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WO2008031835A2 - Méthode de traitement de maladies auto-immunes à l'aide d'inhibiteurs de la voie vegf - Google Patents

Méthode de traitement de maladies auto-immunes à l'aide d'inhibiteurs de la voie vegf Download PDF

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Publication number
WO2008031835A2
WO2008031835A2 PCT/EP2007/059559 EP2007059559W WO2008031835A2 WO 2008031835 A2 WO2008031835 A2 WO 2008031835A2 EP 2007059559 W EP2007059559 W EP 2007059559W WO 2008031835 A2 WO2008031835 A2 WO 2008031835A2
Authority
WO
WIPO (PCT)
Prior art keywords
vegf
pathway inhibitor
treatment
disease
autoimmune disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2007/059559
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English (en)
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WO2008031835A3 (fr
Inventor
Peter C. Hiestand
Christian Schnell
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Novartis AG
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Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis AG filed Critical Novartis AG
Publication of WO2008031835A2 publication Critical patent/WO2008031835A2/fr
Publication of WO2008031835A3 publication Critical patent/WO2008031835A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to a method of treating a warm-blooded animal, especially a human, having an autoimmune disease, such as multiple sclerosis, peripheral neuritis, optical neuritis, amyotrophic lateral sclerosis and uveitis, comprising administering to said animal a therapeutically effective amount of a VEGF-pathway inhibitor, alone or in combination with further therapeutic measures, for example, those defined herein; the use of a VEGF-pathway inhibitor for the preparation of a medicament for the treatment of an autoimmune disease; and to a commercial package comprising a pharmaceutical composition together with instructions for its use in the treatment of an autoimmune disease.
  • an autoimmune disease such as multiple sclerosis, peripheral neuritis, optical neuritis, amyotrophic lateral sclerosis and uveitis
  • Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS) with an unknown pathophysiological cause.
  • CNS central nervous system
  • Clinical manifestations are associated with the infiltration of the central nervous system by immune-competent cells.
  • Specific T cell populations directed towards neuroantigens, such as myelin basic protein, can be demonstrated in the periphery. This suggests the involvement of an autoimmune response in the development of the disease.
  • immunosuppressive therapy including azathioprine and corticosteroids in order to limit the extent of the inflammatory process.
  • Immunosuppressive therapy of multiple sclerosis is only partially effective, and in most cases only offers a delay in disease progression despite anti-inflammatory and immunosuppressive treatment.
  • VEGF-pathway inhibitors are useful for the treatment of autoimmune diseases.
  • VEGF-pathway inhibitors includes, but is not limited to compounds which inhibit the VEGF receptor tyrosine kinase, compounds which inhibit a VEGF receptor and compounds binding to VEGF, and are in particular those compounds, proteins disclosed in WO 00/59509, WO 98/1 1223, WO 00/27819, EP 0 769 947, US 6,624,174, US2004-0224968, US 6,608,071 , US 6,448,277, US 6,706,731 , US2005- 0054692, US 2004-0224986, US2004-0248947, US2005-0032899, US2005-0096356, WO2004/005282, WO2004/052884, WO2006/059234 (disclosing e.g.
  • Bevacizumab, Sunitinib, Sorafenib or a compound disclosed in WO2006/059234 (disclosing e.g. Compound 1 used in the Examples below) or WO2005/070891 is employed.
  • autoimmune diseases means in particular multiple sclerosis, peripheral neuritis, optical neuritis, amyotrophic lateral sclerosis or uveitis.
  • the present invention provides a method for the treatment of multiple sclerosis.
  • Optic neuritis may be a first symptom associated with a high risk of clinically definite multiple sclerosis.
  • Compound 1 prevents clinical relapses when administered orally at a doses of 3 mg/kg/day in the chronic relapsing EAE model.
