HAVING MULTIPLE SCLEROSIS

Field of the Invention

The present invention relates to the use of teriflunomide for maintaining fatigue level of a patient having multiple sclerosis (MS).

Background of the Invention

MS is a neurodegenerative disease which affects young adults and has several features that contributes to a poor health-related quality of life (Benito-Leon et al, Disabil Rehabil (200)3, 25(23):1291-1303). Majority of MS patients will experience severe fatigue during their MS. Fatigue is a common disabling symptom which has been negatively associated with patients' health-related quality of life (Egner et al, NeuroRehabilitation (2003), 18, 125-133).

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.

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

Summary of the Invention

The present invention relates to a method for maintaining fatigue level in a patient having multiple sclerosis, comprising administering to the patient a pharmaceutically acceptable amount of teriflunomide or a pharmaceutically acceptable salt thereof. 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: "Fatigue" means the awareness of a decreased capacity for physical and/or mental activity due to an imbalance in the availability, utilization, and/or restoration of resources needed to perform activity (Aaronson et al Journal of Nursing Scholarship (1999), 1 (31 ), 45-50). The fatigue impact scale (FIS) was developed 'to evaluate the perceived impact of fatigue on the lives of MS, the factors that affect patients' perceptions of fatigue impact and how fatigue may affect the mental health and general health status of MS patients (Fisk et al Canadian Journal of Neurological Sciences (1994),21 , 9-14). The FIS survey has been validated and shown to have good psychometric qualities in MS patient populations and has been identified by Multiple Sclerosis Council for Clinical Practice Guidelines as the most appropriate for assessing the impact of MS-related fatigue on quality of life (Fisk et al Canadian Journal of Neurological Sciences (1994), 21 , 9-14 & Mathiowetz et al, American Journal of Occupational Therapy (2003), 57, 389-395). The FIS consists of 40 statements that measure perceived fatigue impact in 3 areas: cognitive function (10 items), physical function (10 items), and psychosocial function (20 items). The respondent is asked to rate each statement on a Likert scale, ranging from 0 (no problem) to 4 (extreme problem), so higher scores reflect more severe levels of fatigue. In addition to FIS total score (maximum FIS total score=160), there are subscales, Physical FIS (maximum score 40), Cognitive FIS (maximum score 40) and Psychosocial FIS (maximum score 80).

"Maintaining" means a change of FIS score from baseline below the minimally important difference (MID) and/or a mild within Effect Size (ES< 0.2). The minimally important difference (MID) of the FIS total score ranges between 10 and 20 points (Rendas-Baum et al ,Qual Life Res (2010) 19:1349-1358).

"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.

One specific embodiment of the invention is a method for maintaining fatigue level a patient having RMS in need thereof, comprising administering to the patient a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.

Another specific embodiment of the invention is a method for maintaining fatigue level a patient having RMS in need thereof, comprising administering to the patient about 7 mg or about 14 mg of teriflunomide daily.

Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for maintaining fatigue level of a patient having MS.

Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for maintaining fatigue level of a patient having RMS. Another specific embodiment of the invention is the use of about 7 mg or about 14 mg of teriflunomide daily for maintaining fatigue level of a patient having RMS.

Another specific embodiment of the invention is an article of manufacture comprising: a. a packaging material;

b. teriflunomide or a pharmaceutically acceptable salt thereof; and

c. a medication guide which comprises a message selected from the group consisting of:

i. teriflunomide does not make fatigue worse in MS patients; and ii. teriflunomide maintains fatigue level in MS patients.

Another specific embodiment of the invention is a package comprising teriflunomide or a pharmaceutically acceptable salt thereof and a medication guide which comprises a message selected from the group consisting of:

a. teriflunomide does not make fatigue worse in MS patients; and b. teriflunomide maintains fatigue level in MS patients.

The present invention also relates to the use of teriflunomide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for maintaining fatigue level of a patient having MS or RMS. The embodiments as described above also apply to said use.

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

Examples

Example 1

Long-Term Outcomes in Patients Who Receive Teriflunomide for Multiple Sclerosis: Evaluating Fatigue Over 7 Years One objective of this study was to assess fatigue of MS patients treated with oral te flunomide, a novel MS disease-modifying therapy, over 7 years.

Methods: This analysis focused on patients who completed the 36-weeks double- blind placebo control study of tehflunomide and the week 372 assessment of the open-label extension study, [(W372), n=84, completers]. Fatigue was evaluated by the Fatigue Impact Scale (FIS). This instrument was administrated at baseline and every 6 months during the study. Mean change from baseline was calculated at each time point for the completer population, using descriptive statistics. Pearson correlations between EDSS and components of these instruments were calculated at W372.

Results: The study included 84 patients of mean age 40+/-8.4; 80% were female; 92% had a relapsing-remitting course; mean EDSS at baseline was 2.2+/-1 .5. Patients reported a mean increase of only 3.8 points [effect size (ES)=0.12] at W372 on the total FIS (maximum score = 160, MID [10-20]). This same pattern was observed in FIS subscales scores, with increases of less than a point for physical and cognitive subscales. Conclusion: Although uncontrolled this study provides evidence that for MS patients who completed treatment with teriflunomide over 7 years, their level of fatigue remains stable (ES < 0.2 and change < MID, not clinically relevant).

Example 2

Evaluation of fatigue Over 108 weeks in Patients Who Receive Teriflunomide for Multiple Sclerosis:

One objective of this double bind, randomized, placebo controlled study (TEMSO study) was to evaluate the effect of teriflunomide on subject-reported fatigue as assessed by the Fatigue Impact Scale (FIS) over 108 weeks. Methods: Fatigue was evaluated by the Fatigue Impact Scale (FIS). This instrument was administrated at baseline and every 8 weeks during the study until week 108. Mean change from baseline was calculated at each time point on ITT (intention-to- treat) population, using descriptive statistics.

Results: The study randomized 1088 patients. The study population was primarily Caucasian (97.5%) with a mean age of 38 years and 72.2% of the patients were female. The majority of the patients (91 .5%) in the randomized population had relapsing-remitting MS with a median baseline EDSS score of 2.50.

The ITT population was 1086 patients, 363 with placebo, 365 with teriflunomide 7 mg and 358 with teriflunomide 14 mg. Results of FIS change from baseline are summarized in Table 1 .

Table 1 : Change from baseline in FIS total score on ITT population at week 108 (MMRM analysis*)

* MMRM (mixed-effect model with repeated measures) analysis adjusted for EDSS strata at baseline, region, and baseline value

* LS: Least-Squares; SD: Standard deviation

On ITT population, patients reported a change from baseline below MID.

Conclusion: This randomized controlled study provides evidence that level of fatigue remains stable for MS patients treated with teriflunomide over 108 weeks.