Bosentan monohydrate, tablets, 62.5 mg and 125 mg (base), Tracleer, March 2008
Public summary document fo Bosentan monohydrate, tablets, 62.5 mg and 125 mg (base), Tracleer, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Bosentan monohydrate, tablets, 62.5 mg and 125 mg (base), Tracleer
Sponsor: Actelion Pharmaceuticals Australia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The application sought an extension to the current Section 100 (Highly Specialised
Drug) Public and Private Hospital Authority required listing to include treatment
of pulmonary arterial hypertension (PAH) associated with congenital systemic to pulmonary
shunts including Eisenmenger’s physiology.
The application also sought to re-word the current Section 100 (Highly Specialised
Drug) Public and Private Hospital Authority required listing to reflect the current
clinical classification of PAH.
Highly specialised drugs are medicines for the treatment of chronic conditions, which,
because or their clinical use or other special features, are restricted to supply
to public and private hospitals having access to appropriate specialist facilities.
2. Background
At the December 2003 meeting, the PBAC recommended listing for treatment of primary pulmonary arterial hypertension or pulmonary arterial hypertension associated with scleroderma based on an acceptable, but high, cost-effectiveness ratio.
3. Registration Status
Bosentan was registered by the TGA on 20 November 2002 and is indicated for the treatment
of:
- Idiopathic pulmonary arterial hypertension.
- Familial pulmonary arterial hypertension.
- Pulmonary arterial hypertension associated with scleroderma.
- Pulmonary arterial hypertension associated with congenital systemic to pulmonary
shunts including Eisenmenger's physiology; in patients with WHO functional class III
or IV symptoms.
4. Listing Requested and PBAC’s View
Add to current listing
- Pulmonary arterial hypertension associated with congenital systemic to pulmonary shunts including Eisenmenger’s physiology.
Amend current listing
Propose that primary pulmonary hypertension be re-worded for WHO Functional Class
III or IV to:
- Idiopathic pulmonary arterial hypertension (iPAH)
- Familial pulmonary arterial hypertension
- Pulmonary arterial hypertension associated with scleroderma
5. Clinical Place for the Proposed Therapy
Congenital heart disease (CHD) is the most common of the major congenital malformations
occurring in about 5 to 8 cases per 1000 births. Ventricular septal defects (VSDs)
are most frequent, followed by atrial septal defects (ASDs) and patent ductus arteriosus
(PDA). If the defect is large and left-to-right (LR) shunting is chronic; exposure
of the pulmonary vasculature to high systemic arterial pressure with increased blood
flow levels and shear stress will lead to progressive pulmonary vascular injury and
consequently increased pulmonary vascular resistance (PVR) and pulmonary arterial
hypertension.
Primary, or unexplained, pulmonary arterial hypertension (PAH) is a recognised complication
of congenital cardiac shunts. In Eisenmenger’s physiology, initially there is a left
to right shunt which over time increases pressure in the pulmonary vasculature causing
pulmonary hypertension and reversal of the shunt to a right to left shunt with subsequent
deoxygenated blood supplied to the systemic circulation and organs. The natural history
of PAH is usually progressive, intractable and often fatal, with treatment options
aimed at relieving symptoms of the disease and returning the patient to a more functional
lifestyle.
Bosentan would provide a further treatment option for Class III or IV patients who
do not respond to standard therapy.
6. Comparator
The submission nominated standard care as the main comparator. Standard care may include the use of supplemental oxygen, digitalis, diuretics, vasodilators, anticoagulants, or lung transplantation and repair.
7. Clinical Trials
The submission presented one randomised trial (BREATHE-5) comparing bosentan (62.5
mg for 4 weeks, and 125 mg thereafter) with placebo (standard therapy) in patients
with WHO Functional Class III Eisenmenger’s physiology and 11 supplementary observations
(7 open-label studies, and 4 retrospective reviews) of bosentan in patient populations
with PAH associated with congenital heart disease/Eisenmenger’s Associated Pulmonary
Arterial Hypertension – Congenital Heart Disease (APAH-CHD), NYHA/WHO Function Class
(II-IV), and duration of follow-up (12 weeks to 29 months).
Randomised trials presented in the submission
|
Trial ID |
Protocol title/ Publication title |
Publication citation |
|---|---|---|
|
Direct randomised trials |
||
|
BREATHE-5 (AC-052-405) |
BREATHE-5: A Multi-Centre, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of Tracleer (Bosentan) on Oxygen Saturation and Cardiac Haemodynamics in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology 2005, Actelion |
Galie et al. (2006) Bosentan therapy in patients with Eisenmenger syndrome: A multicenter, double-blind, randomized, placebo-controlled study. Circulation, 114(1):48-54. |
Eleven non-randomised studies were identified from external and internal (including
TGA dossier) searches, and provided as supplementary evidence in the submission. These
studies are listed in the table below.
