WO2012061062A1

WO2012061062A1 - Use of teriflunomide for improving motor function

Info

Publication number: WO2012061062A1
Application number: PCT/US2011/057463
Authority: WO
Inventors: Kathleen Mcmonagle-Strucko; Susan E. Hanak; Deborah E. Iglesias-Bregna
Original assignee: Sanofi Aventis US LLC
Current assignee: Sanofi Aventis US LLC
Priority date: 2010-10-25
Filing date: 2011-10-24
Publication date: 2012-05-10
Anticipated expiration: 2013-04-25

Abstract

The present invention relates to the use of teriflunomide for improving motor function of a patient having multiple sclerosis.

Description

USE OF TERIFLUNOMIDE FOR IMPROVING MOTOR FUNCTION

Field of the Invention The present invention relates to the use of teriflunomide for improving motor function of a patient having multiple sclerosis (MS).

Background of the Invention Teriflunomide is a novel oral disease-modifying therapy (DMT) in development for the treatment of relapsing-form 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 or HMR1726, 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. Teriflunomide has been reported to delay onset and progression of experimental autoimmune encephalomyelitis, EAE, disease in the Dark Agouti (DA) rat model of MS. Behaviorally, EAE results in paralysis of rodent limbs, especially hindlimb paralysis, and in electrophysiology, EAE disease causes a delay in latency of somatosensory evoked potentials. Transcranial magnetic stimulation (TMS) is a technique that uses coils to send strong magnetic pulses directly into specific brain regions which induce brain cells to fire safely and painlessly. In humans, TMS is being evaluated for study and treatment of various diseases including depression, epilepsy, chronic pain, and spinal cord injury. In MS patients, TMS-induced-motor evoked potentials (MEPs) have conduction times that are significantly more delayed than controls. In animal studies, TMS applied over the skull of the animal stimulates the descending motor tracts eliciting MEPs in peripheral muscle.

Summary of the Invention

The present invention relates to a method for improving motor function comprising administering to a patient having multiple sclerosis a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.

Brief Description of the Drawings Figure I shows the relationship between magnetic stimulation and latency and amplitude of the MEP response.

Figure 2 shows neurological deficit scores related to EAE. Rats treated with teriflunomide exhibit reduced neurological deficits.

Figure 3 represents the maximum neurological deficit and cumulative neurological deficit during the course of EAE disease. Rats treated with teriflunomide have significantly reduced cumulative disease and maximum disease. Figure 4 shows there was an overall significant increase in the latency of all waveform peaks in MEPs recorded at 60% magnetic output levels in EAE-vehicle treated rats compared to sham rats and EAE rats that received teriflunomide.

Figure 5 shows that from the time of the acute attack of EAE disease, rats treated with teriflunomide exhibit an increase in amplitude out to the first relapse when compared to untreated EAE rats.

Figure 6 shows that during the first relapse when EAE is most synchronized, EAE rats treated with vehicle have a reduction in amplitude compared to sham rats. Rats treated with teriflunomide have an increase in amplitude compared to EAE vehicle treated rats.

Figure 7 represents individual waveform recording overlays from the left and right gastrocnemius muscle of a rat from each of the treatment groups at baseline (black), acute attack (red), remission (green), and relapse (purple).

Figure 8 shows that with EAE there is inflammation, demyelination, axonal damage and axonal loss in specific regions of the spinal cord. Rats treated with teriflunomide have significantly reduced inflammation, demyelination, axonal damage and axonal loss in those spinal cord regions.

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:

"Patient" means mammal or 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, particularly 7 mg daily or 14 mg daily of teriflunomide.

One specific embodiment of the invention relates to a method for improving motor function comprising administering to a patient having relapse-remitting form of 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 improving motor function 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 improving motor function 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 teriflunomide or a

pharmaceutically acceptable salt thereof for use in improving motor function of a patient having multiple sclerosis.

