WO2012061060A1

WO2012061060A1 - Use of teriflunomide for treating brain atrophy

Info

Publication number: WO2012061060A1
Application number: PCT/US2011/057456
Authority: WO
Inventors: Ross Rocklin
Original assignee: Sanofi-Aventis U.S. Llc
Priority date: 2010-10-25
Filing date: 2011-10-24
Publication date: 2012-05-10

Abstract

This invention relates to the use of teriflunomide for slowing the reduction of the volume of white matter in the brain, particularly in a patient having multiple sclerosis.

Description

USE OF TERIFLUNOMIDE FOR TREATING BRAIN ATROPHY

Field of the Invention

This invention relates to use of teriflunomide for slowing the reduction of the volume of white matter in the brain, particularly in a patient having multiple sclerosis (MS).

Background of the invention

Both white matter and grey matter atrophy have been described in MS patients. Their mechanisms and relationship with clinical symptoms remain to be further elucidated. (See Bermel et al., The measurement and clinical relevance of brain atrophy in multiple sclerosis, Lancet Neurol 2006; 5: 158-70; Simon JH, Brain atrophy in multiple sclerosis: what we know and would like to know, Multiple Sclerosis 2006; 12: 679- 687).

Teriflunomide is a novel oral disease-modifying therapy (DMT) in development for the treatment of relapsing-remitting multiple sclerosis (RMS). Teriflunomide blocks de novo pyrimidine synthesis, which inhibits the replication and function of activated (but not resting) lymphocytes.

The compound of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)- amide (also known as teriflunomide, Formula I) is described in U.S. Patent No.

5,679,709.

I

The use of teriflunomide for treating multiple sclerosis is described in U.S. Patent No. 6,794,410. Summary of the Invention

This invention relates to a method for slowing the reduction of the volume of white matter in the brain, comprising administering to a patient in need thereof a

pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.

Brief Description of the Drawings

Figure I shows the change from baseline in volume of white matter over time of the three patient groups in the TEMSO study.

Detailed Description of the Invention

As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

"A compound that slows the reduction of the volume of grey matter in the brain" means a compound that is already known for slowing the reduction of the volume of grey matter in the brain, such as fingolimod.

"Clinically proved effective" means that the results of clinical trial are statistically significant, i.e., the results of the clinical trial are not likely to be due to chance with an alpha level les than 0.05. "Patient" means humans.

"Pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of teriflunomide. "Pharmaceutically effective amount" means an amount of a compound/composition according to the present invention effective in producing the desired therapeutic effect.

"Treating" or "treatment" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to slow the appearance of symptoms of the named disorder or condition. One specific embodiment of the invention relates to a method for slowing the reduction of the volume of white matter in the brain, comprising administering to a patient having multiple sclerosis a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof. Another specific embodiment of the invention relates to a method for slowing the reduction of the volume of white matter in the brain, comprising administering to a patient having multiple sclerosis a pharmaceutically effective amount of teriflunomide.

Another specific embodiment of the invention relates to a method for slowing the reduction of the volume of white matter in the brain, comprising administering to a patient having relapse-remitting form of multiple sclerosis a pharmaceutically effective amount of teriflunomide.

Another specific embodiment of the invention relates to a method for slowing the reduction of the volume of white matter in the brain, comprising administering to a patient having relapse-remitting multiple sclerosis about 7 mg or about 14 mg of teriflunomide daily.

Another specific embodiment of the invention relates to a method for slowing the reduction of the volume of white matter in the brain, comprising administering to a patient having relapse-remitting multiple sclerosis about 14 mg of teriflunomide daily, wherein the method is clinically proven effective. Another specific embodiment of the invention relates to a method for treating brain atrophy, comprising administering to a patient having multiple sclerosis a

pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof and a compound that slows the reduction of the volume of gray matter in the brain.

Another specific embodiment of the invention relates to teriflunomide or a

pharmaceutically acceptable salt thereof for use in slowing the reduction of the volume of white matter in brain in a patient in need thereof.

