Telaprevir, tablet (film coated), 375 mg, Incivo® - November 2011
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Public Summary Document
Product: Telaprevir, tablet (film coated), 375 mg,
Incivo®
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drugs
Program) Authority Required listing for the treatment, in
combination with peginterferon-alfa and ribavirin (PR), of chronic
hepatitis C in a patient 18 years or older who has compensated
liver disease and who has received prior treatment with
interferon-alfa or peginterferon-alfa for hepatitis C and meets
certain criteria.
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate specialist facilities.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
On 6 March 2012, telaprevir was registered by the TGA for the
following indication:
Telaprevir, in combination with peginterferon alfa and ribavirin is
indicated for the treatment of genotype 1 chronic hepatitis C in
adult patients with compensated liver disease (including
cirrhosis):
- who are treatment-naïve;
- who have previously been treated with interferon alfa (pegylated or non-pegylated) alone or in combination with ribavirin, including relapsers, partial responders and null responders.
4. Listing Requested and PBAC’s View
Section 100
Patients who have failed prior interferon based therapies
(pegylated or non-pegylated).
Treatment with telaprevir in combination with peginterferon-alfa
and ribavirin, managed by an accredited treatment centre, of
chronic hepatitis C in patients 18 years or older who have
compensated liver disease and who have received prior treatment
with interferon alfa or peginterferon alfa for hepatitis C and who
satisfy all of the following criteria:
(1) Documented chronic genotype 1 hepatitis C infection (repeatedly
anti-HCV positive and HCV RNA positive);
(2) Female patients of child-bearing age who are not pregnant, not
breast-feeding, and both patient and their partner are using
effective forms of contraception (one for each partner). Female
partners of male patients are not pregnant.
The treatment course is limited to 12 weeks.
Patients may only continue treatment after the first 6 weeks if the
results of a HCV RNA quantitative assay at Week 4 (performed at the
same laboratory using the same test) shows that the plasma HCV RNA
has become ≤ 1000 IU/mL.
NOTE
Treatment centres are required to have access to the following
appropriate specialist facilities for the provision of clinical
support services for hepatitis C:
(a) nurse / educator / councillor for patients; and
(b) 24 hour access by patients to medical advice; and
(c) an established liver clinic; and
(d) facilities for safe liver biopsy.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Hepatitis C is an inflammation of the liver caused by the hepatitis
C virus (HCV). Around 75% of people exposed to hepatitis C develop
chronic infection, defined as the presence of the hepatitis C virus
in the bloodstream for longer than 6 months. The remaining 25% will
spontaneously clear the infection, but will continue to have
detectable antibodies. Chronic hepatitis C (CHC) is a lifelong
chronic condition that can lead to cirrhosis of the liver and liver
cancer.
In 2010, the number of people with (CHC) in Australia was estimated
to be 221,000. There are several HCV genotypes. In Australia, the
genotype 1 is the most common HCV followed by genotype 3 and
genotype 2 which account for 55%, 37% and approximately 5% of all
HCV infections, respectively.
The submission proposed that the place in therapy of telaprevir is
in combination with interferon-alfa or peginterferon-alfa and
ribavirin (PR) for the treatment of a patient with chronic genotype
1 HCV infection who has failed to respond to prior interferon-based
therapies.
6. Comparator
In genotype 1 chronic hepatitis C patients who have received only
one prior course of interferon-based therapy, the submission
nominated peginterferon alfa and ribavarin (PR), without a
concomitant direct acting antiviral agent (DAA), as the comparator
for telaprevir administered in combination with PR.
In genotype 1 CHC patients who have received more than one prior
course of interferon based therapy, the submission nominated
placebo (or no active treatment) as the comparator.
The submission also nominated boceprevir, in combination with PR,
as a minor comparator, in anticipation that boceprevir is likely to
be registered for use in Australia at a similar time to telaprevir.
