(19) TZZ __¥_T (11) EP 2 185 183 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 38/22 (2006.01) C07K 14/47 (2006.01) 16.03.2016 Bulletin 2016/11 A61F 13/00 (2006.01) A61P 43/00 (2006.01) (21) Application number: 08804032.4 (86) International application number: PCT/EP2008/062067 (22) Date of filing: 11.09.2008 (87) International publication number: WO 2009/034134 (19.03.2009 Gazette 2009/12) (54) USE OF NATRIURETIC PEPTIDES FOR TREATING ANGIOEDEMA SYNDROMES VERWENDUNG VON NATRIURETISCHEN PEPTIDEN ZUR BEHANDLUNG VON ANGIOÖDEMEN UTILISATION DE PEPTIDES NATRIURÉTIQUES POUR LE TRAITEMENT DES SYNDROMES DE L’OEDÈME DE QUINCKE (84) Designated Contracting States: (74) Representative: von Kreisler Selting Werner - AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Partnerschaft HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT von Patentanwälten und Rechtsanwälten mbB RO SE SI SK TR Deichmannhaus am Dom Bahnhofsvorplatz 1 (30) Priority: 11.09.2007 EP 07116164 50667 Köln (DE) 08.01.2008 EP 08100213 (56) References cited: (43) Date of publication of application: EP-A- 0 369 474 WO-A-2004/022579 19.05.2010 Bulletin 2010/20 WO-A-2006/110743 WO-A1-88/06596 (73) Proprietor: CardioPep Pharma GmbH Remarks: 30625 Hannover (DE) Thefile contains technical information submitted after the application was filed and not included in this (72) Inventor: FORSSMANN, Wolf-Georg specification 79697 Wies-Wambach (DE) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 185 183 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 185 183 B1 2 Description intubation was required. The occurrence of angioedema varied from a few days to several months. In one case a [0001] The present invention relates to the use of latency of 8 years was recorded, demonstrating that this urodilatin for the manufacture of a medicament for the kind of adverse drug reaction is actually hard to be de- treatment of angioedema. 5 tected. During the administration of ACE-inhibitors ede- [0002] Natriuretic peptides are a family of related pep- ma could recur for up to 20 times. Angiotensin II receptor tides that regulate salt and water balance in the body. antagonists (ARB) are also capable of introducing an- These peptides are originated in different tissues, have gioedema, but the course is usually milder (Schuster et slight variations in their amino acid sequence and in their al., Schweiz. Med. Wochenschr., 1999, 129(9):362-369). capability to induce natriuresis and diuresis in the kidney. 10 This might be due to the fact that ARB inhibits the VEGF- 4 members are known in the human body: atrial natriu- induced vascular hyperpermeability (Sano et al., Arteri- retic peptide (ANP), brain natriuretic peptide (BNP), C- oscl. Thromb. Vasc. Biol., 2006, 26:2673-2680) but in- type natriuretic peptide (CNP), and urodilatin (URO, or crease the bradykinin-induced angioedema. ularitide). While ANP and BNP are distributed in the heart [0005] Besides ACE inhibitors and angiotensin II-re- and brain, CNP is released from the brain and endothelial 15 ceptor antagonists there are also reports on other mech- cells and urodilatin from the kidney. These peptides are anisms for drug-induced angioedema. Among those are part of a hormonal system that keeps a fine balance of cyclooxygenase inhibitors, such as Aspirin (COX-1 in- water and blood volume and pressure in the body. Urodil- hibitor) and rofecoxib (COX-2), which are known to in- atin, secreted directly by kidney cells, is one of the hor- duce asthma, urticaria and angioedema. The aspirin-in- mones responsible for the inhibition of water and Na +-re- 20 duced angioedema is an aspirin-related hypersensitivity absorption in the kidney’s collecting duct. Urodilatin is that is often associated with aspirin-intolerant asthma, also known for its heart protective abilities and has been which causes chronic overproduction of cysteinyl leuko- studied for the use in treatment of renal failure and con- trienes. Ketoprofen,another non-opiodanalgetic, inhibits gestive heart failure (US 5,571,789; US 6,831,064; Elsn- prostaglandins and thus, the production of cyclooxyge- er et al., Am. Heart J. 1995, 129(4):766-773; Forssmann 25 nase, is also known for inducing life-threatening asthma, et al., Clinical Pharmacology and Therapeutics 1998, urticaria and angioedema (Kim et al., Curr. Opin. Allergy 64(3):322-330); Kentsch et al., Eur. J. Clin. Invest. 1992, Clin. Immunol., 2006, 6(4):266-270; Marshall, Ann. Phar- 22(10):662-669; Kentsch et al., Eur. J. Clin. Invest. 