Non-randomised studies presented in the submission
|
Trial identifier |
Title and Source |
Study Design |
|---|---|---|
|
AC-052-405 (OL) 2005 a |
A Multi-Center, Open-Label Extension Study to Protocol AC-052-405 to Evaluate the Safety and Efficacy of Tracleer (bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology |
MC OL Ext |
|
AC-052-403 2005 |
Open-label study to investigate the safety and efficacy of Tracleer (bosentan) in
adult patients with pulmonary arterial hypertension related to Eisenmenger. Allschwil,
CH. Actelion Pharmaceuticals |
MC OL SA |
|
Apostolopoulou et al. 2005 |
"Effect of the oral endothelin antagonist bosentan on the clinical, exercise, and haemodynamic status of patients with pulmonary arterial hypertension related to congenital heart disease." Heart 91(11): 1447-1452 |
P NR OL |
|
Apostolopoulou et al. 2007 |
"Long-term oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study." Heart 93(3): 350-4 |
Ext of Apostolopoulou et al. (2005) |
|
Christensen et al. 2004 |
"Initial experience with Bosentan therapy in patients with the Eisenmenger syndrome." American Journal of Cardiology 94(2): 261-263 |
|
|
Gatzoulis et al. 2005 |
"Safety and tolerability of bosentan in adults with Eisenmenger physiology." International Journal of Cardiology 98(1): 147-151 |
OL SA pilot |
|
Kotlyar et al. 2006 |
"Bosentan for the treatment of pulmonary arterial hypertension associated with congenital cardiac disease." Cardiology in the Young 16(3): 268-274 |
Ret Review of Pts on SAC |
|
Schulze-Neick et al. 2005 |
"Adult patients with congenital heart disease and pulmonary arterial hypertension: First open prospective multicenter study of bosentan therapy." American Heart Journal 150(4): 716.e7-716.e12 |
Obs, OL, MC P |
|
Sitbon et al. 2006 |
"Bosentan for the treatment of pulmonary arterial hypertension associated with congenital heart defects." European Journal of Clinical Investigation 36(SUPPL. 3): 25-31 |
Ret |
|
D'Alto et al. 2007 |
“Long term effects of bosentan treatment in adult patients with pulmonary arterial hypertension related to congenital heart disease (Eisenmenger physiology): safety, tolerability, clinical, and haemodynamic effect." Heart 93(5): 621-5 |
OL P SA |
|
Diller et al. 2007 |
"Long-term safety, tolerability and efficacy of bosentan in adults with pulmonary arterial hypertension associated with congenital heart disease." Heart 93(8): 974-6 |
Ret |
8. Results of Trials
Bosentan significantly improved indexed pulmonary vascular resistance (PVRi) compared
to placebo in Eisenmenger’s patients. No negative effects on haemodynamic measures
or oxygen saturation were observed. Functional improvement was associated with a +53
m (placebo-corrected) improvement in the six-minute walk test (6MWT). WHO Functional
Class improved in 35% and 13% of bosentan treated and placebo patients, respectively.
The results from BREATHE-5 are presented below:
BREATHE-5: Primary outcome: Change from baseline to Week 16 in mean oxygen saturation
at rest with room air (per protocol analysis)
|
O2 saturation at rest with room air |
Bosentan |
Placebo |
|---|---|---|
|
n a |
35 |
17 |
|
Baseline (meansd) |
82.45.3% |
83.65.1% |
|
Week 16(meansd) |
83.85.5 |
846.7 |
|
Change from baseline (meansd) |
1.52.5 |
0.43.7 |
|
Treatment effect (meansd) |
13.0 |
|
|
95%CI |
-0.7, 2.8 |
|
|
PVRi c |
||
|
n b |
36 de |
17 d |
|
Baseline (meansd) |
3425.11410.5 |
2870.01209.3 |
|
Week 16(meansd) |
3108.21342.1 |
3025.11230.0 |
|
Change from baseline (meansd) |
-316.9830.1 |
155.1552.7 |
|
Treatment effect (meansd) |
-472.0754.1 |
|
|
95%CI |
-917.6, -26.5 |
|
|
p-value (t-test) |
p=0.0383 |
|
Note: Missing values at week 16 substituted as per SAP rules.
a=per protocol analysis; b=all randomised analysis; c= PVRi was analysed per country.
The results did not identify any specific outliers; d=Two bosentan-treated patients
and 2 placebo-treated patients had no post-treatment PVRi assessment, and assigned
‘worst rank value’ (baseline value corrected with the highest percentage of worsening
from baseline observed during the study on the patient set under analysis);
e=A bosentan-treated patient was excluded from the analysis because the catheterization
time window was outside the allowed range at screening.
