- The document describes the BENEFIT-ALS clinical trial which evaluated the safety and efficacy of tirasemtiv in people with ALS. - The trial involved over 680 patients across 8 countries who received open-label tirasemtiv followed by 12 weeks of double-blind treatment with escalating doses of tirasemtiv or placebo. - Preliminary results show tirasemtiv was generally well tolerated. While changes from baseline on efficacy measures were small, the direction of effects on respiratory and muscle function were consistent with a potential benefit of tirasemtiv compared to an expected rate of decline in ALS.

1. BENEFIT-ALS: BLINDED EVALUATION OF
NEUROMUSCULAR EFFECTS AND FUNCTIONAL
IMPROVEMENT WITH TIRASEMTIV IN ALS
Jeremy M. Shefner, Donna Barragan, Amy Bian,
Jinsy Andrews, Lisa Meng, Mary Lou Watson,
Jacqueline Lee, Andrew A. Wolff, and the
NEALS/BENEFIT-ALS Study Group
1

2. Tirasemtiv is a Small Molecule Activator of the Skeletal Sarcomere
Tirasemtiv activates the
Tirasemtiv increases the
troponin complex of fast
skeletal muscle
efficiency of sub-maximal
muscle contraction
Force-Frequency Relationship
Specific tension (N cm-2)
50
pre-dose
tirasemtiv
40
30
20
10
0
10
30
40
50
60
70
80
100 200
Stimulation frequency (Hz)
2

3. Prior Clinical Studies of Tirasemtiv in ALS
• Well tolerated, with dizziness the most common AE
seen in about 40% of patients receiving tirasemtiv
• Dose/concentration dependent trends toward
efficacy seen in:
– ALSFRS-R
– Handgrip fatigue
– Respiratory measures
• MVV
• SNIP
– Quantitative muscle testing
3

4. BENEFIT-ALS: Primary Objective and Dosing
• Primary objective: To determine safety and
efficacy of tirasemtiv administered for 12 weeks
at the highest tolerated dose up to 500 mg daily
• Dosing:
– To enrich study population and improve blinding, all
randomized subjects completed 1 week of open label
dosing at 125 mg BID
– Double-blind dose escalated weekly from 125 mg BID
to 250 mg BID over 3 weeks and continued for a total
of 12 weeks of double-blind treatment
4

5. BENEFIT-ALS: Study Schema
~680 Patients with ALS
Multi-national, double-blind, placebo-controlled trial
• 1 week open-label treatment with tirasemtiv at 125 mg twice daily
• 12 weeks double-blind, twice daily oral ascending doses of tirasemtiv vs. placebo
ALSFRS-R, MVV, etc.
ALSFRS-R, MVV, etc.
1:1
Randomization
Screening
Visit 0
Visit 1
Screening Open-label
Tirasemtiv
Lead-in
Visit 2
Visit 3
Dose-Titration
Visit 4
Visit 5
Visit 6
MTD Phase
Visit 7 Visit 8
FU
Tirasemtiv
Washout
5

6. BENEFIT-ALS: Outcome Measures
• Primary: ALS Functional Rating Scale-Revised (ALSFRS-R)
− Mean change in ALSFRS-R at 8 and 12 weeks
− 80% power for a 1.18 point difference vs. placebo;
2-tailed α = 0.05
• Secondary:
− ALSFRS-R endpoints for secondary analyses
− Respiratory function
• Maximum Voluntary Ventilation (MVV)
• Sniff Nasal Inspiratory Pressure (SNIP)
• Slow Vital Capacity (SVC)
− Other measures of skeletal muscle function
• Handgrip strength and fatigability
• Muscle strength by hand-held dynamometry
6

7. BENEFIT-ALS: Enrollment Complete
• First patient screened October 23, 2012
• First patient enrolled November 6, 2012
• Last patient screened November 19, 2013
• Last patient enrolled (# 711) November 27, 2013
• Last patient visit approximately March 25, 2014
7

