14 CLINICAL STUDIES

The efficacy and safety of TECFIDERA were demonstrated in two studies (Studies 1 and 2) that evaluated TECFIDERA taken either twice or three times a day in patients with relapsing-remitting multiple sclerosis (RRMS). The starting dose for TECFIDERA was 120 mg twice or three times a day for the first 7 days, followed by an increase to 240 mg twice or three times a day. Both studies included patients who had experienced at least 1 relapse over the year preceding the trial or had a brain Magnetic Resonance Imaging (MRI) scan demonstrating at least one gadolinium-enhancing (Gd+) lesion within 6 weeks of randomization. The Expanded Disability Status Scale (EDSS) was also assessed and patients could have scores ranging from 0 to 5. Neurological evaluations were performed at baseline, every 3 months, and at the time of suspected relapse. MRI evaluations were performed at baseline, month 6, and year 1 and 2 in a subset of patients (44% in Study 1 and 48% in Study 2).

Study 1: Placebo-Controlled Trial in RRMS

Study 1 was a 2-year randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. The primary endpoint was the proportion of patients relapsed at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of new T1 hypointense lesions, number of Gd+ lesions, annualized relapse rate (ARR), and time to confirmed disability progression. Confirmed disability progression was defined as at least a 1 point increase from baseline EDSS (1.5 point increase for patients with baseline EDSS of 0) sustained for 12 weeks.

Patients were randomized to receive TECFIDERA 240 mg twice a day (n=410), TECFIDERA 240 mg three times a day (n=416), or placebo (n=408) for up to 2 years. The median age was 39 years, median time since diagnosis was 4 years, and median EDSS score at baseline was 2. The median time on study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks on study drug per treatment group were 69% for patients assigned to TECFIDERA 240 mg twice a day, 69% for patients assigned to TECFIDERA 240 mg three times a day and 65% for patients assigned to placebo groups.

TECFIDERA had a statistically significant effect on all of the endpoints described above and the 240 mg three times daily dose showed no additional benefit over the TECFIDERA 240 mg twice daily dose. The results for this study (240 mg twice a day vs. placebo) are shown in Table 2 and Figure 1.

Table 2: Clinical and MRI Results of Study 1
	TECFIDERA 240 mg BID	Placebo	P-value

Clinical Endpoints	N=410	N=408
Proportion relapsing (primary endpoint) Relative risk reduction	27% 49%	46%	<0.0001

Annualized relapse rate	0.172	0.364	<0.0001
Relative reduction	53%

Proportion with disability progression	16%	27%	0.0050
Relative risk reduction	38%

MRI Endpoints	N=152	N=165
Mean number of new or newly enlarging	2.6	17	<0.0001
T2 lesions over 2 years

Percentage of subjects with no new or newly enlarging lesions	45%	27%


Number of Gd+ lesions at 2 years	0.1 (0)	1.8 (0)
Mean (median)

Percentage of subjects with
0 lesions	93%	62%
1 lesion	5%	10%
2 lesions	<1%	8%
3 to 4 lesions	0	9%
5 or more lesions	<1%	11%

Relative odds reduction	90%		<0.0001
(percentage)

Mean number of new T1 hypointense	1.5	5.6	<0.0001
lesions over 2 years

Figure 1: Time to 12-Week Confirmed Progression of Disability (Study 1)

Study 2: Placebo-Controlled Trial in RRMS

Study 2 was a 2-year multicenter, randomized, double-blind, placebo-controlled study that also included an open-label comparator arm in patients with RRMS. The primary endpoint was the annualized relapse rate at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of T1 hypointense lesions, number of Gd+ lesions, proportion of patients relapsed, and time to confirmed disability progression as defined in Study 1.

Patients were randomized to receive TECFIDERA 240 mg twice a day (n=359), TECFIDERA 240 mg three times a day (n=345), an open-label comparator (n=350), or placebo (n=363) for up to 2 years. The median age was 37 years, median time since diagnosis was 3 years, and median EDSS score at baseline was 2.5. The median time on study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks on study drug per treatment group were 70% for patients assigned to TECFIDERA 240 mg twice a day, 72% for patients assigned to TECFIDERA 240 mg three times a day and 64% for patients assigned to placebo groups.

TECFIDERA had a statistically significant effect on the relapse and MRI endpoints described above. There was no statistically significant effect on disability progression. The TECFIDERA 240 mg three times daily dose resulted in no additional benefit over the TECFIDERA 240 mg twice daily dose. The results for this study (240 mg twice a day vs. placebo) are shown in Table 3.

Table 3: Clinical and MRI Results of Study 2
	TECFIDERA 240 mg BID	Placebo	P-value

Clinical Endpoints	N=359	N=363
Annualized relapse rate	0.224	0.401	<0.0001
Relative reduction	44%

Proportion relapsing	29%	41%	0.0020
Relative risk reduction	34%

Proportion with disability progression	13%	17%	0.25
Relative risk reduction	21%

MRI Endpoints	N=147	N=144
Mean number of new or newly enlarging	5.1	17.4	<0.0001
T2 lesions over 2 years

Percentage of subjects with no new or	27%	12%
newly enlarging lesions

Number of Gd+ lesions at 2 years
Mean (median)	0.5 (0.0)	2.0 (0.0)

Percentage of subjects with
0 lesions	80%	61%
1 lesion	11%	17%
2 lesions	3%	6%
3 to 4 lesions	3%	2%
5 or more lesions	3%	14%

Relative odds reduction	74%		<0.0001
(percentage)

Mean number of new T1 hypointense	3.0	7.0	<0.0001
lesions over 2 years