Endothelin receptor antagonists in PAH

Pulmonary arterial hypertension (PAH) has been transformed in the last ten years from a poorly understood condition with median survival of less than three years from diagnosis1 to a condition with a clearly defined diagnostic and treatment pathway and a range of targeted treatments(2) that have greatly prolonged survival.(1) This article will examine one class of targeted therapy – the endothelin (ET) receptor antagonists (ERAs).

PAH is one of six major clinical subcategories of pulmonary hypertension (Table 1). This group, Group 1, although diverse, shares a common pathological appearance and response to PAH-specific treatments.(2)

Multiple biochemical pathways are involved in the triggering of PAH; intimal proliferation and remodelling of the pulmonary vessel wall reduce pulmonary vascular calibre. Endothelial dysfunction leads to reduced production of vasodilating, anti-proliferative nitric oxide (NO) and prostacyclin and overproduction of the vasoconstrictor and proliferative agents, thromboxane A2 and endothelin-1. Inflammatory changes favour the development of thrombi and platelet dysfunction, which further compromise vessel potency.(2,3)

The endothelin, NO and prostacyclin pathways are central to the pathogenesis and management of PAH and there are pharmacological agents targeting each of them. Endothelin-1 acts on ETA and ETB receptors, with ETA having a vasconstrictive and proliferative effect on vascular smooth muscle, ETB has mixed effects and is known to induce vasodilation secondary to production of nitric oxide (NO).

NO is produced by the action of NO synthase and increases the activity of soluble guanylate cyclase (sGC), which increases concentration of cGMP which has vasodilator and antiproliferative properties. cGMP is broken down by the enzyme phosphodiesterase (PDE). Potentiation of sGC is the target of riociguat and inhibition of PDE is the target of the PDE5 inhibitors sildenafil and tadalafil. Prostacyclin (PGI2) produced from arachidonic acid by cyclo-oxygenase also has vasodilator and antiproliferative properties via activation of adenylcyclase (AC) and production of cAMP. Increased activity of AC is the augmented by oral, inhaled and parenteral prostanoids (epoprostenol, iloprost, treprostinil, beraprost).(4,5)

National Registries(5,6) indicate that the prevalence of PAH in Europe ranges between 1.5 and 5.2 cases per 100,000 people, with a 2:1 predominance in women. PAH can develop at any age: mean age at diagnosis has risen to 50 years.(7)

Patients typically present with:

The gradual onset of non-specific symptoms leads to considerable delays in initial diagnosis.(2,8)

In established PAH, there will be clinical signs of right-sided heart failure and the electrocardiogram and chest X-ray may be abnormal.(2) Echocardiography will show enlarged right-sided cardiac chambers and tricuspid regurgitation. Diagnosis will be confirmed with right heart catheterisation with measurements of mean pulmonary artery pressure (mPAP) and pulmonary capillary wedge pressure (PCWP). Diagnosis of idiopathic PAH is defined as an mPAP >25mmHg and PCWP <15mmHg with exclusion of other specific causes.(2)

The severity of PAH is classified according to a functional class (FC) system8 (Table 2). Disease severity defined by the World Health Organization (WHO)-FC has consistently been shown to correlate with mortality risk (Figure 1).6

Registry data has shown that treatment leading to improvements in, or maintenance of, FC translate to improved survival, while progression despite treatment is associated with significantly worse outcomes(10) (Figure 2). This applies across a broad range of PAH aetiologies.

Because PAH is treatable and early treatment is associated with reduced morbidity and mortality, accurate and prompt diagnosis is particularly critical.

General management principles

Pregnancy is poorly tolerated in patients with PAH and associated with mortality of up to 50%, and should be avoided.(2) If hormonal contraception is used, then this should not contain oestrogen because of the risk of thromboembolism(2) (NB: all ERAs are considered teratogenic and bosentan can reduce the effectiveness of oral contraceptives). Influenza and pneumococcal vaccinations are recommended and patients may benefit from oxygen therapy, physiotherapy and psychological support. Patients should be considered for early assessment for heart–lung or lung transplantation.(2)

General pharmacological treatments include anticoagulation, diuretics and digoxin if atrial fibrillation is present; generally, beta blockers and cyclizine are avoided.(2)

During diagnosis, vasoreactivity testing should be carried out. If the patient is a ‘responder’ defined as a reduction in mPAP≥10mmHg to ≤40mmHg with unchanged cardiac output, then high-dose calcium channel blockers will form the mainstay of treatment. Approximately 10% of patients will meet these criteria.(2)

For non-responders treatment options will be based on FC (Table 2). Treatment decisions should also take into account patient circumstances and capacity to comply with treatment, comorbidities, concomitant therapies and associated interactions. The majority of incident cases of PH will present in class III,(7) and for these patients an ERA will be an evidence-based, first-line choice.(2)