8. BENEFIT-ALS: Enrollment by Country
75 Study Centers in 8 Countries Participated
12 Centers
1 Center
SPAIN
(n = 19)
44 Centers
CANADA
(n = 104)
UNITED STATES
(n = 409)
IRELAND
(n = 13)
7 Centers
1 Center
6 Centers
1 Center
3 Centers
UNITED KINGDOM
(n = 38)
FRANCE
(n = 60)
NETHERLANDS
(n = 12)
711 Patients Enrolled
GERMANY
(n = 56)
8

9. BENEFIT-ALS: The Double–Blind Data to Date
• The following slides are based on all available data*
from 670 patients treated with open-label tirasemtiv
as of November 25, 2013, including …
– 99 intolerant to open-label tirasemtiv who never received
double-blind study drug
– 545 who received double-blind study drug
– 342 who completed 12 weeks of double-blind treatment
• These data are not yet completely monitored and
queried, and so are subject to change
*(i.e., entered into the Electronic Data Capture [EDC] system)
9

10. BENEFIT-ALS: Baseline Data - Patients Dosed with Open-Label
Mean (± SD)
Riluzole
(N=438)
No Riluzole
(N=232)
All
(N=670)
Age (years)
56.8 (11.1)
58.7 (10.7)
57.4 (11.0)
Male (n [%])
300 [68.5%]
154 [66.4%]
54 [67.8%]
BMI (kg/m2)
26.3 (4.1)
26.3 (4.3)
26.3 (4.1)
Months from Diagnosis
14.0 (14.1)
16.6 (28.2)
14.9 (20.1)
Months from 1st Symptom
28.8 (24.6)
35.2 (39.4)
31.0 (30.7)
ALSFRS-R Total Score
36.6 (4.6)
36.6 (4.7)
36.6 (4.6)
SVC (% Predicted)
86.9 (17.1)
87.9 (27.1)
87.2 (21.1)
MVV (L/min)
71.6 (33.7)
69.1 (35.6)
70.7 (34.4)
SNIP (cm H2O)
57.6 (25.4)
56.9 (24.9)
57.3 (25.2)
Qualifying Weaker Hand
Fatigability, 60%Target (sec)
74.4 (50.0)
78.4 (49.1)
75.8 (49.7)
(except as noted)
10

11. BENEFIT-ALS: Most Patients Reach Double-Blind Target Dose
100%
80%
60%
40%
20%
0%
1
2
3
4
5
6
7
8
9
10
11
12
Double-Blind Treatment Week
Total Daily Dose:
125mg
250 mg
375 mg
500 mg
11

12. BENEFIT-ALS: MVV Changes from Baseline
L/min
Mean (± SD)
Baseline
Week 4
Week 8
Week 12
100
80
60
40
20
0
-20
-40
-60
-80
-100
-120
Riluzole
(N=327)
72.5 (34.0)
-2.6 (16.2)
-3.5 (18.8)
-6.8 (19.7)
No Riluzole
(N=163)
71.3 (36.3)
-1.5 (20.7)
0.4 (22.2)
-2.4 (18.3)
All
(N=490)
72.1 (34.8)
-2.2 (17.8)
-2.1 (20.1)
-5.3 (19.3)
slope = -1.5 L/min/month
Week 4
Week 8
Week 12
12

13. BENEFIT-ALS: SNIP Changes from Baseline
mm Hg
Mean (± SD)
Baseline
Week 4
Week 8
Week 12
80
Riluzole
(N=327)
58.7 (25.0)
-4.2 (15.7)
-1.4 (15.1)
-4.1 (16.6)
No Riluzole
(N=163)
58.1 (25.6)
-0.0 (16.4)
-1.0 (14.8)
-2.1 (17.0)
All
(N=490)
58.5 (25.2)
-2.8 (16.1)
-1.3 (14.9)
-3.4 (16.8)
slope = -1.1 mm Hg/month
60
40
20
0
-20
-40
-60
-80
Week 4
Week 8
Week 12
13

14. BENEFIT-ALS: Grip Fatigue Changes from Baseline
Seconds to 60% of Target
Mean (± SD)
Baseline
Week 4
Week 8
Week 12
Riluzole
(N=327)
74.8 (49.7)
0.2 (49.1)
1.8 (49.0)
-4.4 (53.0)
No Riluzole
(N=163)
78.7 (48.5)
3.6 (57.4)
3.0 (58.1)
-1.2 (61.1)
All
(N=490)
76.1 (49.3)
1.4 (52.0)
2.2 (52.2)
-3.3 (55.9)
slope = -0.52 sec/month
120
90
60
30
0
-30
-60
-90
-120
Week 4
Week 8
Week 12
14

15. BENEFIT-ALS: Muscle Strength Changes from Baseline
Megascore
Mean (± SD)
Baseline
Week 4
Week 8
Week 12
Riluzole
(N=327)
0.1 (0.6)
-0.1 (0.2)
-0.1 (0.4)
-0.2 (0.5)
No Riluzole
(N=163)
0.0 (0.6)
-0.0 (0.2)
-0.1 (0.3)
-0.2 (0.4)
All
(N=490)
0.1 (0.6)
-0.1 (0.2)
-0.1 (0.4)
-0.2 (0.4)
slope = -0.049 unit/month
3
2
1
0
-1
-2
-3
Week 4
Week 8
Week 12
15

16. BENEFIT-ALS: Most Common Adverse Events (Open-Label)
Preferred Term
Dizziness
Riluzole
(N=438)
No Riluzole
(N=232)
All
(N=670)
171 (39.0%) 94 (40.5%) 265 (39.6%)
Fatigue
62 (14.2%)
41 (17.7%)
103 (15.4%)
Nausea
51 (11.6%)
18 (7.8%)
69 (10.3%)
Somnolence
29 (6.6%)
17 (7.3%)
46 (6.9%)
Asthenia
25 (5.7%)
10 (4.3%)
35 (5.2%)
16

17. BENEFIT-ALS: Most Common Adverse Events (Double-Blind)
Preferred Term
Dizziness
Riluzole
(N=363)
78 (21.5%)
No Riluzole
(N=182)
45 (24.7%)
All
(N=545)
123 (22.6%)
Fatigue
Headache
Nausea
51 (14.1%)
41 (11.3%)
37 (10.2%)
31 (17.0%)
23 (12.6%)
27 (14.8%)
82 (15.0%)
64 (11.7%)
64 (11.7%)
Asthenia
25 (6.9%)
21 (11.5%)
46 (8.4%)
Muscle spasms
21 (5.8%)
20 (11.0%)
41 (7.5%)
Muscular weakness
21 (5.8%)
14 (7.7%)
35 (6.4%)
Confusional state
19 (5.2%)
15 (8.2%)
34 (6.2%)
Insomnia
18 (5.0%)
14 (7.7%)
32 (5.9%)
Contusion
20 (5.5%)
11 (6.0%)
31 (5.7%)
Diarrhoea
21 (5.8%)
10 (5.5%)
31 (5.7%)
Constipation
14 (3.9%)
15 (8.2%)
29 (5.3%)
Somnolence
22 (6.1%)
7 (3.9%)
29 (5.3%)
17

18. Dizziness in BENEFIT-ALS: Onset and Duration
Open-Label1
(N=670)
Duration of 1st Episode of Dizziness (days)
1
265
123
Mean
1.1
15.1
0.6
9.1
Mean
13.6
19.9
Median
Time to 1st Onset of Dizziness (days)
N
Median
Patients Reporting Dizziness
Double-Blind2
(N=545)
6.0
7.2
Onset of dizziness during open-label treatment to its resolution, whether during
open-label or double-blind treatment
2 Dizziness that
began (or worsened) during double-blind treatment; dizziness
persisting from open-label treatment into double-blind treatment is not included
18

19. BENEFIT-ALS: Study Drug Assignment Error and Response
• A programming error in the electronic data capture
system controlling study drug assignment caused
58 patients initially randomized to and treated
with tirasemtiv to be dispensed placebo instead
• To maintain the blind and ensure safety, these 58
patients continued on placebo through the final visit
• Enrollment was suspended until the protocol was
amended to …
– Increase enrollment up to approximately 680 patients
– Exclude from the primary efficacy analysis all 156 patients
randomized in blocks containing any of the 58 affected
patients to ensure tirasemtiv and placebo primary
analysis groups were concurrently randomized
19

