Drugs (2014) 74:1495–1507 DOI 10.1007/s40265-014-0266-9

ADIS DRUG EVALUATION

Macitentan: A Review of Its Use in Patients with Pulmonary Arterial Hypertension Sohita Dhillon

Published online: 25 July 2014 Ó Springer International Publishing Switzerland 2014

Abstract Macitentan (OpsumitÒ) is an orally active, dual endothelin receptor antagonist (ERA) with tissue targeting properties. Macitentan was approved recently in the EU (as monotherapy or combination therapy) for the long-term treatment of pulmonary arterial hypertension (PAH) in adults of WHO functional class II or III, and in the USA for the treatment of PAH (WHO group I) to delay disease progression and reduce hospitalization for PAH. This article reviews the pharmacological properties, efficacy and tolerability data relevant to the use of macitentan in this indication. Treatment with macitentan 10 mg once daily significantly reduced the risk for the primary composite endpoint of morbidity and mortality in patients with PAH (mostly WHO functional class II or III) in the large, randomized, placebo-controlled SERAPHIN study. Other efficacy outcomes, including exercise capacity, haemodynamic parameters and health-related quality of life also improved significantly with macitentan relative to placebo. Macitentan was generally well tolerated in this study. As with other ERAs, haemoglobin levels decreased with macitentan therapy; however, these were not progressive and stabilized following longer-term treatment. Although comparative studies are needed to definitively position macitentan with respect to other approved agents, current evidence suggests that macitentan is a useful treatment

option for initial therapy in patients with WHO functional class II or III PAH, which has the potential advantage of once-daily administration.

Macitentan in pulmonary arterial hypertension: a summary A potent, dual ETA/ETB endothelin receptor antagonist Exhibits prolonged receptor binding and increased tissue distribution Reduces the composite of morbidity and mortality in patients with pulmonary arterial hypertension Generally well tolerated in these patients Most common adverse events occurring more frequently than with placebo include upper respiratory tract infection, nasopharyngitis, headache, anaemia and bronchitis

1 Introduction The manuscript was reviewed by: N. Galie, Institute of Cardiology, University of Bologna, Bologna, Italy; L.J. Rubin, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Diego School of Medicine, La Jolla (CA), USA. S. Dhillon (&) Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand e-mail: [email protected]

Pulmonary arterial hypertension (PAH) is a chronic and progressive disease characterized by the presence of precapillary pulmonary hypertension (PH; defined as pulmonary arterial pressure of C25 mmHg, pulmonary wedge pressure of B15 mmHg, and normal or reduced cardiac output) in the absence of other causes of pre-capillary PH (e.g. lung diseases or chronic thromboembolic PH) [1, 2].

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The most recent estimates of PAH in Europe reported an annual incidence of 2.4 cases/million adults in France (in 2002–2003) [3] and 7.6 cases/million population in Scotland (in 1986–2001) [4] PAH (or group 1 PH) can be classified according to its underlying aetiology (Table 1) [5] and severity (Table 2) [1]. The disease results from functional and structural changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance, right ventricular failure and subsequently death [6–8]. Imbalances in three main biological pathways, the prostacyclin, nitric oxide and endothelin (ET)-1 pathways, have been implicated in the pathogenesis of PAH [9]. Current treatment strategies target these pathways and help to re-establish the equilibrium between vasoconstriction and vasodilation, and control abnormal proliferation [8, 10, 11]. Increased levels of ET-1 have been seen in the plasma and pulmonary vascular endothelium of patients with PH, indicating that ET-1 is likely to contribute to the vasodilator/vasoconstrictor imbalance associated with PAH [12– 14]. ET-1 is released mainly from the basal surface of the endothelium and acts largely on the underlying smooth muscle cells, resulting in vasoconstriction and proliferation [9, 15]. In addition, ET-1 acts on the endothelium to induce proliferation, vasodilation and vasoconstriction, and on the fibroblasts to stimulate contraction, proliferation and fibrosis [15]. ET-1 mediates its effects via two receptor subtypes, the ETA receptors (expressed on smooth muscle cells, fibroblasts and cardiac myocytes) and the ETB receptors (expressed predominantly on endothelial cells

Table 1 Updated clinical classification of pulmonary arterial hypertension (Group 1 of pulmonary hypertension; Nice, 2013) [5] 1. PAH 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis 10 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 100 Persistent pulmonary hypertension of the newborn BMPR bone morphogenic protein receptor type II, CAV1 caveolin-1, ENG endoglin, PAH pulmonary arterial hypertension

S. Dhillon

and to a lesser extent on vascular smooth muscle cells, fibroblasts and macrophages) [9, 15]. Endothelin receptor antagonists (ERAs), along with prostanoids (targeting the prostacyclin pathway) and phosphodiesterase-5 (PDE5) inhibitors (targeting the nitric oxide pathway), are the mainstay of current treatment strategies for PAH. Macitentan (OpsumitÒ) (Fig. 1) is a potent, dual ETA/ETB ERA, which was recently approved for the treatment of PAH [16, 17] (Sect. 6). This article reviews the pharmacological properties, efficacy and tolerability data relevant to the use of macitentan in this indication. Data selection details are presented at the end of Sect. 7.