BREATHE-5 Secondary outcome
|
6MWTdistance |
Placebo |
Bosentan |
|---|---|---|
|
Baseline (meansd) |
366.416.4 m |
331.913.6 m |
|
Wk 16 change from baseline (meansd) |
-9.7 22.3 m |
+43.4 8.1 m |
|
Treatment effect (meansd) |
+53.1 19.2 m |
|
|
p-value (t-test) |
p = 0.0079 |
|
The direction of findings presented as supplementary evidence are consistent with
pivotal trial results, however, the PBAC considered that the strength of reported
outcomes and between-study comparative value should be interpreted cautiously in view
of their observational nature.
The PBAC also considered that the data in support of the younger paediatric patients,
or WHO Functional Class IV symptom severity are either not available or are weak but
noted that high quality evidence is difficult to obtain in these populations.
The toxicity profile of bosentan in Eisenmenger’s appears consistent with iPAH and
Systemic Sclerosis (APAH-SSc). The periodic safety update report did not identify
any unexpected adverse events.
9. Clinical Claim
10. Economic Analysis
An economic evaluation for bosentan in APAH-CHD was not presented. The reason provided
for this omission was that the cost effectiveness of bosentan in APAH-CHD is likely
to be similar to that previously demonstrated for iPAH.
The PBAC previously accepted an economic model (2002) estimating the cost-effectiveness
of bosentan in iPAH. The cost effectiveness of bosentan in Eisenmenger’s patients
was considered to be similar to that previously demonstrated for iPAH. This published
model was used in the current submission for the new indication (APAH-CHD). The original
model presented for iPAH estimated the incremental cost effectiveness ratio at 15
years in the range of $45,000 to $75,000 per year of life (without continuation rules,
or lower but within the same range after continuation rules were added). The PBAC
noted the population in the model was not the population for whom the current submission
was sought.
The PBAC considered the pathophysiology of APAH-CHD was no different to iPAH and that
this condition should respond to the same drugs as iPAH.
11. Estimated PBS Usage and Financial Implications
The submission estimated the number of patients per year to be less than 10,000 in
Year 5 at an estimated financial cost per year to the PBS of less than $10 million
in Year 5.
The PBAC noted the sponsor has previously entered into a confidential Special Pricing
Arrangement that allows a rebate to the PBS from the first day of listing.
12. Recommendation and Reasons
The PBAC recommended the listing of bosentan on the PBS for the treatment of pulmonary
arterial hypertension associated with congenital systemic-to-pulmonary shunts including
Eisenmenger’s physiology (APAH-CHD) based on acceptable cost-effectiveness compared
with standard care.
The PBAC accepted the assumption that APAH-CHD patients are similar to idiopathic
pulmonary arterial hypertension (iPAH) patients and that the cost effectiveness of
bosentan in Eisenmenger’s patients is similar to that demonstrated for iPAH, which
was accepted by the PBAC in 2002, with the original model being the one used in this
submission for the new indication. This original model estimated the ICER for iPAH
at 15 years as between $45,000 and $75,000 (without continuation rules, or lower,
but within the same range after continuation rules were added). The PBAC considered
that the pathophysiology of APAH-CHD was essentially similar to iPAH and that this
condition should respond to the same drugs as iPAH.
The PBAC noted that the previous submissions for bosentan used the 6 minute walk test
(6MWT) as the most widely accepted surrogate clinical outcome. The FDA now mandates
this test as the surrogate outcome for all drugs used to treat PAH and the PBAC has
previously accepted the 6MWT as an appropriate surrogate outcome. In addition, insertion
of a right heart catheter carries a significant risk of serious complications and
even death in some paediatric patients, as a general anaesthetic has to be administered.
However, the PBAC noted that no statistical comparisons are presented on the intermediate
outcomes of 6MWT and WHO Functional Class and that the results are not comparable
due to trial design, population and disease characteristics.
The PBAC considered that the data in support of the younger paediatric patients, or
WHO Functional Class IV symptom severity are either not available or are weak but
noted that high quality evidence is difficult to obtain in these populations. Therefore,
WHO functional class IV patients should be included in the restriction and children
should not be specifically excluded. The PBAC considered that the estimates of patient
numbers used in the financial implications are also uncertain.
The PBAC decided not to change the wording of the restrictions for bosentan and other
drugs used for PAH WHO functional Class III and IV, consistent with discussions from
the 26 February 2008 PAH meeting with sponsors and clinicians, as new Consensus Guidelines,
which will produce significant changes to the current guidelines, will be published
later this year following an International meeting. Further discussion will be needed
with the Thoracic Society regarding the implications of these changes for the drugs
listed on the PBS for PAH.
The PBAC noted advice from the Highly Specialised Drugs Working Party, which supported
the inclusion of bosentan under the HSD program.
Recommendation
BOSENTAN MONOHYDRATE, tablets, 62.5 mg (base) and 125 mg (base),
Restriction: To be finalised
Public and private hospital authority required
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 welcomes the PBAC's recommendation for the listing of bosentan (Tracleer)
for the treatment of pulmonary arterial hypertension associated with congenital systemic
to pulmonary shunts including Eisenmenger’s physiology, as it provides an important
therapy for the treatment of this rare and severe condition.