  • the present invention provides • a method for alleviating or delaying progression of the symptoms of a demyelinating disease, e.g. multiple sclerosis or Guillain-Barre syndrome, in a subject in need of such treatment, which method comprises administering to the subject an effective amount of a VEGF-pathway inhibitor;
  • a demyelinating disease e.g. multiple sclerosis or Guillain-Barre syndrome
  • a method for slowing the progression of physical disability or reducing the rate of clinical relapses in a subject with established multiple sclerosis which method comprises administering to the subject an effective amount of a VEGF-pathway inhibitor;
  • a method for reducing the development of brain lesions or the progression of central nervous system demyelination in a subject with suspected or established multiple sclerosis which method comprises administering to the subject an effective amount of a VEGF-pathway inhibitor;
  • a method for preventing or delaying a second demyelinating event e.g. a second attack of multiple sclerosis, in a subject in need thereof, which method comprises administering to the subject an effective amount of a VEGF-pathway inhibitor;
  • a method for treating optic neuritis in a subject in need thereof comprises administering to the subject an effective amount of a VEGF-pathway inhibitor.
  • treatment comprises the treatment of patients having an autoimmune disease or being in a pre-stage of said disease which effects the delay of progression of the disease in said patients.
  • the VEGF-pathway inhibitors may be administered as the sole active ingredient or in conjunction with, e.g., as an adjuvant to, other drugs, e.g., immunosuppressive or immunomodulating agents or other anti-inflammatory agents for the treatment of the aforementioned autoimmune disorders.
  • other drugs e.g., immunosuppressive or immunomodulating agents or other anti-inflammatory agents for the treatment of the aforementioned autoimmune disorders.
  • the compounds may be used in combination with interferons, e.g., pegylated or non-pegylated ⁇ -interferons, ⁇ -interferons or ⁇ - interferons, e.g., administered by subcutaneous, intramuscular or oral routes; an altered peptide ligand, such as Glatiramer, e.g., in the acetate form; monoclonal antibodies to various T-cell surface markers, e.g.
  • interferons e.g., pegylated or non-pegylated ⁇ -interferons, ⁇ -interferons or ⁇ - interferons
  • interferons e.g., pegylated or non-pegylated ⁇ -interferons, ⁇ -interferons or ⁇ - interferons
  • interferons e.g., pegylated or non-pegylated ⁇ -interferons, ⁇ -inter
  • natalizumab (Tysabri® or ANTEGREN®) or alemtuzumab; an ascomycin having immunosuppressive properties, e.g., ABT-281 , ASM981 , etc.; a steroid, e.g.
  • immunosuppressive monoclonal antibodies e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD58, CD80, CD86 or their ligands; other immunomodulatory compounds, e.g., a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g., an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4
  • a 4-pyridylmethyl- phthalazine derivative of formula I is administered in combination with interferon beta-1 b (marketed e.g. as Betaseron i®) or natalizumab (marketed e.g. as Tysabri®).
  • interferon beta-1 b marketed e.g. as Betaseron i®
  • natalizumab marketed e.g. as Tysabri®
  • the present invention pertains in another aspect to
  • a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a VEGF-pathway inhibitor and at least a second drug substance, e.g. as indicated above; and to
  • a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a VEGF- pathway inhibitor and b) at least a second drug substance, e.g. as indicated above.
  • the kit may comprise instructions for its administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g., a compound of the invention and a second drug substance, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g., a compound of the invention and a second drug substance, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g., the administration of three or more active ingredients.
  • a VEGF-pathway inhibitor The person skilled in the pertinent art is fully enabled to select relevant test models to prove the hereinbefore and hereinafter mentioned beneficial effects on autoimmune diseases of a VEGF-pathway inhibitor.