2 Pharmacodynamic Properties Macitentan is a potent inhibitor of ETA receptors (half maximal inhibitory concentration [IC50] of 0.5 nmol/L in an in vitro assay) with significant affinity for ETB receptors (IC50 391 nmol/L) [18, 19]. Its ETA/ETB inhibitory potency ratio was 50:1 in functional assays in isolated organs [19, 20]. The major metabolite of macitentan ACT132577 is also pharmacologically active at these receptors (ETA/ETB inhibitory potency ratio was 16:1) [20] and is &20 % as potent as the parent compound [17]. Compared with other ERAs, the in vitro antagonistic potency (Kb) of macitentan was generally similar to that of ambrisentan (0.14 vs. 0.12 nmol/L) and tenfold higher than that of bosentan (0.14 vs. 1.1 nmol/L) [21]. Macitentan displayed slower receptor dissociation kinetics than ambrisentan and bosentan (receptor occupancy half-life of &17 min vs. &40 and &70 s) and, unlike ambrisentan and bosentan, blocked ET-1 receptor activation across a wide range of ET-1 concentrations [21], suggesting a more complete block of ET-1 binding under conditions of locally fluctuating ET-1 levels [22]. The increased ability of macitentan to block ET-1 receptors was also demonstrated in rat models of hypertension and PH, where the addition of macitentan to bosentan decreased mean arterial BP (in hypertensive rats) and mean pulmonary artery pressure (in rats with PH) to a greater extent than bosentan alone [23]; conversely, add-on treatment with bosentan did not cause any additional decrease in these parameters over the decrease seen with macitentan alone. In vitro, macitentan partitions 40- and 2,000-fold better into lipids than bosentan and ambrisentan, respectively, suggesting stronger affinity for tissue [20]. Indeed, in a rat model of pulmonary fibrosis associated with PAH, radiolabelled macitentan distributed into the parenchyma to a greater extent than radiolabelled bosentan (no quantitative data available) [24]. The ability of macitentan to achieve better blockade of ET-1 receptors and its increased tissue

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Table 2 WHO classification of functional status of patients with pulmonary hypertension (modified from the New York Heart Association functional classification) [1] Class

Description

I

Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope

II

Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope

III

Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope

IV

Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity

O

O N H

S

Br

NH

N N

O N

O N Br

Fig. 1 Chemical structure of macitentan

distribution relative to bosentan are thought to contribute to its efficacy. The key pharmacodynamic effects of macitentan relevant to pulmonary arterial hypertension are summarized in Table 3 and its efficacy in a large clinical study in patients with PAH is discussed in Sect. 4.

3 Pharmacokinetic Properties This section focuses on the pharmacokinetic properties of oral macitentan that have been assessed largely in healthy volunteers. Some data discussed were obtained from the manufacturer’s EU [16] and US [17] prescribing information. In patients with PAH, the exposure to oral macitentan was &1.2-fold higher and the exposure to its major active metabolite ACT-132577 was &1.3-fold higher than that in healthy volunteers [16]. The systemic exposure to ACT132577 in these patients is expected to be three times the exposure to macitentan, and the metabolite is expected to account for &40 % of the pharmacological activity at steady state [17]. The severity of disease does not affect the pharmacokinetics of macitentan in these patients [16]. Oral macitentan was absorbed slowly after single- [25] or multiple-dose [26] administration in healthy volunteers, with peak plasma concentrations (Cmax) reached &8 h after administration [16, 17, 26]. Its pharmacokinetics were dose

proportional over a dose-range of 1 to 30 mg administered once daily for 10 days in healthy volunteers [16, 17, 26], with the steady state of macitentan reached on day 3 and that of ACT-132577 reached on day 7 [26]. After administration of macitentan 10 mg once daily for 10 days in healthy volunteers, the mean Cmax and area under the plasma concentration-time curve values for macitentan were 371 ng/mL and 5,400 ngh/mL, respectively, and those for ACT-132577 were 802 ng/mL and 15,541 ngh/ mL [26]. At steady state, macitentan did not accumulate to a great extent (&1.5-fold), but there was significant accumulation of ACT-132577 (&8.5-fold) [26, 27] The estimated oral bioavailability of macitentan is 74 % [27]. The exposure to macitentan and ACT-132577 was not altered when macitentan was administered with or without food in healthy volunteers [16, 17]; therefore, macitentan may be taken without regard to food. The pharmacokinetic/pharmacodynamic relationship between steady-state macitentan trough concentrations and efficacy and safety parameters was assessed in an analysis [28] of data from the pivotal clinical study in patients with PAH (see Sect. 4) [29]. Results showed that macitentan improved haemodynamic parameters and functional exercise capacity in a concentration-dependent manner; however, no clear relationship was seen between safety parameters and the trough concentrations of macitentan [28]. Macitentan and ACT-132577 are highly plasma protein bound ([99 %), largely to albumin and to a lesser extent to a1-acid glycoprotein [16, 17]; both the parent compound and the active metabolite poorly bind to and penetrate into erythrocytes [30]. Macitentan and ACT-132577 are well distributed into tissues [16], with apparent volumes of distribution of &50 and &40 L, respectively, in healthy volunteers [16, 17]. Macitentan is metabolized largely by oxidative depropylation of the sulfamide to its metabolite ACT-132577 [30], with the reaction mediated primarily (&99 %) by cytochrome P450 (CYP) 3A4 [16, 17] and minor contributions by CYP2C8, CYP2C9 and CYP2C19 [16].

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Table 3 Pharmacodynamic effects of macitentan relevant to pulmonary arterial hypertension In vitro and animal studies Increased plasma ET-l levels in normotensive rats and was more potent than bosentan in this regard (the increase from baseline in ET-1 plasma levels was achieved with a 10-fold lower dose of macitentan than bosentan) [20] Macitentan and its major metabolite (ACT-132577) inhibited ET-1-mediated deleterious effects in in vitro functional assays (e.g. inhibited ETA receptor-mediated contraction of isolated rat aorta and ETB receptor-mediated contraction of isolated rat trachea) [20] Chronic administration of macitentan prevented the development of PH and right ventricle hypertrophy at a 10-times lower dose than bosentan in a rat model of PH; survival was also improved with macitentan in this model [20] Macitentan attenuated the progression of PH with angioproliferative occlusive lesions in a rat model of PAH, suggesting that its beneficial effects on PH may be mediated by preventing arteriopathy [57] Like bosentan, macitentan dose-dependently increased mean arterial BP, but did not affect heart rate in hypertensive rats [20] Human studies Dose-dependently decreased plasma ET-l levels in healthy volunteers [25, 26]; at steady state (day 10), the maximum effect on ET-1 levels (twofold increase from baseline) was seen with a macitentan dosage of 10 mg/day [26] Generally did not affect serum total bile salt levels in healthy volunteers [25, 26], suggesting an improved safety profile compared with other ET-1 receptor antagonists Macitentan 10 mg od for a median of 115 months delayed disease progression in patients with PAH [29] (see Sect. 4) There was no evidence of prolonged cardiac repolarization or other ECG changes with therapeutic (10 mg od) or supratherapeutic dosages (30 mg od) of macitentan in healthy volunteers in a thorough corrected QT study in healthy volunteers [58] ET-1 endothelin-1, PAH pulmonary arterial hypertension, od once daily, PH pulmonary hypertension

