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Treatment of Lupus Nephritis Using Laquinimod Behandlung Von Lupus Nephritis Mit Laquinimod Traitement De La Néphrite De Lupus À L’Aide Du Laquinimod

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Treatment of Lupus Nephritis Using Laquinimod Behandlung Von Lupus Nephritis Mit Laquinimod Traitement De La Néphrite De Lupus À L’Aide Du Laquinimod (19) TZZ Z_T (11) EP 2 542 078 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/47 (2006.01) A61K 31/4704 (2006.01) 07.10.2015 Bulletin 2015/41 A61K 31/5355 (2006.01) A61K 31/573 (2006.01) A61P 37/00 (2006.01) (21) Application number: 11751295.4 (86) International application number: (22) Date of filing: 02.03.2011 PCT/US2011/026879 (87) International publication number: WO 2011/109526 (09.09.2011 Gazette 2011/36) (54) TREATMENT OF LUPUS NEPHRITIS USING LAQUINIMOD BEHANDLUNG VON LUPUS NEPHRITIS MIT LAQUINIMOD TRAITEMENT DE LA NÉPHRITE DE LUPUS À L’AIDE DU LAQUINIMOD (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB WO-A2-2010/001257 US-A1- 2007 218 062 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO US-A1- 2007 293 537 US-A1- 2008 118 553 PL PT RO RS SE SI SK SM TR US-A1- 2009 156 542 Designated Extension States: BA ME • Anonymous: "Laquinimod study in systemic lupus erythematosus (SLE) patients with active (30) Priority: 03.03.2010 US 339363 P lupus nephritis", , 4 March 2010 (2010-03-04), XP002698011, Retrieved from the Internet: URL: (43) Date of publication of application: http://www.clinicaltrials.gov/ct2/show 09.01.2013 Bulletin 2013/02 /NCT01085097?term=laquinimod&rank=1 [retrieved on 2013-05-31] (73) Proprietor: Teva Pharmaceutical Industries Ltd. • FOR THE LAQ/5062 STUDY GROUP ET AL: 49131 Petach-Tikva (IL) "Effect of laquinimod on MRI- monitored disease activity in patients with relapsing-remitting (72) Inventors: multiple sclerosis: a multicentre, randomised, • HAVIV, Asi double-blind, placebo-controlled phase IIb 76802 (IL) study", THE LANCET, LANCET LIMITED. • TARCIC, Nora LONDON, GB, vol. 371, no. 9630, 21 June 2008 Modiin (IL) (2008-06-21), pages 2085-2092, XP022758605, ISSN: 0140-6736, DOI: 10.1016/S0140-6736(08) (74) Representative: D Young & Co LLP 60918-6 [retrieved on 2008-06-19] 120 Holborn London EC1N 2DY (GB) Remarks: Thefile contains technical information submitted after the application was filed and not included in this specification 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 2 542 078 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 542 078 B1 Description Background 5 Lupus Nephritis (LN) [0001] Lupus nephritis (LN), characterized by inflammation of the kidney, is a complication which occurs in a subpop- ulation of patients with Systemic Lupus Erythematosus (SLE) and is one of the most serious complications caused by SLE. (MedlinePlus) 10 [0002] SLE is a debilitating autoimmune disease of great clinical diversity and can manifest itself in different ways and lead to a number of complications, e.g., arthritis, arthralgia, and myalgia, depending on the patient and the parts of the body affected. The precise etiology of SLE has not yet been determined, but hormonal, genetic, viral and environmental factors may precipitate the disease. SLE prevalence varies across ethnicities and geographic regions with an occurrence rate of 15 to 50 cases per 100,000 persons. SLE is most common in women of childbearing age (15-44) with a female- 15 to-male ratio varying from 4.3 to 13.6 (Petri, 2002). Virtually all body systems may be involved, including the muscu- loskeletal, mucocutaneous, cardiovascular, neurological, respiratory, renal, ophthalmic hematological and gastrointes- tinal systems. [0003] Due to the great clinical diversity and idiopathic nature of SLE, management of idiopathic SLE depends on its specific manifestations and severity. (The Merck Manual, 1999) Therefore, medications suggested to treat SLE generally 20 are not necessarily effective for the treatment of all manifestations of and complications resulting from SLE, e.g., LN. [0004] LN usually arises early in the disease course, within 5 years of diagnosis. The pathogenesis of LN is believed to derive from deposition of immune complexes in the kidney glomeruli that initiates an inflammatory response (Brent, 2008). [0005] An estimated 30-50% of patients with SLE develop nephritis that requires medical evaluation and treatment. 