfa and ribavirin. Expected August 2013 15.
NICE technology appraisal. Boceprevir for the treatment of genotype 1 chronic
hepatitis C. (TA253). April 2012 16.
NICE technology appraisal. Telaprevir for the treatment of genotype 1 chronic
hepatitis C. (TA252). April 2012 17.
NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of
chronic hepatitis C. (TA200). 20103.
NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of mild
hepatitis C. (TA106). 2006 18.
NICE technology appraisal. Interferon alfa (pegylated and non-pegylated) and
ribavirin for the treatment of chronic hepatitis C. (TA75). 2004 19.
Other Guidance
European Association for the Study of the LIVER (EASL) Clinical Practice
Guidelines: Management of hepatitis C virus infection. 2011 20.
Department of Health. Hepatitis C: quick reference guide for primary care. 2009 21.
Royal College of General Practitioners. Guidance for the prevention, testing,
treatment and management of hepatitis C in primary care. 2007 22.
SIGN. Management of hepatitis C. 2013 23.
British Association of Sexual Health and HIV. United Kingdom national guideline on
the management of the viral hepatitides A, B & C. 2005 24.
British Society of Gastroenterology. Guidance on the treatment of hepatitis C

incorporating the use of pegylated interferon. 2003 25.
EXISTING COMPARATORS and TREATMENTS

The choice of therapy for HCV is influenced by genotype. Patients with genotype 1 are
treated with dual and triple combination therapy for a duration influenced by pre-treatment
factors (including cirrhosis) or response to therapy. Patients with genotype 2 or 3 are usually
treated with 24 weeks of PEG-IFN-2 and RBV, whilst genotype 4 patients are treated with
48 weeks PEG-IFN-2 and RBV. All patients with chronic HCV (irrespective of the stage of
the disease) are considered for therapy5, with the aim of preventing the development of
compensated and decompensated liver disease, and hepatocellular carcinoma.
Current treatment options include5,19:
A combination of RBV and PEG-IFN-2a (Pegasys, Roche) or PEG-IFN-2b
(ViraferonPeg, Schering-Plough).
Telaprevir in combination with PEG-IFN and RBV.
Boceprevir in combination with PEG-IFN and RBV.
Successful treatment is usually indicated by a sustained viral response (SVR), which is
defined as undetectable serum HCV RNA 6 months after the end of treatment4. The
proportion of people with HCV genotype 1 who show an SVR finishing a course of treatment
with PEG-IFN/RBV is about 40% to 50%4,10 and 60% to 80% in patients treated with triple
therapy boceprevir/telaprevir and PEG-IFN/RBV a. This compares to approximately 75% to
85% of people with HCV genotype 2 or 3, and 50% to 75% for other genotypes (4, 5, and 6)
treated with dual therapy PEG-IFN/RBV4,10.
EFFICACY and SAFETY

Trial
Sponsor
Status
Source of
information
Location
Design
Participants
COMMAND-3,
NCT01492426, AI444-052,
2011-004237-14;
daclatasvir with PEGIFN-2a and RBV vs
telaprevir with PEG-IFN2a and RBV; phase III.
Ongoing.
26
Trial registry .
NCT01389323, AI444-038;
daclatasvir with PEG-IFN2a and RBV; phase III.
NCT01448044, AI444-042,
2011-002793-23;
daclatasvir with PEG-IFN2a and RBV vs placebo
with PEG-IFN-2a and
RBV; phase III.
Ongoing.
27
Trial registry .
Ongoing.
28
Trial registry .
EU (incl UK), USA,

Canada and other
countries.
Randomised, activecontrolled.
n=600 (planned); aged
18 years; chronically
infected with HCV
genotype 1a or 1b;
treatment naive.
USA and Puerto Rico.
EU (incl UK), USA and

Puerto Rico.
Uncontrolled, single arm.
Randomised, placebocontrolled.
n=120 (planned); aged 18
years; chronically infected
with HCV genotype 4;
treatment nave.

years; chronically infected
with HCV genotype 1a or
1b; treatment nave.
Expert personal communication.

