Pulmonary Arterial Hypertension (PAH)

The treatment of pulmonary arterial hypertension (PAH) requires the use of supportive therapy, such as rehabilitation and oxygen supplementation, as well as the use of pharmacological therapy when appropriate. Current therapeutic approaches for addressing pulmonary hypertension are approved for patients with PAH (group 1) and few patients with chronic thromboembolic pulmonary hypertension (CTEPH) (group 4). Therapeutics rely on the targeting of 3 major pathways of interest: nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling, endothelin signaling, Tx, NO, and prostacyclin signaling. Different drugs have been developed to address each compromised pathway, such as phosphodiesterase type 5 (PDE5) inhibitors (tadalafil and sildenafil), endothelin receptor antagonists (ERAs; bosentan (ETB receptors non-selectively) and ambrisentan (ETA receptors selectively)), and prostacyclin analogues (iloprost).1 The use of these drugs in other forms of pulmonary hypertension still needs further support, and many clinical trials are underway to understand the benefit of their use in PAH and boost the development of new therapeutic strategies for tackling this disease. 

Phase 1 Clinical Trials

Two clinical trials focused on the interplay between epigenetic alterations and different metabolic pathways are ongoing. A phase 1, two-center, open-label trial is currently active to investigate bromodomain-containing protein 4 (BRD4) inhibition with apabetalone as an effective and safe therapy for PAH, considering the existing evidence pointing toward BRD4 intervention in the pathogenesis of the disease.The phase 1 trial OPTION will be addressing the roles of DNA damage and poly(ADP-ribose) polymerase (PARP) inhibition in PAH management using a PARP1 inhibitor, olaparib. This study will assess the safety and efficacy of olaparib in patients with PAH and determine a sample size for a phase 2 trial. It is currently recruiting.3

A different open-label trial aims to recruit 25 participants with severe PAH to evaluate mammalian target of rapamycin (mTOR) inhibition using ABI-009, an mTOR inhibitor that is an albumin-bound version of nab-rapamycin (Phase 1).1,4

The use of stem cell therapy, specifically allogeneic cardiosphere-derived stem cells, is being studied in patients with PAH in a phase 1, randomized, double-blind clinical trial with the aim to reduce the vascular remodeling observed in the disease. This study is designed to evaluate the safety and efficacy of this biological therapy through dose escalation following a placebo-controlled study phase.5

Phase 2 Clinical Trials

The phase 2 trial PHANTOM is ongoing to determine potential improvements in 6-minute walk distance by using the aromatase inhibitor anastrozole. This is a first-line treatment in hormone receptor-positive locally advanced or metastatic breast cancer, and its safety and side effects will be determined in 84 participants with PAH for up to 12 months.6 Other hormonal modulators are also being investigated as potential PAH therapies. The T3PAH trial is a single-center, randomized, double-blind, placebo-controlled trial that will be studying the effects of tamoxifen, a common selective estrogen receptor modulator, in patients with PAH. Several parameters will be examined, including changes in tricuspid annular plane systolic excursion (TAPSE).7

A trial assessing the efficacy and safety of sotatercept, a fusion protein formed by fusing the extracellular domain of the human activin receptor type IIA to the Fc domain of human immunoglobulin G1 (IgG1), is ongoing. Sotatercept (novel fusion protein) promotes the balance between the growth-promoting activin growth differentiation factor pathway and the growth-inhibiting bone morphogenetic protein (BMP) pathway.8 In the PULSAR trial, a double-blind, randomized, placebo-controlled study, 106 participants received treatment for 6 months in a placebo-controlled treatment period, and then they were eligible to enroll in an 18-month extension period to continue receiving sotatercept. The efficacy and safety of sotatercept were compared to those of a placebo when added to standard of care PAH treatment.9 The study has shown that sotatercept reduced pulmonary vascular resistance in patients that received background treatment for PAH.8 Several phase 3 clinical trials involving sotatercept are underway.

