Apabetalone for Pulmonary Arterial Hypertension — APPROACH-2  

Pulmonary Arterial Hypertension Clinical Trial

Official title: Apabetalone for Pulmonary Arterial Hypertension: a Phase 2 Clinical Study

Status Not yet recruiting

Clinical Trial Summary

Throughout the past twenty years, numerous specific pharmacologic agents targeting the endothelial dysfunction associated with PAH have emerged. Short term placebo-controlled randomized trials assessing PAH-specific monotherapy with these molecules have reported improvements in pulmonary hemodynamics and exercise capacity. A recent meta-analysis also documented a reduction in short-term mortality of about ≈40% with such therapies. Several randomized clinical trials evaluating PAH-specific combination therapy have been conducted. Our recent meta-analysis showed that combination therapy was associated with a 35% risk reduction for the occurrence of clinical worsening compared to monotherapy. Nonetheless, the investigators also showed 17% of PAH patients receiving combination therapy still experienced clinical worsening over a median exposure of 16 weeks. Moreover, long-term survival on PAH-specific also therapy remains poor in the modern era, with a yearly mortality rate of 15 % in incident idiopathic PAH. The identification of innovative therapeutic targets and validation of these complementary therapeutic interventions are thus urgently needed in PAH.

The investigators and others (K. Stenmark, University of Colorado and H. Bogaard, VU University Medical Center, Amsterdam, personal communications), have published strong evidence that BRD4 plays a key role in the pathological phenotype in PAH accounting for disease progression and showed that BRD4 inhibition can reverse PAH in several animal models. Intriguingly, coronary artery disease (CAD) and metabolic syndrome are more prevalent in PAH compared with the global population, suggesting a link between these diseases. Interestingly, BRD4 is also a trigger for calcification and remodeling processes and regulates transcription of lipoprotein and inflammatory factors, all of which are important in PAH and CAD. Apabetalone, an orally available BRD4 inhibitor, is now in a clinical development stage with a good safety profile.

The overall objective of the study is to explore the efficacy and safety of apabetalone as an add-on therapy for adult PAH patients and to inform the conduct and the design of a Phase 3 trial.

The primary objective of the study is to assess the efficacy of apabetalone as evaluated by the change in PVR over a period of 24 weeks compared to placebo in adult subjects with PAH on stable background therapy.

Secondary objectives include changes at week 24 in 6MWD, plasma NT-proBNP concentration, WHO functional class, ESC/ERS risk stratification score, health-related quality of life and additional hemodynamic data from right heart.

Exploratory objectives are to evaluate the effects of apabetalone compared to placebo in adult subjects with PAH on mortality and clinically relevant morbidity events, and on circulating levels and transcription changes in whole blood markers of metabolism, vascular calcification, inflammation, DNA damage and leucocyte expression of BMPR2.

Clinical Trial Description

This is a standard-design, double-blind, parallel-group, placebo-controlled trial.

Overall, 72 well-characterized PAH patients, 36 subjects in each treatment group (apabetalone 100 mg BID or matching placebo), that have been stable for >4 months on standard PAH-therapies, as per guidelines (Galie, Humbert et al. 2015) will be recruited in 8-15 participating centres (site selection currently ongoing). The participating centres will be recruited if they have the same approach to PAH patients in terms of choice and timing of treatments, and have expertise in performing trials in PAH. The initial Health Canada approval will be obtained. Apabetalone will be provided by Resverlogix Corp. Canada, but Resverlogix had no input into the trial design and will not be involved in the conduct of the trial, analysis, interpretation of the results or the final manuscript.

A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of PAH medication. Patients will be given apabetalone 100mg BID or placebo.

Patients will be regularly followed to assess whether side effects. At baseline and week 24, a cardiac catheterization will assess changes in pulmonary hemodynamics and RV function.

An end-of-study visit is planned at week 28. ;

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

• NCT number: NCT04915300
• Study type: Interventional
• Source: Laval University
• Contact: Steeve Provencher, MD, MSc
• Phone: 418-656-4747
• Email: steeve.provencher@criucpq.ulaval.ca
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: October 2023
• Completion date: March 2025