Another specific embodiment of the invention relates to teriflunomide or a

pharmaceutically acceptable salt thereof for use in improving motor function of a patient having relapse-remitting form of multiple sclerosis.

Another specific embodiment of the invention relates to teriflunomide for use in improving motor function of a patient having multiple sclerosis. Another specific embodiment of the invention relates to teriflunomide for use in improving motor function of a patient having relapse-remitting form of multiple sclerosis.

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 Objective: To determine motor pathway function in experimental autoimmune encephalomyelitis (EAE) rats treated therapeutically with teriflunomide starting at disease onset. Methods:

Animals:

Male DA rats (Harlan Laboratories) were housed, in a fully accredited Association for Assessment and Accreditation of Laboratory Animal Care facility. Animals acclimated to the facility 3 weeks prior to study initiation.

EAE:

EAE disease was induced by immunizing rats with an encephalitogenic emulsion prepared from frozen rat spinal cord in complete Freund's adjuvant. Sham animals received the same emulsion minus the rat spinal cord homogenate. Animals in this study were inoculated at approximately 10 weeks of age, and weighed at least 150 grams at the time of EAE inoculation. Daily neurological behavioral assessments began at day 5 post EAE induction and continued to the completion of the study. Teriflunomide (10 mg/kg, po, qd) or vehicle treatment, started at onset of EAE symptoms. Sham animals received vehicle and began treatment as EAE animals were placed into the treatment groups.

TMS:

All TMS electrophysiological recordings were conducted in restrained awake animals. Approximately one week prior to EP recordings, animals were handled daily and acclimated to the restraint. The restraint fabric was placed over the rat such that the animal was kept immobilized, but the head, limbs, and the tail were exposed. Nonmagnetic pins were used to attach the fabric to a wooden board, thus restraining the rat without inflicting any injury or pain. Baseline EP recordings were taken one or two days prior to EAE inoculation, and at several stages throughout EAE disease.

After the rat was restrained, EMG stainless steel needle (27 gauge) electrodes were inserted bilaterally into the gastrocnemius muscles. Reference electrodes were inserted into the distal tendon. A ground was placed underneath the skin on the rat's back. A circular coil (40 mm) attached to a Magstim unit was placed over the vertex of the rat's head with the leading edge of the coil lying over its inion. Recording electrodes were connected to the inverting input of the head stage preamplifier and the reference electrodes were connected to the non-inverting input. Head stage leads were connected to a Cambridge Electronics Design (CED) 1902 amplifier which in turn was connected to a CED1401 /Spike 2 program and computer. Latency was measured as the length of time in seconds between the stimulus artifact and the onset, to the negative peak, and to the positive peak P of the evoked waveform response. The amplitude was defined as the peak to peak of the N-P part of the evoked potential.

Histology:

All rats were perfusion fixed with 4% paraformaldehyde. The lumbar and cervical regions of the spinal cord were dissected out. The cervical region of the spinal cord was stained with H&E, Luxol fast blue and total neurofilament immunocytochemistry (SMI31/SMI32 combination, 1 :1000, Sternberger Inc.). The lumbar region of the spinal cord were stained with FD NeuroSilver Kit II for detection of neuronal/axonal damage.

Results: There was an overall significant increase in the latency of all waveform peaks in MEPs recorded at 60 and 80 % magnetic output levels in EAE-vehicle treated animals as compared to sham animals and EAE animals that received teriflunomide. In contrast to sham animals and to EAE animals that received teriflunomide, EAE vehicle-treated animals exhibited an increase in the latency of all waveform parameters during the relapse-remission phase and an increase in the latency of N and P during the acute phase of disease. Histopathology revealed an increase in inflammation, demyelination, and axonal loss in the EAE vehicle group compared to the EAE-teriflunomide group and sham group.

Claims

We claim:

1 . A method for improving motor function comprising administering to a patient having multiple sclerosis a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.

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

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

4. The method according to claim 2, comprising administering to the patient a pharmaceutically effective amount of teriflunomide.