Macitentan is excreted largely via the kidneys, with &50 % of a radiolabelled dose recovered in the urine [16, 17, 30] (none in the form of unchanged drug or as ACT132577) and 24 % of the dose recovered in the faeces [17, 30]. The apparent elimination half-life of macitentan was &16 h and that of ACT-132577 was &48 h [16, 17]. 3.1 Special Populations Age, sex and ethnicity do not affect the pharmacokinetics of macitentan and ACT-132577 to a clinically relevant extent [16, 17]. There were no clinically relevant differences in the pharmacokinetics of macitentan between Caucasian and Japanese healthy volunteers [31]. The effects of severe renal impairment (creatinine clearance 15–29 mL/min) and mild, moderate or severe hepatic impairment (Child-Pugh class A, B and C) on the pharmacokinetics of macitentan and ACT-132577 were not considered clinically relevant, according to pharmacokinetic data in patients who did not have PAH and, therefore, no dosage adjustment is required [16, 17, 32]. However, no studies have evaluated the pharmacokinetics of macitentan in patients with PAH who have moderate or severe hepatic impairment or severe renal impairment [16]. Consequently, in the EU, its use is contraindicated in patients with PAH who have severe hepatic impairment (with or without cirrhosis) and in patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels[3 times the upper limit of normal (ULN) at baseline [16]; macitentan is also not recommended in patients with PAH and moderate hepatic impairment and in patients undergoing dialysis [16].

3.2 Potential Drug Interactions In in vitro studies, macitentan and ACT-132577 did not have clinically relevant inhibitory or inducing effects on CYP enzymes [16, 17]. Macitentan and ACT-132577 also did not inhibit hepatic or renal transporters [including organic anion transporting polypeptide (OATP) 1B1 and OATP1B3], and hepatic or renal efflux pumps [including P-glycoprotein (P-gp)/multidrug resistance protein-1 (MDR-1), and multidrug and toxin extrusion transporters 1 and 2K], and did not interact with proteins involved in hepatic bile transport [i.e. bile salt export pump (BSEP) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP)] at clinically relevant concentrations. Macitentan and ACT-132577 are not relevant substrates of OAT1B1, OAT1B3, OATP2B1 and NTCP, but enter the liver by passive diffusion [16, 17, 33]; macitentan is also not a substrate of P-gp/MDR-1 [16, 17]. In vitro macitentan inhibits the breast cancer resistance protein at clinically relevant intestinal concentrations [16, 17]. See also Sect. 7 for further discussion of drug-drug interactions. Studies in healthy volunteers showed that the concomitant use of macitentan with strong CYP3A4 inhibitors (e.g. ketoconazole) approximately doubles the exposure to macitentan [17, 34]; therefore, the concomitant use of macitentan and strong CYP3A4 inhibitors (e.g. antiretroviral drugs such as ritonavir) should be avoided [17] or caution should be exercised when these agents are coadministered [16]. Strong inducers of CYP3A4 [e.g. rifampicin (rifampin)] significantly reduce macitentan exposure when coadministered [17, 35]; consequently, coadministration of macitentan with these agents should be avoided [16, 17].

Macitentan: A Review

The pharmacokinetics of macitentan and sildenafil were not altered to a clinically relevant extent when the two drugs were used concomitantly in healthy volunteers [16, 17, 36]; therefore, no dosage adjustment is required [17]. Macitentan administered concomitantly with warfarin did not alter the exposure to R- (CYP3A4 substrate) and S(CYP2C9 substrate) warfarin or alter the pharmacodynamic effect of warfarin on the international normalized ratio in healthy volunteers [16, 17, 37]; the pharmacokinetics of macitentan and ACT-132577 were also not significantly affected [16, 37]. Coadministration of macitentan with cyclosporine A (CYP3A4 and OATP inhibitor) in healthy volunteers did not alter the steadystate exposure to macitentan and ACT-132577 to a clinically relevant extent [16, 35]; therefore, no dosage adjustment is required [17].

4 Therapeutic Efficacy The efficacy of oral macitentan was evaluated in the randomized, double-blind, multicentre, placebo-controlled, event-driven SERAPHIN study (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) [29]. Discussed here are data relevant to the approved dosage of macitentan 10 mg once daily; results pertaining to a lower dosage of macitentan (3 mg once daily) are tabulated for completeness, but are not discussed further. Some data are available only as abstract presentations [38–43]. The SERAPHIN study included patients aged C12 years who had idiopathic or heritable PAH, or PAH related to connective-tissue disease, repaired congenital systemic-to-pulmonary shunts, HIV infection or drug use/ toxin [29]. Patients were required to have a confirmed diagnosis of PAH (using right heart catheterization), a 6-min walk distance of C50 m and WHO functional class II–IV disease. Patients were eligible regardless of whether they were receiving background therapy for PAH; concomitant treatment with stable-dose oral PDE5 inhibitors, oral or inhaled prostanoids, calcium-channel antagonists or L-arginine was permitted. Exclusion criteria included treatment with intravenous or subcutaneous prostanoids [29]. Patients (n = 742) were randomized to receive macitentan 3 or 10 mg once daily or placebo until study end, which was declared when a predefined number (n = 285) of events had occurred [29]. Patients who discontinued double-blind therapy because of a nonfatal primary endpoint event, as well as those who received double-blind treatment until study end, were eligible to receive openlabel macitentan 10 mg once daily in an extension study. The mean duration of double-blind treatment in the