A phase 2/3 trial relying on stem cell therapy is currently recruiting and will investigate the efficacy and safety of repeated monthly dosing of autologous endothelial progenitor cells (EPCs) transfected with human endothelial nitric oxide synthase (eNOS), which are designed to promote lung microvascular repair and regeneration in patients with severe symptomatic PAH. This is a multicenter, randomized, double-blind, placebo-controlled trial enrolling 45 participants.10

Phase 3 Clinical Trials

The STELLAR study is currently ongoing to evaluate the safety and efficacy of sotatercept when used with background therapy compared to those of a placebo in participants with PAH. About 284 participants are expected to participate in this trial.11 Two other phase 3 trials focused on sotatercept activity are currently recruiting. The SOTERIA trial will investigate the long-term safety, tolerability, and efficacy of sotatercept in patients with PAH.12 This is an open-label, long-term follow-up study that aims to enroll 700 participants and is supported by the results obtained from the PULSAR trial.12 The ZENITH trial is a randomized, double-blind study that is recruiting about 166 participants to evaluate the effects of sotatercept compared to those of a placebo when using maximum tolerated background PAH therapy.13


1. Sommer N, Ghofrani HA, Pak O, et al. Current and future treatments of pulmonary arterial hypertension. Br J Pharmacol. 2021;178(1):6-30. doi:10.1111/bph.15016

2. Apabetalone for pulmonary arterial hypertension: a pilot study (APPRoAcH-p). ClinicalTrials.gov. August 31, 2018. Updated November 29, 2021. Accessed March 28, 2022.

3. Olaparib for PAH: a multicenter clinical trial (OPTION). ClinicalTrials.gov. December 20, 2018. Updated August 30, 2021. Accessed March 28, 2022.

4. ABI-009, an mTOR inhibitor, for patients with severe pulmonary arterial hypertension. ClinicalTrials.gov. October 27, 2015. Updated October 11, 2021. Accessed March 28, 2022.

5. Allogeneic cardiosphere-derived stem cells (CDCs) for pulmonary hypertension therapy (ALPHA). ClinicalTrials.gov. May 9, 2017. Updated March 9, 2022. Accessed March 28, 2022.

6. Pulmonary hypertension and anastrozole trial (PHANTOM). ClinicalTrials.gov. July 25, 2017. Updated December 6, 2021. Accessed March 28, 2022.

7. Tamoxifen therapy to treat pulmonary arterial hypertension (T3PAH). ClinicalTrials.gov. May 18, 2018. Updated February 18, 2021. Accessed March 28, 2022.

8. Humbert M, McLaughlin V, Gibbs JSR, et al; PULSAR Trial Investigators. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med. 2021;384(13):1204-1215. doi:10.1056/NEJMoa2024277

9. A study of sotatercept for the treatment of pulmonary arterial hypertension (PAH) (PULSAR). ClinicalTrials.gov. April 12, 2018. Updated March 14, 2022. Accessed March 28, 2022.

10. Study of angiogenic cell therapy for progressive pulmonary hypertension: intervention with repeat dosing of eNOS-enhanced EPCs (SAPPHIRE). ClinicalTrials.gov. December 23, 2016. Updated July 13, 2021. Accessed March 28, 2022.

11. A study of sotatercept for the treatment of pulmonary arterial hypertension (STELLAR). ClinicalTrials.gov. October 6, 2020. Updated February 9, 2022. Accessed March 28, 2022.

12. A long-term follow-up study of sotatercept for PAH treatment (SOTERIA). ClinicalTrials.gov. March 12, 2021. Updated January 24, 2022. Accessed March 28, 2022.

13. A study of sotatercept in participants with PAH WHO FC III or FC IV at high risk of mortality (ZENITH). ClinicalTrials.gov. May 21, 2021. Updated February 3, 2022. Accessed March 28, 2022.

Reviewed by Debjyoti Talukdar, MD, on 3/29/2022.