Final Appraisal Report: GlaxoSmithKline. Advice No: 2508 April Recommendation of AWMSG

Transcription

1 Final Appraisal Report: Ambrisentan (Volibris ) for pulmonary arterial hypertension GlaxoSmithKline Advice No: 2508 April 2009 Recommendation of AWMSG Ambrisentan (Volibris ) is recommended for use within NHS Wales for the treatment of patients with pulmonary arterial hypertension (PAH) classified as World Health Organisation (WHO) functional class (FC) II and III, to improve exercise capacity. Ambrisentan (Volibris ) is restricted for use as directed by a physician experienced in the treatment of PAH at one of the National Commissioning Group (NCG) centres across the UK. Ambrisentan (Volibris ) is not considered suitable for shared care within NHS Wales. Statement of use: No part of this advice may be used without the whole of the advice being quoted in full. This report should be cited as: Page 1 of 28

2 1.0 RECOMMENDATION OF AWMSG The AWMSG recommendation is based on: the Preliminary Appraisal Report, the Company Response to this, the independent review, medical expert opinion, lay perspective and discussions at the AWMSG meeting. Date: Wednesday, 29 th April 2009 The recommendation of AWMSG is: Ambrisentan (Volibris ) is recommended for use within NHS Wales for the treatment of patients with pulmonary arterial hypertension (PAH) classified as World Health Organisation (WHO) functional class (FC) II and III, to improve exercise capacity. Ambrisentan (Volibris ) is restricted for use directed by a physician experienced in the treatment of PAH at one of the National Commissioning Group (NCG) centres across the UK. Ambrisentan (Volibris ) is not considered suitable for shared care within NHS Wales. Page 2 of 28

3 2.0 PRODUCT DETAILS 2.1 Licensed indication Ambrisentan (Volibris ) is indicated for the treatment of patients with pulmonary arterial hypertension (PAH) classified as World Health organisation (WHO) functional class (FC) II and III, to improve exercise capacity 1. Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease 1. Ambrisentan is not recommended for use in patients below 18 years of age due to lack of data on safety and efficacy Dosing Ambrisentan is an oral treatment taken as one 5mg tablet once daily. Some additional efficacy has been observed with a 10mg dose in patients with class III symptoms, however an increase in peripheral oedema has been observed. Patients with PAH associated with connective tissue disease may require 10mg of ambrisentan for optimal efficacy. It should be confirmed that the 5mg dose is well tolerated before consideration of a dose increase to 10mg in such patients Market authorisation date 21 st April UK Launch date 23 rd June DECISION CONTEXT Pulmonary hypertension is defined by a mean pulmonary arterial pressure (PAP) greater than 25 mmhg at rest or greater than 30 mmhg with exercise 3. PAH is one of five subtypes of pulmonary hypertension categorised by the Venice 2003 clinical classification system 4. It is characterised by a progressive increase in pulmonary vascular resistance, which leads to right ventricular heart failure and premature death. Symptoms of PAH include dyspnoea, fatigue, chest pain, syncope and oedema. Within the PAH category, there are a further five subcategories: idiopathic (IPAH); familial (FPAH); associated with other conditions (APAH); associated with significant venous or capillary involvement; and persistent pulmonary hypertension of the newborn (PPHN). People with PAH are classified according to their functional capacity (FC I to IV) originally devised by the New York Heart Association (NYHA) and revised by WHO 2,5. Refer to Appendix 1, Table 2. PAH is a rare condition, the estimated annual incidence of IPAH is one to two cases per million population, and the annual incidence of other types of PAH is a further one to two cases per million population. Females are almost twice as likely to develop the condition compared to males 2. In the UK, the likely prevalence of PAH has been estimated to be cases per million population 5. The company estimate a prevalence of 78 patients in Wales 2. Survival of untreated patients with IPAH in the 1980s was a median of 2.8 years after diagnosis (CI: 95%; 1.9 to 3.7 years) 6. Patient survival was estimated as 68% at one year, 48% at three years and 24% at five years 5. With consensus on conventional therapy and the introduction of new treatments, this is likely however to have improved. Page 3 of 28

