1. FREEDOMS II TRIAL

2. Study Design 24-month, RCT of fingolimod 0.5 mg and 1.25 mg vs placebo
3 years into the study, 1.25 mg discontinued and patients placed on 0.5 mg in blinded manner
Relapsing-remitting MS patients
>1 relapses within previous year or >2 relapses in previous 2 years; no relapses or steroids within 30 days of randomization
EDSS score: 0 to 5.5
Any IFN B or GA stopped >3 months prior to randomization; any natalizumab stopped >6 months prior
Abbreviations: EDSS, Expanded Disability Status Scale; GA, glatiramer acetate;
IFN B, interferon beta; RCT, randomized controlled trial
Calabresi PA, et al. Lancet Neurol. 2014; 13:

3. Study Endpoints Primary endpoint: Annualized relapse rate
Key secondary endpoints:
Percent brain volume change from baseline
Time to disability progression confirmed at 3 months
Other
Safety and tolerability
Time to first relapse and proportion of relapse-free patients
Effect on MRI measures of inflammatory disease activity
Time to disability progression confirmed at 6 months
Change on MSFC score
Abbreviation: MSFC, Multiple Sclerosis Functional Composite
Calabresi PA, et al. Lancet Neurol. 2014; 13:

4. Efficacy: Relapse Endpoint 0.5 mg (n=358) 1.25 mg (n=370) Placebo
Primary Endpoint:
Annualized relapse rate
Rate ratio vs placebo
0.21
0.52*
0.20
0.50*
0.40
Time to first relapse
HR vs placebo
0.50 *
Patients relapse-free (%)
71.5%*
73.2%*
52.7%
* P<.0001 vs placebo
Calabresi PA, et al. Lancet Neurol. 2014; 13:

5. Efficacy: MRI Measures
Endpoint
0.5 mg
(n=358)
1.25 mg
(n=370)
Placebo
(n=355)
Key Secondary Endpoint:
Brain volume change
Mean
Difference from placebo
-0.858%
-0.41% a
-0.595%
-0.63% b
-1.279%
New Gd+ T1 lesions at 24 months
Mean number
Patients free of lesions (%)
Mean change in volume (%)
0.4 b
87% b
12.64% c
0.2b
96% b
-4.69% d
1.2
65%
26.42%
New/enlarging T2 lesions at 24 months
2.3 b
50% b
13.74% b
1.6 b
63% b
-7.69 b
8.9
26%
25.06%
Free of new inflammatory activity
All P values vs placebo:
a P=.0002 ; b P<.0001; c P=0.372; d P=0.205.
Calabresi PA, et al. Lancet Neurol. 2014; 13:

6. Efficacy: Disability Progression
Endpoint
0.5 mg
(n=358)
1.25 mg
(n=370)
Placebo
(n=355)
Key Secondary Endpoint:
Patients without disability progression at 3 months (%)
Mean HR
74.7%
(P=.320)*
0.83
(P=.227)*
78.3%
(P=.056)*
0.72
(P=.041)*
71.0%
Patients without disability progression at 6 months (%)
86.2%
(P=.101)*
86.9%
(P=.113)*
82.2%
* P vs placebo
Calabresi PA, et al. Lancet Neurol. 2014; 13:

7. Adverse Events More Frequent with Fingolimod
(0.5 mg)
Placebo
Lymphopenia
27 (8%)
0 (0%)
Increased ALT
29 (8%)
6 (2%)
Herpes zoster infection
9 (3%)
3 (1%)
Hypertension
32 (9%)
11 (3%)
First-dose bradycardia
5 (1%)
1 (<0.5%)
First-degree atrioventricular block
17 (5%)
7 (2%)
Abbreviations: ALT, alanine transaminase
Calabresi PA, et al. Lancet Neurol. 2014; 13:

8. Serious Adverse Events
Fingolimod
(0.5 mg)
Placebo
All serious events
53 (15%)
45 (13%)
Basal cell carcinoma
10 (3%)
2 (1%)
Macular edema
3 (1%)
Infections
11 (3%)
4 (1%)
Neoplasms
13 (4%)
8 (2%)
Calabresi PA, et al. Lancet Neurol. 2014; 13:

9. Conclusions Compared to placebo, fingolimod 0.5 mg resulted in
Reduction in annualized relapse rate and time to first relapse; increase in % patients relapse-free
Reduction in % brain volume loss, number/ volume of new Gd+T1 lesions, and number/ volume of new/enlarging T2 lesions; increase in patients free of new inflammatory activity
Increase in quality of life
No difference in disability progression
Calabresi PA, et al. Lancet Neurol. 2014; 13:

10. Conclusions
Certain adverse events occurred with greater frequency with fingolimod than placebo, but there were no new safety signals observed
No clinically relevant effects of fingolimod were noted in terms of cardiac or pulmonary toxicity
However, clinicians should be aware of contraindications in patients with specific cardiac risks
Calabresi PA, et al. Lancet Neurol. 2014; 13: