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Cytokinetics, Incorporated
provided a program update today relating to tirasemtiv, the company's
lead drug candidate from its skeletal muscle contractility program. The
company announced that it has completed its review of results from BENEFIT-ALS
(Blinded Evaluation of Neuromuscular Effects and Functional Improvement with
Tirasemtiv in ALS) and has concluded that effects observed on Slow Vital
Capacity (SVC) in patients treated with tirasemtiv are robust and potentially
clinically meaningful. In addition, following consultation with clinical and
statistical experts, the company believes that data from BENEFIT-ALS support
progression of tirasemtiv to a potential Phase III clinical trial in patients
with amyotrophic lateral sclerosis (ALS). The company also announced that it
has begun regulatory interactions with the U.S. Food and Drug Administration
(FDA) regarding results from BENEFIT-ALS and has received initial feedback
from the FDA. The company believes that effects on SVC could be a Phase III
clinical trial endpoint and could support registration of tirasemtiv as a
potential treatment for patients with ALS. As a result, Cytokinetics has
initiated planning for a potential Phase III clinical trial of tirasemtiv that
could begin in 2015.
"We have engaged in an objective and comprehensive review of results from
BENEFIT-ALS and have concluded that data favoring the effects of tirasemtiv
relative to placebo on Slow Vital Capacity from this large, international
Phase IIb trial are robust and warrant further investigation. BENEFIT-ALS is
the first clinical trial in patients with ALS to demonstrate a positive and
potentially clinically meaningful effect on Slow Vital Capacity, an important
measure of disease progression and predictor of survival," stated Robert I.
Blum, Cytokinetics' President and CEO. "We are encouraged by our initial
interactions with the FDA relating to the results of BENEFIT-ALS and believe
that our continuing discussions can inform our plans to pursue a potential
registration program based on effects observed on respiratory function
measured by Slow Vital Capacity in patients with ALS."
Effects of Tirasemtiv on SVC in BENEFIT-ALS
In BENEFIT-ALS, treatment with tirasemtiv resulted in a statistically
significant and potentially clinically meaningful reduction in the decline of
SVC, a measure of the strength of the skeletal muscles responsible for
breathing that has been shown to be an important predictor of disease
progression and survival in prior trials of patients with ALS. This
pre-specified secondary efficacy endpoint in BENEFIT-ALS declined less
on tirasemtiv than on placebo at each assessment time point.
Slow Vital Capacity Placebo Tirasemtiv All
(n = 210) (n = 178) (N = 388)
Baseline 89.7 (17.2) 85.7 (19.3) 87.8 (18.3)
(% Predicted, mean ± SD)
Time Point Changes from Baseline p-value
(Least Square Mean ± Standard Error)
Week 4 -3.89 (0.62) -0.99 (0.68) 0.001
Week 8 -5.81 (0.68) -2.85 (0.77) 0.004
Week 12 -8.66 (0.80) -3.12 (0.90) <0.0001
Slope of decline
(Percentage Points per day)
Week 0 to Week 12 -0.0905 -0.0394 0.0006
In addition, the reduced decline in SVC on tirasemtiv versus placebo in
BENEFIT-ALS was observed consistently across all subgroups of patients.
Tirasemtiv reduced the decline in SVC versus placebo by a similar magnitude
regardless of age (>65 versus <65), sex, geographic region (Europe versus
North America), riluzole use, site of ALS onset (bulbar versus limb), baseline
pulmonary function, baseline weight, and baseline BMI. The reduced decline in
SVC versus placebo was statistically significant within each subgroup examined
except patients enrolled in Europe, those with bulbar onset, and those with a
percent predicted SVC less the median at baseline. Outcome measures obtained
at 1 and 4 weeks after the last dose of double-blind study medication in
BENEFIT-ALS also provide evidence of the durability of the effect of
tirasemtiv on SVC.
Changes from Baseline
Outcome Measure Baseline After 12 Weeks 1 Week after Last 4 Weeks after Last
Double-Blind Double-Blind Dose Double-Blind Dose
SVC (%
predicted)
Placebo 89.7 -8.66 -8.03 -10.30
Tirasemtiv 85.7 -3.12 -3.75 -5.39
p-value <0.0001 0.0002 0.0002
Cytokinetics has performed extensive statistical analyses as well as
simulations and sensitivity tests on data from BENEFIT-ALS. In addition, the
company has consulted with neuromuscular and pulmonary specialists and key
opinion leaders, both in the United States and internationally, and has
concluded that the results from BENEFIT-ALS provide compelling evidence that
tirasemtiv may preserve respiratory function in patients with ALS that
warrants investigation in a potential Phase III trial.
Ongoing Regulatory Interactions and Next Steps
Cytokinetics has received feedback from the FDA following initial
communications regarding tirasemtiv and BENEFIT-ALS. The company believes
that the FDA may be willing to consider a potential registration path for
tirasemtiv relating to effects on SVC. The company expects to have additional
interactions with the FDA and other regulatory authorities. In addition, the
company has commenced Phase III readiness activities including designing a
potential Phase III clinical trial in order to inform plans, timelines and
costs associated with the further development of tirasemtiv.
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