Boceprevir was submitted for consideration by the PBAC at its July
2011 meeting.
The PBAC considered the nominated comparators (placebo added to peg
interferon and ribavarin in patients with one prior treatment with
interferon-based therapy and placebo for no treatment in patients
with more than one prior treatment with interferon-based therapy)
to be appropriate. The PBAC also noted the secondary comparison
with boceprevir added to peginterferon and ribavarin.
7. Clinical Trials
Telaprevir + PR versus placebo + PR in patients who have
failed one prior attempt at interferon based therapy
The submission presented two randomised trials comparing telaprevir
in combination with PR, with placebo in combination with PR in
patients with genotype 1 CHC patients who have previously failed
prior PR therapy:
- REALIZE – a three-armed direct randomised trial comparing two regimens of 12 weeks of telaprevir therapy (with and without a 4 week delayed start), in combination with a 48 week course of peginterferon alfa-2a plus ribavirin, with placebo in combination with 48 weeks of peginterferon alfa-2a plus ribavirin in treatment experienced genotype 1 CHC patients; and
- PROVE 3 – a four-armed direct randomised trial comparing various regimens of telaprevir in combination with peginterferon alfa-2a with or without ribavirin, with placebo in combination with 48 weeks of peginterferon alfa-2a and ribavirin.
The primary endpoint in both trials was sustained virological
response (SVR), defined as undetectable HCV RNA 24 weeks after the
end of treatment.
Telaprevir + PR versus placebo + no active treatment
(patients who have failed more than one prior attempt at interferon
based therapy)
The submission presented the results of an open-label
non-comparative, extension study, in which patients who were
randomised to the placebo/PR arm of the PROVE 3 trial were
subsequently treated with telaprevir + PR. There was no placebo/no
active treatment in support of the requested listing for treatment
of genotype 1 CHC patients who have failed more than one prior
attempt at interferon based therapy.
Telaprevir + PR versus boceprevir + PR
The basis of the submission was an indirect comparison of two
randomised controlled trials:
- REALIZE as described above.
- RESPOND 2 – a three-armed randomised trial comparing two regimens of boceprevir (response guided therapy and a fixed 48 week regimen), in combination with peginterferon alfa-2b plus ribavirin, with placebo in addition to 48 weeks of peginterferon alfa-2b plus ribavirin in treatment experienced genotype 1 CHC patients.
Details of the studies published at the time of submission are
shown in the following table:
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Direct randomised trials | ||
| HCV treatment experienced clinical trials | ||
| PROVE 3 (VX06-950-106) | ||
| McHutchison JG et al 2010 | Telaprevir for previously treated chronic HCV infection. | New England Journal of Medicine 2010; 362 (14):1292-1303. |
| Burney T et al | Overview of the PROVE studies evaluating the use of telaprevir in chronic hepatitis C genotype 1 patients. | Expert Review of Anti-infective Therapy 2011; 9 (2):151-160. |
| REALIZE (VX-950-TiDP24-C216) | ||
| Zeuzem S et al 2011 | Telaprevir for retreatment of HCV infection. | New England Journal of Medicine 2011; 364 (25):2417-2428. |
| RESPOND 2 | ||
| Bacon BOC et al 2011 | Boceprevir for previously treated chronic HCV genotype 1 infection. | New England Journal of Medicine 2011; 364 (13):1207-1217. |
| Poordad F et al 2011 | Boceprevir combined with peginterferon alfa-2b/ribavirin for treatment-experienced patients with hepatitis C virus (HCV) genotype-1: RESPOND-2 final results. | Hepatology International 2011; 5(3-558): 13. |
The submission classified patients who have failed a prior attempt
at interferon based therapy as prior relapsers, partial responders,
null responders, and patients with prior viral breakthrough,
according to the type of treatment failure on prior peginterferon
alfa and ribavirin (PR) therapy. The definitions of these
subgroups, as used in the submission, are summarised in table
below.