  • the pharmacological activity of a VEGF-pathway inhibitor may, for example, be demonstrated in a suitable clinical study. Suitable clinical studies are, for example, randomized studies in patients with multiple sclerosis alone or in combination with additional therapeutic measures, e.g., those mentioned herein.
  • the beneficial effects on autoimmune diseases can be determined directly through the results of such studies or by changes in the study design which are known as such to a person skilled in the art.
  • the most widely used animal model for multiple sclerosis is experimental autoimmune encephalomyelitis (EAE), based on shared histopathological and clinical features with the human disease.
  • EAE experimental autoimmune encephalomyelitis
  • the effective dosage of a VEGF-pathway inhibitor may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the type of the autoimmune disease being treated, the severity of the autoimmune disease being treated and the co-medication.
  • the dosage regimen of the VEGF-pathway inhibitor is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the VEGF-pathway inhibitor required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites.
  • the present invention provides a commercial package comprising a VEGF- pathway inhibitor together with instructions for its use in the treatment of an autoimmune disease.
  • the present invention also relates to the use of a VEGF-pathway inhibitor for the preparation of a medicament for the treatment of an autoimmune disease.
  • EAE acute experimental autoimmune encephalomyelitis
  • chronic relapsing form Animal models: The monophasic model of acute experimental autoimmune encephalomyelitis (EAE) and the chronic relapsing form are considered to be instructive animal models for multiple sclerosis.
  • EAE can be induced in susceptible animals by a single injection of CNS tissue or MBP emulsified in complete Freund's adjuvant into the base of the tail.
  • a monophasic acute paralytic disease appears in susceptible rat strains, e.g., Lewis, Wistar rat, about 8-1 1 days post-sensitization.
  • the symptomatic rats recover within the following 7 days, but in other species the attack is usually lethal.
  • rats undergo one to three relapses following the acute disease bout. These relapses are usually from very mild to severe and are observed within 10-100 days after the acute bout.
  • Chronic-relapsing EAE is induced by injecting an emulsion of guinea pig spinal cord in complete Freund's adjuvant in the hind paws of Lewis rats. Six to ten rats per group are used and somatic symptoms are judged daily on a scale of 0-3. The number of diseased animals as well as the time of onset of the disease is recorded.
  • Treatment with the test compound e.g. a compound mentioned herein, e.g. 6-(6-hydroxymethyl-pyrimidin-4-yloxy)- naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (Compound 1 ), is started on day 16 (after first disease bout) and continued until day 31.
  • Compound 1 leads to prevention of disease symptoms when administered at doses of 3 mg/kg/day in this model.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une méthode permettant de traiter un animal à sang chaud atteint d'une maladie auto-immune, telle que la sclérose en plaques, une névrite périphérique, une névrite optique, la sclérose latérale amyotrophique ou une uvéite. La méthode selon l'invention consiste à administrer audit animal une dose thérapeutiquement efficace d'un inhibiteur de la voie VEGF, par exemple Bevacizumab, Sunitinib or Sorafenib, seule ou en combinaison avec d'autres mesures thérapeutiques. L'invention a également trait à l'utilisation d'un inhibiteur de la voie VEGF pour préparer un médicament destiné à traiter une maladie auto-immune, et à un emballage commercial contenant un tel médicament ainsi que des instructions d'utilisation associées dans le cadre du traitement d'une maladie auto-immune.
PCT/EP2007/059559 2006-09-13 2007-09-12 Méthode de traitement de maladies auto-immunes à l'aide d'inhibiteurs de la voie vegf Ceased WO2008031835A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06120606.6 2006-09-13
EP06120606 2006-09-13