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macitentan 3 and 10 mg groups and the placebo group was 99.5, 103.9 and 85.3 weeks, respectively [29]. The composite primary endpoint was the time from the initiation of therapy to the occurrence of the first PAHrelated event (i.e. worsening of PAH, initiation of treatment with intravenous or subcutaneous prostanoids, lung transplantation or atrial septostomy) or death from any cause up to the end of treatment (see Table 4 for further definitions) [29]. At baseline, the mean age of patients was &46 years, the mean duration of disease was 2.7 years and &77 % of patients were female [29]. Patients had idiopathic (55 %) or heritable (2 %) PAH, or PAH associated with connective-tissue disorders (31 %), congenital shunts (8 %), drug use/toxin exposure (3 %) or HIV infection (1 %) [29]. Approximately 52, 46 and 2 % of patients were in WHO functional class II, III and IV, respectively; one patient (0.1 %) in WHO functional class I was erroneously included in the study [29]. Sixty-four percent of patients were receiving background therapy for PAH (61 % PDE5 inhibitors and 5 % oral or inhaled prostanoids); 51 % of patients were receiving anticoagulant therapy [29]. The three treatment groups were generally well-balanced in terms of demographic and disease activity/health status characteristics [44]. 4.1 Morbidity and Mortality Macitentan 10 mg once daily was effective in delaying disease progression in patients with PAH [29]. Over a median double-blind treatment duration of 115 weeks (up to a maximum of 188 weeks of macitentan [16, 17]), macitentan significantly reduced mortality and morbidity relative to placebo, as indicated by a 45 % reduction in the risk of experiencing a primary composite endpoint event, with the treatment effect largely attributable to a reduction in clinical worsening events (Table 4). These data were supported by sensitivity analyses of the primary endpoint undertaken to account for premature treatment discontinuation, with results demonstrating significant (p \ 0.01) benefit with macitentan over placebo [29]. Kaplan–Meier estimates of the primary endpoint showed that the macitentan versus placebo treatment effect was established early and sustained over the course of treatment (median duration of [2 years) [16, 44]. The number needed to treat to avoid one primary endpoint event at 2 years was estimated as six patients [44]. Macitentan treatment also significantly reduced the risk of PAH-related death or hospitalization (secondary composite endpoint event) by 50 % relative to placebo (Table 4), with a reduction in the rate of hospitalization accounting for the majority of the treatment effect [29]. In addition, macitentan recipients experienced significant

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Table 4 Efficacy of oral macitentan once daily in patients with pulmonary arterial hypertension in the SERAPHIN study [29] Outcome

Incidence (% of pts) [HR; 97.5 % CI] MAC 3 mg (n = 250)

MAC 10 mg (n = 242)

PL (n = 250)

38.0*

31.4**

46.4

Primary endpoint Composite of first event related to PAH or death from any cause All events

[0.70; 0.52–0.96]

[0.55; 0.32–0.76]

Worsening of PAHa

28.8

24.4

Death from any cause

8.4

6.6

6.8

Prostanoid initiation Lung transplantation

0.4 0.4

0.4 0

2.4 0

33.6

37.2

Secondary endpoints Death due to PAH or hospitalization due to PAH as the first event All events

26.0*

20.7**

[0.67; 0.46–0.97]

[0.50; 0.34–0.75]

Hospitalization for PAH

22.4

18.6

31.6

Death due to PAH

3.6

2.1

2.0

Death from any cause

8.4

5.8

7.6

[0.97; 0.48–1.98]

[0.64; 0.29–1.42]

Death due to PAHb

5.6

2.9

[0.87; 0.37–2.04]

[0.44; 0.16–1.25]

18.8

14.5

[1.05; 0.65–1.67]

[0.77; 0.46–1.28]

Death from any cause by study endc

5.6 17.6

Results are for the intent-to-treat population. Unless otherwise specified, outcomes were evaluated at the end of the double-blind period (median duration of treatment 115 weeks) BL baseline, HR hazard ratio (MAC vs. PL), MAC macitentan, PAH pulmonary arterial hypertension, PL placebo, pts patients * p = 0.01, ** p \ 0.001 vs. PL a

Defined as the occurrence of all of the following: a C15 % decrease from BL in the 6-min walk distance (confirmed by a second 6-min walk test performed on a different day within 2 weeks); worsening of symptoms of PAH; and the need for additional treatment for PAH. Worsening of symptoms of PAH included C1 of the following: a change from BL to a higher WHO functional class (or no change in patients who were in WHO functional class IV at BL) and the appearance or worsening of signs of right heart failure that did not respond to oral diuretic therapy

b

Including deaths that occurred during the double-blind period or deaths that occurred within 4 weeks after the end of treatment, after a confirmed worsening of PAH

c

Included pts who were eligible to receive other treatments for PAH, including open-label MAC 10 mg (median duration of follow-up 129 weeks)

reductions in the annual rate of PAH-related hospitalizations (treatment effect ratio 0.45; 95 % CI 0.30–0.69; p = 0.0002) [38], the annual rate of inpatient hospital days (treatment effect ratio 0.48; 95 % CI 0.24–0.97; p = 0.042) [38], the annual rate of all-cause hospitalization (27.7 vs. 41.5 hospitalizations per 100 patient-years; p = 0.0005) [41] and the risk of all-cause hospitalization [hazard ratio (HR) 0.677; 95 % CI 0.514–0.891; p = 0.0051] [41] relative to placebo. Other outcomes, including the incidences of all-cause death and death because of PAH did not differ significantly between macitentan and placebo recipients (Table 4) [29]. The lack of a significant treatment effect in terms of mortality outcomes is not unexpected, as PAH is a progressive disease and clinical deterioration is likely to precede death [29].

