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Novartis to request conditional marketing authorisation in EU



Novartis has announced it will shortly submit a revised filing package, including new data analyses, for re-examination for conditional approval of RLX030 (serelaxin) for acute heart failure by the Committee for Medicinal Products for Human Use (CHMP) following a negative opinion issued today. In accordance with CHMP process a revised opinion could be granted in Q2 2014.
The file for regulatory approval is continuing review by the Food and Drug Administration (FDA) in the US where RLX030 was granted Breakthrough Therapy designation status in June 2013.[2] Reviews are also underway with health authorities in 16 countries around the world.
“With the results from RELAX-AHF showing significant mortality  benefits  with RLX030 in patients with AHF and recognising that there had been no treatment breakthroughs in this area for 20 years, Novartis took a decision to file for regulatory approval,” said David Epstein, Division Head of Novartis Pharmaceuticals. “It has become apparent through the review process and in accordance with advice we’ve received that the current evidence package may be more compatible with an application for conditional approval in the EU. We look forward to providing a revised package for review to the CHMP shortly.”
In September 2013 the second phase III study RELAX-AHF-2 started recruitment of the over 6000 patients who are expected to be enrolled. The goal is to replicate the key findings of RELAX-AHF and the study will assess cardiovascular mortality as the primary endpoint. This would be one of the largest and most robust programs undertaken by a company for an AHF drug.
RLX030, a relaxin receptor agonist,[3] is a form of a naturally occurring hormone (human relaxin 2) present in both men and women which rises in women during pregnancy to help the body cope with the additional cardiovascular demands.[4,5] RLX030 is thought to have multiple effects including relaxing the blood vessels, reducing fluid buildup and protecting the heart and vital organs from the cascade of damage that occurs during an AHF episode.[3,6–9] More than 1.5 million AHF episodes happen every year in Europe alone,[10,11] with 1 in 5 patients not surviving a year afterwards.[12–17]
RLX030 was studied in the phase III RELAX-AHF trial, which showed it had both short and longer-term effects, relieving symptoms and reducing the rate of heart failure worsening.[1] In the trial patients who received RLX030 also had a 37% reduction in mortality at six months after an AHF episode compared to those who received conventional treatment.[1] Data from clinical trials has shown that RLX030 was generally well tolerated.[1,18]
About acute heart failure
Heart failure is a debilitating and potentially life-threatening condition where the heart cannot pump enough blood around the body. More than 15 million people suffer from heart failure globally and this number is increasing.[10,19] The condition is often fatal when patients have one or repeated acute heart failure episodes.[19] As an AHF episode approaches, patients become severely breathless and rapidly gain weight due to fluid build-up in the lungs and around the body. This is often compared to the sensation of drowning.[20]
Patients experiencing an AHF episode need to be rushed to the emergency room for urgent treatment, making AHF the most common cause of hospitalisation in patients over 65 years.[10,21] Currently 20 to 30% of patients die within 1 year after experiencing an AHF episode, and 3-4% do not survive the initial episode.[12–17] This means AHF causes more deaths than some advanced cancers, including breast and bowel cancer.[22]
  1. Teerlink et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet, 2013;381:29-39
  2. Novartis press release ‘FDA grants Breakthrough Therapy designation to Novartis’ serelaxin (RLX030) for acute heart failure’ issued on June 21, 2013
  3. Du X., et al. Cardiovascular effects of relaxin: from basic service to clinical therapy. Nat. Rev. Cardiol. 7, 48-58 (2010);
  4.  Teichman S et al. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev. 2009;14:321-329
  5. Teichman SL et al. Relaxin: Review of biology and potential role in treating heart failure. Curr Heart Fail Rep. 2010;7:75-82
  6. Fijalkowska A & Torbicki A. Role of cardiac biomarkers in assessment of RV function and prognosis in chronic pulmonary hypertension. Eur Heart J Supplements 2007;9(Supplement H):H41-H47
  7. Shlipak MG, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005;352:2049-60
  8. Metra M, et al. Hemoglobin concentration in acute decompensated heart failure J Am Coll Cardiol 2013;61:196-206.
  9. Waikar SS, et al. Can we rely on blood urea nitrogen as a biomarker to determine when to initiate dialysis. Clin J Am Soc Nephrol 2006;1:903-904
  10. Gheorghiade M, Pang P, Acute heart failure syndromes, Journal of the American College of Cardiology 2009; 53 (7):557-73
  11. Novartis data on file, approximately 1.6 million in the top 5 EU markets
  12. Mosterd A, Hoes, A, Clinical epidemiology of heart failure, Heart 2007;93:1137-1146
  13. Harrison’s ‘Principles of Internal Medicine’, Seventeenth Edition pages 1442 – 1455
  14. Hunt S et al. Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. Circulation. 2009;119:e391-e479
  15. Lloyd-Jones et al. Heart disease and stroke statistics–2010 update: a report from the American Heart Association. Circulation. 2010;121:e46-215
  16. National heart failure audit: April 2010 – March 2011, NICOR and The British Society for Heart Failure, commissioned by the Healthcare Quality Improvement Partnership (HQIP)
  17. O’Connor M et al. Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: Results from efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) program, American Heart Journal 2010;159(5): 842-849
  18. Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet. 2009;373:1429 -1439
  19. Zannad F. et al, Heart failure burden and therapy, Europace 2009, 11; v1-v9.
  20. Irish Heart Foundation. Living well with heart failure patient booklet. Accessed November 2013
  21. Felker et al. Clinical trial of pharmacological therapies in acute heart failure syndromes, Circ Heart Fail. 2010;3:314-325
  22. Stewart et al. More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure Eur J Heart Fail. 2001;3:315322

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