(19) *EP002068889B1* (11) EP 2 068 889 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 38/20 (2006.01) A61K 31/70 (2006.01) (2006.01) (2006.01) 23.10.2019 Bulletin 2019/43 C07K 14/715 A61K 9/00 A61P 11/00 (2006.01) (21) Application number: 07836707.5 (86) International application number: (22) Date of filing: 10.08.2007 PCT/US2007/017800 (87) International publication number: WO 2008/021237 (21.02.2008 Gazette 2008/08) (54) ANAKINRA FOR USE IN THE TREATMENT OF BRONCHIOLITIS OBLITERANS SYNDROME ANAKINRA ZUR VERWENDUNG IN DER BEHANDLUNG VON BRONCHIOLITIS OBLITERANS SYNDROM ANAKINRA POUR L’UTILISATION DANS LE TRAITEMENT DU SYNDROME DE BRONCHIOLITE OBLITÉRANTE (84) Designated Contracting States: US-B1- 6 294 655 US-B1- 6 365 726 AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • CHUNG K F: "Cytokines as targets in chronic SI SK TR obstructive pulmonary disease.", CURRENT DRUG TARGETS JUN 2006 LNKD- (30) Priority: 10.08.2006 US 836760 P PUBMED:16787167, vol. 7, no. 6, June 2006 04.01.2007 US 878385 P (2006-06), pages 675-681, XP009159291, ISSN: 16.03.2007 US 907028 P 1389-4501 • WOO ET AL.: ’VCAM-1 Upregulation Via (43) Date of publication of application: PKCdelta-p38 kinase-Linked Cascade Mediates 17.06.2009 Bulletin 2009/25 the TNF-alpha-Induced Leukocyte Adhesion and Emigration in the Lung Airway Epithelium’ AM. J. (73) Proprietor: Levitt, Roy C. PHYSIOL. LUNG CELL MOL. vol. 288, 2005, pages Coconut Grove, FL 33133 (US) L307 - L316, XP008103286 • QIN ET AL.: ’In Vivo Evaluation of a Morholino (72) Inventor: Levitt, Roy C. Antisense Oligomer Directed Against Tumor Coconut Grove, FL 33133 (US) Necrosis Factor-alpha’ ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT vol. 10, 2000, pages (74) Representative: Gevers & Orès 11 - 16, XP008103355 Immeuble le Palatin 2 • STENTON ET AL.: ’Inhibition of Allergic 3-5 Cours du Triangle Inflammation in the Airway Using Aerosolized 92036 Puteaux La Défense cedex (FR) Antisense to Syk Kinase’ THE JOURNAL OF PHYSIOLOGY vol. 169, 2002, pages 1028 - 1036, (56) References cited: XP008103309 WO-A1-99/27086 WO-A1-2004/098596 • BOLON ET AL.: ’Impact of Systemic Antagonism WO-A2-00/62736 WO-A2-01/02571 of Interleukin-1 (IL-1) or Tumor Necrosis Factor WO-A2-01/40291 WO-A2-2005/080338 (TNF) on Arthritis Induced by Intra-Articular WO-A2-2006/059108 US-A1- 2004 010 119 Instillation of IL-1 beta, TNF-alpha, or Lipopolysaccharide (LPS)’ ANNALS OF RHEUMATIC DISEASES vol. 62, no. SUPPL. 1, July 2003, page 123, XP008103302 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 2 068 889 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 068 889 B1 Remarks: The file contains technical information submitted after the application was filed and not included in this specification 2 1 EP 2 068 889 B1 2 Description response to certain stimuli that act on receptors on the membrane of target cells. These regulatory proteins are Field of the Invention generally described in references such as Cytokines, A. Mire-Sluis and R. Thorne, ed., Academic Press, New [0001] The current invention relates to the use of proin- 5 York, (1998). Recently, scientists have come to suspect flammatory cytokine inhibitors to treat inflammatory dis- that proinflammatory cytokines, in particular tumor necro- orders of the lower airways. sis factor alpha (TNF-alpha), may be the driving force behind numerous lower airways disorders. Increased Related Application levels of cytokines such as interleukin (IL)-6, IL-1beta, 10 tumor necrosis factor-alpha (TNF-alpha) and IL-8 have [0002] This application claims the benefit of U.S. Pro- been measured in sputum, with further increases occur- visional Application 60/836,760 (filed August 10, 2006), ring during exacerbations. Cytokines are also implicated U.S. Provisional Application 60/878,385 (filed January 4, involved in tissue remodeling. The cytokine profile seen 2007) and U.S. Provisional Application 60/907,028 (filed in COPD is unique to these inflammatory disorders and March 16, 2007), all of which are herein incorporated by 15 differs from allergic disorders. reference in their entirety. [0006] Numerous investigators have reported a poten- tial role for nonallergic proinflammatory cytokines such Background of the Invention as IL-8, IL-6, IL-1, and TNF in lower airways inflammatory disorders including COPD. IL-1 promotes inflammation [0003] Chronic Obstructive Pulmonary Disease 20 by recruiting neutrophils to the lung. Inflammation per- (COPD) is a major cause of morbidity and mortality world- sists with the release by neutrophils of additional IL-1 that wide. It is estimated that by 2020 COPD will be the third upregulates the expression of other pro-inflammatory cy- leading cause of mortality and fifth leading cause of