WO2008031835A2

WO2008031835A2 - Method of treating autoimmune diseases using vegf-pathway inhibitors

Info

Publication number: WO2008031835A2
Application number: PCT/EP2007/059559
Authority: WO
Inventors: Peter C. Hiestand; Christian Schnell
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2006-09-13
Filing date: 2007-09-12
Publication date: 2008-03-20
Anticipated expiration: 2009-03-13
Also published as: WO2008031835A3

Abstract

The present invention relates to a method of treating a warm-blooded animal having an autoimmune disease, such as multiple sclerosis, peripheral neuritis, optical neuritis, amyotrophic lateral sclerosis or uveitis, comprising administering to said animal a therapeutically effective amount of a VEGF-pathway inhibitor, e.g. Bevacizumab, Sunitinib or Sorafenib, alone or in combination with further therapeutic measures; 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 such a medicament together with instructions for its use in the treatment of an autoimmune disease.

Description

METHOD OF TREATING AUTOIMMUNE DISEASES USING VEGF-PATHWAY INHIBITORS

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.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS) with an unknown pathophysiological cause. 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. Although there is no specific treatment for this T cell- mediated autoimmune disorder, patients receive immunosuppressive therapy including azathioprine and corticosteroids in order to limit the extent of the inflammatory process. Immunosuppressive therapy of multiple sclerosis, however, is only partially effective, and in most cases only offers a delay in disease progression despite anti-inflammatory and immunosuppressive treatment.

Accordingly, there is a need for other therapeutics which are effective in the treatment of multiple sclerosis and other related diseases including those involving T-cell mediated damage to central or peripheral nerve tissue, such as peripheral neuritis, optical neuritis and amyotrophic lateral sclerosis.

Surprisingly, it was found that VEGF-pathway inhibitors are useful for the treatment of autoimmune diseases.

The term "VEGF-pathway inhibitors" as used herein 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. Compound 1 used in the Examples below) and WO2005/070891 ; those as described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci U S A, Vol. 93, pp. 14765-14770 (1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209-3214 (1998); and Mordenti et al., Toxicol Pathol, Vol. 27, No. 1 , pp. 14-21 (1999); in WO 00/37502 and WO 94/10202; ANGIOSTATIN, described by O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994); ENDOSTATIN, described by O'Reilly et al., Cell, Vol. 88, pp. 277-285 (1997); anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; as well as anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g. Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and Bevacizumab (Avastin™); furthermore Sunitinib and Sorafenib. In preferred embodiments of the present invention 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.

The term "autoimmune diseases" as used herein means in particular multiple sclerosis, peripheral neuritis, optical neuritis, amyotrophic lateral sclerosis or uveitis. In one embodiment 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.

Short Description of the Figures

As shown in Figure 1 , Compound 1 prevents clinical relapses when administered orally at a doses of 3 mg/kg/day in the chronic relapsing EAE model.

In a broader sense, 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 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; and

• a method for treating optic neuritis in a subject in need thereof, which method comprises administering to the subject an effective amount of a VEGF-pathway inhibitor.

The term "treatment" as used herein 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. For example, the compounds may be used in combination with interferons, e.g., pegylated or non-pegylated α-interferons, β-interferons or γ- 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. natalizumab (Tysabri® or ANTEGREN®) or alemtuzumab; an ascomycin having immunosuppressive properties, e.g., ABT-281 , ASM981 , etc.; a steroid, e.g. methylprednisolone, prednisone or dexamethasone; a corticosteroid; cyclophosphamide; azathioprine; methotrexate; mitoxantrone; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; 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 protein sequence, e.g., CTLA41 g, e.g., designated ATCC 68629, or a mutant thereof, e.g., LEA29Y; adhesion molecule inhibitors, e.g., LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; cathepsin S inhibitors; mTOR inhibitors, e.g., rapamycin, 40-O-(2- hydroxyethyl)-rapamycin, CCI779 or ABT578; calcineurin inhibitors, e.g., cyclosporin A , FK 506 or ISA Tx247. In one embodiment of the present invention, 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®).

The structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference.

Hence, 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.

The terms "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. The term "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. The term "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. The term "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. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

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.

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. Thus, 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.

Moreover, 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.

Examples

The following examples are illustrative, but do not serve to limit the scope of the invention described herein. The examples are meant only to suggest a method of practicing the present invention.

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. In the chronic relapsing disease models 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.

Example 1 : Chronic-Relapsing EAE Model

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. The statistical significance between treated and untreated groups is analyzed on each day using ANOVA analysis of variance followed by Dunn's multiple comparisons. In the absence of drug treatment 80- 100% of the sensitized rats show clinical relapses during the first 40 days following immunization. Clinical grades:

1 = loss of tail tonicity

2 = weakness of one or both hind legs, or mild ataxia

3 = severe ataxia or paralysis accompanied by urinary incontinence

As shown in Table 1 below, Compound 1 leads to prevention of disease symptoms when administered at doses of 3 mg/kg/day in this model.

Table 1

Compound Dose Number of Animals with EAE/total mg/kg p.o. Day 22 Mean score in control

Control - 7 / 7 severity = 1.8

Compound 1 3 0 / 7 severity = 0

Severity = clinical grades 0-3

Claims

What is claimed

1. A method of treating an autoimmune disease comprising administering a therapeutically effective amount of a VEGF-pathway inhibitor to a warm-blooded animal in need thereof.

2. Method of claim 1 wherein the VEGF-pathway inhibitor is Bevacizumab.

3. Method of claim 1 wherein the VEGF-pathway inhibitor is Sunitinib.

4. Method of claim 1 wherein the VEGF-pathway inhibitor is Sorafenib.

5. Method according to any one of claims 1 to 4 wherein the disease is selected from multiple sclerosis, peripheral neuritis, optical neuritis, amyotrophic lateral sclerosis or uveitis.

6. Method according any one of claims 1 to 4 wherein the disease is multiple sclerosis.

7. Method according to any one of claims 1 to 6 wherein the warm-blooded animal is a human.

8. A commercial package comprising a VEGF-pathway inhibitor together with instructions for use thereof in the treatment of an autoimmune disease.

9. The use of a VEGF-pathway inhibitor for the manufacture of a medicament for the treatment of an autoimmune disease.

10. Use according to claim 9 wherein the VEGF-pathway inhibitor is selected from Bevacizumab, Sunitinib and Sorafenib.