2. Background This drug had not previously been considered by the PBAC.

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1 PUBLIC SUMMARY DOCUMENT Product: Ambrisentan, tablets, 5 mg and 10 mg, Volibris Sponsor: GlaxoSmithKline Australia Pty Ltd Date of PBAC Consideration: July Purpose of Application The submission requested a Section 100 (Highly Specialised Drugs) listing for treatment of primary pulmonary hypertension (PPH) or pulmonary arterial hypertension secondary to connective tissue disease (PAH-CTD) in patients with WHO functional class III or IV severity. 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 Ambrisentan was TGA registered on 24 November 2008 for the treatment of idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with connective tissue disease in patients with WHO functional class II, III or IV symptoms. 4. Listing Requested and PBAC s View The requested restriction for ambrisentan was similar to the restrictions for bosentan (class III and IV) and sitaxentan (class III), which are the other endothelin receptor antagonists listed on the PBS. For PBAC s views see Recommendation and Reasons. 5. Clinical place for the proposed therapy Ambrisentan would provide an alternative oral therapy for primary pulmonary hypertension and pulmonary arterial hypertension secondary to connective tissue disease, in patients with WHO Function Class III or IV severity. 6. Comparator The submission nominated bosentan as the comparator. 7. Clinical trials The submission presented a placebo based indirect comparison of ambrisentan with bosentan using two randomised ambrisentan placebo controlled 12 week trials (AMB320 and AMB321) and two randomised bosentan placebo controlled 16 week trials (AC351 and AC352). The following table details the trials presented in the submission: Page 1 of 5

2 Trials considered in the submission for the indirect comparison. Trial ID/First Protocol title/publication title Author Common reference placebo Bosentan AC (AC-352) Bosentan therapy for pulmonary arterial hypertension Publication citation Rubin et al (2002). New England Journal of Medicine. 346 (12): AC (AC-351) Ambrisentan AMB 320 (ARIES-1) AMB 321 (ARIES-2) Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study. ARIES-1: A placebo-controlled, efficacy and safety study of ambrisentan in patients with pulmonary arterial hypertension. Ambrisentan therapy for pulmonary arterial hypertension: A comparison by PAH aetiology. AMB-321 (ARIES-2). Ambrisentan in PAH, a phase III, randomised, double-blind, placebocontrolled, multicentre, efficacy study of ambrisentan in subjects with pulmonary arterial hypertension. Channick et al (2001). The Lancet. 358 (9288): Oudiz et al (2006). Chest; 130(4):121S. Badesch DB (2007). Chest, 132 (4):488S ARIES-C Ambrisentan for the treatment of pulmonary arterial hypertension: Results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicentre efficacy (ARIES) study 1 and 2 Galie et al (2008). Circulation,117: PAH = pulmonary arterial hypertension; od = once daily; bd = twice daily; WHO = World Health Organization; FC = functional class The indirect comparison was based on 1) combined ambrisentan data (termed ARIES C in the submission) rather than on the individual ambrisentan trial data (5mg treatment arms were combined as were the placebo arms from AMB321 and AMB320) and pooled bosentan data (125 mg bd) from AC351 (Channick et al (2001) and AC352 (Rubin et al (2002); and 2) sub group data (for WHO class III and IV patients at baseline) given that the ambrisentan trials recruited patients with other WHO functional classes (I-IV) at baseline (40% of patients were WHO class I-II at baseline). The primary outcome was mean change from baseline in 6 minute walk distance (6MWD), which the submission claimed was a valid surrogate for survival. The submission also presented survival data for ambrisentan from ARIES E (an extension study to AMB321 and AMB320) and different bosentan studies (without conducting a formal comparison). 8. Results of trials The submission conducted a placebo based indirect comparison of ambrisentan and bosentan. Page 2 of 5

