Tipranavir, capsule, 250 mg, Aptivus®, March 2007
Public summary document for Tipranavir, capsule, 250 mg, Aptivus®, March 2007
Page last updated: 29 June 2007
Printable Version of Tipranavir, capsule, 250 mg, Aptivus® (PDF 24 KB)
Public Summary Document
Product: Tipranavir, capsule, 250 mg,
Aptivus®
Sponsor: Boehringer Ingelheim Pty Limited
Date of PBAC Consideration: March 2007
1. Purpose of Application
The application requested a Section 100 (Highly Specialised Drugs)
listing for the treatment, in combination with other antiretroviral
agents and co-administered with 200 mg ritonavir twice daily, of
HIV infection in antiretroviral experienced patients who have
failed previous treatment with, or have resistance to, 3 different
antiretroviral regimens, including regimens with at least 1
non-nucleoside reverse transcriptase inhibitor, 1 nucleoside
reverse transcriptase inhibitor, and two protease inhibitors.
2. Background
Tipranavir was considered for the first time at the July 2006 PBAC meeting. The PBAC
noted that listing was sought for use in HIV patients who had failed at least three
different antiretroviral regimens.
The PBAC rejected the submission because of the high and uncertain cost-effectiveness
ratio because of concerns with the model, including the lack of modelling of the cost
of managing toxicity.
Please refer to the Public Summary Document from the July 2006 PBAC meeting.
3. Registration Status
Tipranavir was registered by the TGA on 8 June 2006 for
co-administration with 200mg of ritonavir in combination treatment
of HIV infection in highly antiretroviral treatment experienced
adult patients with evidence of viral replication, who have HIV-1
strains resistant to multiple protease inhibitors.
4. Listing Requested and PBAC’s View
Section 100 listing (Highly Specialised
Drug)
Treatment, in combination with other antiretroviral agents, and
co-administered with 200 mg ritonavir twice daily, of HIV infection
in antiretroviral experienced adults with:
- Evidence of HIV replication (viral load greater than 10,000 copies per mL) and/or
- CD4 cell counts of less than 500 per cubic millimetre.
Patients must have failed previous treatment with, or have
resistance to, 3 different antiretroviral regimens, including
regimens with at least 1 non-nucleoside reverse transcriptase
inhibitor, 1 nucleoside reverse transcriptase inhibitor, and two
protease inhibitors.
See Recommendation and Reasons for PBAC’s
view.
5. Clinical Place for the Proposed Therapy
Tipranavir will be used in the treatment of HIV infection in
antiretroviral treatment experienced patients with accumulating
protease inhibitor resistance.
6. Comparator
The submission nominated ritonavir-boosted protease inhibitor
aggregate, which includes amprenavir, indinavir, lopinavir and
saquinavir. This was previously agreed by the PBAC.
7. Clinical Trials
The submission presented new trial data, with Week 96 results of
the two randomised, open-label trials for which Week 48 results
were presented in the July 2006 submission. The 48 week data was
published at the time of the submission (as Hicks et al (1996)
Durable efficacy of tipranavir-ritonavir in combination with an
optimised background regimen of antiretroviral drugs for
treatment-experienced HIV-1-infected patients at 48 weeks in the
Randomized Evaluation of Strategic Intervention in multi-drug
reSistant patients with Tipranavir (RESIST) studies: an analysis of
combined data from two randomised open-label trials. The Lancet
368(9534):466-75).
8. Results of Trials
The statistically significant advantage for tipranavir was
maintained at week 96 however, the proportion of responders had
decreased in both treatment arms from week 48 to week 96.
As at week 48, the time to treatment failure at week 96 was
statistically significantly longer in patients treated with
tipranavir compared to those treated with comparator protease
inhibitor as well as in those who used enfuvirtide compared to
those who did not use enfuvirtide.
The re-submission provided the Kaplan Meier estimate of time to
treatment failure in only those patients who had a treatment
response. The time to treatment failure was statistically
significantly longer in the tipranavir responder groups compared to
the comparator protease inhibitor responder group.
The re-submission also presented a summary of “FDA
requested” sensitivity analyses of treatment response at week
48, designed to demonstrate that despite patients being able to
alter their optimised background regimen, this potential source of
bias did not impact the overall results of the trials.
The re-submission stated that these analyses support the findings
of the key analysis (week 48) and provide evidence that despite
patients being able to alter their optimised background regimen,
this potential source of bias did not impact the overall results of
the trials.
The re-submission provided updated results for the occurrence of
AIDS defining events (ADEs) and death at week 96. There were no
statistically significant differences between tipranavir-treated
and comparator protease inhibitor-treated patients in the rate of
ADEs or deaths at week 96 of the trials.