Schedule
Randomised to oral
daclatasvir 60mg once
daily for 24 weeks in
combination with
subcutaneous (SC) PEGIFN-2a 180g weekly
and oral RBV 1,000mg or
1,200mg per day, both for
24 or 48 weeks; or oral
telaprevir 750mg three
times daily for 12 weeks,
in combination with SC
PEG-IFN-2a 180g
weekly and oral RBV
1,000mg or 1,200mg per
day, both for 24 or 48
weeks.
Oral daclatasvir 60mg once

daily for 24 weeks in
combination with SC PEGIFN-2a 180g weekly and
oral RBV 1,000mg or
1,200mg per day, both for
24 or 48 weeks.
Randomised to oral
daclatasvir 60mg once daily
for 24 weeks in
oral RBV 1,000mg or
1,200mg daily (dependent
on weight), both for 24 or
48 weeks; or placebo in
oral RBV 1,000mg or
1,200mg daily (dependent
on weight), both for 48
weeks.
Follow-up
Active treatment period 24

or 48 weeks. Follow-up 24
or 48 weeks thereafter.
b
SVR12 in genotype 1b
patients.
Haemoglobin <10g/dL;
rash events; SVR12;
SVR4; HCV RNA
undetectable at week 4
and 12; SVR24; SVR12
based on IL28B
rs12979860 single
nucleotide polymorphism
(SNP).
Estimated study
completion date Mar 2014.

SVR24.

SVR12.
Safety; SVR proportion of

patients with CC, CT or TT
genotype at the IL28B
rs12979860 SNP who
achieve SVR.
SVR; safety; SVR12 or

SVR24 by IL28B
rs12979860 SNP.
Estimated study completion

date Apr 2014.

date May 2014.
NCT01573351, AI447-029,
2011-005422-21;
asunaprevir with
daclatasvir, PEG-IFN-2a
and RBV; phase III.
Ongoing.
2
Trial registry .
NCT01581203, AI447-028,
2011-005446-35;
asunaprevir with
daclatasvir; phase III.
NCT01428063, AI444-026,
2011-000836-27;
asunaprevir with
daclatasvir, PEG-IFN-2a
and RBV; phase II.
Ongoing.
30
Trial registry .
EU, USA, Canada and

other countries.
Uncontrolled, single arm.
EU (incl UK), USA, Canada

and other countries.
Randomised, placebocontrolled for treatment
nave cohort only; nonrandomised single arm for
all other cohorts.
Primary
outcome/s
Secondary
outcome/s
Expected
reporting
date
Trial
Sponsor
Status
Source of
information
Location
Design
Ongoing.
29
Trial registry .
EU (incl UK), USA, Canada

and other countries.
Non-randomised.
SVR, defined as HCV RNA < limit of quantification (LOQ). SVR12 defines SVR after 12 weeks of
therapy.

Participants
n=390 (planned); aged

18 years; HCV genotype
1 or 4; null or partial
response to treatment with
PEG-IFN-2a and RBV.
Schedule
Oral asunaprevir 100mg

twice daily in combination
with oral daclatasvir 60mg
once daily, SC PEG-IFN2a 180g once weekly and
oral RBV 1,000mg or
1,200mg per day; all for 24
weeks.
Follow-up

weeks. Follow-up 24
weeks thereafter.
SVR12 in genotype 1
patients.
Primary
outcome/s
Secondary
outcome/s
Safety; SVR; SVR12 by

the rs12979860 SNP;
SVR12 in genotype 4
patients.

years; HCV genotype 1b;
null or partial response to
treatment with PEG-IFN2a and RBV, ineligible for
treatment with PEG-IFN2a and RBV due to
neutropenia, anaemia
depression or
thrombocytopenia with
cirrhosis, or treatment
nave.
Arm 1
Null or partial responders to
PEG-IFN-2a and RBV.
once daily.
Arm 2
Intolerant or ineligible to
receive PEG-IFN-2a and
RBV.
once daily, both for 24
weeks.
Arm 3
PEG-IFN-2a and RBV
treatment nave.
Randomised to oral
asunaprevir 100mg twice
daily in combination with
oral daclatasvir 60mg once
daily, both for 24 weeks; or
placebo for 12 weeks.

weeks. Follow-up 24 weeks
thereafter.
SVR12 in null or partial
responders and treatment
nave groups.
SVR; SVR12 in intolerant
or ineligible groups; safety;
laboratory abnormalities;
genotype 1b patients with
SVR12 by the rs12979860
SNP.