Definitions of type of treatment failure on prior PR
therapy used in the submission
| Prior treatment failure | Definition | |
|---|---|---|
| Prior non-responder | A subject who did not achieve undetectable HCV RNA during or at the end of a prior course of at least 42 weeks of PR therapy. This group consists of prior partial-responders and prior null-responders. | |
| Prior null-responder | A subject who failed to suppress HCV RNA by at least 2 logs after at least 12 weeks of PR therapy | |
| Prior partial-responder | A subject who achieved a least a 2 log decrease in HCV RNA level at Week 12 of a prior course of at least 12 weeks of PR treatment, but never achieved undetectable HCV RNA levels. | |
| Prior relapser | A subject who had an undetectable HCV RNA level at the end of a course of PR therapy but did not achieve an SVR. | |
| Viral breakthrough | A subject who had an undetectable HCV RNA level during prior PR therapy but became detectable again before completion of therapy. | |
HCV RNA = Hepatitis C Virus ribonucleic acid; PR= pegylated interferon alfa + ribavirin; SVR = sustained virological response
8. Results of Trials
1. Telaprevir+ PR versus placebo + PR
The submission presented two sets of analyses, because the proposed PR treatment duration
for non cirrhotic prior relapsers who attain an eRVR (undetectable HCV RNA at Week
4 and Week 12) is shortened to 24 weeks whereas prior non-responders, cirrhotic patients
and prior relapsers who did not achieve an eRVR receive 48 weeks of PR. The shorter
PR treatment regimen is not included in REALIZE:
- A review of the results of the REALIZE trial [12 weeks telaprevir therapy in combination with 48 weeks peginterferon alfa and ribavarin regimen (T12/PR48) and telepravir placebo for 12 weeks in combination with 48 weeks peginterferon alfa and ribavarin regimen (Pbo12/PR48) treatment arms], which are applicable to all prior partial responders and null responders and to prior relapsers who have cirrhosis or who fail to achieve an eRVR;
- A comparison of the results for prior relapsers, stratified by eRVR status, in the T12/PR48 treatment arm of the REALIZE trial (relevant to prior relapsers who have cirrhosis or who fail to achieve an eRVR) and the T12/PR24 (12 weeks telaprevir therapy in combination with 24 weeks peginterferon alfa and ribavarin regimen) treatment arm of the PROVE 3 trial (representative of the proposed duration of treatment in non-cirrhotic prior relapsers who achieve an eRVR).
REALIZE
The results of the primary outcome in the REALIZE trial, SVR24planned, for both the full analysis set (FAS), and categorised by prior treatment response
are presented in the following table:
Results for the primary outcome, SVR24planned*, in the REALIZE trial
| Telaprevir/PR arm n/N (%) | Placebo/PR arm n/N (%) | Absolute difference b % (95% CI) | Relative Risk (95% CI) | Odds Ratio (95% CI) | |
|---|---|---|---|---|---|
| REALIZE | T12/PR48 | PboPR48 | |||
| FAS | 171/266 (64.3) | 22/132 (16.7) | 46.8 (36.8, 56.7) | 3.9 (2.6, 5.7) | 9.0 (5.4, 15.1) |
| Prior non-responders | |||||
| All prior non-responders | 50/121 (41.3) | 6/64 (9.4) | 35.0 (22.9, 47.0) | 4.4 (2.0, 9.7) | 6.8 (2.7, 17.0) |
| Null-responder | 21/72 (29.2) | 2/37 (5.4) | 24.7 (11.6, 37.7) | 5.4 (1.3, 21.8) | 7.2 (1.6, 32.7) |
| Partial responder | 29/49 (59.2) | 4/27 (14.8) | 44.1 (24.7, 63.6) | 4.0 (1.6, 63.6) | 8.3 (2.5, 27.8) |
| Prior relapsers | |||||
| All prior relapsers | 121/145 (83.4) | 16/68 (23.5) | 60.5 (48.8, 72.2) | 3.6 (2.3, 5.5) | 16.4 (8.1, 33.4) |
CI = confidence interval; eRVR = extended rapid virological response; FAS = full analysis
set; NR = not reported; Pbo = placebo; PR = peginterferon alfa and ribavirin; T =
telaprevir
a bThe results reported in the table are the adjusted absolute difference, as reported
in the CSR
* SVR24planned is defined as the proportion of patients with undetectable HCV RNA levels 24 weeks
after the last planned dose of study drug (i.e. at Week 72). The results for SVRactual, defined as the proportion of patients with undetectable HCV RNA levels 24 weeks
after the last actual dose of study medication, were identical.