4 Different measures are used to monitor the severity, progression and response to treatment of PAH. Clinically, no single measure or composite measure is utilised to measure the disease. Key measures include: the six-minute walk test/distance (6MWT/D), dyspnoea scores on the Borg or Mahler scales, pulmonary artery pressure (PAP), right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR) and cardiac output/cardiac index 5. Treatment approaches for PAH can be broadly split into two categories: general therapeutic strategies which include anticoagulants, diuretics and calcium channel blockers, and disease specific therapies that target one of three major biological pathways involved in the development of PAH: phosphodiesterase-5 inhibitor (oral sildenafil), usually used first-line endothelin receptor antagonists (ERAs), usually reserved after failure of firstline therapy prostacyclins (parenteral epoprostenol and inhaled iloprost) 2. Recent UK and Ireland consensus guidelines recommend sildenafil as a first line treatment option in patients with idiopathic WHO FC II who require disease targeted therapy 7. There are three ERAs all administered orally, that are currently licensed in the UK; bosentan (Tracleer ), sitaxentan (Thelin ) and ambrisentan (Volibris ) 1,8,9. Bosentan and sitaxentan are both sulphonamide-based ERAs, licensed for PAH WHO FC III. Bosentan has also recently received European Union approval for the treatment of PAH WHO FC II 10. Endothelin-1 is a potent vasoconstrictor that binds to endothelin-1 receptors A (ET A ) and B (ET B ) resulting in vasoconstriction in smooth muscle cells and smooth muscle cell proliferation. ET A receptors are predominantly found on vascular smooth muscle cells and cardiac myocytes. Activation of ET B on endothelial cells results in vasodilation due to release of nitric oxide and prostacyclin. Ambrisentan is a propanoic acid-class ERA and like sitaxentan is selective for the Et A receptor hence production of ET B -mediated vasodilation should remain unaffected 1. Bosentan has a slightly higher affinity for ET A receptors than ET B receptors 8. Ambrisentan s long (9-15 hours) half-life allows for once daily dosing 2. Sitaxentan is also administered once-daily and bosentan twice-daily 8,9. Unlike bosentan and sitaxentan, ambrisentan is not metabolised via cytochrome P450-dependent pathways and does not induce or inhibit cytochrome P450 activity hence pharmacokinetic-based drug interactions are less likely to occur 2. Ambrisentan does not meet the AWMSG criterion for ultra-orphan status, as it is for treatment of a condition affecting more than 1 in 50,000 persons in the UK (i.e. 60 persons in Wales) at the time of submission 11. Page 4 of 28

5 4.0 EXECUTIVE SUMMARY 4.1 Review of the evidence on clinical effectiveness The company submission is based on two randomised, double-blind, multi-centre, placebo-controlled, Phase III pivotal studies: ARIES-1 (n=201) and ARIES-2 (n=192) and a combined analyses of these trials. ARIES-1 compared ambrisentan 5mg and 10mg daily with placebo and ARIES-2 compared ambrisentan 2.5mg and 5mg daily with placebo. One-third of patients had WHO FC II symptoms, the vast majority of the remaining patients had Class III IPAH or PAH. There was a clinically and statistically significant change from baseline in the 6MWD after 12 weeks for all doses (2.5mg, 5mg, 10mg) of ambrisentan when compared to placebo. Clinically relevant changes in 6MWD for all doses of ambrisentan remained when considered by FC (II/III). There are no head to head studies comparing ambrisentan with other PAH treatments though ambrisentan is considered to be comparable in efficacy to the currently available ERAs. Ambrisentan may be associated with fewer significant drug interactions and liver toxicity, although further follow up data are required to confirm whether these potential advantages over other ERAs are clinically meaningful. Ambrisentan and bosentan are the only medicines licensed for treatment of PAH WHO FC II. 4.2 Review of the evidence on cost-effectiveness A cost utility analysis comparing ambrisentan with the ERAs, bosentan and sitaxentan, is described. The case made in the company submission effectively represents patients in which sildenafil is not a first-line treatment option or for patients who have experienced an insufficient response to, or are intolerant of, sildenafil. A hypothetical cohort of patients has been modelled in a discrete event simulation using the baseline characteristics of the ARIES-1 and -2 studies. The model estimates that, overall, ambrisentan is less expensive and more effective than both bosentan and sitaxentan, i.e. ambrisentan dominates the comparators. However, there are a number of limitations to the model. A five year time horizon has been employed, although a lifetime time horizon would more appropriately capture the associated costs and outcomes over the natural course of the disease. Selective studies of bosentan and sitaxentan have been used to derive comparator efficacy and adverse event parameter inputs which, taken in isolation of the other available evidence, may have resulted in estimates that are biased in favour of ambrisentan. The probabilities of elevations in liver enzymes appear to be a key driver of the overall cost differences, but are based on very small patient numbers that are potentially very sensitive to small changes due to the play of chance. Sensitivity analyses have been conducted but do not address all of these issues. 5.0 LIMITATIONS OF DECISION CONTEXT There are no head to head studies comparing ambrisentan with active treatments for PAH. The pivotal trials were of short duration (12 weeks); patients were eligible to take part in an open label extension study which is ongoing. PAH is a rare condition. The number of patients included in clinical studies is relatively small. Meaningful indirect comparison between many of the subpopulations of PAH and between different treatments is therefore very difficult. Page 5 of 28

