Emerging biologics for the treatment of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rare pulmonary vascular disorder, wherein mean systemic arterial pressure (mPAP) becomes abnormally high because of aberrant changes in various proliferative and inflammatory signalling pathways of pulmonary arterial cells. Currently used anti-PAH drugs chiefly target the vasodilatory and vasoconstrictive pathways. However, an imbalance between bone morphogenetic protein receptor type II (BMPRII) and transforming growth factor beta (TGF-β) pathways is also implicated in PAH predisposition and pathogenesis. Compared to currently used PAH drugs, various biologics have shown promise as PAH therapeutics that elicit their therapeutic actions akin to endogenous proteins. Biologics that have thus far been explored as PAH therapeutics include monoclonal antibodies, recombinant proteins, engineered cells, and nucleic acids. Because of their similarity with naturally occurring proteins and high binding affinity, biologics are more potent and effective and produce fewer side effects when compared with small molecule drugs. However, biologics also suffer from the limitations of producing immunogenic adverse effects. This review describes various emerging and promising biologics targeting the proliferative/apoptotic and vasodilatory pathways involved in PAH pathogenesis. Here, we have discussed sotatercept, a TGF-β ligand trap, which is reported to reverse vascular remodelling and reduce PVR with an improved 6-minute walk distance (6-MWDT). We also elaborated on other biologics including BMP9 ligand and anti-gremlin1 antibody, anti-OPG antibody, and getagozumab monoclonal antibody and cell-based therapies. Overall, recent literature suggests that biologics hold excellent promise as a safe and effective alternative to currently used PAH therapeutics.

Keywords: BMPRII; GDF; Pulmonary arterial hypertension (PAH); TGF-β; activin; biologics; ligand trap; monoclonal antibody; sotatercept.

Figure 1:

(A) Clinical classification of pulmonary hypertension. (B) FDA approved small molecule drugs for pulmonary arterial hypertension.

Figure 2:

(A) Novel biologics targeting two dominant pathways implicated in pulmonary arterial hypertension. PAH pathophysiology involves multifactorial etiology that causes maladaptive pulmonary vascular remodeling and vasoconstriction. Small molecule drugs currently target only vasoconstricting pathways, which relieve symptoms. The underlying dysregulated immune modulation, vascular proliferation, and reduced apoptosis remained untargeted. Emerging biologics targeting two major PAH pathophysiologic pathways could improve pulmonary hemodynamics and ameliorates right ventricular hypertrophy.

Figure 2:

(B) Classification of emerging biologics based on preclinical and clinical studies.

Figure 3:

Two counter-regulatory pathways control gene transcriptions that determine the fate of pulmonary vascular modeling. Activin pathway promotes pulmonary vascular cell proliferation, differentiation, and survival, whereas BMP pathways encourage cell apoptosis and inhibit proliferation and differentiation. In a healthy individual, the activin and BMP pathway are well balanced. Abbreviations: BMPs (Bone Morphogenetic Proteins), BMPRII (Bone Morphogenetic Protein Receptor II), GDFs (Growth Differentiation Factors), ALK (Activin receptor-Like Kinase), ActRIIA/IIB (Activin Receptor type IIA/IIB), Smad (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic), GTF (general transcription factor).

Figure 4:

(A) Excessive levels of activin and GDF ligand binding to ActRIIA/B receptor overstimulate the activin pathway. Reduced BMP ligand activity of the BMP pathway is responsible for maladaptive pulmonary arterial remodeling.

Figure 4:

(B) Sotatercept monoclonal antibody intercepts activin and GDF ligands before receptor binding and helps downregulation of the activin pathway at the level of the existing BMP pathway. Thus, sotatercept establishes a balance between activin and BMP signaling.

Figure 5:

A sustained release vasoactive intestinal peptide (VIP) analog -Pemziviptadil. Pemziviptadil is a long-circulating (60 hours in humans) VIP biopolymer for treating PAH, addressing the limitation of short-acting natural VIP (1 minute in humans).