SINGAPORE – September 8, 2020 – MiRXES Pte Ltd, a leading microRNA (miRNA)a diagnostic company headquartered in Singapore, in collaboration with Actelion Pharmaceuticals Ltd, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, has presented the preliminary results of a study revealing that miRNA biomarker signatures have the potential to support early identification and diagnosis of pulmonary hypertension (PH). The data were presented today at the annual European Respiratory Society (ERS) International Congress.1

There is currently no simple, non-invasive test to identify and diagnose PH, a serious condition which results in high blood pressure in the blood vessels that supply the lungs.2,3 Pulmonary arterial hypertension (PAH) is a progressive form of PH that takes, on average, two years to diagnose from the onset of symptoms. Many patients are diagnosed at an advanced stage of the disease while many others remain unidentified.4,5 As PAH is progressive, delays in diagnosis can prevent early treatment and impact on patients’ prognoses, worsening clinical outcomes and survival.6

The positive results of this study show the potential of miRNA-based diagnostic signatures as a tool to help identify those in the early stages of PH,” said Aaron Waxman, M.D., Ph.D., Director of the Pulmonary Vascular Disease Program at Brigham and Women’s Hospital, Boston, USA, and Associate Professor of Medicine at Harvard Medical School.

Assessment of the biomarker N-terminal pro-brain natriuretic peptide (NTproBNP) is routinely used in PH centers today, but this measure is not specific for PH and can be elevated in patients with almost any type of heart disease, making its utility in detecting PH very limited, especially in the early stages.2,7

Increasing evidence suggests that patients with borderline PH (bPH)b and exercise PH (ePH)c may represent those in the early stages of PH.8 This study aimed to assess miRNA-based biomarker signatures in patients in the early stage of the disease, as well as those with established PH using MiRXES’ proprietary assay technology and biomarker discovery platform. In total, 245 plasma samples were collected from bPHb, (ePH)c, established PH, and non-PH symptomatic patients. All samples were assessed for NTproBNP and 600 miRNAs. The performance of NT-proBNP and miRNAs, alone or in combination, for distinguishing PH, bPH and ePH were analyzed.1

The analysis showed that miRNAs outperformed NT-proBNP for distinguishing non-PH symptomatic patients from bPH+ePH, bPH, and PH+bPH+ePH, with an area under the curved (AUC) of 0.71 vs 0.59; 0.60 vs 0.56; and 0.75 vs 0.70 respectively, suggesting that miRNAs may uniquely identify early stages of PH, prior to disease progression.1 The results also showed that combining miRNA with NTproBNP allows distinguishing of non-PH symptomatic patients from established PH patients.1

These results build on promising data from an earlier phase of the global research collaboration conducted in the UK and presented last month at the American Thoracic Society International Conference.9 The UK study demonstrated the feasibility of developing miRNA-based diagnostics for early detection of PH using 1,521 samples from PH patients, symptomatic non-PH patients, and healthy people collected at 3 UK National PH centres. AUC of miRNA signatures in identifying PH patients from healthy people and symptomatic non-PH patients were 0.94 and 0.75, respectively.

Building on these data, Janssen has initiated the CIPHER trial11, the design of which is also being presented at ERS. The CIPHER trial is an ongoing, prospective, multi-centre study that aims to identify miRNA biomarker signatures for early detection of pulmonary hypertension.

We are very excited with the promising early PH miRNA biomarker data generated from the current studies. Having launched our first regulatory-approved blood-based miRNA oncology test in 2019, MiRXES is committed to leveraging our end-to-end In Vitro Diagnostic (IVD) test development and manufacturing capabilities to support the translation of the PH miRNA biomarker signatures from bench to bedside,” said Lihan Zhou, Ph.D., CEO of MiRXES Pte Ltd.

Additional clinical studies are being planned in Asia, starting with Singapore and Japan, to provide further evidence to support the development and validation of the miRNA-based diagnostic test for early identification and diagnosis of PH.