6 6.0 SUMMARY OF THE EVIDENCE ON EFFICACY AND SAFETY The company submission is based on two randomised, double-blind, multi-centre, placebo-controlled, Phase III pivotal studies (ARIES-1 [AMB-320] and ARIES-2 [AMB- 321]) and a combined analyses of these trials 12,13,14. ARIES-1 included 201 patients and compared ambrisentan 5mg and 10mg (patients received 5mg for first two weeks before increasing to 10mg) with placebo. ARIES-2 included 192 patients and compared ambrisentan 2.5mg and 5mg with placebo. Refer to Table 1A, 1B and 1C in Appendix 1 for the main study results. Patients enrolled had IPAH or PAH associated with connective tissue disease, anorexigen use or HIV infection. The majority of patients had WHO FC II (38.4%) or class III (55.0%) symptoms. Patients with pre-existing liver disease (e.g. alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >1.5x upper limit of normal [ULN]) and those receiving other targeted therapy for PAH were excluded from the trials 14. Patients with WHO FC II symptoms at baseline had a substantially greater mean 6MWD in both the placebo group (373.7m) and the combined ambrisentan group (375.7m), compared with patients with WHO FC III symptoms at baseline; placebo group (325.9m) and combined ambrisentan group (330.4m) 14. The French National Registry of PAH which included a substantial number of patients (n=674) with PAH diagnosed according to clinical criteria found that for FC II subjects the 6MWD was 415m (SD: 86) and for Class III 319m (SD: 92) 15. WHO FC II subjects were younger, had a less severe degree of dyspnoea and slightly less haemodynamic impairment than FC III patients; FC II patients were also receiving fewer concomitant medications compared with WHO FC III subjects 14. Patients continued any supportive care which included digoxin, anticoagulants, diuretics, oxygen and vasodilators (calcium channel blockers, angiotensin converting enzyme inhibitors). The most frequently used concomitant medications were furosemide (44.1%), spironolactone (23.8%) and warfarin (23.4%) 14. Oxygen was used by around 26% and 14% of patients in ARIES 1 and 2, respectively 12,13. Due to the placebo-controlled design of both studies, there was a one out of three chance that a patient would not receive ambrisentan for a period of 12 weeks. Therefore, after a minimum treatment period of four weeks, patients who met two or more of the following predefined early escape criteria were permitted to prematurely discontinue the study for ethical reasons: a decrease from baseline of at least 20% in 6MWD; an increase of one or more WHO FC; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure; refractory systolic hypotension (systolic blood pressure < 85 mmhg) 14. All requests for early escape were adjudicated in a blinded fashion by the ARIES Steering Committee and all study assessments were collected prior to unblinding of treatment. 11/132 (8.3%) of the placebo and 5/262 (1.9%) of the combined ambrisentan group met the early escape criteria 14. Page 6 of 28

7 The primary endpoint for both studies was improvement in exercise capacity assessed by change from baseline in 6MWD at 12 weeks. Baseline was defined as the mean 6MWD of the last two 6MWD tests prior to randomisation. For missing data last observation carried forward (LOCF) was used unless the patient withdrew prematurely due to clinical worsening 14. Patients enrolled into ARIES 1 and 2 were eligible to enter a long term open label extension study ARIES E (n=383). Results are available as a conference abstract only Clinical efficacy 2,12,13,17 ARIES-1 and ARIES-2 single analysis: For each of the placebo-controlled studies there was a clinically and statistically significant change from baseline in the 6MWD after 12 weeks for all doses (2.5mg, 5mg, 10mg) of ambrisentan when compared to placebo. Clinically relevant changes in 6MWD for all doses of ambrisentan remained when considered by FC (II/III). A doseresponse relationship was observed, although the effect on the 6MWD for the 5mg ambrisentan dose group in ARIES-2 was almost double that of ARIES-1. No reasons for the different effect observed have been identified 17. Two-thirds of patients enrolled on the studies had IPAH; for this patient group the results from both studies indicated statistically and clinically significant changes in 6MWD for all doses. For patients with non-ipah (mainly connective tissue disorder [CTD]-associated PAH), only the 10mg dose in ARIES-1 showed statistically and clinically significant changes in this group of patients. The Committee for Medicinal Products for Human use (CHMP) commented that patients with PAH-CTD have a consistently smaller response to other ERAs compared to patients with IPAH 17. Therefore the greater efficacy with 10mg may be due to a dose-response relationship and this has been reflected in the dosing guidance within the summary of product characteristics 1 (see section 2.2). In ARIES-1 neither of the two key secondary endpoints, time to clinical worsening or change in WHO FC were significant versus placebo 17. Due to the multiple comparisons procedure, a statistically significant improvement compared with placebo could not be stated for WHO class or other secondary endpoints. In ARIES-2 time to clinical worsening was statistically significantly greater for the combined groups than placebo, though the change in WHO FC was not. Statistical testing was also significant for the Borg dyspnoea index (BDI) and change in SF-36 health survey 2. Page 7 of 28

8 ARIES-1 and ARIES-2 combined analysis: In the combined analysis (ARIES-1 plus ARIES-2) the placebo-adjusted improvement in 6MWD at week 12 remained significantly greater for all doses. Improvement occurred as early as week four and evidence of a dose-response was observed by week 12 2,14. Results indicated a significant delay in the time to clinical worsening in the combined ambrisentan group (p=0.003 using Kaplan-Meier analysis) and change in FC (p=0.009) compared with placebo group, although change in FC was only significant versus placebo for the 5mg group when comparing each dose regimen. The proportions of patients who had no change in WHO FC were 62.1% in the placebo group compared with 74.3% of patients treated with ambrisentan (combined ambrisentan dose). The results demonstrated a 71% (95% CI: 41% to 86%) reduction in the probability of clinical worsening occurring at any given time for a patient receiving ambrisentan (combined doses) compared with placebo. This was mainly driven by FC III patients as those subjects who had FC II symptoms at baseline did not show a demonstrable difference between treatment groups, partially due to the small number of events in this subgroup. There was a statistically significant improvement compared with placebo in the physical component summary of the SF-36 survey for the combined doses (p=0.008) but not for the 5mg group (p=0.158). No statistically significant differences were observed for any of the groups for the mental component summary Points to note In ARIES-1 and -2 the majority of patients had FC II or III symptoms and eligibility criteria were consistent with the accepted definition of PAH; therefore the results are representative of the patient population under consideration. No patients in either of the pivotal phase III studies were from the UK; overall 22.7% of subjects were from Western Europe/Israel 14. As treatments are likely to vary across the world it is not known whether the results are directly applicable to patients in Wales. Though the treatment period of 12 weeks in ARIES-1 and -2 was considered to be long enough to provide efficacy results of clinical relevance, it is not long enough to evaluate the long-term effect of ambrisentan or improvement on survival Safety The most common adverse effects recorded in the pivotal trials, ARIES-1, ARIES-2 and in the combined analysis were consistent with those observed with existing ERAs. There was a higher incidence ( 1% difference in incidence) of peripheral oedema, nasal congestion, sinusitis, flushing, nasopharyngitis, abdominal pain, constipation, palpitations, dyspnoea and headache in the combined ambrisentan group compared with the placebo group 2. Peripheral oedema is a common side effect (>1/100) associated with ERAs. In the combined analysis of the phase III trials peripheral oedema was reported by 17.2% of patients in the combined ambrisentan group and 10.6% in the placebo group 14 This adverse effect was much more common at higher doses (2.5mg, 3.1% versus 5mg, 18.5% versus 10mg, 28.4%) 14 and in the elderly in whom it may be more severe 1. Patients with WHO FC II symptoms at baseline have a lower risk of developing peripheral oedema with the 5mg dose compared with patients with class III symptoms 17. Peripheral oedema was reported as a treatment related serious adverse event in only 2 (0.8%) subjects receiving ambrisentan 14,17. Page 8 of 28