Another specific embodiment of the invention relates to teriflunomide or a

pharmaceutically acceptable salt thereof for use in slowing the reduction of the volume of white matter in brain in a patient having multiple sclerosis.

Another specific embodiment of the invention relates to teriflunomide for use in reducing the volume of white matter in brain in a patient having multiple sclerosis.

Another specific embodiment of the invention relates to teriflunomide for use in slowing the reduction of the volume of white matter in brain in a patient having relapse-remitting form of multiple sclerosis.

Another specific embodiment of the invention relates to teriflunomide for use in slowing the reduction of the volume of white matter in brain in a patient having relapse-remitting form of multiple sclerosis, wherein teriflunomide is administered to the patient about 7 mg or about 14 mg daily.

Another specific embodiment of the invention relates to teriflunomide for use in slowing the reduction of the volume of white matter in brain in a patient having relapse-remitting form of multiple sclerosis, wherein teriflunomide is administered to the patient about 14 mg daily, and wherein the use is clinically proved effective.

Another specific embodiment of the invention relates to a combination of

teriflunomide and a compound that slows the reduction of the volume of grey matter in the brain of a patient. Another specific embodiment of the invention relates to a combination of teriflunomide and a compound that slows the reduction of the volume of grey matter in the brain of a patient for use in treating brain atrophy.

The present invention may be better understood by reference to the following non- limiting Example, which is exemplary of the invention. They should in no way be construed, however, as limiting the broad scope of the invention. Example

The efficacy, relative to a placebo, of teriflunomide in reducing the volume of white and grey matter in the brain of patients having multiple sclerosis, in the following multicenter, multinational, randomised, placebo-controlled, double-blind, parallel- group, stratified study.

Patient selection:

Patients eligible for enrolment were aged 18-55 years, met McDonald's criteria for MS diagnosis, and exhibited a relapsing clinical course, with or without progression. They were required to have a score of no more than 5.5 on the Kurtzke Expanded Disability Status Scale (EDSS), a minimum of two clinical relapses in the previous 2 years or one relapse during the preceding year, but no relapses in the 60 days before randomization. During the 4 weeks prior to randomization, patients were required to be clinically stable and have signed both the informed consent form and informed consent for H IV testing .

Patients presenting with any of the following were excluded from the study. - Patients with significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia:

o Hematocrit <24% and/or

o Absolute white blood cell count <4.0 x10⁹/L and/or

o Platelet count <150 x10⁹/L and/or

o Absolute neutrophil count <1 .5 x10⁹/L - Patients with a congenital or acquired severe innnnunodeficiency, a history of cancer (except for basal or squamous cell skin lesions which had been surgically excised with no evidence of metastasis), lymphoproliferative disease, or any patients who had received lymphoid irradiation

- Known history of active tuberculosis not adequately treated

- Persistent significant or severe infection

- Patients who were pregnant or breastfeeding or who planned to conceive during the course of the trial; women of childbearing potential and men were required to use an acceptable method of contraception

- Use of disallowed therapies including phenytoin, warfarin, tolbutamide, St John's Wort or cholestyramine in the 4 weeks prior to randomization

- Treatment with adrenocorticotrophic hormone (ACTH) or systemic corticosteroids 4 weeks prior to randomization

- Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporine, methotrexate or mycophenolate

- Previous treatment with teriflunomide or leflunomide

- Prior use of natalizumab

- Prior use of interferons or cytokine therapy in the preceding 4 months

- Prior use of glatiramer acetate therapy in the preceding 6 months

- Prior use of intravenous immunoglobulins in the preceding 6 months

- Prior use of any investigational drug in the preceding 6 months

- Patients likely to require treatment during the study period with drugs not permitted by the clinical study protocol