4.2 Symptomatic Endpoints and Health-Related Quality of Life At 6 months, macitentan 10 mg once daily significantly improved the 6-min walk distance by 22 m relative to placebo (Table 5) [29], with significant improvements seen by month 3 and maintained for the duration of the study [17]. When patients were stratified according to background PAH therapy and WHO functional class at baseline, significant improvements in 6-min walk distance were seen with macitentan relative to placebo in patients receiving background therapy and in those with worse functional class (i.e. class III or IV; Table 5) [29]. In addition, WHO functional class improved from baseline to month 6 in significantly (p = 0.006) more macitentan than placebo recipients (22 vs. 13 %) [29],

Macitentan: A Review

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which translates to a 74 % higher chance of experiencing improvement in this outcome (macitentan vs. placebo risk ratio 1.74; 97.5 % CI 1.10–2.74) [16]. Health-related quality of life (HR-QOL) also improved with macitentan therapy, as assessed by the Short-Form 36 health survey (SF-36) [39]. Macitentan recipients had significant improvements in the SF-36 physical component summary (PCS) scores at months 6 (treatment effect 3.0; 95 % CI 1.5–4.5) and 12 (treatment effect 2.4; 95 % CI 0.9–4.0) and in the SF-36 mental component summary (MCS) scores at months 6 (treatment effect 3.4; 95 % CI 1.2–5.6) and 12 (treatment effect 2.6; 95 % CI 0.2–4.9). Moreover, macitentan therapy significantly reduced the risk of deterioration of physical function, as assessed by the time to a C5-point decrease in the SF-36 PCS scores from baseline to the end of treatment (HR 0.65; 95 % CI 0.50–0.85; p = 0.001); the HR for a similar deterioration in SF-36 MCS scores was 0.79 (95 % CI 0.61–1.01) [39]. 4.3 Haemodynamic Endpoints A haemodynamic sub-study of SERAPHIN involving patients who had right heart catheterization at baseline and month 6 (n = 145 evaluable) showed that macitentan 10 mg once daily treatment significantly reduced pulmonary vascular resistance (38.5 % decrease in the fold-change from baseline) and significantly increased cardiac index (by 0.63 L/min/m2) at 6 months relative to placebo (Table 6) [29], with the benefit of treatment seen regardless

of background PAH therapy or WHO functional class at baseline [40]. 4.4 Other Analyses Subgroup analyses of the primary composite endpoint suggested that macitentan therapy was beneficial across a broad range of subgroups (based on sex, race, PAH therapies at baseline, PAH aetiology and geographical regions), as there were no significant subgroup-by-treatment interactions [29]. For example, the risk of experiencing a primary composite endpoint event was significantly (p \ 0.01) reduced with macitentan relative to placebo both in patients with (HR 0.62; 95 % CI 0.43–0.89) and in those without (HR 0.45; 95 % CI 0.28–0.72) background therapy at baseline (p-value for interaction 0.24) [29]. Moreover, the benefit of macitentan therapy was observed regardless of WHO functional class at baseline, with the risk of experiencing a primary composite endpoint event reduced to a significantly greater extent with macitentan than with placebo in patients who were WHO functional class I/II (n = 251; HR 0.58; 95 % CI 0.35–0.95), as well as in those of functional class III/IV (n = 241; HR 0.49; 95 % CI 0.35–0.71) (p-value for interaction = 0.64) [42]. The risk of PAH-related death or hospitalization was also reduced with macitentan relative to placebo regardless of WHO functional class at baseline (p-value for interaction = 0.60) [42].

Table 5 Effect of oral macitentan once daily on 6-min walk distance (m) in patients with pulmonary arterial hypertension in SERAPHIN [29] Population

No. of pts

Meana change from baseline to month 6 (baseline value) [treatment effect vs. PL; 97.5 % CI] MAC 3 mg

MAC 10 mg

7.4*(364)

12.5** (363)

[16.8; -2.7 to 36.4]

[22.0; 3.2 to 40.4]

163/154/154

9.8 (367)

17.9* (364)

No

85/88/95

[17.9; -5.0 to 40.8] 2.9 (358)

[25.9; 4.5 to 47.3] 3.1 (360)

[17.3; -19.2 to 53.8]

[17.8; -17.8 to 53.3]

I/II

138/121/129

2.4 (400)

8.5 (403)

[6.3; -19.0 to 31.6]

[12.3; -8.1 to 32.7]

13.7* (319)

16.5* (322)

[32.8; 2.4 to 63.1]

[37.0; 5.4 to 68.6]

248/242/249

Overall

PL -9.4 (352)

Subgroups Background PAH therapy:

WHO functional class:

Yes

III/IV

110/121/120

-7.8 (360) -12.2 (340) -3.9 (400) -15.4 (301)

MAC Macitentan, PAH pulmonary arterial hypertension, PL placebo, pts patients * p \ 0.05, **p \ 0.01 vs. PL a

Reported are the mean values (unadjusted for baseline 6-min walk distance) for the overall population and least squares mean values (adjusted for baseline 6-min walk distance) for the subgroups

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Table 6 Effect of oral macitentan once daily on haemodynamic parameters in patients with pulmonary arterial hypertension in a sub-study of SERAPHIN [29] Outcome

PVRb CInb

Measurea

Treatment MAC 3 mg (n =47)

MAC 10 mg (n = 48)

PL (n = 50)

Ratio of month 6/BL (%)

76.9

71.3

115.8

[treatment effect vs. PL; 97.5 % CI]

[66.4; 56.6–77.8]

[61.5; 51.0–74.3]

Change from BL (L/min/m2)

0.36

0.30

[treatment effect vs. PL; 97.5 % CI]

[0.69; 0.40–0.97]

[0.63; 0.28–0.97]