9 All ERAs can cause reductions in haemoglobin (Hb) and haematocrit values. During the phase III studies with ambrisentan, mean Hb concentrations decreased by 0.84 g/dl 2 as early as week four of treatment though no clinically significant reductions were observed beyond week four 17. A similar frequency of adverse events possibly related to Hb and Haematocrit (e.g. anaemia and epistaxsis) was observed in the ambrisentan groups compared to placebo 17. Adverse effects on the liver including dose dependent raised liver enzymes and rarely hepatitis, cirrhosis and liver failure have been reported with ERA therapy. As a nonsulphonamide ERA, ambrisentan does not inhibit the bile salt export pump which may avoid accumulation of bile salts and liver cell damage 2. Due to the association between ERA therapy and elevations in liver functions tests (LFTs), liver monitoring was undertaken as part of the phase III trial protocols. The combined analysis of the ARIES-1 and ARIES-2 trials showed that none of the 261 patients who received ambrisentan had ALT/AST values >3xULN compared with three patients receiving placebo, over the same 12 week period 14. Results from an on-going long-term study (n=383) of patients with a mean exposure of 1.4 years (maximum 2.8 years), found eight (2.1%) patients had AST/ALT >3xULN. Seven (1.8%) patients had AST/ALT >3xULN and <5xULN; two confirmed on retest with none resulting in discontinuation of ambrisentan. One (0.3%) patient had AST/ALT >8xULN that resulted in discontinuation of multiple drugs, including ambrisentan 16. One fatal event of abdominal pain was reported, but there is insufficient data to link to a hepatotoxicity event 17. An open label study evaluated the incidence of increased serum aminotransferase concentrations with ambrisentan in patients who had previously discontinued bosentan (86%), sitaxentan (6%) or both (8%) due to LFT abnormalities. During a mean exposure of 32 weeks, no patient had a confirmed serum ALT/AST elevation >3xULN which resulted in discontinuation of treatment, though one patient did require a dose reduction 18. STRIDE-6 considered the use of sitaxentan in PAH patients previously exposed to bosentan 12 of whom had experienced aminotransferase elevations while on bosentan. Only one patient re-developed this side effect during the 12 weeks on sitaxentan 19. These results should be viewed with caution particularly due to the low number of patients included in the studies and relatively short lengths of treatment. Despite the potentially favourable results for ambrisentan regular monitoring of liver function enzyme concentrations is recommended for all ERAs 17. Ambrisentan is metabolised primarily by hepatic glucuronidation and does not induce or inhibit cytochrome P450 enzymes resulting in a low probability of pharmacokineticbased drug interactions 1,17. Bosentan induces and is metabolised by CYP2C9 and CYP3A4. Plasma concentrations of substances metabolised via these isoenzymes will be decreased if bosentan is co-administered. The manufacturers recommend avoiding combination with potent inhibitors of CYP2C9 and 3A4 as this could lead to large increases in plasma concentrations of bosentan 8. Sitaxentan is an inhibitor of CYP2C9 and to lesser extent CYP2C19, CYP3A4/5 and CYP2C8. Sitaxentan is metabolised by CYP2C9 and CYP3A4/5. Though administration of sitaxentan with CYP2C9 and CYP2C19 inhibitors is not expected to result in clinically significant drug interactions; clinically significant interactions may occur with drugs metabolised via CYP2C9. Sitaxentan may also be a substrate for organic anion transporting polypeptide (OATP) proteins 9. Page 9 of 28