Telaprevir administered in combination with PR significantly increased the proportion
of patients achieving SVR, in both the FAS population and in each category of prior
treatment response (prior relapsers, partial responders and null responders).
Comparison of prior relapsers in REALIZE and PROVE 3
The submission presented an unadjusted comparison of single arms extracted from each
trial T12/PR48 (12 weeks telaprevir therapy in combination with 48 weeks peginterferon
alfa and ribavarin regimen) versus T12/PR24 (12 weeks telaprevir therapy in combination
with 24 weeks peginterferon alfa and ribavarin regimen). It was not possible to perform
an adjusted indirect comparison between the subgroup of prior relapsers who attained
an eRVR as no patients in the placebo/PR treatment group in the PROVE 3 trial achieved
an eRVR.
The submission presented this comparison to justify the reduction in the duration
of PR treatment (when given in combination with telaprevir) from 48 weeks to 24 weeks
in non-cirrhotic relapsers who attain an eRVR. The submission implied that both regimens
are equally effective in this specific subgroup of patients.
Study C107 was a supportive premodelling single-arm study in which 82 patients who
had previously been treated in the PR arm of the PROVE 3 study were given telaprevir/PR.
This represented 70.1% of all patients in the PR arm of the PROVE 3 study
For PBAC’s view, see Recommendation and Reasons.
2. Telaprevir + PR versus boceprevir + PR
The submission presented an indirect comparison of the T12/PR48 arm of the REALIZE
trial and both boceprevir + PR regimens included in the RESPOND 2 trial: boceprevir
+ PR response guided therapy (RGT) and boceprevir + PR fixed duration therapy. The
control arm of each of the two trials was used as the common-reference arm for the
indirect comparison.
The PBAC noted that no minimal clinically important difference to determine non-inferiority
was specified. In addition, the width of the confidence intervals suggested that many
of the comparisons were inadequately powered for testing non-inferiority. Combined
with concerns regarding the exchangeability of the trials, [for example the boceprevir
trial (RESPOND 2) did not include prior null responders and the teleprevir trial (REALIZE)
contained more cirrhotic patients] the PBAC considered it difficult to draw conclusions
regarding the relative efficacy of telaprevir/PR and boceprevir/PR in treatment experienced
genotype 1 CHC patients who are either prior relapsers or prior partial responders.
For PBAC’s view of these results, see Recommendation and Reasons.
During the overall treatment phase, telaprevir + PR was associated with a greater
incidence of grade 3 AEs and more AEs that required a dose reduction of peginterferon
alfa and/or ribavirin, compared to placebo+ PR. The incidence of serious AEs also
tended to be higher in the telaprevir + PR treatment arm compared to the placebo +
PR arm.
9. Clinical Claim
The submission described telaprevir in combination with PR as
superior in terms of comparative effectiveness over PR alone. The
submission acknowledged that telaprevir in combination with PR is
inferior in terms of comparative safety to PR alone during the 12
week telaprevir treatment phase, but argued that, across the entire
course of therapy, the comparative safety trends towards being
non-inferior.