-0.33

BL baseline, CIn cardiac index, MAC macitentan, PL placebo, PVR pulmonary vascular resistance a

Geometric mean values for PVR and arithmetic mean values for CIn

b

Baseline values in the MAC 3 mg, MAC 10 mg and PL groups were 945, 907 and 886 dynessec/cm5 for PVR and 2.34, 2.63 and 2.54 L/min/ m for CIn 2

5 Tolerability The tolerability data for oral macitentan were obtained from the SERAPHIN study discussed in Sect. 4 and supplemented with data from the US [17] and EU [16] manufacturer’s prescribing information. The discussion in this section focuses on the approved dosage of 10 mg once daily; adverse event rates in patients receiving a lower dosage of macitentan (3 mg once daily) are presented in the figure, but not discussed further. The safety of macitentan was assessed during double-blind treatment (median 115 weeks) in the safety population (which excluded one patient in the placebo group who did not receive study drug) and up to 28 days after discontinuation of therapy [29, 44]. Oral macitentan 10 mg once daily was generally well tolerated in patients with PAH and had a tolerability profile generally similar to that of placebo. During double-blind treatment, adverse events occurred in 94.6 and 96.4 % of patients in the macitentan and placebo groups and serious adverse events were reported in 45.0 and 55.0 % of patients, respectively [29]. Adverse event-related withdrawal rates

during this period were 10.7 and 12.4 % in the respective groups [29]. The most common adverse event that occurred more frequently with macitentan than placebo was upper respiratory tract infection (Fig. 2). Numerically fewer macitentan than placebo recipients had worsening of PAH (21.9 vs. 34.9 %) or right ventricular failure (13.2 vs. 22.5 %); it should be noted that the majority of these events were also reported as primary efficacy endpoint events [29]. The incidence of peripheral oedema, a known safety concern with ERAs and also a clinical manifestation of right heart failure and underlying PAH disease, was similar between the macitentan and placebo groups (18.2 vs. 18.1 %) [29]. After adjusting on the basis of patient years [44], oedema/fluid retention occurred at an incidence of 11.0 events/100 patient-years in macitentan recipients compared with 12.5 events/100 patient-years in placebo recipients [16]. Cases of oedema have been reported in patients with pulmonary veno-occlusive disease who were receiving vasodilators (mainly prostacyclins); therefore, Macitentan 3 mg (n = 250)

25.0

Incidence ( % of patients)

In addition, a subgroup analysis of patients who were not receiving PAH-specific background therapy (i.e. treatment-naı¨ve patients) showed that macitentan treatment benefitted newly diagnosed (B6 months between diagnosis and study entry) as well as prevalent ([6 months between diagnosis and study entry) patients with PAH [43]. The risk of experiencing a primary composite endpoint event was reduced significantly both in the incident (HR 0.40; 95 % CI 0.20–0.79) and in the prevalent (HR 0.47; 95 % CI 0.24–0.91) group. Significant reductions in the risk of PAH-related death or hospitalization in the incident (HR 0.22; 95 % CI 0.09–0.57) and in the prevalent (HR 0.38; 95 % CI 0.16–0.92) groups were also seen with macitentan therapy relative to placebo [43].

Macitentan 10 mg (n = 242) Placebo (n = 249)

20.0

15.0

10.0

5.0

0.0 URTI

Nasopharyngitis

Headache

Anaemia

Bronchitis

Fig. 2 Tolerability of oral macitentan once daily in patients with pulmonary arterial hypertension in the SERAPHIN trial [29]. The most common adverse events occurring at least 2 % more frequently with macitentan than with placebo during double-blind treatment (median 115 weeks) and up to 28 days after discontinuation of therapy. URTI upper respiratory tract infection

Macitentan: A Review

the possibility of veno-occlusive disease should be considered if signs of pulmonary oedema develop in patients with PAH who are being treated with macitentan [16]. PAH and treatment with ERAs has been associated with elevations of ALT or AST levels [16]. During double-blind treatment in SERAPHIN, 3.4 % of macitentan compared with 4.5 % of placebo recipients had ALT or AST levels of [3 times the ULN [29], 2.1 and 0.4 % of patients in the respective groups had ALT or AST levels of [8 times the ULN [17], and 1.7 % of patients in each group had ALT or AST levels of [3 times the ULN and bilirubin levels of [2 times the ULN [29]. Hepatic adverse events resulted in treatment discontinuation in 3.3 % of macitentan and 1.6 % of placebo recipients [17]. Therefore, it is recommended that liver enzyme tests be conducted prior to initiating macitentan treatment and patients be monitored during treatment as clinically indicated for elevations of ALT and AST, and for signs and symptoms of hepatic injury [16, 17]. Macitentan therapy should be discontinued if patients exhibit sustained, unexplained, clinically relevant elevations in aminotransferase levels, have elevated aminotransferase levels along with an increase in bilirubin levels of[2 times the ULN, or exhibit clinical symptoms of liver injury [16, 17]; treatment may be reinitiated after the hepatic enzyme levels have returned to within the normal range. Macitentan, like other ERAs, has also been associated with a decrease in haemoglobin levels [16, 17]. During double-blind treatment in SERAPHIN, haemoglobin levels of B8 g/dL were reported in 4.3 % of macitentan and 0.4 % of placebo recipients [29], and 8.7 and 3.4 % of patients in the respective groups had haemoglobin levels of \10 g/dL [16, 17]; one patient in each group discontinued therapy because of anaemia [29]. The decrease in haemoglobin levels with macitentan was not progressive, stabilized after the first 4–12 weeks of therapy and remained stable during chronic treatment [16, 17]; patients seldom require transfusions for decreases in haemoglobin levels [17]. It is recommended that haemoglobin levels be measured prior to and during treatment as clinically indicated, with the initiation of macitentan therapy not recommended in patients with severe anaemia [16, 17]. Of the other adverse events considered to be of special interest (based on experience with other ERAs) [44], hypotension occurred in 7.0 % of macitentan compared with 4.4 % of placebo recipients (3.5 vs. 2.7 events/100 patient-years) during double-blind treatment in SERAPHIN [16].