10 7.0 SUMMARY OF CLINICAL EFFECTIVENESS ISSUES 7.1 Comparator medications Ambrisentan would be considered as an alternative option for patients suitable for existing ERAs: Bosentan is a non-selective, sulphonamide-class endothelin receptor antagonist and was originally approved for the treatment of PAH in patients with WHO FC III in primary (idiopathic and familial) PAH, PAH secondary to scleroderma without significant interstitial pulmonary disease and PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger s physiology 8. Bosentan now has European Union approval for the treatment of Class II PAH 10. Sitaxentan is a sulphonamide-class, selective ET A receptor antagonist currently licensed for treatment in patients with PAH WHO FC III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and in pulmonary hypertension associated with connective tissue disease Comparative effectiveness The two pivotal phase III trials compared ambrisentan against placebo. There are no trials directly comparing ambrisentan with an active comparator. In their report the CHMP commented that although comparisons versus placebo are considered to be acceptable bearing in mind the methodological difficulties in performing a non-inferiority trial in this specific population, it would have been desirable to have included an active control arm for descriptive purposes, especially considering that there are other orally administered medicinal products available 17. Indirect comparisons suggest that a clinically meaningful difference between the currently licensed ERAs in respect of ET-receptor selectivity has not been demonstrated 20. There is no definitive study providing a survival benefit for any ERA 20. Survival rates for PAH treatments are based on comparisons with historical controls not receiving specific PAH therapy. One year survival rates with ERA therapies are over 90%, compared with an approximate predicted survival of around 70% with no PAH specific treatment 20. Bosentan has recently received European approval for the treatment of WHO FC II PAH on the basis of results from the EARLY (Endothelin Antagonist trial in mildly symptomatic PAH patients) randomised, double-blind, placebocontrolled study that enrolled 185 patients with mildly symptomatic WHO FC II. Bosentan was associated with a lower incidence of worsening FC compared with placebo (3.4% versus 13.2%; p= ). No additional safety or tolerability issues were identified 10,21. Ambrisentan is not metabolised by and does not inhibit or induce cytochrome P450 activity 1,17. Therefore there is a low probability of pharmacokinetic-based drug interactions when compared to the other ERAs, although pharmacodynamic interactions between ambrisentan and other medicines may still occur. Available data suggests that ambrisentan may have a lower potential than the other ERAs for causing liver dysfunction. Despite this, regular monitoring of liver function is currently recommended with all ERAs 17. Page 10 of 28

11 8.0 REVIEW OF HEALTH ECONOMIC EVIDENCE 8.1 Overview of the key economic issue for AWMSG to consider The key economic issues for AWMSG to consider are whether any additional benefits offered by ambrisentan over the relevant comparator(s) justify any additional costs and, if so, whether the total budgetary impact of supporting the use of ambrisentan is acceptable. 8.2 Description and critique of the company s submission The company submission 2 describes a cost utility analysis comparing ambrisentan with the ERAs bosentan or sitaxentan. Discrete event simulation has been employed in which a hypothetical cohort of patients is modelled, defined by the baseline characteristics of patients in the ARIES-1 and -2 studies. The model has a five year time horizon, although a lifetime time horizon would be appropriate to capture the associated costs and outcomes over the natural course of the disease. Regression analysis of the ARIES study data has been undertaken to predict the probability of increasing 6MWD, the key efficacy parameter in the model. The efficacy equation derived for ambrisentan has been calibrated for bosentan and sitaxentan based on published studies, as patient level data were reportedly not available for these comparators. However, only single studies of each comparator have been used for this calibration and their use in isolation of the other available evidence may have resulted in biased estimates of their efficacy. The estimated 6MWD generated from these regressions has been used to derive predictive equations for other parameters such as clinical worsening, WHO FC and quality of life. Any biased estimate of 6MWD therefore has the potential to bias other parameters. This includes the estimated utility values, which are reportedly based only on data from US patients in the ARIES studies. The key adverse event in the model is elevations in liver enzymes. Estimates of the probability of this event are based on published studies and trial reports. However, only one study is considered for each of the comparators and the derived probabilities of events are based on very small patient numbers. Small changes due to chance in the number of patients experiencing liver enzyme elevations can lead to significant changes in the assumed probabilities of experiencing elevated liver enzymes in the model. This is important given that the overall cost differences in the model are driven in large part by the differences in costs attributed to switching therapy due to elevations in liver enzymes. There are therefore a number of uncertainties in the model parameters, which may bias the model in favour of ambresentan. The model has been provided to WMP. 8.3 Population A hypothetical patient cohort is generated using the baseline characteristics of patients in the ARIES-1 and -2 studies 2. These patients (mean age 50.5 years) had WHO FC II and III PAH, reflecting the licensed indication for ambrisentan Perspective and time horizon The analysis was conducted from the perspective of NHS Wales. A five year time horizon has been used in the base case analysis. Page 11 of 28

