Etravirine, tablet, 100 mg, Intelence® , March 2009
Public Summary Documnet for Etravirine, tablet, 100 mg, Intelence® , March 2009
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Public Summary Document
Product: Etravirine, tablet, 100 mg,
Intelence®
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drug),
private hospital authority required listing for the treatment of
human immunodeficiency virus (HIV) in an antiretroviral experienced
patient who 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
Etravirine was TGA registered on 19 December 2008 for treatment, in
combination with other antiretroviral agents, of HIV-1 infection in
antiretroviral treatment-experienced adults who have evidence of
viral replication and resistance to Non-nucleoside reverse
Transcriptase Inhibitors and other antiretroviral agents.
4. Listing Requested and PBAC’s View
Section 100
Highly Specialised Drugs Program
Private hospital authority required
Treatment, in combination with other antiretroviral agents, of HIV
infection in an antiretroviral experienced patient with:
(a) evidence of HIV replication (viral load greater than 10,000
copies per mL); and/or
(b) CD4 cell counts of less than 500 per cubic millimetre.
A patient 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 1 protease inhibitor
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Human Immunodeficiency Virus (HIV) infection is a chronic,
immunosuppressive infection that is characterised by a continuous,
high-level viral replication and a slow, insidious, progressive
destruction of the human immune system. In the absence of effective
antiretroviral treatment, HIV infection leads to severe immune
deficiency and the development of the systemic opportunistic
infections and cancers that define the onset of the final stage of
HIV infection, the acquired immune deficiency syndrome (AIDS), and
ultimately results in death.
Typically, standard medical management of HIV-1 infection consists
of combinations of different antiretroviral therapies (e.g.
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs),
non-nucleoside reverse transcriptase inhibitors (NNRTIs) and
protease inhibitors (PIs)). In clinical practice, etravirine will
be used in treatment experienced patients who have received 3 prior
Highly Active Antiretroviral Therapy (HAART) regimens and whose
current regimen is failing because of virological failure or
treatment-limiting toxicity.
6. Comparator
The submission nominated placebo as the main comparator and
raltegravir as an alternative comparator.
The PBAC considered that raltegravir was the most appropriate
comparator given that etravirine is proposed as an alternative to
raltegravir as an addition to 4th line antiretroviral
therapy.
7. Clinical Trials
The following trials were presented as the basis of the
submission:
a) A direct analysis of etravirine vs placebo presented as:
- two key randomised trials of etravirine + optimised background therapy (OBR) including darunavir vs placebo + OBR including darunavir (DUET 1 & 2) with pooled analysis (Pooled DUET)
- one supportive trial of etravirine + OBR vs placebo + OBR (Trial C223)
b) An indirect analysis of etravirine vs raltegravir (placebo as
common comparator) presented as:
- DUET 1 & 2 (as above) with pooled analysis (Pooled DUET); compared with,
- two randomised trials of raltegravir + OBR vs placebo + OBR
(BENCHMRK
1 & 2) with pooled analysis (Pooled BENCHMRK)
The trials published at the time of submission are presented below:
| Trial ID/First author | Protocol title / Publication title | Publication citation |
| Etravirine vs placebo | ||
| Valdez Madruga et al 2007 | Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial | The Lancet 2007; 370:29-38 |
| Lazzarin et al 2007 | Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial | The Lancet 2007: 370:39-48 |
| TMC125-C223 Writing Group 2007 | Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis | AIDS 2007,21:F1-F10 |
| Raltegravir vs placebo | ||
| Steigbigel et al 2008 | Raltegravir with optimised background therapy for resistant HIV-1 infection. | NEJM 2008; 359:339-354. |
| Cooper et al, 2008 | Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. | NEJM 2008; 359:355-365. |
| BENCHMRK 1 5 Sept 2007 | Merck Research Laboratories Merck & Co., Inc. FDA Antiviral Drugs Advisory Committee Meeting Isentress (raltegravir) 400 mg for the treatment of HIV (NDA 22-145). Briefing Document. | http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4314b1-01-Merck.pdf . |
| BENCHMRK 2 5 Sept 2007 | Merck Research Laboratories Merck & Co., Inc. FDA Antiviral Drugs Advisory Committee Meeting Isentress (raltegravir) 400 mg for the treatment of HIV (NDA 22-145). Briefing Document. | http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4314b1-01-Merck. pdf . |
8. Results of Trials
The results of the pooled DUET trials showed that the relative risk
of a virological response (plasma viral load < 50 copies/mL)
with etravirine treatment compared to placebo was 1.44 (1.28, 1.61)
at 24 weeks and 1.53 (1.36, 1.72) at 48 weeks.
The results of the indirect comparison of etravirine (pooled DUET
trials) with raltegravir (pooled BENCHMRK trials), with placebo as
the common comparator, (ITT analysis) showed a statistically
significant lower effect at week 24 of etravirine treatment
compared with raltegravir (in plasma viral load < 50 copies/
mL), with an indirect relative risk of 0.77 (95% CI: 0.62, 0.97),
but was not statistically significant at week 48, with an indirect
relative risk of 0.81 (95% CI: 0.65, 1.02).
Antiretroviral drugs used in the OBR of both trials differed, both
within and between the DUET and BENCHMRK trials and differed from
the intended PBS population, therefore the submission presented an
indirect analysis of etravirine and raltegravir for the subgroups
in both sets of trials who received darunavir (all patients in the
DUET trials) but did not receive enfuvirtide (ENF) in their OBR, as
this would more closely reflect the intended PBS population.
