Field of the Invention The present invention relates to the use of te flunomide for treating brain atrophy in a patient in need thereof.

Background of the Invention Patients with multiple sclerosis (MS) develop irreversible CNS tissue injury because of chronic inflammation and the end result of this process is brain and spinal-cord atrophy. Compared with normal population, MS patients have reduced brain parenchyma and reduced gray matter and white matter of the brain. In patients with MS the standardized MRI is used to measure the brain and spinal cord atrophy. CNS atrophy is a clinically relevant biomarker for longitudinal monitoring of patients with MS that provides information complimentary to lesion assessments. Brain atrophy begins in the early stages of MS, even within the first 1 to 2 years in patients who have CIS (clinically isolated syndrome) and early relapsing- remitting MS, and longitudinal studies have shown a link between brain atrophy and subsequent long-term progressive neurologic impairment with physical disability including cognitive dysfunction. These findings suggest that patients should be treated early with disease-modifying drugs and that atrophy measures should be included in clinical trials and in clinical practice.

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 treating brain atrophy, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.

Brief Description of the Drawings

Figure 1 shows the percent change from baseline in brain volume over 7 years of the patients in the study of Example 1 .

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:

"EDSS" means the Kurtzke Expanded Disability Status Scale. "Patient" means humans.

"Pharmaceutically effective amount" means an amount of a compound/composition according to the present invention effective in producing the desired therapeutic effect. "Treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, slow the appearance of symptoms, or slow the progression of the named disorder or condition. One specific embodiment of the invention is a method for treating brain atrophy, in a patient having MS 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 treating brain atrophy, in 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 treating brain atrophy, in a patient 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 treating brain atrophy.

Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for treating brain atrophy in a patient having MS.

Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for treating brain atrophy in a patient having RMS. Another specific embodiment of the invention is the use of about 7 mg or 14 mg of teriflunomide daily for treating brain atrophy.

It is now found that teriflunomide is useful for treating brain atrophy in a patient, particularly a patient having multiple sclerosis. 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 Brain MRI And Clinical Assessments of Teriflunomide For the Treatment of Multiple Sclerosis: Extension of A Phase II Study

Background: Teriflunomide was previously shown to reduce MRI disease activity in a 36-week placebo-controlled study of 179 patients with relapsing MS (RMS). (See O'Connor PW et al. Neurology 2006; 66: 894-900)

One bbjective of the study was to evaluate long-term effects of teriflunomide on brain atrophy.

Methods:

Study design

• In the original study, patients were randomised ( 1 : 1 : 1 ) to receive an oral dose of placebo, teriflunomide 7 or 14 mg/day for 36 weeks. Randomisation was stratified by baseline expanded disability status scale (EDSS) score (<3.5 and >3.5).

· Following completion of the 36-week placebo- controlled phase, patients

entered the open-label extension study. Patients either continued with teriflunomide or, in the case of placebo, were re-allocated to teriflunomide, 7 or 14 mg. The extension study is still ongoing. Patients

• For inclusion, patients originally enrolled in the Phase II trial were required to be aged 18-65 years, with clinically definite MS and an EDSS score of <6 and to have had at least two clinical relapses in the previous 3 years and one clinical relapse during the preceding year.

• Patients were excluded from the study if they had clinically relevant

cardiovascular, hepatic, endocrine or other major systemic disease, since this would make implementation of the protocol or interpretation of the study results difficult.

• Patients were required to use effective contraception during the trial and to either continue this practice for 24 months after drug discontinuation, or to undergo a drug washout procedure.

Efficacy evaluations

• MRI scans and proportions of relapse-free patients were evaluated every 48 weeks and EDSS scores every 24 weeks from the beginning of the extension study (Week 36) to Week 372 (Year 7).

o A central reading centre ensured standardisation of the collection and analysis of MRI data.

Statistical analysis

• Data are presented for analysis in the intention-to-treat (ITT) population,

defined as all randomised patients exposed to study medication in the extension period.