12 The resource implications section of the company submission 2 refers to a USA-based registry study that followed patients with PAH between 1981 and 1988, which estimated five-year survival rates to be 34% 6. A more recent study of epoprostenol treatment in patients with WHO FC III or IV PAH found overall survival rates at five years to be 55% 22. Although it is acknowledged that life expectancy may be relatively short for many patients with PAH 7, a lifetime time horizon would be appropriate for this condition (as has been used in previous models of the cost effectiveness of drugs for PAH 5 ). The five year time horizon employed for this analysis may be insufficient to capture the associated costs and outcomes over the natural course of the disease, and will result in a biased estimate of cost-effectiveness. The model provided by the company suggests that 77% of patients taking bosentan, 79% patients taking sitaxsentan, and 81% of patients taking ambrisentan remain alive at five years. 8.5 Comparator The analysis compares treatment with ambrisentan against treatment with bosentan or sitaxentan 2. Sildenafil is permitted as a treatment option following failure of other agents but is not considered as a direct comparator in the analysis. Ambrisentan and bosentan are licensed for use in patients with WHO FC II or III PAH, 1,8 whereas sitaxentan, and sildenafil, are licensed for use in patients with FC III PAH 9,23. Recent UK and Ireland consensus guidelines recommend sildenafil as a first line treatment option in patients with idiopathic WHO FC II who require disease targeted therapy 7. The omission of sildenafil as a comparator therefore limits the applicability of the analysis to patients in whom sildenafil is not a first-line treatment option or those who have experienced an insufficient response to, or are intolerance of, sildenafil. 8.6 Clinical inputs Baseline characteristics Baseline characteristics of the hypothetical patient cohort are derived from the ARIES-1 and -2 study populations. Patients were initially assigned as primary or secondary PAH, WHO FC and status of warfarin use, with gender and age conditional on type of PAH. Disease duration and 6MWD were assumed to follow beta distributions defined by the WHO FC 2. Baseline data were also reportedly analysed to obtain predictive equations for estimation of BDI, haemodynamic parameters, quality of life, and brain natriuretic peptide (BNP), based on 6MWD and other baseline covariates Efficacy data The 6MWD is the key efficacy parameter of the model 2. Logistic regression on the data from the ARIES-1 and -2 studies has been undertaken to generate an equation that predicts the probability of improving 6MWD with treatment. Dose, baseline age, gender and baseline 6MWD were found to be significant predictors for ambrisentan users. For bosentan and sitaxentan, it is reported that patient-level data was not available. Therefore, the efficacy equation for bosentan and sitaxentan is derived from the ambrisentan data-derived equation by removing the dose variable and considering only treatment versus placebo 2. Page 12 of 28

13 For bosentan, the analysis was based on a published retrospective analysis of 16-week data from 103 consecutive patients with WHO FC III/IV attending a French treatment centre 24. Important clinical characteristics (e.g. 6MWD, proportion with WHO FC III or IV, proportions using anticoagulants) of these patients were less favourable than the baseline characteristics of patients in the ARIES studies (see Table 1A to 1C, Appendix 1), so it is possible that the treatment effect calculated for bosentan from these data and used to predict the 6MWD for bosentan in this model, would be biased. For sitaxentan, treatment effect was calculated from a double-blind dose-finding study in 245 patients with WHO FC II-IV, of which 61 received sitaxentan 100mg once daily 25 over 18 weeks. As the proportion achieving an improvement in 6MWD was not reported in this study, this has been calculated using the 6MWD equation discussed above. It is not clear why these two studies were selected to represent the efficacy of bosentan and sitaxentan, and their use in isolation of other available data may lead to biased efficacy estimates. It is assumed that the constant parabolic increase or decrease implied by the 6MWD efficacy equations would not hold for long time periods. Therefore, a stabilisation period has been incorporated after which the 6MWD is recalculated. This is set to 12 weeks in the base case analysis, although the reason for this period is not explicit. Other measures such as BDI, haemodynamic parameters and BNP are estimated from the predictive equations based on 6MWD and other baseline covariates. Clinical worsening is reported to be dependent on 6MWD and baseline age, and is considered to include PAH hospitalisation, lung transplantation, addition or switch of therapy, and death. However, the probability of lung transplant as a result of a clinical worsening is assumed to be zero in the base case analysis 2 (and appears not to be explored in sensitivity analysis). The proportions estimated to experience PAH specialist centre visits, switch in treatments and death are reportedly taken from a study of bosentan 26, although the actual figures assumed in the model are not immediately obvious and verifiable from this study. Change in WHO FC is also dependent on 6MWD 2. Any biased estimate of 6MWD would therefore impact on the estimates of these other derived parameters Adverse events Elevated liver enzymes are the principal adverse event considered in the model. Patients with >3x and <5x the ULN range for ALT/AST level may continue with their treatment at the same or a lowered dose or stop the treatment. If the patient is already on the lowest dose possible, treatment is switched. Those with ALT/AST >5x ULN are switched, as are those experiencing symptoms. Those who switch to another ERA continue in the model until death or the end of the analytic time horizon. Those switched to a non-era (e.g. a prostacyclin) are removed from the model 2. The monthly probability of developing elevated liver enzymes is reportedly calculated for each treatment based on the published literature and trial reports. The total number of patients with ALT/AST level >3x ULN was 17 in ARIES-1 and -2 trials, with mean exposure of 79.5 weeks in 483 patients. Using these figures, the monthly risk of having elevated liver enzymes was calculated to be 0.18%; of which 76.5% (13/17) had an increase from 3-5 fold and 23.5% (4/17) >8 times the upper limit 2. Page 13 of 28