6 Dosage and Administration In the EU, oral macitentan as monotherapy or combination therapy is indicated for the long-term treatment of PAH in

1503

adults of WHO functional class II or III [16]. In the USA, oral macitentan is indicated for the treatment of PAH (WHO group I) to delay disease progression and reduce hospitalization for PAH [17]. The recommended dosage of oral macitentan is 10 mg once daily, with or without food [16, 17]. The use of macitentan may be associated with elevations of liver aminotransferases (ALT or AST) and a decrease in haemoglobin levels (Sect. 5); therefore, patients should be monitored prior to and during treatment as clinically indicated [16, 17]. No dosage adjustment is required in elderly patients aged [65 years; however, caution is advised in patients aged [75 years, as data are limited in these patients [16]. As macitentan may cause foetal harm, its use is contraindicated in pregnant [16, 17] or breast feeding women and in women of child bearing potential who are not using reliable contraception [16]. The US prescribing information carries a boxed warning regarding embryo-foetal toxicity of macitentan [17]. Recommendations regarding the use of macitentan in other special populations and the coadministration of macitentan with other drugs are discussed in Sect. 3. Local prescribing information should be consulted for comprehensive information on dosage adjustments, contraindications, warnings and precautions.

7 Place of Macitentan in the Management of Pulmonary Arterial Hypertension PAH is a chronic, incurable disease and the aim of therapy is to manage symptoms, ultimately prolonging patient survival and improving HR-QOL [1, 45]. Important treatment goals in these patients include enhancing functional capacity (as assessed by exercise endurance, such as the 6-min walk distance), lowering pulmonary artery pressure, normalizing cardiac output, and reversing or preventing progression of disease [45]. Optimal therapy is highly individualized and dependent on several factors, including the severity of disease, route of administration, adverse events and treatment goals, as well as the survival prognosis, which is crucial for planning appropriate therapy [1, 45]. The evaluative process for a patient with suspected PH includes confirmation of the diagnosis (with right heart catheterization mandatory for patients with PAH), determining the clinical group of PH and the aetiology within the PAH group, and the assessment of functional and haemodynamic impairment [1, 45]. The suggested initial approach to the management of PAH includes the adoption of general measures, initiation of supportive therapy and referral to an expert centre [1, 45]. Acute vasoreactivity

1504

testing, preferably with inhaled nitric oxide, is required for patients with PAH, particularly in those with idiopathic PAH [1, 45, 46]. According to the latest treatment algorithm [46], patients with vasoreactive PAH of WHO functional class I– III should be treated with high and optimally tolerated doses of calcium-channel antagonists. For patients who are not vasoreactive or are vasoreactive but do not respond adequately to calcium-channel antagonists, ERAs, prostanoids and PDE5 inhibitors are recommended as initial therapy (Table 7). Monotherapy with oral agents (e.g. ERAs and PDE5 inhibitors) should be considered for nonvasoreactive patients with WHO functional class II PAH, while non-vasoreactive patients or vasoreactive patients who remain in (or progress to) WHO functional class III PAH can receive any of the approved agents (Table 7). Continuous intravenous epoprostenol is recommended as first-line treatment in patients with WHO functional class IV PAH [46], owing to the survival benefit seen in these patients [47]. In addition, initial combination therapy may be considered in patients with WHO functional class III or IV PAH [46]. Patients with inadequate clinical response (based on parameters such as WHO functional class and exercise capacity) after 3–6 months of initial therapy should be considered for sequential combination therapy with two or more drug classes [46]. Patients who have inadequate response despite maximal combination therapy should be referred for lung transplantation; balloon arterial septostomy can be undertaken in these patients as a palliative or bridging procedure [46]. Macitentan, is a dual ETA/ETB ERA approved recently for the treatment of PAH [16, 17]. It is a derivative of bosentan designed (in a medicinal chemistry program) to enhance tissue distribution and to optimize efficacy and safety [18, 20]. Macitentan exhibits prolonged receptor binding and increased tissue distribution in in vitro and animal studies (Sect. 2). Like ambrisentan, which has an elimination half-life of &14–17 h [48], macitentan has a long elimination half-life (Sect. 3) that allows for oncedaily dosing, whereas bosentan with a shorter half-life (&5 h [49]) is administered twice daily. In vitro studies show that macitentan has similar or higher potency for the induction and inhibition of drugmetabolizing enzymes (CYP3A4 and CYP2C19) and transporters (e.g. P-gp) than bosentan [50]. However, because of the low plasma (&0.63 lmol/L) and free (&2.5 nmol/L) steady-state concentrations of macitentan at therapeutic dosages (10 mg/day) [35], it is unlikely to inhibit these enzymes and transporters [50]. Indeed, in vitro and clinical studies did not show a relevant effect of