years; prior participation in
any BMS-790052, BMS650032 or BMS-791325
trial and assigned to control
arm (PEG- IFN-2a /RBV
and/or placebo); HCV
genotype 1, 2, 3 or 4
(mixed genotypes not
permitted).
Arm 1
HCV genotypes 1 and 4,
prior non-responders to
PEG-IFN-2a and RBV.
Oral asunaprevir 100mg or
200mg twice daily in
combination with oral
daclatasvir 60mg once
daily, SC PEG-IFN-2a
180g once weekly and
oral RBV 1,000mg or
1,200mg daily; all for 24
weeks.
Arm 2
HCV genotypes 2 and 3,
prior non-responders to
PEG-IFN-2a and RBV.
Oral daclatasvir 60mg once
SC PEG-IFN-2a 180g
once weekly and oral RBV
1,000mg or 1,200mg daily;
all for 24 weeks.
Arm 3
Treatment nave genotype
1b.
once daily; all for 24
weeks.
thereafter.
SVR12 in genotype 1 prior
non-responders to PEGIFN-2a and RBV.
SVR; SVR12 in genotype 2,
3 and 4 prior nonresponders to PEG-IFN2a and RBV and treatment
nave genotype 1b patients;
safety; drug-resistant
variants associated with
virologic failure for each
HCV genotype and
treatment regimen.

Expected
reporting
date
Estimated study
completion date Mar 2014.

date Nov 2014.

date May 2017.
Trial
NCT00874770, AI444-014,
2009-010149-29;
daclatasvir with PEGIFN-2a and RBV vs
placebo with PEG-IFN-2a
and RBV; phase II.
NCT01170962, AI444-011,
2010-019378-34;
daclatasvir with PEG-IFN2a and RBV vs placebo
with PEG-IFN-2a and
RBV; phase II.
Sponsor
Status
Source of
information
Location
Completed.
31
Publication .
Complete but unpublished.
32
Trial registry .
NCT01012895, AI447-011,
2011-005446-35;
asunaprevir and daclatasvir
vs asunaprevir, daclatasvir
and RBV vs daclatasvir,
asunaprevir, RBV and
PEG-IFN-2a; phase II.
Ongoing.
33
Trial registry .
USA and France.
Design
n=48; 18 to 70 years;
chronic HCV genotype 1
infection; treatment nave.
EU, USA, Canada and

other countries.
n=421; 18 to 70 years; non
or partial responders to
prior PEG-IFN-2a and
RBV therapy.
Participants
Schedule
Randomised to:
Arm 1
Oral daclatasvir 3mg daily
PEG-IFN-2a 180g once
weekly and oral RBV
all for 48 weeks.
Arm 2
Oral daclatasvir 10mg
SC PEG-IFN-2a 180g
all for 48 weeks.
Arm 3
Oral daclatasvir 60mg
SC PEG-IFN-2a 180g
all for 48 weeks.
Arm 4
Placebo in combination
with SC PEG-IFN-2a
oral RBV 1,000mg or
weeks.
Randomised to:
Arm 1
Prior non-responders.
weekly, and oral RBV
all for 24 weeks.
Arm 2
Prior non-responders.
all for 24 weeks.
Arm 3
Prior partial responders.
all for 24 weeks.
Arm 4
Prior partial responders
all for 24 weeks.
USA, France and Puerto

Rico.
Randomised, activecontrolled.
n=120 (planned); 18 to 70
years; HCV genotype 1 null
responders; arms 3 and 4
restricted to genotype 1b
patients.
Randomised to:
Arm 1
in combination with oral
daily for 24 weeks.
Arm 2
oral RBV 1,000mg or
1,200mg daily (depending
on weight); all for 24
weeks.
Arm 3
daily for 24 weeks.
Arm 4
asunaprevir 200mg once
daily for 24 weeks.
Arm 5
oral RBV 1,000mg or
Arm 5
Prior partial responders
Placebo in combination
with SC PEG-IFN-2a
180g once weekly, and
oral RBV 1,000mg or
1,200mg daily, all for 24
weeks.
Follow-up
Primary
outcome/s
Secondary
outcome/s
Key results
Adverse
effects
(AEs)
Expected
reporting
date

weeks. Follow-up 24
weeks thereafter.
Safety; HCV RNA
determined by extended
rapid virologic response
(eRVR).
RVR; early virologic
response (EVR); complete
early virological response
(cEVR) SVR; resistant
variants with clinical
failure.
For daclatasvir 3mg, 10mg
60mg and placebo
respectively (80% CI):
eRVR, 42% (22-64%),
83% (61-69%), 75% (5390%), 8% (1-29%); RVR,
42% (22-64%), 92% (7199%), 83% (61-96%), 8%
(1-29%); cEVR, 58% (3678%), 83% (61-96%), 83%
(61-96%), 42% (22-64%);
SVR at 12 weeks, 42%
(22-64%), 92% (71-99%),
83% (61-96%), 25% (1048%); SVR at 24 weeks,
42% (22-64%), 83% (6196%), 83% (61-96%) 25%
(10-48%); virological
failure, 58%, 17%, 17%,
75%.
AEs occurred with similar
frequency across groups.