The PBAC considered that the results of the REALIZE trial were
supportive of the claim of superior efficacy of telaprevir in
combination with peginterferon and ribavirin (48 weeks) over
placebo in combination with peginterferon and ribavirin (48 weeks)
in patients with chronic HCV who have failed one prior attempt at
interferon based therapy, as measured by the proportion of patients
achieving a sustained virological response (SVR). The PBAC further
considered that telaprevir in combination with PR is of inferior
safety to PR alone.
In addition, the submission claimed that overall, the comparative
efficacy of boceprevir in prior relapser and prior partial
responder patients is non-inferior to telaprevir, when both are
administered in combination with PR.
The PBAC considered that the comparison of the relative efficacy of
telaprevir + PR with boceprevir + PR in treatment experienced prior
relapsers or partial responders was uncertain due to concerns with
the exchangeability of the trials and lack of power to test
non-inferiority.
10. Economic Analysis
The submission presented two stepped economic analyses of
telaprevir to reflect the different comparators for patients who
have received one, and those who have received more than one prior
treatment with interferon based therapies. The models were
cost-utility analyses that adopted a health care sector
perspective. The trial based outcome, sustained virological
response (SVR), was translated into health outcomes by applying
different transition probabilities to patients who achieve SVR and
to those who do not.
The base case incremental cost/extra QALY gained for both patient
groups was between $15,000 and $45,000.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost to the PBS (excluding treatment naïve
patients) was estimated by the submission to be between $30 - $60
million in Year 5. This estimate was uncertain and may be an
underestimate.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC considered that the appropriateness of the requested
restriction was uncertain noting that evaluation by the TGA was
still in process and the final indication, recommended treatment
duration with peg/interferon and ribavirin, and the number of
quantitative hepatitis C virus (HCV) RNA assays required were all
factors that will inform the appropriateness of the requested
restriction. The PBAC and Sponsor also noted that there could be
flow on changes required to the restrictions for peg/interferon
with ribavirin treatments for CHV currently listed on the PBS if
telaprevir was recommended for PBS listing. However, these changes
cannot be assessed in the absence of completion of the TGA
evaluation and a TGA Delegate’s overview. In relation to the
two quantitative HCV RNA assays included in the requested
restriction, the PBAC noted that these would be subsidised under
the current Medical Benefits Schedule (MBS). However, if further
quantitative HCV RNA assays were to be included in the restriction,
requiring MBS subsidy, then a joint co-dependent technology
submission would be required for evaluation by both the Medical
Services Advisory Committee (MSAC) and the PBAC.
The PBAC also considered that the restriction should exclude use of
telaprevir in patients who have failed to respond to other HCV N3S
4A protease inhibitors.
The PBAC considered the nominated comparators (placebo added to
peg/interferon and ribavirin in patients with one prior treatment
with interferon-based therapy and placebo for no treatment in
patients with more than one prior treatment with interferon-based
therapy) to be appropriate. The PBAC also noted the secondary
comparison with boceprevir added to peg/interferon and
ribavirin.
The PBAC considered the results of the REALIZE trial were
supportive of the claim of superior efficacy of telaprevir in
combination with peginterferon and ribavirin (48 weeks) over
placebo in combination with peginterferon and ribavirin (48 weeks)
in patients with chronic HCV who have failed one prior attempt at
interferon based therapy, as measured by the proportion of patients
achieving a sustained virological response (SVR). The PBAC
considered the comparison of the results for prior relapsers,
(stratified by extended rapid virological response (eRVR) status),
in the telaprevir with peginterferon and ribavirin (PR) 48 week
treatment arm of the REALIZE trial (relevant to prior relapsers who
have cirrhosis or who fail to achieve an eRVR) and the
telaprevir/PR 24 treatment arm of the PROVE 3 trial (representative
of the proposed duration of treatment in non-cirrhotic prior
relapsers who achieve an eRVR) was uncertain. The comparison was
inadequately powered for statistical testing of non-inferiority and
the PBAC noted that it was a comparison of subgroup results from
single treatment arms from two separate trials, with no common
reference group. The PBAC hence considered the estimated
comparative efficacy of the reduction in the duration of PR
treatment (when given in combination with telaprevir) from 48 weeks
to 24 weeks in non-cirrhotic relapsers who attain an eRVR was
uncertain.
