Paradigm for PAH

The American Thoracic Society 2022 International Conference brought together worldwide experts to present and discuss state-of-art research including the recent advancements related to the Pulmonary Arterial Hypertension (PAH) therapeutic landscape. PAH is characterized by pulmonary vascular remodeling, which causes elevated pulmonary arterial pressure (PAP) and progressive right ventricular dysfunction. Defective transforming growth factor-β and bone morphogenetic protein signaling is associated with PAHs. According to the DelveInsight’s epidemiology insights, in 2019, the total prevalent cases of Pulmonary Arterial Hypertension (PAH) were 68,835 cases in the 7MM (The USA, EU5, Japan), which is expected to reach 74,031 cases by 2032. New therapies that target these underlying mechanisms of vascular remodeling are needed to slow the onset and progression of the disease.

On this note, DelveInsight analyzed the discussions around the PAH intervention and introduced some major late breaking abstracts that will revolutionize the future treatment patterns of PAH addressing the unmet needs and improving the patients outcome.

Sotatercept- First in class novel therapeutic approach in PAH

Sotatercept is a new first-in-class fusion protein that is thought to function by rebalancing signal transduction between proliferative and antiproliferative pathways. Preclinically, Sotatercept has been shown to reverse vascular muscles, normalize pulmonary artery pressure (PAP) and improve right ventricular function.

The PULSAR Study by Acceleron Pharma is a Phase II, double blind, randomized, placebo-controlled, parallel-group study of Sotatercept plus SOC versus placebo plus SOC in participants with PAH. The first report of PULSAR's open-label prolongation suggests that continued Sotatercept treatment in patients with PAH maintains clinical efficacy across multiple study endpoints for up to 48 weeks. The improvements observed in patients randomized from placebo to Sotatercept treatment are consistent with the initial results from the placebo-controlled treatment stage. Importantly, the placebo assignment did not affect responsiveness in 24 weeks. Safety was consistent with previous reports in PAH and other patient populations. These long-term results underscore the diversity of Sotatercept as a new treatment for PAH.

The SPECTRA Study by Acceleron Pharma is a Phase IIa, multi-center, single arm, open label exploratory study to determine the effects of Sotatercept. The preliminary analysis of patients in SPECTRA study showed promising results in terms of hemodynamics and exercise tolerance and capacity. Safety was consistent with previous reports in PAH and other patient populations. These results underscore the clinical efficacy of Sotatercept and its potential as a new treatment option for PAH patients.

Merck in its latest press release announced successful acquisition of Acceleron. This acquisition will reinforce Merck’s cardiovascular pipeline with Acceleron’s Sotatercept (potential first in class therapy) for PAH treatment. The clinical trial results from the study will be published under the late breaking abstracts that are expected to establish clinical efficacy and benefits in PAH patients.

Oral treprostinil- Watchful waiting on patient selection and management of adverse events

Insmed Incorporated reported data on treprostinil palmitil inhalation powder (TPIP) at the American Thoracic Society (ATS) 2022 International Conference. Three treprostinil posters containing preclinical data were presented at the ATS.

The first showed that treprostinil exerts an anti-fibrotic effect by acting through the prostanoid receptor subtype EP2. The anti-fibrotic effect of treprostinil may also be enhanced by its ability to inhibit the secretion of pro-fibrotic cytokines.

The second study showed that treprostinil did not alter the integrity of the bronchial epithelium or induce any inflammatory response, and that prostaglandin E2 release is caused by administering treprostinil on the basolateral but not the apical surface, suggesting a polarized distribution of the prostanoid receptors present on the bronchial epithelium. Therefore, the degree and duration of treprostinil-induced vasodilation can be controlled by regulating the epithelial penetration of inhaled treprostinil.

Finally, in the third study, the binding affinity of treprostinil to rat prostanoid receptors is similar for prostaglandin I2 (IP) receptors compared with that to humans and about 7-fold higher for the EP2 receptor compared with that in humans. Researchers may find these data useful in interpreting the results of a rat study of treprostinil palmitil to inform dose selection in studies of patients with pulmonary arterial hypertension (PAH).

Inhaled Seralutinib- Evaluation for potential treatment for PAH

Seralutinib (also known as GB002) is a unique compound specifically designed for the treatment of PAHs with an optimized kinase specific profile targeting PDGFRα / β, cKIT, and CSF1R. Seralutinib is administered using a dry powder inhaler and may maximize the therapeutic index of kinase inhibitors by directly targeting affected pulmonary arterioles.

In some preclinical PAH models, Seralutinib reversed pulmonary vascular remodeling, improved hemodynamic parameters, increased pulmonary BMPR2, and decreased circulating NTproBNP.

The TORREY Study trial is an ongoing trial in patients who have reported progressive PAH despite standard-of-care therapy. Seralutinib is being evaluated and assessed as a potential treatment for PAH in Phase II with elevated PVR (pulmonary vascular resistance) on current standard-of-care.