1995, macother., 2005,39(5):944-908; Grzelewska-Rzymows- 25(4):281-283). ka et al., Allergol. Immunopathol. (Madrid), 1988, [0003] Besides natriuretic peptides ACE inhibitors and 30 16(5):305-308; Higashi et al., Allergy Clin. Immunol., angiotensin II-receptor blockers are used as therapeutic 2002, 110(4):666-667; Asero, Ann. Allergy Asthma Im- drugs in patients with hypertension and congestive heart munol., 2006, 37(2):187-189; Frith et al., Lancet, 1978, failure. But an often under-recognized side effect of ACE 14(2):847-888). inhibitors as well as angiotensin II receptor antagonists [0006] Hereditary and acquired angioedemas can also is the development of angioedema. This is a particularly 35 result from a deficiency of the first complement compo- important side effect to realize since it can be life threat- nent (C1)- or plasma protease inhibitor. The most obvi- ening if not treated properly. The term angioedema is ous role of the C1-Inhibitor is the prevention of excessive used to describe an abrupt and short lived swelling of the vascular permeability where bradykinin is a key player. skin, mucuos membranes including upper respiratory The lack of this enzyme leads to recurrent subcutaneous and oropharyngeal areas. Although it can occur in any 40 and submucosal angioedema. Acquired C1-esterase in- part of the body, it most frequently involves the head, hibitor deficiency has been observed in association with neck, lips, mouth, tongue, larynx, pharynx, and subglottal lymphoproliferative, disorders, malignancy, autoimmune areas and rarely accompanied with urticaria. It has been diseases and infections (Davis, Immunol. Allergy Clin. demonstrated that bradykinin levels were 12-fold in- North Am., 2006, 26(4):633-651; Agostoni and Cicardi, creased during acute angioedema attacks (heredetary 45 Medicine (Baltimore), 1992, 71(4):206-215; Longhurst et or acquired). ACE-Inhibitors extend the vasodilating ef- al., Clin. Exp. Immunol., 2006, 147:11-17). fect of bradykinin due to the inhibition of its breakdown [0007] WO8806596 A1 discloses the use of a fragment (Flattery and Sica, Prog. Cardiovasc. Nurs. 2007, of the natriuretic peptide urodilatin for the preparation of 22(1):47-51; Sica, J. Clin. Hypertens. 2004,medicaments for treating generalised edema, lung ede- 6(7):410-416; Campbell, Hypertension, 502003,ma, brain edema, primary and secondary lymphinter alia 41:383-389; Hedner et al., Br. Med. J., 1992,generalised edema, lung edema, brain edema, primary 304:941-946; Cupido and Rayner, S. Afr. Med. J, 2007, and secondary lymph edema. 97(4):244-245). [0008] Angioedema is an underestimated clinical prob- [0004] The Swiss Drug Monitoring Center (SANZ) re- lem, since many cases are nonallergic reactions such as ported on 98 cases of drug-induced angioedema, 94 cas- 55 bradykinin-induced angioedema caused either by genet- es of ACE inhibitor-induced and 4 cases of angiotension ic defects or by ACE-inhibitors. Some angioedema which II-receptor antagonist-induced angioedema. 28 of these manifest in the larynx are life threatening. The vast ma- cases were classified severe and in three patients even jority of angioedema are caused by ACE-inhibitors block- 2 3 EP 2 185 183 B1 4 ing the renin-arigiotensin-aldosterone system (RAAS). induced angioedema. So far ACE inhibitors and angiotensin II antagonists are [0013] Natriuretic peptides, such as Urodilatin, are fur- the drugs of choice for patients associated with cardio- ther effective in treating heart failure patients. A new vascular diseases, which constitute the leading cause of method for administering urodilatin that is surprisingly death in the United States regardless of gender or eth- 5 effective for the purpose of treating angioedema is one nicity. Among these diseases, congestive heart failure further embodiment of the present invention. (CHF) is of particularly high prevalence. This life-threat- [0014] As used herein, the term "angioedema" encom- ening condition is accompanied by great financial impact. passes all types of cardiovascular conditions that, re- So far, ACE inhibitors and angiotensin II-antagonists gardless of their cause, are generally recognized by a have been used to counteract this threat more or less 10 physician as angioedema, which includes but are not lim- successfully. Both groups of inhibitors are known to in- ited to hereditary angioedema, acquired angioedema, duce yet another threat, angioedema, ACE inhibitors and particularly drug-induced angioedema. These con- more than AII-antagonists. Angioedema can lead to rapid ditions typically involve weakened heart function com- swelling of the skin, mucosa and submucosal tissue and bined with a build-up of body fluid resulting in abrupt and becomes life-threatening whenever airway obstruction 15 short lived swelling of the skin, mucuos membranes in- and suffocation occurs. cluding upper respiratory and oropharyngeal areas. Al- [0009] Thus, there is a new strong need for providing though it can occur in any part of the body, it most fre- new and more effective methods for treating heart failure quently involves the head, neck, lips, mouth, tongue, lar- without the negative side effects of angioedema.