The PBAC noted that the REALIZE trial included an unknown
proportion of subjects who had previously failed more than one
prior attempt at interferon-based therapy. The PBAC considered that
it is likely that the evidence presented is applicable to
previously treated patients overall and considered that the data
presented from the C107 study were supportive.
The PBAC considered that telaprevir in combination with PR is of
inferior safety to PR alone. The PBAC noted that telaprevir + PR
was associated with a greater incidence and severity of rash and
anaemia (including anaemia requiring blood transfusion) than PR
alone.
The PBAC noted two stepped economic analyses were presented to
reflect the different comparators for patients who have received
one or more than one prior treatment with interferon based
therapies. The PBAC noted that the economic analyses assumed that
patients in viral positive health states have a lower quality of
life than those who achieve sustained virological response and that
this assumption is responsible for more than a third of the
incremental QALYs in the telaprevir arm. The PBAC considered that
this was a source of uncertainty. However, the PBAC noted that the
scenario presented in the sponsor’s Pre-PBAC Response that
modified this assumption that the utility of patients who achieve a
SVR is equivalent to the utility of patients without an SVR. The
result of this analysis was a cost/QALY of between $15,000 and
$45,000 for patients who had received one prior treatment with
interferon based therapy. The PBAC also considered that the
possibility of re-infection among patients who achieve a SVR and
the development of viral resistance to telaprevir/PR should have
been included in the economic evaluation.
The PBAC considered the sensitivity analyses presented in the
submission were limited and did not involve combinations of changes
to variables that would result in higher ICERs. The PBAC noted that
high ICERs can be generated by using plausible values as calculated
during the evaluation. The PBAC considered that the presentation of
more extensive sensitivity analyses would have been informative.
The PBAC also noted that Markov traces of the ICER over time would
have been informative.
The PBAC considered the submission’s utilisation estimates to
be highly uncertain. The PBAC noted that the submission assumed
that telaprevir would be listed on the PBS for the treatment of
genotype 1 CHC patients naïve to interferon based therapies at
the same time as the listing for treatment experienced patients.
The PBAC also noted that the submission subsequently assumed that,
as telaprevir + PR would be standard care for treatment naïve
patients, there would be no new treatment experienced patients
eligible for retreatment with telaprevir. Hence the estimated cost
to the PBS was based only on the prevalent treatment experienced
patient pool at the time of listing, who are assumed to be
subsequently retreated over the first 5 years of listing. The PBAC
noted that utilisation figures for telaprevir/PR in treatment
experienced patients only (for the prevalent population) were
provided in the sponsor’s Pre-Sub-Committee Response.
However, the PBAC considered the utilisation remained uncertain and
noted the difference in the results calculated during the
evaluation based on the inclusion of both prevalent and incident
treatment-experienced patients.
The PBAC therefore rejected the submission on the basis of
uncertainty about the impact of the final product information
resulting from the evaluation by the TGA on all aspects of the
submission with resultant uncertain cost effectiveness and highly
uncertain utilisation.
The PBAC considered there is a clinical need for additional
treatment options for chronic HCV. The PBAC considered that
consultation with clinicians would assist in determining the place
in therapy in chronic HCV of direct acting anti-viral agents,
noting that the standard of care in chronic HCV is currently an
area of rapid change.
The PBAC noted that the Highly Specialised Drugs (HSD) Working
Party considered that telaprevir did not meet all the criteria for
the HSD Program and hence did not support the listing as a HSD
under Section 100.
The PBAC acknowledged and noted the consumer comments on this
item.
Recommendation:
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor had no further comment.
