Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study

Summary

The main OBJECTIVE of this proposal is to extend the investigator's preclinical findings on the role of epigenetics and DNA damage and Bromodomain-Containing Protein 4 (BRD4) inhibition as a therapy for a devastating disease, pulmonary arterial hypertension (PAH). There is strong evidence that BRD4 plays a key role in the pathological phenotype in PAH accounting for disease progression and 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. At this stage, the investigators propose a pilot study to assess the feasibility of a Phase 2 clinical trial assessing apabetalone in the PAH population. The overall HYPOTHESIS is that BRD4 inhibition with apabetalone is a safe and effective therapy for PAH.

Timeline

Start

2019-08-22

Primary completion

2021-10-15

Completion

2021-12-13

Publications

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• Background Gallagher SJ, Mijatov B, Gunatilake D, Tiffen JC, Gowrishankar K, Jin L, Pupo GM, Cullinane C, Prinjha RK, Smithers N, McArthur GA, Rizos H, Hersey P. The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells. J Invest Dermatol. 2014 Nov;134(11):2795-2805. doi: 10.1038/jid.2014.243. Epub 2014 Jun 6.
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• Background ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. No abstract available.
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• Background Taylor GJ, Wainwright P. Open label extension studies: research or marketing? BMJ. 2005 Sep 10;331(7516):572-4. doi: 10.1136/bmj.331.7516.572.
• Background Micetich KC. The ethical problems of the open label extension study. Camb Q Healthc Ethics. 1996 Summer;5(3):410-4. doi: 10.1017/s0963180100007210. No abstract available.
• Background Yorke J, Corris P, Gaine S, Gibbs JS, Kiely DG, Harries C, Pollock V, Armstrong I. emPHasis-10: development of a health-related quality of life measure in pulmonary hypertension. Eur Respir J. 2014 Apr;43(4):1106-13. doi: 10.1183/09031936.00127113. Epub 2013 Nov 14.
• Background Yorke J, Deaton C, Campbell M, McGowen L, Sephton P, Kiely DG, Armstrong I. Symptom severity and its effect on health-related quality of life over time in patients with pulmonary hypertension: a multisite longitudinal cohort study. BMJ Open Respir Res. 2018 Mar 1;5(1):e000263. doi: 10.1136/bmjresp-2017-000263. eCollection 2018.
• Background Favoccia C, Kempny A, Yorke J, Armstrong I, Price LC, McCabe C, Harries C, Wort SJ, Dimopoulos K. EmPHasis-10 score for the assessment of quality of life in various types of pulmonary hypertension and its relation to outcome. Eur J Prev Cardiol. 2019 Aug;26(12):1338-1340. doi: 10.1177/2047487318819161. Epub 2018 Dec 19. No abstract available.
• Provencher S, Potus F, Blais-Lecours P, Bernard S, Martineau S, Breuils-Bonnet S, Weatherald J, Sweeney M, Kulikowski E, Boucherat O, Bonnet S. BET Protein Inhibition for Pulmonary Arterial Hypertension: A Pilot Clinical Trial. Am J Respir Crit Care Med. 2022 Jun 1;205(11):1357-1360. doi: 10.1164/rccm.202109-2182LE. No abstract available.

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