Treatment of multiple sclerosis with combination of laquinimod and fingolimod

• US 8,889,627 B2
• Filed: 10/11/2012
• Issued: 11/18/2014
• Est. Priority Date: 10/12/2011
• Status: Expired due to Fees

• Current Assignee: Teva Pharmaceutical Industries Limited
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Hallak, Hussein, Tarcic, Nora, Kaye, Joel Flaxman
• Primary Examiner(s): Lundgren, Jeffrey S.
• Assistant Examiner(s): STRONG, TORI
• Application Number:
  US13/650,060
• Publication Number:
  US 20130096158A1
• Time in Patent Office: 768 Days
• Field of Search: None
• US Class Current: 514/17.9
• CPC Class Codes: A61J 1/035 Blister-type containers blisters in general B65D75/36
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

This invention provides a method of treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising administering to the subject laquinimod as an add-on therapy to or in combination with fingolimod. This invention also provides a package and a pharmaceutical composition comprising laquinimod and fingolimod for treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome. This invention also provides laquinimod for use as an add-on therapy or in combination with fingolimod in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome. This invention further provides use of laquinimod and fingolimod in the preparation of a combination for treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome.

Claims

1. A method of treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising periodically administering to the subject an amount of laquinimod and an amount of fingolimod, wherein the amounts when taken together are effective to achieve a greater than additive therapeutic result in treating the subject.

2. The method of claim 1, wherein the amount of laquinimod and the amount of fingolimod when administered together is more effective to treat the subject than when each agent at the same amount is administered alone.

3. The method of claim 1, wherein the amount of laquinimod and the amount of fingolimod when taken together is effective to reduce a symptom of multiple sclerosis in the subject.

4. The method of claim 3, wherein the symptom is a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, decreased time to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, deterioration of visual function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormalities observed in whole Brain MTR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work.

5. The method of claim 4, wherein the amount of laquinimod and the amount of fingolimod when taken together is effective to decrease or inhibit reduction of brain volume.

6. The method of claim 4, wherein the amount of laquinimod and the amount of fingolimod when taken together is effective to increase time to confirmed disease progression.

7. The method of claim 4, wherein the amount of laquinimod and the amount of fingolimod when taken together is effective to decrease abnormalities observed in whole Brain MTR histogram.

8. The method of claim 1, wherein laquinimod is laquinimod sodium.

9. The method of claim 1, wherein fingolimod is fingolimod hydrochloride.

10. The method of claim 1, wherein the laquinimod and/or the fingolimod is administered via oral administration.

11. The method of claim 1, wherein the laquinimod and/or the fingolimod is administered daily.

12. The method of claim 1, wherein the amount laquinimod administered is 0.1-40.0 mg/day.

13. The method of claim 12, wherein the amount laquinimod administered is 0.6 mg/day.

14. The method of claim 12, wherein the amount laquinimod administered is 1.2 mg/day.

15. The method of claim 1, wherein the amount fingolimod administered is 0.01-2.5 mg/day.

16. The method of claim 15, wherein the amount fingolimod administered is 0.5 mg/day.

17. A package comprising:

a) a first pharmaceutical composition comprising an amount of laquinimod and a pharmaceutically acceptable carrier;

b) a second pharmaceutical composition comprising an amount of fingolimod and a pharmaceutically acceptable carrier; and

c) instructions for use of the first and second pharmaceutical compositions together to treat a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome.

18. A pharmaceutical composition consisting essentially of an amount of laquinimod and an amount of fingolimod.

19. A therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which comprises:

a) one or more unit doses, each such unit dose consisting essentially of;

i) an amount of laquinimod; and

ii) an amount of fingolimod,

wherein the respective amounts of said laquinimod and said fingolimod in said unit dose are effective, upon concomitant administration to said subject, to achieve a greater than additive therapeutic result in treating the subject, and

b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.

20. A pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which consists essentially of:

a) an amount of laquinimod; and

b) an amount of fingolimod,

wherein the respective amounts of said laquinimod and said fingolimod in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said composition, to achieve a greater than additive therapeutic result in treating the subject.