The first commercially available ERA, bosentan, is an oral sulfonamide-class antagonist of both ETA and ETB.(11,12) The terminal half-life is ~5–6 hours, necessitating twice-daily dosing, with steady-state concentrations achieved within three to five days. Bosentan induces its own metabolism and the metabolism of other CYP2C9, 3A4 and 2C19 substrates resulting in clinically significant interactions with sildenafil, oral contraceptives and warfarin. Bosentan is cleared by hepatic metabolism to active metabolites that are excreted hepatically. Severe renal impairment (creatinine clearance 15–30ml/min) has no clinically relevant impact on bosentan clearance. Concomitant use of potent inhibitors of 2C9 and 3A4 is contraindicated.

Bosentan is associated with hepatic dysfunction in ~11% of patients, necessitating monthly monitoring of liver functions tests during use; if abnormal and depending on extent of elevation, this may require temporary or permanent discontinuation.(12)

The efficacy of bosentan was demonstrated in the BREATHE-1,(13) BREATHE-5,(14 )and EARLY(15) studies of between 16 and 24 weeks, using surrogate endpoints of improvement in six-minute walk distance (6MWD), oxygen saturations (SpO2) and pulmonary vascular resistance (PVR).

Bosentan was followed by sitaxsentan, another sulfonamide-class antagonist, developed with enhanced ETA selectivity and oral bioavailability. As with bosentan, short studies using surrogate endpoints were used to demonstrate efficacy.(16,17) Post-marketing surveillance identified idiosyncratic and fatal hepatotoxic events, leading to its withdrawal in 2010.

The third ERA to market was the propanoic acid derivative ambrisentan.(11) Ambrisentan does not appear to inhibit or induce drug metabolising systems.(17,18) As with bosentan, clinical trials on ambrisentan were of relatively short duration and used 6MWD as the primary outcome.(19)

Registry data, such as REVEAL, have consistently demonstrated a survival benefit in patients treated with targeted therapies with a median survival of >7 years compared with previously dismal ‘untreated’ median survivals of ~2.8 years(1) (Figure 3).

While the 6MWD is widely used in practice and clinical trials, pooled analysis of randomised, controlled trials (RCTs) has indicated that this may not be a sufficient surrogate for clinical outcome in contemporary studies (Table 3).(20)

Macitentan, an analogue of bosentan, is due for European launch. Theoretically, its lipophilicity will increase its tissue penetration leading to improved efficacy (80% of ET is released into the vessel wall rather than into the circulation).(21) The SERAPHIN trial was a multicentre randomised, controlled trial including 742 patients randomised 1:1:1 to receive 3mg or 10mg macitentan once daily or placebo with follow-up over 36 months.(21)

Approximately 55% of patients in each study arm had idiopathic PAH, 30% PAH associated with connective-tissue disease and the remainder associated with other conditions. Approximately 50% of patients in each arm had class II symptoms and around 45% had class III symptoms. The trial was designed to mimic real life, with incident and prevalent patients and background therapy with either PDE5 inhibitors or oral/inhaled prostanoids allowed. Approximately 60% of patients in each group were receiving a baseline PDE5 inhibitor. Patients requiring intravenous prostanoids were excluded. The primary outcome was the composite of death, worsening of PAH (progression to a higher WHO functional class, or if class IV at baseline, no improvement or worsening signs of right heart failure unresponsive to diuretics), or need for septostomy, lung transplant or initiation of parenteral prostanoids.

Per protocol analysis demonstrated a reduction in the primary endpoint for both doses of macitentan with greater benefit with the higher dose, with a number needed to treat of 7 (95% CI 5–16) over the treatment period, and in patients not receiving baseline treatment. This was largely accounted for by a reduction in the incidence of worsening PAH, which was statistically significant even when considered alone.

There was also a statistically significant reduction in the rates of hospitalisation for PAH.

Macitentan was well tolerated, with similar adverse event and discontinuation rates between the three study arms. In the absence of head-to-head studies against other ERAs and given the different study designs it is not possible to draw conclusions on non-inferiority or superiority.

Figure 4 summarises the mechanisms of action of the various PH drugs.

Table 4 shows a comparison of the characteristics and adverse events of the ERAs.

Despite limitations in trial methodologies, ERAs have transformed the management of PAH and have contributed to the improved survival seen in this disease. Macitentan has been shown to be effective and well tolerated in a large trial in both incident and prevalent patients. The SERAPHIN trial is the start of a new approach in PAH trials, looking at patient outcomes over a longer period of time rather than by using surrogate markers. We await further data of effects of treatment in subgroups of PAH aetiologies and disease severities as well as further experience of its effects in the ageing PAH population who have more co-morbidities and polypharmacy.(5)