mor- tokines, chemokines, additional downstream inflamma- bidity (Malhotra et al. (2006) Expert. Opin. Emerg. Drugs tory mediators such as e.g., neutrophil elastase (NE), 11(2):275-91). Overall health status and mortality are 25 mucous overproduction, tissue fibrosis, airways remod- tightly associated with the severity of airflow obstruction. eling, and adhesion molecules including E-selectins and COPD is an inflammatory condition and neutrophil ICAM-1 that recruit additional neutrophils (Suzuki et al. elastase has long been considered a significant mediator (2002) Current Drug Targets - Inflammation & Allergy of the disease. Often, subjects are inadequately treated, 1:117-26). Importantly, this IL-lb dependent "positive resistant, or refractory to current therapies. COPD affects 30 feedback" mechanism is thought to be critical in propa- the peripheral airways and is associated with chronic ir- gating the underlying inflammation in various pulmonary reversible obstruction of expiratory flow. This inflamma- inflammatory disorders, likely including CF. tory disorder of the small airways includes chronic bron- [0007] Another mechanism of IL-lb mediated inflam- chitis (mucus hypersecretion with goblet cell and submu- mation is the promotion of reactive oxygen species via cosal gland hyperplasia) and emphysema (destruction 35 xanthine oxidase upregulation thought important in tis- of airway parenchyma) associated with fibrosis and tis- sue fibrosis (Komaki (2005) Pulm. Pharmacol. Ther. sue damage. 18(4):297-302). TGF-beta1 is believed to play an impor- [0004] Historically, treatments of COPD largely fo- tant role in the pathogenesis of a number of chronic in- cused on addressing the symptoms of the condition es- flammatory and immune lung diseases, including asth- pecially exacerbations through acute antibiotic therapy, 40 ma, chronic obstructive pulmonary disease, and pulmo- inhaled or oral corticosteroids, bronchodilators and more nary fibrosis. IL-1beta-stimulated transcription of TGF- recently anti-cholinergics. While antibiotics are useful in beta1 may play an important role in CF, other pulmonary treating the acute exacerbations of COPD, antibiotics inflammatory disorders, and sinusitis (Lee (2006) J. Im- alone do not eliminate the underlying often-chronic in- munol. 76(1):603-15). flammation. Inhaled and oral corticosteroids have been 45 [0008] Increases in IL-lb are closely associated with used extensively to nonspecifically reduce the inflamma- the severity of pulmonary disease (Chung (2006) Curr. tory conditions of the lower airways that play a critical Drug Targets. 7(6):675-81). IL-lb is produced by macro- role in COPD, but corticosteroids can cause serious side phages or epithelial cells upon exposures to stimuli like effects. These include thinning of membranes, bleeding, cigarette smoke or lipopolysaccharide from bacterial col- growth retardation in children, and osteoporosis; and 50 onization in cystic fibrosis (CF). IL-lb also stimulates TN- when possible must be avoided or cautiously used with Falpha expression and many other downstream cy- patients that have certain conditions, such as gastroin- tokines and chemokines and (de Boer (2005) DDT 10(2) testinal ulcers, renal disease, hypertension, diabetes, os- 93-106) thus may regulate inflammatory pathways in the teoporosis, thyroid disorders, and intestinal disease. airways. Increased IL-1 is well documented in CF, smok- Nonetheless, steroids provide limited benefit in lower air- 55 ers and in COPD patients at baseline and increases fur- ways inflammatory disease associated with proinflam- ther with disease exacerbations (Chung (2005) Curr. matory cytokines. Drug Targets Inflamm. Allergy 4(6):619-25; Dal Negro et [0005] Cytokines are regulatory proteins produced in al. (2005) COPD 2(1):7-16; Tomaki et al. (2007) 3 3 EP 2 068 889 B1 4 20(5):596-605; Gessner et al. (2005) Respir. Med. olar walls are progressively destroyed. This suggests cell 99(10):1229-40; Chung (2001), Eur. Respir. J. Suppl death by necrosis and/or apoptosis. Based on a study 34:50s-59s; Rusznak et al. (2000) Am. J. Respir. Cell concerning apoptosis-related factors in COPD patients, Mol. Biol. 23:530-6). Pulmonary function tests (PFTs) are researchers have suggested that TNF-alpha, IL-6 and strongly associated with lung IL-1 lung levels (Ekberg- 5 inflammation maybe associated with progression of Jansson et al. (2001) Respir Med 95:363-73; Joos et al. COPD (Yasuda (1998) Respir. Med. 92(8): 993-9). Ad- (2001) Thorax 56:863-6). Recently, IL-1 and IL-IRa hap- ditionally, IL-4 and TNF-alpha were found to be the only lotypes (genes) have been shown to differ in subjects two cytokines present in the inflammatory infiltrate of pa- with rapidly declining PFTs (Hegab et al.