25 LN is a progressive disease, running a course of clinical exacerbations and remissions. Early detection and treatment can significantly improve renal outcome and prognosis. Although over the last decades, treatment of LN has been greatly improved, 5 and 10-year survival rates are documented as 85% and 73%, respectively (Brent, 2008). LN morbidity is related to the renal disease itself, as well as to treatment-related complications. [0006] Renal biopsy is considered for any patient with SLE who has clinical or laboratory evidence of active nephritis, 30 in order to determine the histological type as well as the appropriate treatment management and prognosis. (Bevra, 2001; Brent, 2008) [0007] The histological classification of LN was revised by the International Society of Pathology/Renal Pathology Society (ISN/RPS) in 2003 and is based on light microscopy, immunofluorescence, and electron microscopy findings from renal biopsy specimens (Foster, 2004). These classifications describes 6 major classes of LN: Class I and II - 35 mesangial LN, Class III and IV - proliferative LN, class V - membranous LN and class VI - advanced sclerosis LN. The ISN/RPS classifications were based on earlier classifications by the World Health Organization (WHO) published in 1974 and 1982. [0008] There is no definitive treatment or cure for LN. The principal goals of therapy is to normalize renal function, urine sediment and proteinuria, reduce the frequency of relapses or prevent the progressive loss of renal function through 40 mild, moderate and severe renal impairment to end stage renal disease (ESRD) requiring dialysis or kidney transplan- tation. Therapy varies pending on the histopathological findings as well as the clinical manifestations. [0009] Corticosteroids and cytotoxic or immunosuppressive agents, particularly cyclophosphamide, azathioprine, or mycophenolate mofetil (MMF) are the standard of care for patients with aggressive proliferative LN, while less aggressive treatment options may be considered for purely membranous LN or mesangial LN. Angiotensin Converting Enzyme 45 (ACE) inhibitors or Angiotensin II Receptor Blockers (ARBs) may control blood pressure and reduce proteinuria. [0010] Most of the above mentioned treatments are not specifically indicated for the treatment of SLE/LN and treatment protocols vary. [0011] Treatment of accompanying SLE signs, symptoms, and complications may additionally include a combination of NSAIDs, antimalarial agents, antihypertensives, calcium supplements or bisphosphonate, anti-coagulants and others. 50 [0012] While many patients fail to respond or respond only partially to the standard of care medications listed above, the long-term use of high doses of corticosteroids and cytotoxic therapies may have profound side effects such as bone marrow depression, increased infections with opportunistic organisms, irreversible ovarian failure, alopecia and increased risk of malignancy. Infectious complications coincident with active SLE and its treatment with immunosuppressive med- ications are the most common cause of death in patients with SLE. 55 [0013] There is, therefore, a need for alternative therapies with better risk-benefit profiles for the treatment of lupus nephritis. [0014] Laquinimod is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-Wollheim, 2005). Laquinimod and its 2 EP 2 542 078 B1 sodium salt form are described, for example, in U.S. Patent No. 6,077,851. The effects of laquinimod on lupus nephritis have not been reported. [0015] WO 2010/001257 provides a crystalline form, as well as amorphous and polymorphic forms of laquinimod sodium, process for the preparation, pharmaceutical compositions, and method of treating thereof. 5 [0016] US 2007/218062 provides methods of treating lupus by administering a non-depleting CD4 antibody and another compound used to treat lupus. D2 also provides a method of treating lupus nephritis by administering a non-depleting CD4 antibody, and a method of treating multiple sclerosis by administering a non-depleting CD4 antibody, optionally in combination with another compound used to treat MS. 10 Mycophenolate mofetil (MMF) [0017] Mycophenolate mofetil (MMF), sold under the brand name CellCept ®, is the 2-morpholinoethyl ester of myco- phenolic acid (MPA), an immunosuppressive agent, and inosine monophosphate dehydrogenases (IMPDH) inhibitor. The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoehtyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7- 15 methyl-3-oxo-5-isogenzofur.anyl)-4-methyl-4-hexenoate. It has an empirical formula of 23CH31NO7 and a molecular weight of 433.50. CellCept ® is indicated for prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants (Physician’s Desk Reference, 2009). [0018] CellCept® is available for oral administration as capsules containing 250 mg of mycophenolate mofetil, tablets containing 500 mg of mycophenolate mofetil, and as a powder for oral suspension, which when constituted contains 20 200 mg/mL mycophenolate mofetil. CellCept® is also available for Intravenous administration as a sterile white to off- white lyophilized powders in vials containing mycophenolate mofetil hydrochloride. Each vial of IV contains the equivalent of 500 gm MMF as the hydrochloride salt. The recommended dose for CellCept® is 1 g administered orally or via IV (over no less than 2 hours) twice daily (daily dose of 2 g) for use in renal transplant patients. The recommended dose of CellCept® oral suspension is 600 mg/m2 administered twice daily up to a maximum daily dose of 2 g/1-mL oral 25 suspension (Physician’s Desk Reference, 2009).
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