Publications (2)

Publication Number Publication Date
WO2008031835A2 true WO2008031835A2 (fr) 2008-03-20
WO2008031835A3 WO2008031835A3 (fr) 2008-05-22

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010005527A1 (fr) 2008-06-30 2010-01-14 Angioblast Systems, Inc. Traitement de maladies oculaires et d’une néovascularisation excessive utilisant un traitement combiné
WO2010128259A1 (fr) * 2009-05-07 2010-11-11 Sanofi-Aventis Combinaison antitumorale comprenant l'ave8062 et le sorafenib
WO2011003858A3 (fr) * 2009-07-06 2011-03-03 Novartis Ag Compositions pharmaceutiques et formes solides
WO2012029994A1 (fr) 2010-09-02 2012-03-08 Kyoto University Composition pharmaceutique destinée à la prévention et au traitement de la sclérose latérale amyotrophique
RU2523146C1 (ru) * 2013-04-08 2014-07-20 федеральное государственное бюджетное учреждение "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации Способ лечения монокулярного оптического неврита при рассеянном склерозе
WO2016114322A1 (fr) * 2015-01-13 2016-07-21 国立大学法人京都大学 Agent pour la prévention et/ou le traitement de la sclérose latérale amyotrophique
US10308943B2 (en) 2016-02-08 2019-06-04 Vitrisa Therapeutics, Inc. Compositions with improved intravitreal half-life and uses thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040120950A1 (en) * 2002-12-20 2004-06-24 Kari Alitalo Modulation of VEGF-C/VEGFR-3 interactions in the treatment of rheumatoid arthritis
US20060234931A1 (en) * 2003-07-17 2006-10-19 Biggs William H Iii Treatment of diseases with kinase inhibitors
EP1778224B1 (fr) * 2004-07-19 2014-03-26 The Johns-Hopkins University Inhibiteurs de flt3 a des fins d'immunodepression
PE20060664A1 (es) * 2004-09-15 2006-08-04 Novartis Ag Amidas biciclicas como inhibidores de cinasa
WO2006066086A1 (fr) * 2004-12-17 2006-06-22 Genentech, Inc. Therapie antiangiogenique de maladie auto-immune chez des patients qui n'ont pas reagi a une therapie anterieure

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010005527A1 (fr) 2008-06-30 2010-01-14 Angioblast Systems, Inc. Traitement de maladies oculaires et d’une néovascularisation excessive utilisant un traitement combiné
CN102438608A (zh) * 2009-05-07 2012-05-02 赛诺菲 包含ave8062和索拉非尼的抗肿瘤组合
WO2010128259A1 (fr) * 2009-05-07 2010-11-11 Sanofi-Aventis Combinaison antitumorale comprenant l'ave8062 et le sorafenib
FR2945210A1 (fr) * 2009-05-07 2010-11-12 Sanofi Aventis Combinaison antitumorale comprenant l'ave8062 et le sorafenib
WO2011003858A3 (fr) * 2009-07-06 2011-03-03 Novartis Ag Compositions pharmaceutiques et formes solides
JP2012051888A (ja) * 2010-09-02 2012-03-15 Kyoto Univ 筋萎縮性側索硬化症の予防および治療用医薬組成物
WO2012029994A1 (fr) 2010-09-02 2012-03-08 Kyoto University Composition pharmaceutique destinée à la prévention et au traitement de la sclérose latérale amyotrophique
US9856210B2 (en) 2010-09-02 2018-01-02 Kyoto University Pharmaceutical composition for prevention and treatment of amyotrophic lateral sclerosis
RU2523146C1 (ru) * 2013-04-08 2014-07-20 федеральное государственное бюджетное учреждение "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации Способ лечения монокулярного оптического неврита при рассеянном склерозе
WO2016114322A1 (fr) * 2015-01-13 2016-07-21 国立大学法人京都大学 Agent pour la prévention et/ou le traitement de la sclérose latérale amyotrophique
JPWO2016114322A1 (ja) * 2015-01-13 2017-10-19 国立大学法人京都大学 筋萎縮性側索硬化症の予防及び／又は治療剤
CN107530430A (zh) * 2015-01-13 2018-01-02 国立大学法人京都大学 用于预防和/或治疗肌萎缩性侧索硬化症的药剂
EP3246046A4 (fr) * 2015-01-13 2018-12-05 Kyoto University Agent pour la prévention et/ou le traitement de la sclérose latérale amyotrophique
EP3789027A1 (fr) * 2015-01-13 2021-03-10 Kyoto University Bosutinib, sunitinib, tivozanib, imatinib, nilotinib, rebastinib ou bafetinib pour la prévention et/ou le traitement de la sclérose latérale amyotrophique
US10308943B2 (en) 2016-02-08 2019-06-04 Vitrisa Therapeutics, Inc. Compositions with improved intravitreal half-life and uses thereof

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