Sotatercept: A First-In-Class Activin Signaling Inhibitor for Pulmonary Arterial Hypertension

Abstract

Objective: The objective of the study is to review the characteristics, efficacy, safety, and clinical relevance of sotatercept in pulmonary arterial hypertension (PAH). Data Sources: A literature search containing search terms related to sotatercept and PAH was conducted. Embase via Elsevier, MEDLINE via Ovid, the medRxiv preprint server, Cochrane Library CENTRAL trials registry, and ClinicalTrials.gov were searched from inception through October 31, 2024. The package insert was utilized to obtain drug information and additional data. Study Selection and Data Extraction: Phase II-III clinical trials investigating sotatercept for PAH were included. Articles written in English were extracted while animal studies and phase I clinical trials were excluded. Data Synthesis: In patients with WHO Group 1, functional class II-III PAH, adding sotatercept to background therapy increased 6-minute walk distance in phase II-III trials. Pooled analysis from PULSAR (phase II) and STELLAR (phase III) showed improvements in pulmonary vascular resistance and NT-proBNP. Exploratory data from PULSAR revealed that BMPR2 genetic variant status was not associated with significant differences in treatment effects. SPECTRA (phase IIb) demonstrated improved right ventricular structure and function. Interim analysis from SOTERIA showed that treatment effects persist at 1 year. Conclusions: Sotatercept is a viable add-on therapy for patients with PAH Group 1 and functional class II-III. Additional data are needed to assess long-term outcomes among treatment-naïve patients and those with the most severe symptomatology.

Keywords: activin signaling inhibitor; pulmonary arterial hypertension; sotatercept; sotatercept-csrk; transforming growth factor-beta.

Figure 1.

Mechanisms of action of FDA-approved PAH therapies. Prior to sotatercept approval, there were 3 major target pathways for PAH: (1) activation of the prostacyclin pathway using prostacyclin analogs or selexipag, (2) stimulation of the nitric oxide pathway by activating sGC with riociguat or using PDE5 inhibitors (sildenafil, tadalafil), and (3) blunting the effects of endothelin with endothelin receptor antagonists (ambrisentan, bosentan, macitentan). Sotatercept acts within the TGF-beta superfamily pathway, which is imbalanced in patients with PAH due to reduced antiproliferative BMPR2, ALK 1/2/3/6, and SMAD 1/5/8 signaling. Sotatercept acts as a “decoy” to the ActRIIa and ALK 4/5/7 receptor, binding to activin and other ligands to prevent the subsequent activation of proliferative pathways (SMAD 2/3).^, Abbreviations: ActRIIa, activin receptor type IIa; ALK, activin receptor-like kinase; BMPR2, bone morphogenetic protein receptor type 2; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ET, endothelin receptor type; GTP, guanosine triphosphate; IP, prostacyclin; NO, nitric oxide; PAH, pulmonary arterial hypertension; PDE5, phosphodiesterase type 5; sGC, soluble guanylate cyclase.