Serelaxin

Serelaxin
Systematic (IUPAC) name
L-Serine, L-α-aspartyl-L-seryl-L-tryptophyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-valylL-isoleucyl-L-lysyl-L-leucyl-L-cysteinylglycyl-L-arginyl-L-α-glutamyl-L-leucyl-L-valyl-L- arginyl-L-alanyl-L-glutaminyl-L-isoleucyl-L-alanyl-L-isoleucyl-L-cysteinylglycyl-L- methionyl-L-seryl-L-threonyl-L-tryptophyl-, cyclic (11→11'),(23→24')-bis(disulfide) with 5-oxo-L-prolyl-L-leucyl-L-tyrosyl-L-seryl-L-alanyl-L-leucyl-L-alanyl-L-asparaginyl-L-lysyl-L- cysteinyl-L-cysteinyl-L-histidyl-L-valylglycyl-L-cysteinyl-L-threonyl-L-lysyl-L-arginyl-L- seryl-L-leucyl-L-alanyl-L-arginyl-L-phenylalanyl-L-cysteine cyclic (10'→15')-disulfide
Clinical data
  • N/A
  • Investigational
Intravenous
Identifiers
99489-94-8
C01DX21
Chemical data
Formula C256H408N74O74S8
5963 g/mol

Serelaxin (RLX030) is an investigational drug for the treatment of acute heart failure (AHF), targeting the relaxin receptor. Serelaxin is a recombinant form of human relaxin-2, a hormone that (among other functions) is produced during pregnancy and mediates the haemodynamic changes that occur during this time,[1][2] such as increased blood output of the heart and blood flow in the kidney.[3] Human-relaxin-2 mediates vasodilation (widening of blood vessels) by increasing the production of nitric oxide (NO), a potent vasodilator.[4] Activation of the relaxin receptor RXFP1 activates several enzymes in a phosphorylation cascade that eventually results in the activation of NO synthase in endothelial cells and the subsequent production of NO.[5] Relaxin can also bind to a secondary receptor, endothelial B receptor, which is upregulated as a result of the previous pathway.[6] Relaxin binding to endothelial B receptor on endothelial cells also induces vasodilation.[7]

Relaxin causes vasodilation by an indirect mechanism, where it inhibits the potent vasoconstrictors angiotensin II and endothelin.[8] In addition to vasodilation, the effects of relaxin are also seen in the kidneys, by significantly increasing creatinine clearance,[9] which is a measure of kidney function, as well as increased renal blood flow.[7] Relaxin also functions as a cardiac stimulant.[5] Studies have demonstrated that relaxin increases calcium sensitivity of cardiac myofilaments as well as increasing phosphorylation of the myofilaments by protein kinase C (PKC).[10] These modifications both function to increase the force generated by the myofilaments without increasing the energy consumption of the cardiac myocytes.[10] Thus relaxin and serelaxin can increase stroke volume, the amount of blood pumped per heart beat, without increasing the energy demand on the already strained heart of acute heart failure patients.

Acute heart failure

Serelaxin is currently undergoing clinical trials in patients with acute heart failure,[11] and is being developed by Novartis. Serelaxin has completed several clinical trials as a therapy for AHF. Phase I trials examined safety and tolerability,[12] while phase II trials evaluated its haemodynamic effects and symptom relief. The Pre-RELAX-AHF phase II trial administered a dose of 30 µg/kg/day and showed a decrease in blood pressure, improved dyspnoea, and increased renal blood flow.[7] In phase III the RELAX-AHF trial gave a 48hr intravenous infusion of the same dose.[13] It significantly improved patients' dyspnoea, resulted in a 30% reduction in worsening of heart failure symptoms, a decreased hospital stay and a reduction in signs and symptoms of congestion.[11][14] The FDA has granted serelaxin "breakthrough therapy" designation, meant to expedite the development and review of drugs for life threatening conditions and is set to be reviewed in February 2014.[15]

References

  1. ↑ H. Spreitzer (4 March 2013). "Neue Wirkstoffe – Serelaxin". Österreichische Apothekerzeitung (in German) (5/2013): 36.
  2. ↑ Dirk Einecke (23 November 2012). "Schwangerschaftshormon gegen Herzschwäche" [Pregnancy hormone against heart failure]. ÄrzteZeitung.
  3. ↑ Conrad KP (August 2011). "Maternal vasodilation in pregnancy: the emerging role of relaxin". Am. J. Physiol. Regul. Integr. Comp. Physiol. 301 (2): R267–75. doi:10.1152/ajpregu.00156.2011. PMC 3154715. PMID 21613576.
  4. ↑ Tousoulis, D; Kampoli, A.; Papageorgiou, C.; Stefanadis, C. (2012). "The role of nitric oxide on endothelial function". Curr Vasc Pharmacol 10: 4–18.
  5. ↑ 5.0 5.1 Bathgate, R.; Halls, M., van der Westhuizen, E., Callander, G., Kocan, M. et al (2013). "The Relaxin family peptides and their receptors". Physiol Rev 93: 405–480. doi:10.1152/physrev.00001.2012.
  6. ↑ Miyares, M; Davis, K. (2013). "Serelaxin, a breakthrough investigational intravenous agent for acute heart failure". P.T 38: 606–611.
  7. ↑ 7.0 7.1 7.2 Teichman, S; Unemori, E.; Teerlink, J.; Cotter, G.; Metra, M. (2010). "Relaxin, review of biology and potential role in treating heart failure". Curr Heart Fail Rep 75: 75–82.
  8. ↑ Teichman, S; Unemori, E.; Dschietzig, T.; Conrad, K.; Voors, A. et al. (2009). "Relaxin, a pleiotropic vasodilator for the treatment of heart failure". Heart Fail Rev 14: 321–329. doi:10.1007/s10741-008-9129-3.
  9. ↑ Ponikowski, P.; Mitroic, V.; Rude, M.; Fernandez, A.; Voors, A. et al. (2014). "A randomized, double-blind, placebo controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure". Eur Heart J 35: 431–441. doi:10.1093/eurheartj/eht459.
  10. ↑ 10.0 10.1 Shaw, E.; Wood, P.; Kulpa, J.; Yang, F.; Summerlee, A. et al. (2009). "Relaxin alters cardiac myofilament function through a PKC-dependent pathway". Am J Physiol Heart Circ Physiol 297: 29–36.
  11. ↑ Du, X.; Hewitson, T.; Nguyen, M.; Samuel, C. (2014). "Therapeutic effects of Serelaxin in acute heart failure". Circ J 12: 6–19.
  12. ↑ King, A (2013). "Heart failure-promising data for Serelaxin". Nat Rev Cardiol 10: 3. doi:10.1038/nrcardio.2012.174.
  13. ↑ Filippatos, G.; Teerlink, J.; Farmakis, D.; Cotter, G.; Davison, B. et al. (2014). "Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial". Eur Heart 89: 90–103.
  14. ↑ Novartis Global. "FDA grants breakthrough designation to Novartis' serelaxin (RLX030) for acute heart failure". Novartis Global.