The re-submission presented updated toxicity data for overall
adverse events, medically selected terms and Grade 3 or 4
laboratory abnormalities, but did not provide updated data for
hepatic events or the use of lipid lowering agents.
The proportion of patients experiencing adverse events or
discontinuing due to adverse events was greater in the tipranavir
group compared to the comparator PI group. When adjusted for
differences in exposure, the rate of events was greater in the
comparator PI group than in the tipranavir group.
There was a statistically significant advantage for tipranavir in
the occurrence of systemic or severe infections per unit time of
exposure, however the rate per patient was still higher in the
tipranavir arm due to longer exposure. There were statistically
significantly higher rates of hepatitis and hyperlipidemia in
tipranavir-treated patients compared to comparator protease
inhibitor-treated patients.
9. Clinical Claim
The re-submission described tipranavir as significantly more
effective than an optimal alternative protease inhibitor, but with
more toxicity. The PBAC considered tipranavir offered a clinical
advantage in the high-risk patient group for whom subsidy was
sought.
10. Economic Analysis
The resubmission presented an updated preliminary economic
evaluation. The evaluation assessed the incremental cost per
treatment responder at 48 weeks and the incremental cost per month
responding to treatment. The approach taken in the preliminary
economic evaluation was the same as that presented in the July 2006
submission, but included costs associated with the management of
toxicity.
The re-submission estimated the trial-based incremental cost/extra
treatment responder at 48 weeks to be in the range of $45,000 to
$75,000.
The resubmission presented an updated modelled economic evaluation.
The updated model differed considerably from the July 2006 model in
order to address the concerns of the PBAC with the previous model,
including:
- use of week 96 trial data;
- inclusion of costs and effects for toxicity data, which were not included in the July 2006 model;
- use of updated drug costs;
- use of revised utility values;
- increased model duration from the July 2006 model;
- decreased cycle length;
- revised health states.
The resubmission estimated the base case incremental discounted
cost/extra discounted QALY and the base case incremental discounted
cost per extra discounted life year gained to be in the range of
$15,000 - $45,000.
11. Estimated PBS Usage and Financial Implications
The re-submission estimated the likely number of packs dispensed
per year to be up to less than 10,000 in Year 4. The re-submission
estimated the financial cost/year to the PBS to be less than $10
million in Year 4.
12. Recommendation and Reasons
The PBAC noted that this resubmission included an updated price and
a new economic model compared with that provided in the previous
submission. The revised 12 health states included in the model and
the overall assumed transitions between them were a source of
concern as it was not clear whether they allow a clinically valid
mapping of HIV and risk of death in the patient population for the
proposed restriction. However, the PBAC acknowledged that the 12
health states were consistent with the trial data, although there
was concern about the extension of the transitions across these
health states for the full duration of the model of 28 years. The
incremental cost effectiveness ratios (ICERs) per extra QALY and
per extra life year gained were more favourable to tipranavir
compared to those of the previous submission.
The PBAC noted that there were no statistically significant
differences between tipranavir-treated and comparator protease
inhibitor-treated patients in the rate of AIDS-defining events or
deaths at week 96 of the trials presented in the submission.
However the trials did demonstrate that tipranavir has a benefit in
terms of reducing viral load in this high risk group of patients
who have failed other protease inhibitor therapy, and that a
reduced viral load has been accepted internationally as a strong
surrogate end point in this disease. In particular, the PBAC
accepted a trial-based assessment of viral load results comparing
tipranavir with the lopinavir/ritonavir combination as the most
frequently prescribed protease inhibitor and with enfuvirtide as
the HIV drug with the closest restriction to that requested for
tipranavir.
Overall the PBAC considered, despite concerns over the plausibility
of the model, that tipranavir offers a clinical advantage in the
high risk salvage patient group for whom subsidy is sought and
recommended listing on a cost-effectiveness basis over the
comparator.
Recommendation
TIPRANAVIR, capsule, 250 mg
Restriction: Private hospital authority required (Highly
Specialised Drug)
Treatment, in combination with other antiretroviral agents, and
co-administered with 200 mg ritonavir twice daily, of HIV infection
in antiretroviral experienced adults with:
(a) Evidence of HIV replication (viral load greater than 10,000
copies per mL); or
(b) CD4 cell counts of less than 500 per cubic millimetre.
Patients must have failed previous treatment with, or have
resistance to, 3 different antiretroviral regimens which have
included:
i) at least 1 non-nucleoside reverse transcriptase inhibitor;
and
ii) at least 1 nucleoside reverse transcriptase inhibitor;
and
iii) at least 2 protease inhibitors.
Pack size: 120
NOTE:
These prices are based on special supply arrangements – see
Pharmaceutical Benefits Pricing Authority relativity sheet for full
details.
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
Boehringer Ingelheim is pleased that the PBAC has recommended the approval of tipranavir for use in antiretroviral experienced patients in Australia.