S. Dhillon

macitentan on CYP enzymes or transporters (Sect. 3.2). Of note, coadministration of macitentan and sildenafil did not alter the pharmacokinetics of either agent to a clinically significant extent [36], which is important as combination treatment with drugs of different classes may benefit patients who respond inadequately to monotherapy. Ambrisentan also has a low potential for drug interactions, as it does not inhibit or induce phase I or II drug metabolizing enzymes at clinically relevant concentrations [48]. In vitro studies also show that unlike bosentan which is actively transported by OATP transporters, macitentan because of its increased lipophilicity enters the liver by passive diffusion, resulting in low intrahepatic macitentan concentrations and limiting its interaction with NTCP and BSEP transport proteins involved in hepatic bile homeostasis [33, 35, 50]. Indeed in healthy volunteers, multipledose administration of macitentan did not affect serum total bile salt levels to a significant extent [26]. Results also indicate that macitentan does not accumulate in hepatocytes [33]; although there is significant partitioning of the drug into human hepatocytes in vitro [33, 51] (probably because of the increased lipophilicity of the drug), the drug is highly bound, with the free fraction being only &0.1 % [33]. The clinical efficacy of macitentan was demonstrated in the randomized, placebo-controlled SERAPHIN study [29]. This is the first large-scale, event-driven study of ERAs to assess the composite of morbidity and mortality as a primary endpoint [22, 29], unlike previous ERA trials that had assessed short-term outcomes, such as 6-min walk distance and WHO functional class [52, 53]. SERAPHIN enrolled a broad PAH patient population, including patients with different aetiologies, WHO functional classes and background therapy [44]. Results showed that treatment with oral macitentan 10 mg once daily for a median of 115 weeks significantly reduced morbidity and mortality, as assessed by the primary composite endpoint, in patients with PAH (mostly of WHO functional class II or III), with the treatment effect largely attributable to a reduction in clinical worsening events (Sect. 4.1). Significant improvements with macitentan were also seen in other outcomes, including the rate of PAH-related death or hospitalization, the 6-min walk distance, WHO functional class, haemodynamic parameters, as well as HR-QOL (Sect. 4). Moreover, subgroup analyses suggested the benefit of macitentan therapy across a broad range of subgroups, including in patients who were or were not receiving background PAH therapy (Sect. 4.4). Macitentan was generally well tolerated in patients with PAH and had a tolerability profile generally similar to that of placebo (Sect. 5); the most common adverse event that

Macitentan: A Review

1505

Table 7 Pharmacological treatment options recommended as initial therapy in patients with pulmonary arterial hypertension who are not vasoreactive or are vasoreactive but do not respond to calcium-channel antagonists [46] Druga

Route of admin

Mechanism of action

WHO-FC IIb

IIIb

IV

Targeting the ET-1 pathway Ambrisentan

po

ETA receptor antagonist

c

Bosentan Macitentan

po po

ETA and ETB receptor antagonist ETA and ETB receptor antagonist

c

Targeting the nitric oxide pathway Riociguat

po

sGC stimulator

Sildenafil

po

Selective PDE5 inhibitor

Tadalafil

po

Selective PDE5 inhibitor

c

Targeting the prostacyclin pathway Beraprost

po

Prostacyclin analogue

Epoprostenol

iv

Prostacyclin analogue

Iloprost

inhaled, iv

Prostacyclin analogue

Treprostinil

sc, iv, inhaled

Prostacyclin analogue

(first-line option)

Admin administration, ET endothelin, iv intravenous, PDE5 phosphodiesterase-5, po oral, pts patients, sc subcutaneous, sGC soluble guanylate cyclase, WHO-FC World Health Organization functional class a

Not all agents/formulations are currently approved for use in all markets (e.g. inhaled and po treprostinil approved only in the USA; iv iloprost approved only in New Zealand; beraprost approved only in Japan and South Korea)

b

Non-vasoreactive pts in WHO-FC II should be treated with an oral agent; non-vasoreactive pts or vasoreactive pts who remain in (or progress to) WHO-FC III can receive any of the approved agents

c

Randomized clinical trials of ambrisentan, bosentan and sildenafil included only a small number of pts classified as WHO-FC IV; therefore, these agents are generally considered as second-line options

occurred more frequently with macitentan than placebo was upper respiratory tract infection. The incidences of peripheral oedema and elevations in liver enzyme levels of [3 times the ULN (class effects) were similar between macitentan and placebo recipients (Sect. 5). However, the incidence of ALT or AST elevations of [8 times the ULN was several fold higher in macitentan than placebo recipients (Sect. 5). Macitentan, like other ERAs, was associated with a decrease in haemoglobin levels, which were not progressive and stabilized following longer-term treatment (Sect. 5). Based on its efficacy and tolerability in SERAPHIN, macitentan has been included in the latest PAH treatment algorithm as an option for initial therapy in patients of WHO functional class II or III, and as a second-line option for patients of WHO functional class IV [46] (Table 7). Currently there are no direct head-to-head comparisons between macitentan and other drugs approved for use in PAH, and such comparative studies would help to definitively position macitentan with respect to these agents. Additional longer-term data would also help to further establish its efficacy and safety. In addition to its use in PAH, macitentan is also being evaluated in several phase I–III trials in other indications,

including in patients with Eisenmenger’s syndrome (MAESTRO; NCT01743001), glioblastoma (NCT01499251), PH due to ventricular dysfunction (MELODY-1; NCT02070991) or inoperable chronic thromboembolic PH (MERIT-1; NCT02021292). Macitentan was evaluated in the DUAL 1 (NCT01474109) and DUAL 2 (NCT01474122) studies in patients with ischemic digital ulcers secondary to systemic scleroderma, and while the DUAL 1 study was completed as planned, the DUAL 2 study was terminated as the independent data monitoring committee determined that although there were no unexpected safety findings, additional data were unlikely to result in a positive primary endpoint [54]. Macitentan was also assessed for use in patients with idiopathic pulmonary fibrosis in the MUSIC (NCT00903331) trial, but the primary endpoint (change in forced vital capacity relative to placebo) of the study was not met [55] and further investigation in this indication was discontinued [56]. To conclude, macitentan significantly reduced mortality and morbidity, and was generally well tolerated in patients with PAH in the SERAPHIN study. Although comparative studies and additional long-term data would help to further establish its efficacy and safety, current evidence suggests that macitentan is a useful treatment option for initial therapy in patients with WHO functional class II or III

1506

PAH, which has the potential advantage of once daily administration. Data selection sources: Relevant medical literature (including published and unpublished data) on macitentan was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 2 July 2014], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Macitentan, pulmonary arterial hypertension, pulmonary hypertension, hypertension, pulmonary, PAH. Study selection: Studies in patients with pulmonary arterial hypertension who received macitentan. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Sohita Dhillon is a salaried employee of Adis/Springer.

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