The results of the indirect comparison of etravirine with
raltegravir using these subgroups, with placebo as the common
comparator showed no statistically significant difference between
etravirine and raltegravir in virological response at 24 and 48
weeks, but the point estimate favours etravirine rather than
favouring raltegravir as in the ITT analysis. However, due to much
smaller sample sizes in the subgroups analysis the 95% confidence
intervals for the indirect relative risks are much wider than the
indirect comparisons of the ITT groups.
No statistically significant difference was found in the
comparative safety of etravirine compared with placebo, with the
exception of transient rash and nausea. Etravirine was equivalent
to raltegravir in terms of comparative safety. Etravirine has not
yet been marketed anywhere for longer than 6 months, so no data are
available on extended assessment of comparative harm.
For PBAC’s comments, see Recommendation and
Reasons.
9. Clinical Claim
The submission claimed that etravirine is superior in efficacy
compared with placebo, with similar safety and tolerability, with
the exception of transient rash and nausea. The PBAC agreed that
etravirine added to OBR is superior to OBR alone at 24 and 48
weeks.
The submission also claimed that etravirine has similar efficacy
and safety compared with raltegravir, based on an indirect analysis
of subgroups who received darunavir but not enfuvirtide in their
optimised background regimen. The PBAC accepted this claim.
10. Economic Analysis
The submission presented a cost-minimisation analysis of etravirine
compared to raltegravir based on the clinical claim of non-inferior
efficacy and safety at daily doses of 400mg etravirine and 800mg
raltegravir.
The submission presented a stepped economic evaluation
(cost-utility analysis) comparing the costs and health outcomes for
patients treated with either etravirine (plus OBR) versus
OBR.
For PBAC’s view, Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year to
be less than 10,000 in Year 5. The estimation was considered
reasonable.
The submission estimated the financial cost per year to the PBS to
be less than $10 million in Year 5 of listing.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC recommended the listing of etravirine on a
cost-minimisation basis compared with raltegravir, with the
equi-effective daily doses being etravirine 400 mg and raltegravir
800 mg. Listing is suitable for etravirine under section 100.
The PBAC considered that raltegravir was the most appropriate
comparator given that etravirine is proposed as an alternative to
raltegravir as an addition to 4th line antiretroviral
therapy.
The PBAC considered the clinical trial data, based on the pooled
DUET trials, demonstrated that etravirine added to OBT is superior
to OBT alone at 24 weeks and 48 weeks, with the relative risk of a
virological response (plasma viral load < 50 copies/mL) with
etravirine treatment compared to placebo being 1.44 (1.28, 1.61) at
24 weeks and 1.53 (1.36, 1.72) at 48 weeks.
Further, the PBAC considered that the indirect comparison of
relative risks of virological response for etravirine treatment
versus placebo with raltegravir verus placebo (using the subgroup
receiving darunavir treatment but not enfuviritide) showed no
statistically significant difference between etravirine and
raltegravir in virological response at 24 and 48 weeks, with the
indirect relative risk point estimate slightly favouring
etravirine. Hence etravirine was considered to be no worse than
raltegravir based on the sub-group analysis. The Committee accepted
that it was reasonable to use the subgroup analysis and also as the
basis of the cost-minimisation analysis, as it more closely
reflected the intended PBS population.
However, the indirect analysis of the ITT groups showed a
statistically significant lower effect at week 24 week of
etravirine treatment compared with raltegravir (in plasma viral
load < 50 copies/ mL), with an indirect relative risk of 0.77
(95% CI: 0.62, 0.97), but was not statistically significant at week
48 with an indirect relative risk of 0.81 (95% CI: 0.65, 1.02). The
PBAC agreed that the ITT analysis suggests that etravirine may be
inferior to raltegravir and that uncertainty remained due to an
unconfirmed understanding of why the therapeutic relativity between
these two drugs varied according to which antiretrovirals
(darunavir and enfuvirtide) had been tried as prior therapy.
The PBAC noted that there was no statistically significant
difference in the comparative safety of etravirine compared with
placebo, with the exception of transient rash and nausea and that
etravirine was similar to raltegravir in terms of comparative
safety.
The PBAC noted that the submission calculated the base case
modelled incremental discounted cost/extra discounted QALY for
etravirine plus OBR versus OBR alone to be between $45,000 -
$75,000 per /QALY. The PBAC noted that the stepped economic
evaluation over OBR alone is most sensitive to the magnitude of the
treatment effect applied to the change in viral load over the trial
period. Substituting the lower 95% confidence limit into the model
increased the incremental cost per QALY gained from the base case
to the highest value in the range of $75,000 - $105,000.
The PBAC noted that the calculation of PBS expenditure associated
with the listing of etravirine did not take into account any
substitution of raltegravir and that in clinical practice, patients
may use both etravirine and raltegravir, with either of them being
part of OBR at one time or another. However, the PBAC also noted
that the sponsor’s pre-sub-Committee response which claimed
that if substitution for raltegravir occurred, the net cost to the
PBS listing of etravirine would be less than that estimated.
Recommendation
ETRAVIRINE, tablet, 100 mg
Restriction:
Highly Specialised Drugs Program
Private hospital authority required
Treatment, in combination with other antiretroviral agents, of HIV
infection in an antiretroviral experienced patient with:
(a) evidence of HIV replication (viral load greater than 10,000
copies per mL); and/or
(b) CD4 cell counts of less than 500 per cubic millimetre.
A patient 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 1 protease inhibitor.
Pack size: 120
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
Janssen-Cilag welcomes this decision by the PBAC to provide access
to an additional treatment option for Australians living with
HIV/AIDS.