eRVR; SVR; safety.

weeks.
Arm 6
asunaprevir 200mg once
oral RBV 1,000mg or
weeks.
Arm 7
daily and RBV 1,000mg or
weeks.
thereafter.
HCV RNA.
RVR; cEVR; SVR12;

genotypic substitutions
associated with virologic
failure.
Safety; pharmacokinetics.
eRVR daclatasvir 20mg

group, 18.0% and 25.7%
for prior null responders or
prior partial respectively;
eRVR daclatasvir 60mg
group, 19.7% and 35.8%
for prior null responders or
prior partial responders
respectively; SVR24
daclatasvir 20mg group,
18.8% and 24.3% for prior
null responders and prior
partial responders
respectively; SVR24
daclatasvir 60mg group,
22.0% and 43.3% for prior
null responders and prior
partial responders
respectively.
Previously reported as
December 2012.

date Feb 2014.
ESTIMATED COST and IMPACT

COST
The cost of daclatasvir and asunaprevir is not yet known. The costs of currently licensed
treatments are 34:
Drug
PEG-IFN-2a
PEG-IFN-2b
RBV
Telaprevir
Boceprevir
Dose
180g once weekly
120g once weekly
1,200mg daily
2,250mg daily
800mg daily
24 week cost
2,986
3,828
2,220
44,796
16,800
48 week cost
5,971
7,656
4,440
-
IMPACT - SPECULATIVE
Impact on Patients and Carers
Reduced mortality/increased length of survival
Reduced symptoms or disability
Other
No impact identified
Impact on Services
Increased use of existing services
Decreased use of existing services: oral

treatment option.
Re-organisation of existing services
Need for new services
Other
None identified
Impact on Costs
Increased drug treatment costs
Reduced drug treatment costs
Other increase in costs
Other reduction in costs
Other: uncertain unit cost compared to

existing treatments
None identified
Other Issues
Clinical uncertainty or other research question
None identified
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Guedj J, Dahari H, Rong L et al. Modelling shows that the NS5A inhibitor daclatasvir has two modes
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ribavirin in patients who failed prior treatment (HEPCAT)
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ClinicalTrials.gov. Study to determine the effectiveness of antiviral combination therapy to treat
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11

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Horizon Scanning Centre

Daclatasvir and asunaprevir for

NIHR HSC ID: 6864 & 6865

This briefing presents independent research funded by the National Institute

NIHR Horizon Scanning Centre

INNOVATION and/or ADVANTAGES

AVAILABILITY, LAUNCH OR MARKETING

NIHR Horizon Scanning Centre

NHS or GOVERNMENT PRIORITY AREA

CLINICAL NEED and BURDEN OF DISEASE

NICE technology appraisal in development. Hepatitis C (children and young people)

NIHR Horizon Scanning Centre

British Society of Gastroenterology. Guidance on the treatment of hepatitis C

EXISTING COMPARATORS and TREATMENTS

EFFICACY and SAFETY

EU (incl UK), USA,

USA and Puerto Rico.

EU (incl UK), USA and

Uncontrolled, single arm.

n=230 (planned); aged 18

Expert personal communication.

NIHR Horizon Scanning Centre

Oral daclatasvir 60mg once

Active treatment period 24

Active treatment period 24

Active treatment period 24

Safety; SVR proportion of

SVR; safety; SVR12 or

Estimated study completion

Estimated study completion

EU, USA, Canada and

EU (incl UK), USA, Canada

EU (incl UK), USA, Canada

NIHR Horizon Scanning Centre

n=390 (planned); aged

Oral asunaprevir 100mg

Active treatment period 24

Safety; SVR; SVR12 by

n=725 (planned); aged 18

Active treatment period 24

n=300 (planned); aged 18

NIHR Horizon Scanning Centre

Estimated study completion

Estimated study completion

USA and France.

EU, USA, Canada and

USA, France and Puerto

NIHR Horizon Scanning Centre

Active treatment period 48

Active treatment period 24

1,200mg daily (depending

RVR; cEVR; SVR12;

eRVR daclatasvir 20mg

Estimated study completion

NIHR Horizon Scanning Centre

ESTIMATED COST and IMPACT

Reduced symptoms or disability

Decreased use of existing services: oral

Re-organisation of existing services

Need for new services

Reduced drug treatment costs

Other increase in costs

Other reduction in costs