3 Primary endpoint - the 6 Minute Walk Distance (6MWD) The claim of non-inferiority in the submission was based on two different estimates of the minimal clinically important difference (MCID) in the 6MWD: -35m (based on the power of the ambrisentan trials to detect this difference) and -50m (based on differences observed in the bosentan trials). The results indicated that treatment with either dose of ambrisentan, or with bosentan 125 mg twice daily (bd), is associated with a statistically significant improvement from baseline in 6MWD compared with placebo. There was no statistically significant difference between ambrisentan and bosentan in the placebo based indirect comparison of 6MWD. Secondary endpoints - Borg Dyspnea Index (BDI), change from baseline for WHO functional class and clinical worsening: The placebo based indirect comparisons indicated that there was no statistically significant difference in mean BDI change from baseline between ambrisentan 5 mg daily and bosentan 125mg twice daily, whereas there was a statistically significant difference in mean BDI change from baseline between ambrisentan 10 mg daily and bosentan 125 mg twice daily in favour of ambrisentan. There was no statistically significant difference between ambrisentan (5 mg or 10 mg daily doses) and bosentan 125 mg twice daily dose with respect to improvement in WHO functional class from baseline. The indirect comparison results indicated that there was no statistically significant difference in clinical worsening rates between ambrisentan and bosentan. Haemodynamic data from AMB321/AMB320 were not provided in the submission. With respect to adverse events, the incidence of serious adverse effects (SAEs) was higher for patients treated in the placebo arms compared to patients treated with either dose of ambrisentan. The incidence of any reported serious adverse events was similar for both doses of ambrisentan. With the exception of right ventricular failure for the 5 mg ambrisentan group, no other individual serious adverse event occurred at an incidence greater than 2 %. The most common adverse event in the long term extension ambrisentan study (ARIES E) was peripheral oedema. SAE data for bosentan were predominantly not reported. Abnormal liver function is recognised to be a class effect of endothelin receptor antagonists. The bosentan trials indicated that treatment with the active drug increases the risk of elevated transaminase levels compared to treatment with placebo. Liver function test levels in patients treated with ambrisentan appeared unremarkable throughout the 108 week study period. From the Periodic Safety Update Report for ambrisentan, two new safety issues were identified: fluid retention, requiring intervention with a diuretic or hospitalisation for fluid Page 3 of 5

4 management within weeks of starting ambrisentan therapy, and dyspnoea occurring shortly after initiating ambrisentan therapy. 9. Clinical Claim The submission described the 5 mg daily and 10 mg daily doses of ambrisentan as noninferior in terms of comparative effectiveness and non-inferior in terms of comparative safety over bosentan 125 mg twice daily. 10. Economic Analysis The submission presented a cost minimisation analysis. Ambrisentan 5 mg once daily or ambrisentan 10mg once daily and bosentan 125 mg twice daily were claimed to be equieffective from the placebo-based indirect comparison of ambrisentan to bosentan using two ambrisentan trials (AMB320 and AMB321) and two bosentan trials (AC351 and AC352). 11. Estimated PBS Usage and Financial Implications The submission estimated the likely number of patients/year to be less than 1000 in Year The net financial implications to the PBS were claimed to be nil through all the years of extrapolation (up to 2014). 12. Recommendation and Reasons The PBAC recommended the listing of ambrisentan as a Section 100 Highly Specialised Drugs (HSD) Program Public and Private Hospital Authority required benefit for the treatment of primary pulmonary hypertension (PPH) or pulmonary arterial hypertension secondary to connective tissue disease (PAH-CTD) in patients with a World Health Organisation (WHO) functional class III or IV severity on a cost minimisation basis to bosentan. The equi-effective doses are ambrisentan 5 mg daily and bosentan 125 mg twice daily. The PBAC accepted that bosentan was the appropriate comparator, considering the two drugs belong to the same therapeutic class. The PBAC considered that ambrisentan was non-inferior to bosentan on the basis of the indirect comparison of the mean change from baseline in the six minute walk distance (6MWD) results. The PBAC noted that it would have been informative for haemodynamic data and/ or outcome data to be presented, considering that haemodynamic parameters correlate with clinical state, functional class, exercise capacity, and prognosis in patients with PAH. The PBAC considered the toxicity of ambrisentan appeared non-inferior to bosentan. It was noted that liver function tests in patients treated with ambrisentan appeared to be within acceptable range in the study period, however the PBAC considered that additional time is required to determine whether ambrisentan is associated with liver toxicity as such adverse effects may emerge with longer term treatment. The PBAC considered economic uncertainty remained in the cost effectiveness of ambrisentan, however the uncertainty was similar to that accepted for the other PBS listed endothelin receptor antagonists for the treatment of PPH and PAH. The PBAC noted that the patient population for which listing of ambrisentan was sought are already eligible to receive subsidised treatment with the currently PBS listed PAH therapies and hence that Page 4 of 5

5 ambrisentan will only provide an additional treatment option, with no unique patient group. The PBAC recommended the restriction eligibility and continuation criteria should take account of the TGA approved indications and dosage recommendations for ambrisentan, as should the clinical interchangeability arrangements specified in the PBS restrictions for the agents used in PPH and PAH. The PBAC noted that the Highly Specialised Drugs Working Party support the inclusion of ambrisentan on the HSD Program. Recommendation AMBRISENTAN, tablets, 5 mg and 10 mg Restriction: Section 100 (Highly Specialised Drugs Program) Public and private hospital authority required Complex - to be finalised Pack size: 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 Page 5 of 5