14 The company submission states that a trial of bosentan found enzymes elevated to >3x ULN in 11.6% of bosentan treated patients (125 mg twice daily), of which 18.2% (2/11) had an increase from three to five fold, 63.6% (7/11) from five to eight fold, and 18.2% (2/11) more than eight-fold over 16 weeks, giving a monthly risk of elevated enzymes of 3.0% 2. However, the reference cited for this trial does not appear to report the number of patients experiencing enzymes elevated to >3x ULN, and only reports that three patients experienced abnormal hepatic function, and that two patients in the 125mg twice daily group experiencing elevations >8x ULN 26. The monthly risk of elevated liver enzymes assumed in the model would therefore appear to be uncertain and may bias the model against bosentan. The company submission reports the results of a trial of sitaxentan which observed an incidence of elevated liver enzymes for sitaxentan 100mg at a median exposure time of 26 weeks as 4 events out 77 patients 27. The monthly risk was therefore assumed to be 0.8% in the base case 2. The level of elevation is assumed to be distributed similarly to the elevation profiles with ambrisentan. As with the efficacy data, it is not clear why these two particular studies were selected to represent the effect on liver enzymes of bosentan and sitaxentan, and their use in isolation of other available data may lead to biased estimates. It should also be noted that small patient numbers are involved, which means that small changes due to chance in the number of patients experiencing liver enzyme elevations can lead to significant changes in the assumed probabilities of experiencing liver enzyme elevations in the model. This is important given that the overall cost differences in the model are driven in large part by the differences in costs attributed to switching therapy due to elevations in liver enzymes (see section 8.9.1). Other adverse events of headache, dizziness, flushing, peripheral oedema are counted in the model but incur no costs. The probability of these other adverse events occurring is reported to be based on the published literature, but no further details are provided Utility weights Utility values were reportedly derived from the SF-36 scores in the ARIES-1 and -2 studies. A utility prediction equation based on 6MWD was reportedly then derived. The company submission states that this utility prediction equation was based on the US population of the ARIES studies, and asserts that this was done on the basis that there is no notable difference between the general US and UK populations on the eight SF-36 domains 2. It should be noted that ARIES-1 involved 202 patients from the USA, Mexico, South America, Australia and Europe, whereas ARIES-2 involved 192 patients from Europe, Israel and South America 2. The actual SF-36 data from ARIES-1 show few statistically significant improvements from baseline in the eight domains, and the scores for those domains that are significantly different from baseline for ambrisentan are not statistically significantly different from placebo 13. In contrast, the SF-36 data from ARIES-2 show significant improvements from baseline and versus placebo for ambrisentan in most of the eight domains 12. When the ARIES-1 and -2 SF-36 scores are combined, the scores for some domains are statistically significantly improved for ambrisentan 14. The SF-36 data specific to the US population is not provided and it is not possible to determine the influence of deriving the utility prediction equation based only on US subjects. This is a potential source of bias in the model, which may be compounded by prediction based on potentially biased 6MWD estimates, as discussed in section Page 14 of 28

15 Utility values associated with prostacyclin treatment and supportive care are based on EQ-5D scores obtained from a trial of iloprost, and those associated with lung transplant from a cross sectional study of lung transplant recipients (any cause) Healthcare resource utilisation and cost Drug costs The drug acquisition costs are based on British National Formulary costs 28. Ambrisentan is confirmed as having the same cost as bosentan and sitaxentan. Drug initiation and monitoring costs included monthly liver function monitoring for ERAs and INR monitoring for warfarin recipients. Initiation of prostacyclins requires hospitalisation for several days and patient training delivered by specialist nurses Adverse event costs Only the costs associated with liver enzyme monitoring appear to be included as adverse event costs in the model. All patients on ERAs are assumed to undergo monthly liver enzyme monitoring (see 8.7.1), and the company submission states that patients with elevated liver enzymes experience more frequent visits and accrue higher costs at these visits, but few details beyond this are included. This is a potentially important aspect of the overall costs of treatment, as the cost differences between ambrisentan and the comparators is driven primarily by the costs of switching treatment due to elevated liver enzymes (see section 8.9.1). Patients on prostacyclins (presumably just epoprostenol) are assumed to develop sepsis and line infection at rates observed in published studies Other resource use and costs Other costs that are listed include lung transplantation (although no patients were considered to have had lung transplantation over the five year time horizon), emergency department visits, deaths, and post acute care costs such as home help, etc. Assumptions are made regarding the proportions of patients discharged to home, home care, etc., but few details are provided. Resource use dependent on WHO FC are also included. These entail GP visits, nonspecialist nurse time, etc., and resource use profiles are included for each WHO FC, but the source of these and other details are lacking. 8.8 Discounting Costs and outcomes are discounted at 3.5% per annum 2, which is the preferred discount rate. 8.9 Results Base-case analysis Ambrisentan is estimated by this model to be less expensive and to result in a greater gain of quality adjusted life years (QALYs) than both bosentan and sitaxentan, i.e. ambrisentan dominates bosentan and sitaxentan 2. Compared with bosentan, ambrisentan was estimated to be around 21,000 less expensive and to result in a gain of 0.15 QALYs over five years. Compared with sitaxentan, ambrisentan was estimated to be around 4,000 less expensive and to result in a gain of 0.06 QALYs over five years. The net cost differences are primarily driven by the significantly lower costs of switching treatment due to elevated liver enzymes that are estimated for ambrisentan compared with the comparators. The assumptions around elevations in liver enzymes are therefore key 2. Page 15 of 28