• Analyses of all efficacy variables presented here are limited to descriptive summary statistics (mean, median, standard deviation).

• Data are presented for six treatment groups, separated by treatment allocation at randomisation and by treatment re-allocation at the start of the extension study (placebo/7 mg, placebo/14 mg, 7 mg/7 mg or 14 mg/14 mg) and for teriflunomide treatment groups combined (7 mg combined and 14 mg combined). Results:

Demographics • Of the 160 patients who completed the original 36-week study (89% of the 179 patients originally randomised), 147 (92%) entered the long-term extension phase of the study.

• The original study population consisted predominantly of patients with

relapsing-remitting disease, but with some secondary progressive MS (Table

1 )-

• At baseline, patients displayed demographic characteristics typical of an RMS population.

• Generally, disease characteristics were similar across treatment groups, with a trend for patients in the 7 mg groups to have a slightly longer duration since diagnosis and slightly more patients with secondary progressive disease than those in the 14 mg groups.

Table 1 . Patient demographics and baseline MRI variables A. Baseline demographics

B. Baseline MRI disease characteristics

SD, standard deviation; Gd, gadol

MRI: For MRI parameters, data shown are from PBO/7 mg (n=29), 7 mg/7 mg (n=52), PBO/14 mg (n=26) and 14 mg/14 mg (n=40) groups, respectively. There was a numerically lower reduction in cerebral volume (percentage change from baseline) in the 14 mg groups compared with the 7 mg groups. Loss of cerebral volume over the treatment period [mean (SD) change of brain (fractional) volume from baseline] was: -0.0042 (0.0106), 0.0003 (0.0099), -0.0035 (0.0108), -0.0028 (0.0100) at Week 36; -0.0063 (0.0149), -0.0039 (0.01 15), -0.0122 (0.0157), -0.0078 (0.01 14) at Week 84; -0.0332 (0.0280), -0.0263 (0.0174), -0.0181 (0.0153), -0.0207 (0.0102) at Week 372 (See Figure 1 ).

Conclusion: This reflected a trend for the greatest reduction in the placebo/7mg group, and a lower percentage change in cerebral volume from baseline over time in the 14 mg groups.

Example 2:

One objective of this study (TEMSO study) was to assess the effects of oral teriflunomide on brain atrophy 108 weeks. Methods

Study design

• TEMSO was a multicenter, multinational, randomised, placebo-controlled, double- blind, parallel-group, stratified study.

· Eligible patients were stratified according to baseline EDSS score (<3.5 vs >3.5) and treatment centre, and were randomised (1 :1 :1 ) to once-daily oral

teriflunomide, 7 mg or 14 mg, or placebo.

Study subjects

· MS patients aged 18-55 years who were ambulatory (EDSS <5.5), exhibited a relapsing clinical course, and had a minimum of two relapses in the previous 2 years or one relapse in the year preceding randomisation (but with no relapse within 60 days) were eligible for entry into TEMSO. Study evaluations

• The effect of teriflunomide on a range of MRI parameters including brain atrophy was evaluated.

• MRI scans were performed at baseline, and Weeks 24, 48, 72 and 108. Results: 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. Results of change from baseline in atrophy on ITT population are summarized in Table 1 .

Table 1 : Change from baseline in atrophy on ITT population

teriflunomide

Placebo 7 mg 14 mg (N=363) (N=365) (N=358)

Baseline (Week 0)

Value

Number 358 359 355 Mean (SD) 0.762 (0.024) 0.762 (0.024) 0.762 (0.022) Median 0.760 0.760 0.760 Min : Max 0.71 : 0.84 0.71 : 0.84 0.72 : 0.84

Week 24

Value

Number 331 339 329 Mean (SD) 0.762 (0.024) 0.764 (0.025) 0.762 (0.023) Median 0.762 0.762 0.760 Min : Max 0.71 : 0.83 0.71 : 0.83 0.72 : 0.83

Change from

baseline

Number 329 333 328

Mean (SD) -0.000 (0.008) 0.001 (0.009) 0.000 (0.009)

Median -0.001 0.001 0.000

Min : Max -0.02 : 0.05 -0.04 : 0.05 -0.02 : 0.05

Change from

baseline (MMRM)

Number 329 333 328

LS Mean (SE) -0.000 (0.001 ) 0.001 (0.000) 0.000 (0.001 )

LS Mean Difference

from placebo (SE) 0.002 (0.001 ) 0.001 (0.001 )

95% CI ( 0.000 to 0.003) (-0.001 to 0.002)

P-value (vs.