- Contraindication for MRI including presence of pacemaker, metallic implants in high-risk areas (e.g. artificial heart valves, aneurysm/vessel clips), presence of metallic material (e.g. shrapnel) in high-risk areas, known history of allergy to any contrast medium, or history of claustrophobia that would prevent completion of all protocol-scheduled MRI visits; hip implants were not contraindicated

- Patients with liver function impairment or persisting elevations of alanine aminotransferase, serum aspartate aminotransferase, or direct bilirubin greater than 1 .5-times the upper limit of normal (ULN) - Persisting elevations of serum amylase or lipase greater than 2x ULN

- Known history of active hepatitis

- Hypoproteinemia (e.g. in case of severe liver disease or nephrotic syndrome) with serum albumin <3.0 g/dL

- Known history of chronic pancreatic disease or pancreatitis

- Moderate-to-severe impairment of renal function, as shown by serum creatinine >1 .5 mg/dL

- Clinically relevant cardiovascular, hepatic, neurologic, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult or that would put the subject at risk by participating in the study

- History of drug or alcohol abuse

- Psychiatric condition rendering the subject unable to understand the nature, scope, and possible consequences of the study

- Patients who were unlikely to comply with protocol (e.g. uncooperative attitude, inability to return for follow-up visits), and known unlikelihood of completing the study

- Patient was the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol

- Human immunodeficiency virus (HlV)-positive subject

- Patients were not allowed to be randomized into the study more than once

Study design and randomization:

Following a screening phase of up to 4 weeks, eligible patients were randomized (1 :1 :1 ) to receive a once-daily oral dose of placebo or teriflunomide, 7 mg or 14 mg, for 108 weeks. Randomization was stratified by baseline EDSS score (<3.5 and >3.5) and by trial site. A total of 1 ,088 patients were randomised to the study, with 1086 exposed to study treatment (intention-to-treat population), 363 with placebo, 365 with teriflunomide 7 mg and 358 with teriflunomide 14 mg. On the randomized population the mean (SD) age, EDSS and number of relapse within the past 2 years were respectively: 38 years (8.8), 2.7 (1 .3) and 2. 2 (1 .1 ). Method: MRI scans were performed at baseline and Weeks 24, 48, 72 and 108. Changes from baseline to Week 108 in volume of white and gray matter were analyzed using a mixed-effect model with repeated measures (MMRM). Results: Both 7 mg and 17 mg groups reduced the mean decrease from baseline in volume of white matter at Week 108: -3.741 (1 .217) -0.635 (1 .207), 2.406 (1 .216) for PBO, 7 and 14 mg (p=0.0609 and 0.0002 for 7 and 14 mg vs PBO). There was no significant difference between groups in change from baseline in volume of gray matter.

Claims

We claim:

1 . A method for slowing the reduction of the volume of white matter in the brain, comprising administering to a patient in need thereof a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein the patient has multiple sclerosis.

3. The method according to claim 1 , wherein the patient has relapse-remitting form of multiple scloerosis.

4. The method according to claims 1 -3, comprising administering to the patient a pharmaceutically effective amount of teriflunomide.

5. The method according to claims 1 -4, comprising administering to the patient about 7 mg or about 14 mg of teriflunomide daily.

6. The method according to claim 3, comprising administering to the patient about 14 mg of teriflunomide daily, wherein the method is clinically proven effective.

7. A method for treating brain atrophy comprising administering to a patient in need thereof a pharmaceutically effective amount of teriflunomide or a

pharmaceutically acceptable salt thereof and a compound that slows the reduction of the volume of grey matter in the brain.

8. The method according to claim 7, wherein the patient has multiple sclerosis.

9. The method according to claim 7, wherein the patient has relapse-remitting form of multiple scloerosis.

10. The method according to claims 7-9, comprising administering to the patient a pharmaceutically effective amount of teriflunomide and a compound that slows the reduction of the volume of grey matter in the brain.

1 1 . The method according to claims 7-1 , comprising administering to the patient about 7 mg or about 14 mg of teriflunomide daily and a compound that slows the reduction of the volume of grey matter in the brain.