20. BENEFIT-ALS: Baseline Demographics Changed Over Time
Randomization Date
Mean (± SD)
(except as noted)
Age (years)
Male (n, [%])
By April 30th, 2013
No
Riluzole Riluzole
56.1
56.3
(11.2)
(11.3)
All
56.2
(11.2)
May 1st – July 31st , 2013
No
Riluzole Riluzole
56.6
59.2
(11.0)
(10.8)
78
43
121
130
[69.0%] [68.3%] [68.8%] [71.0%]
BMI (kg/m2)
26.9
(4.2)
26.5
(3.8)
26.7
(4.0)
Months from Diagnosis
13.5
(10.2)
21.9
(37.1)
16.5
(23.9)
Months from 1st Symptom
27.7
(18.9)
36.0
(39.4)
30.7
(28.2)
ALSFRS-R Total Score
36.1
(5.1)
35.6
(4.9)
35.9
(5.0)
SVC (% Predicted)
85.8
(16.9)
85.2
(17.6)
85.6
(17.1)
MVV (L/min)
77.5
(35.1)
67.1
(39.4)
73.8
(36.9)
SNIP (cmH2O)
58.4
(25.3)
59.6
(25.2)
58.8
(25.2)
Grip Fatigue to 60%Target (sec)
75.3
(48.4)
76.8
(45.1)
75.8
(47.0)
26.3
(4.3)
15.0
(14.8)
28.1
(19.9)
36.9
(4.3)
87.4
(17.4)
69.7
(32.3)
57.5
(23.6)
75.8
(50.8)
All
57.5
(11.0)
After July 31st , 2013
No
Riluzole Riluzole
56.6
57.9
(11.3)
(11.1)
All
57.0
(11.2)
63
[71.6%]
193
[71.2%]
57
[71.3%]
26
[66.7%]
83
[69.7%]
27.0
(4.6)
14.9
(27.6)
31.7
(33.6)
37.1
(4.4)
90.8
(37.3)
71.1
(33.2)
56.5
(25.5)
77.9
(51.4)
26.5
(4.4)
15.0
(19.9)
29.3
(25.2)
37.0
(4.3)
88.5
(25.5)
70.2
(32.5)
57.2
(24.2)
76.4
(50.9)
26.3
(3.6)
11.6
(12.0)
30.0
(39.2)
37.4
(3.8)
87.6
(16.3)
70.5
(36.5)
62.1
(30.1)
68.0
(49.3)
25.6
(4.6)
10.3
(16.5)
31.6
(35.3)
37.4
(5.0)
86.4
(21.8)
70.9
(40.2)
55.8
(26.2)
84.6
(49.7)
26.1
(3.9)
11.2
(13.5)
30.5
(37.9)
37.4
(4.2)
87.2
(18.2)
70.7
(37.6)
60.0
(28.9)
74.0
(49.8)
Concurrent randomization of treatment groups minimizes temporal confounding
and may be critical to preserve the integrity of the primary efficacy analysis!
20

21. BENEFIT-ALS: Summary and Conclusions
• BENEFIT-ALS is completely enrolled (711 patients)
• The open-label tirasemtiv lead-in period …
– Helps to maintain the study blind
– Reduces dropouts after randomization
• Tirasemtiv is generally well tolerated
– Most patients complete the study at 250 mg BID
– Dizziness generally resolves quickly (median duration 6 – 7 days)
• All 156 patients randomized in blocks containing any of the
58 patients subject to the study drug assignment error will be
excluded from the primary efficacy analysis
− Ensures the tirasemtiv and placebo groups in the primary efficacy
analysis were concurrently randomized
– Changes in baseline demographics over time support this approach
• Results will be reported in the 2nd quarter of 2014
21

22. BENEFIT-ALS: BLINDED EVALUATION OF
NEUROMUSCULAR EFFECTS AND FUNCTIONAL
IMPROVEMENT WITH TIRASEMTIV IN ALS
Jeremy M. Shefner, Donna Barragan, Amy Bian,
Jinsy Andrews, Lisa Meng, Mary Lou Watson,
Jacqueline Lee, Andrew A. Wolff, and the
NEALS/BENEFIT-ALS Study Group
22