Reducing the pressure in PAH: Sotatercept, hemodynamics, and the right ventricle

Pulmonary arterial hypertension (PAH) is a severe progressive disease characterised by obliterative vascular remodelling and increased resistance in small and medium sized pulmonary arteries. Contributing factors to PAH pathogenesis include genetic mutations including those in bone morphogenetic protein receptor type 2 (BMPR2), perivascular inflammation, systemic immune dysregulation, and imbalanced pulmonary vascular cell proliferation versus apoptosis [1]. PAH remains a malignant condition despite therapeutic advances, with usually irreversible remodelling of resistance vessels. Morbidity relates to exercise related breathlessness symptoms, reduced quality of life, and ultimately, increased mortality follows the onset of right ventricular (RV) dysfunction due to uncoupling of the pulmonary arterial-RV unit [2]. The focus of the PAH therapeutic approach has until now promoted vasodilatation, targeting endothelial dysfunction via the prostacyclin, endothelin-1 and nitric oxide pathways to slow the progression of pulmonary vascular remodelling, and the resulting RV dysfunction over time [3]. Intensity of therapy is based on “risk assessment” estimation of a low, intermediate, or high risk of death using multimodal clinical parameters, with clinical guidelines suggesting that low and intermediate risk patients are initiated on combination therapy; those with high-risk disease may initiate triple therapy [4]. Ultimately, lung or heart-lung transplantation may be necessary. PAH therapies improve pulmonary haemodynamics, exercise capacity and transplant-free survival; however, even with treatment, median survival after diagnosis is 5 to 7 years [5].

A treatment goal would therefore include reverse remodelling, rather than just to slow or stabilise disease progression by pulmonary vasodilatation. Drug development has looked to cancer biology for targets in other conditions characterised by dysfunctional TGF-β superfamily signaling, the pathway perturbed by the most common mutations in PAH, those involving BMPR2 signalling [6, 7]. Of these, sotatercept is a first in class activin receptor type IIA-Fc fusion protein that traps activins and relevant growth differentiation factors and is administered as a subcutaneous injection every 21 days. Sotatercept has been shown in PAH to inhibit cellular proliferation and promotion of apoptosis of pulmonary vascular cells [8], and to reduce perivascular inflammation [9]. Sotatercept is the first potential anti-remodelling drug subjected to two randomised placebo-controlled trials in different populations with PAH, first in PULSAR, a safety study confirming a reduction in pulmonary vascular resistance (PVR) [10]. This was followed by the landmark phase 3 STELLAR, in which Hoeper et al. assessed 163 patients with PAH in World Health Organisation (WHO) II and III, of whom over 60% were already receiving stable background therapy and demonstrated a 34.4 m improvement in 6-minute walk distance in those taking sotatercept [11]. The first eight secondary end points also improved compared to placebo, including PVR, N-terminal brain natriuretic peptide (BNP), WHO class improvement, time to death or clinical worsening, and changes in risk score. Adverse events included non-significant bleeding (gingival bleeding, epistaxis), dizziness, telangiectasia, thrombocytopenia, and (surprisingly) increased haemoglobin and increased systemic blood pressure.

In this issue of the Journal, Souza et al. report a post-hoc analysis of right heart catheterisation (RHC) and echocardiographic data from the STELLAR trial where sotatercept significantly improved mean pulmonary artery (PA) pressure (PAP), PVR, PA compliance and elastance, and parameters of right ventricular (RV) work and efficiency. Echocardiographic parameters also showed improvements in RV-PA coupling expressed as the TAPSE/sPAP ratio, RV end-systolic and end-diastolic areas, severity of tricuspid regurgitation and RV fractional area change (FAC). However, left ventricular ejection fraction (LVEF) was also found to reduce in those receiving sotatercept, possibly in response to mildly increased systemic vascular resistance in this group. The authors conclude from this post-hoc analysis that, in line with long-term extension data now available from PULSAR which demonstrated reduction in PVR at both tested doses (0.3 and 0.7 mg·Kg⁻¹) over 24 weeks [10, 12], clinically relevant parameters of RV performance are also favourably influenced by sotatercept.

The haemodynamic data presented confirm an impressive reduction in PAP in response to sotatercept with availability of additional echocardiographic data allowing a more detailed evaluation of right ventricular responses. The somewhat unusual nature of endpoints employed in this study which include validated surrogates of RV-PA coupling, RV power, PA elastance and cardiac efficiency should alert the reader to their derivation all of which lean heavily on PAP reduction as a key component. To this end, the haemodynamic data of Souza et al. aligns well the marked reduction in PAP now demonstrated in two different PAH populations (STELLAR and PULSAR) and which in this study correlated strongly with changes in NT-proBNP levels at week 24. What remains more contentious however is the explanation for the lack of improvement in cardiac output even assessed by those with higher and low baseline values of cardiac index. Moreover, the data of Souza et al. also hints at a possible detrimental effect on LVEF from sotatercept, a finding that will warrant further investigation.

Addressing the question over sotatercept and RV response, the authors rightly discuss the near normal cardiac index and TAPSE values at baseline in both drug and placebo groups as well as the small improvement in RV FAC noted in the sotatercept group. Similarly, a small reduction in LVEF may yet turn out to be of minor significance considered alongside larger cardiovascular studies that included populations with predisposition to systemic hypertension as in STELLAR. To contextualise the somewhat profound effects of sotatercept on PAP therefore, it is perhaps relevant to consider also the erythropoietic effect of sotatercept which along with vascular obstruction may predispose to an increase in PVR (and thus RV work), via an increase in blood viscosity [13]. This should provide additional reassurance that reported PVR reductions which in STELLAR correlated closely with improvements in functional capacity are if anything an underestimation of the true effect.

Notwithstanding this benefit on PAP, there remains uncertainty around the mechanism of action of sotatercept in PAH including any potential contribution toward a reduction in LVEF implicated in this study. In particular, the selectivity profile of sotatercept for the ACTR-II receptor remains under scrutiny with demonstration of different binding affinities between sotatercept and several other ligands involved in BMP signalling [14]. The consequence of broader targeting of multiple ligands could be that sotatercept may not only neutralise Activin A and B but also multiple alternative ligands including GDF 8 (myostatin), GDF 11 and BMP 9 which have important pleotropic properties relating to cardioprotection and endothelial cell homeostasis. More specifically, in a zebrafish model of cardiac regeneration, inverse modulation of Smad 3 phosphorylation by myostatin has shown ACTR-II receptor activation may in fact have inhibitory effects on cardiac proliferation during cardiac regeneration [15]. The relevance of such changes to patients with PAH remain unclear, however direct myocardial actions of sotatercept warrant consideration in the downstream effects of ACTR-II receptor activation. At the clinical interface, the effect of sotatercept on RV contractile reserve and exercise pulmonary vascular recruitment also carries interest with the forthcoming iCPET study of sotatercept (Clinicaltrials.gov NCT03738150) likely to shed light on dynamic parameters of RV performance including effects on peripheral oxygen utilisation.

PAH is, fundamentally, a problem of elevated pressure. When pressure overload leads to maladaptive RV remodeling, RV-PA uncoupling and RV failure ensue, and the risk of death increases. While our overall goal is to cure PAH, disease-modifying treatments that prevent hemodynamic and RV decompensation, reverse the underlying proliferative vasculopathy, and improve survival would be a great step forward. Currently, there is no accepted definition for reverse remodelling nor is there a validated way to measure this in PAH patients. Similarly, there is no accepted criteria for what constitutes “disease modification” in PAH. In other conditions, disease modifying therapies have been defined as those having effects on disease manifestations and disease outcomes, which are sustained after treatment discontinuation [16]. Using this definition, is sotatercept disease modifying? The answer to this question is not yet clear. Animal studies suggest reverse remodeling properties with sotatercept but obtaining histologic evidence in human patients with PAH treated with sotatercept would not be feasible. Likewise, studies showing sustained clinical improvement after discontinuation of sotatercept do not exist. A recent small study of 15 sotatercept-treated patients observed small improvements in the haemoglobin-corrected diffusion capacity for carbon monoxide of 4% (95%CI 1–6%) [17]. This could indicate increased pulmonary capillary surface area [8], which we might expect with a reverse remodelling treatment, but this study did not parse out the relative contribution of changes in DLCO components of alveolar-capillary membrane conductivity (Dm) and pulmonary capillary blood volume (Vc).

We can also speculate and generate hypotheses about the expected changes in cardiopulmonary physiology if a therapy truly reversed the remodelled pulmonary vasculopathy of PAH. Consider the equation for calculating PVR shown below: Thus, a reduction in PVR can be explained by a reduction in mPAP, an increase in PAWP or increase in cardiac output. Monotherapy with the existing PAH therapies reduce PVR and increase cardiac output modestly, with little or no effect on mPAP [18]. Using high doses of parenteral prostacyclins, larger drops in PVR and mPAP are possible, but this effect is mediated by potent vasodilation and supranormal cardiac output [19]. Using triple combination therapy with oral therapies and parenteral prostacyclins, large (70%) reductions in PVR and clinically relevant reductions in mPAP (18–20 mmHg) can also be achieved at lower doses of prostacyclin and to a high-normal cardiac index [20, 21, 22]. Other than in acute vasoreactive patients, vasodilation does not recruit new vessels to increase pulmonary vascular surface area but rather increases flow through distention of the already maximally recruited vascular bed [23].

If a new therapy regressed pulmonary vascular remodeling, we would expect pulmonary vascular surface area to increase from previously obstructed vessels being recruited rather than just distended by increasing pulmonary flow. As obstructed vessels open up, there would be a reduction in PVR mediated largely by a reduction in mPAP. Resting cardiac output would likely improve if low but remain unchanged if already in the normal physiologic range; there would be no physiologic reason for cardiac output to increase to supranormal values. With reverse remodelling, the stiffness of the pulmonary microvessels should decrease so overall pulmonary arterial compliance should increase. RV-PA coupling should also improve, and the RV function should recover. The hemodynamic changes in the STELLAR trial, as reported by Souza et al., are concordant with the expected findings for a treatment that has reverse remodelling effects, though these data on their own are not sufficient. Notwithstanding the possibility that other mechanisms may explanation the observed hemodynamic, echocardiographic, and clinical improvements in STELLAR, the data confirm that sotatercept improves clinically meaningful physiologic endpoints, which is exciting for clinicians and provides a new hope for patients with a terrible disease. Ongoing studies may provide additional data to back a claim for disease modification which, if established, would also represent another landmark achievement.