Placebo) 0.0145 0.3523 teriflunomide

Placebo 7 mg 14 mg

(N=363) (N=365) (N=358)

Week 48

Value

Number 310 306 294 Mean (SD) 0.760 (0.024) 0.763 (0.025) 0.760 (0.023) Median 0.759 0.760 0.759 Min : Max 0.71 : 0.82 0.71 : 0.83 0.71 : 0.81

Change from

baseline

Number 309 301 293

Mean (SD) -0.002 (0.008) -0.001 (0.009) -0.001 (0.008)

Median -0.002 -0.001 -0.001

Min : Max -0.03 : 0.03 -0.05 : 0.03 -0.03 : 0.02

Change from

baseline (MMRM)

Number 309 301 293

LS Mean (SE) -0.002 (0.000) -0.001 (0.000) -0.001 (0.000)

LS Mean Difference

from placebo (SE) 0.001 (0.001 ) 0.001 (0.001 )

95% CI (-0.001 to 0.002) (-0.001 to 0.002)

P-value (vs.

Placebo) 0.2548 0.2808

Week 72

Value

Number 276 277 274 Mean (SD) 0.760 (0.024) 0.762 (0.025) 0.760 (0.023) Median 0.758 0.759 0.758 Min : Max 0.72 : 0.82 0.71 : 0.83 0.72 : 0.81

Change from

baseline

Number 272 273 273

Mean (SD) -0.003 (0.009) -0.002 (0.009) -0.002 (0.009)

Median -0.003 -0.002 -0.003

Min : Max -0.04 : 0.02 -0.05 : 0.02 -0.03 : 0.02 teriflunomide

7 mg 14 mg

(N=365) (N=358)

Change from

baseline (MMRM)

Number 272 273 273

LS Mean (SE) -0.003 (0.001 ) -0.002 (0.001 ) -0.002 (0.001 ) LS Mean Difference

from placebo (SE) 0.002 (0.001 ) 0.001 (0.001 )

95% CI ( 0.000 to 0.003) (-0.001 to 0.002) P-value (vs.

Placebo) 0.0335 0.3977

Week 108

Value

Number 258 265 261

Mean (SD) 0.759 (0.024) 0.761 (0.024) 0.758 (0.023)

Median 0.757 0.758 0.757

Min : Max 0.71 : 0.82 0.70 : 0.83 0.71 : 0.82

Change from

baseline

Number 256 262 260

Mean (SD) -0.004 (0.010) -0.003 (0.010) -0.003 (0.009)

Median -0.004 -0.003 -0.003

Min : Max -0.05 : 0.04 -0.04 : 0.04 -0.03 : 0.02

Change from

baseline (MMRM)

Number 256 262 260

LS Mean (SE) -0.004 (0.001 ) -0.003 (0.001 ) -0.003 (0.001 )

LS Mean Difference

from placebo (SE) 0.001 (0.001 ) 0.001 (0.001 )

95% CI (-0.000 to 0.003) (-0.001 to 0.002)

P-value (vs.

Placebo) 0.1853 0.3519

* MMRM (mixed-effect model with repeated measures) analysis adjusted for EDSS strata at baseline, region, and baseline value Conclusion: This reflected a trend for greater cerebral volume reduction in the placebo group, and a lower percentage change from baseline in atrophy over time in the teriflunomide 7 mg and 14 mg groups comparing to placebo group.