 

Definitions

aMicroRNAs (miRNAs) are a class of small non-coding RNAs that play an important role in regulating gene expression. Deregulation of miRNA expression can lead to pathological processes such as PAH.12

bBorderline pulmonary hypertension (bPH) in this study was defined as having a mean pulmonary artery pressure (mPAP) between 21 and 24mmHg.1,13

cExercise pulmonary hypertension (ePH) in this study was defined as having a normal mPAP at rest and a mPAP of >30mmHg during exercise.1,14

dArea Under the ROC Curve (AUC) is a parameter that compares the usefulness of tests. The receiver operating characteristic (ROC) curve allows researchers to graphically compare the connection between clinical sensitivity and specificity. The AUC of the perfect test is 1, a value of 0.5 indicates there is no difference.15

 

About Pulmonary Hypertension (PH) and Pulmonary Arterial Hypertension (PAH)

PH is elevated pressure in the blood vessels of the lungs, which causes the heart to work harder to pump blood through the lungs.2 It is a serious, progressive disease and can lead to heart failure and early death. There are five groups of PH: group 1 includes PAH which could be inherited, caused by drugs or toxins or related to other conditions; group 2 refers to PH caused by a disease of the left side of the heart; group 3 includes PH resulting from lung disease and reduced oxygen in the body; group 4 refers to chronic thromboembolic pulmonary hypertension (CTEPH) and group 5 includes PH of unclear origin and mechanisms.16,17

PAH (group 1) causes the walls of the pulmonary arteries (blood vessels leading from the right side of the heart to the lungs) to become thick and stiff, narrowing the space for blood to flow, and causing an increased blood pressure to develop within the lungs. PAH is a serious, progressive disease with a variety of aetiologies, and has a major impact on patients’ functioning, as well as their physical, psychological and social well-being. There is currently no cure for PH and it is often fatal.2,3,17 However, the last decade has seen significant advances in the understanding of the pathophysiology of PAH, transforming the prognosis for PAH patients from symptomatic improvements in exercise tolerance 10 years ago, to delayed disease progression today.

 

References

  1. Waxman A, et al. Presented at European Respiratory Society Conference 2020 (Abstract 22823).
  2. Galiè N, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016;37:67–119.
  3. Vachiéry JL and Gaine S. Challenges in the diagnosis and treatment of pulmonary arterial hypertension. Eur Respir Rev 2012;21:313–20.
  4. Prins KW, et al. WHO Group I Pulmonary Hypertension: Epidemiology and Pathophysiology. Cardiol Clin 2016;34:363–74.
  5. Humbert M, et al. Arterial Hypertension in France. Results from a National Registry. Am J Respir Crit Care Med 2006;173:1023–30.
  6. Brown LM, et al. Delay in Recognition of Pulmonary Arterial Hypertension. Factors Identified From the REVEAL Registry. CHEST 2011;140:19–26.
  7. Cao Z, et al. BNP and NT-proBNP as Diagnostic Biomarkers for Cardiac Dysfunction in Both Clinical and Forensic Medicine. Int J Mol Sci. 2019;20:1820.
  8. Simonneau G, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:1801913.
  9. Lawrie A, et al. Feasibility of microRNA-based signatures for early detection of pulmonary hypertension using machine learning methods. Am J Respir Crit Care Med 2020;201:A6352.
  10. Howard L, et al. Presented at European Respiratory Society Conference 2020 (Abstract 24264).
  11. gov. A Study for the Identification of Biomarker Signatures for Early Detection of Pulmonary Hypertension (PH) (CIPHER). Identifier NCT04193046. Available at https://www.clinicaltrials.gov/ct2/show/NCT04193046?term=NCT04193046&draw=2&rank=1. (Last accessed July 2020).
  12. Lee A, et al. Therapeutic implications of microRNAs in pulmonary arterial hypertension. BMB Rep. 2014;47:311–
  13. Nemoto K, et al. Borderline pulmonary hypertension is associated with exercise intolerance and increased risk for acute exacerbation in patients with interstitial lung disease. BMC Pulm Med. 2019;19:167.
  14. Wallace, WD et al. Treatment of exercise pulmonary hypertension improves pulmonary vascular distensibility. Pulm Circ. 2018;8:2045894018787381.
  15. Acute Care Testing. ROC curves – what are they and how are they used? Available at https://acutecaretesting.org/en/articles/roc-curves-what-are-they-and-how-are-they-used. (Last accessed July 2020).
  16. Rose-Jones LJ, Mclaughlin VV. Pulmonary hypertension: types and treatments. Curr Cardiol Rev. 2015;11:73–
  17. About Pulmonary Hypertension. Types of PH. Available at https://phassociation.org/types-pulmonary-hypertension-groups/. (Last accessed July 2020).
  18. Hoeper MG and Gibbs SR. The changing landscape of pulmonary arterial hypertension and implications for patient care. Eur Respir Rev 2014;23:450–7.