16 8.10 Sensitivity analysis One way sensitivity analyses A range of one way scenario analyses are reported, including doubling the probability of liver enzyme elevations with ambrisentan (but not exploring the effect of different probabilities for bosentan or sitaxentan, or the same probability for ambrisentan and the comparators). The model appears insensitive to the parameter values explored, with ambrisentan still dominating the comparators Probabilistic sensitivity analysis (PSA) PSA has been carried out by assuming normal distributions around the efficacy prediction equation coefficients. Life expectancy with prostacyclin treatment and lung transplantation is assumed to have a triangular distribution. Few further details are provided. Ambrisentan was reported to be dominant over bosentan in 81% of simulations and over sitaxentan in 68.9% of simulations 2. The PSA results are a function of the model inputs, and this analysis does not address the adverse event issues (i.e. probability of elevations in liver enzymes) discussed above Review of published evidence on cost-effectiveness Standard literature searches conducted by WMP have not identified any published evidence on the cost effectiveness of ambrisentan. 9.0 REVIEW OF EVIDENCE ON BUDGET IMPACT 9.1 Description and critique of the company s submission Scottish prevalence and incidence data are combined with assumptions on mortality rates to simulate the net number of patients with PAH in Wales over the five years from Internal company market research data are used to estimate the proportions of patients treated with ERAs and anticipated market share for ambrisentan. Only drug acquisition costs are considered in the budget impact analysis, and as ambrisentan is stated to be the same price as bosentan and sitaxentan, there is estimated to be little or no net cost impact from its introduction in Wales. This assumes that ambrisentan will only replace ERAs as they are currently used and will not be used instead of sildenafil or other PAH treatments. 9.2 Perspective and time horizon The budget impact analysis is conducted from the perspective of NHS Wales and considers a time horizon of five years from 2009 to Data sources Incident and prevalent cases In the absence of Welsh specific data (there is no PAH specialist centre in Wales), prevalence and incidence data are based on estimates of the Scottish Pulmonary Vascular Unit, which treats all patients with PAH in Scotland. The prevalence is estimated as 26 cases per million population, which when extrapolated to the Welsh population suggests there are 78 patients in Wales with PAH. The incidence is estimated as 7.6 per million, which suggests there would be 23 new cases each year 2. It should be noted that other estimates of the prevalence have been as high as 50 per million 5,29, which would effectively double the estimated number of patients in Wales. Mortality has been estimated at 30% per year, reportedly based on two studies that determined survival rates over 3 to five years, although the 30% estimate still amounts to being an assumption 2. Page 16 of 28

17 On the basis of the assumptions in the company submisison, the total number of patients with PAH is estimated at 71 in the year 2009, declining to 58 patients in (as the rate of increase in the population of Wales over the five years and the incidence rate of PAH is lower than the assumed rate of death of patients with PAH) Projected rate of adoption and market share It is assumed that all patients who are diagnosed with PAH are receiving treatment, due to the debilitating nature of the condition. Internal company market research data is reported to indicate that around 40% of patients are currently treated with prostacyclins, with the remainder being treated with ERAs or sildenafil. The company submission considers that ERAs are likely to be prescribed second line (after sildenafil), and assumes that a third of patients would be eligible for treatment with ambrisentan. The number of patients estimated to receive ambrisentan is 14 in 2009, declining to 11 in 2013 (rounding of figures) 2. These estimates make no allowance for the incident cases that would be likely to be treated with sildenafil initially Costs and resource use Only direct drug acquisition costs are considered in the budget impact analysis. Ambrisentan is the same price as bosentan and sitaxentan 2, which is 1,541 for 28 days based on usual doses Results As only drug acquisition costs are the same for the ERAs, and the budget impact analysis only considers drug acquisition costs, there is estimated to be little or no net cost impact arising from the introduction of ambrisentan in Wales. This assumes that ambrisentan will only replace ERAs as they are currently used and will not be used instead of sildenafil or other PAH treatments. 9.5 Sensitivity analysis No sensitivity analysis was conducted in the budget impact analysis ADDITIONAL INFORMATION 10.1 Guidance and audit requirements Designated by the National Commissioning Group (NCG) (previously known as the National Specialist Commissioning Advisory Group [NSCAG]) since September 2001 there are currently seven centres (six adult and one paediatric centre) in England (none in Wales) that provide UK services for PH. Unlike most NCG services, the service costs of PH for adults continue to be funded by the NHS 30. Ambrisentan should be initiated and monitored by a physician experienced in the treatment of PH at one of the NCG centres across the UK and would therefore not be deemed suitable for shared care. The ERAs are classified as teratogens and hence are contraindicated in pregnancy. As other ERAs, ambrisentan is subject to controlled distribution Related advice National Pulmonary Hypertension Centres of the UK and Ireland: consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland (2008) 7. European Society of Cardiology guidelines on diagnosis and treatment of pulmonary arterial hypertension (2004) 3. Page 17 of 28

18 10.3 Previous AWMSG advice In March 2007 the Minister for Health and Social Services ratified the AWMSG recommendation to support the use of iloprost in NHS Wales (with restrictions) Ongoing studies A long term extension study of ARIES-1 and ARIES-2 is currently on-going. Patients in the trial who received placebo went on to receive ambrisentan. The primary outcome measure of this study is the incidence of and severity of adverse effects associated with long term exposure to ambrisentan in the treatment of PAH 2. A phase IV multicenter double-blind randomised study is currently recruiting patients with PAH who have shown a suboptimal response to sildenafil. Patients will be randomised to receive ambrisentan or placebo as add on therapy to their current sildenafil treatment. The primary outcome is change from baseline in the PVR after 24 weeks Patient organisation information A patient organisation submission by the Pulmonary Hypertension Association was provided to members. Page 18 of 28