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Cytokinetics, Inc.: Cytokinetics Announces Additional Results from BENEFIT-ALS

First Clinical Trial in Patients with ALS to Show a Significant Reduction in
Decline of Slow Vital Capacity

Adverse Events on Tirasemtiv May Have Confounded Primary Efficacy Results

and Warrant Additional Analyses to Inform Potential Continued Development


Cytokinetics, Incorporated (Nasdaq: CYTK) announced today additional results
linded E
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euromuscular E
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irasemtiv in AL
), which will be presented later today during the 66th Annual Meeting of the
American Academy of Neurology at the Pennsylvania Convention Center in
Philadelphia by Jeremy M. Shefner, M.D., Ph.D., Professor and Chair,
Department of Neurology at the Upstate Medical University, State University
of New York and the Lead Investigator for BENEFIT-ALS.

In BENEFIT-ALS, 711 patients with amyotrophic lateral sclerosis (ALS) were
enrolled into the open-label phase; subsequently 605 patients were randomized
1:1 to double-blind treatment with eithertirasemtiv
or placebo for 12 weeks. As previously announced, BENEFIT-ALS did not achieve
its primary efficacy endpoint, the mean change from baseline in the ALS
Functional Rating Scale in its revised form (ALSFRS-R). Secondary endpoints
evaluated measures of respiratory performance and other measures of skeletal
muscle function and fatigability.

Treatment withtirasemtiv
resulted in a statistically significant and potentially clinically meaningful
reduction in the decline of Slow Vital Capacity (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 also declined less ontirasemtiv
than on placebo at each assessment time point.

|Slow Vital Capacity Placebo Tirasemtiv All |
| |
| (n = 210) (N = 388) |
| (n = 178) |
|Baseline (% Predicted, mean ± SD) 89.7 (17.2) 85.7 (19.3) 87.8 (18.3) |
|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 |

The analyses of other pre-specified secondary efficacy endpoints in
BENEFIT-ALS produced mixed results. The Muscle Strength Mega-Score, a
measure of strength combining the data from several muscle groups in each
patient, declined more slowly ontirasemtiv
versus placebo (p = 0.016 for the difference in slope of decline); however,
there were no differences at any time point that reached statistical
significance. The rate of decline for Sniff Nasal Inspiratory Pressure
(SNIP) was not statistically significant different (p = 0.21); however, SNIP
decreased more ontirasemtiv
compared with placebo in a statistically significant manner at 4 and 12 weeks
(p values at 4, 8, and 12 weeks were 0.012, 0.066, 0.050, respectively). No
differences in Maximum Voluntary Ventilation and Hand Grip Fatigue were
observed ontirasemtiv
versus placebo.

"I am pleased to present the results of BENEFIT-ALS at the American Academy of
Neurology," stated Dr. Shefner. "While this clinical trial did not meet its
primary efficacy endpoint, it 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. In addition, muscle strength appeared to decline more
slowly ontirasemtiv
versus placebo. The results of BENEFIT-ALS support continued investigation
into the roletirasemtiv
may play in the treatment of patients with ALS."

Serious adverse events (SAE) during double-blind treatment were more frequent
than on placebo (9.0% vs. 5.4%). The most common SAE was respiratory failure
which occurred in 1 patient ontirasemtiv
and 3 patients on placebo, while confusional state and delirium occurred in 2
patients ontirasemtiv
and no patients on placebo. More patients ontirasemtiv
withdrew from the trial following randomization than on placebo (99 vs. 33
patients, respectively). Adverse events more common ontirasemtiv
than on placebo (>10% difference) were dizziness (50.8% vs. 19.7%), fatigue
(33.2% vs. 14.2%), and nausea (21.9% vs. 7.8%).

Patients ontirasemtiv
lost more weight than patients on placebo (change from baseline to Week 12:
-1.70 kg vs. -0.79 kg; p = 0.006). Weight loss was significantly greater in
patients with gastrointestinal adverse events (e.g. nausea and decreased
appetite) which occurred more frequently ontirasemtiv
than on placebo (43.5% vs. 25.8%). The weight loss ontirasemtiv
appeared to negatively impact the effect oftirasemtiv
on the ALSFRS-R when compared to placebo (p value for weight
change-by-treatment interaction = 0.052). ALSFRS-R declined less
than on placebo in those patients treated withtirasemtiv
who lost less weight.

"On behalf of Cytokinetics, I want to extend our gratitude to the patients and
investigators who participated in BENEFIT-ALS. We are pleased that
BENEFIT-ALS provides the first evidence that fast skeletal muscle troponin
activation withtirasemtiv
may slow the progression of skeletal muscle weakness in patients with ALS,"
stated Andrew A. Wolff, M.D., F.A.C.C., Cytokinetics' Chief Medical Officer
and Senior Vice President of Clinical Research and Development. "Adverse
events ontirasemtiv
in BENEFIT-ALS may have confounded certain results of the trial. We will
continue to analyze the results of BENEFIT-ALS to understand how to approach
the potential further development oftirasemtiv


, a novel skeletal muscle activator, is the lead drug candidate from
Cytokinetics' skeletal muscle contractility program. Tirasemtiv
selectively activates the fast skeletal muscle troponin complex by increasing
its sensitivity to calcium and, in preclinical studies and early clinical
trials, demonstrated increases in skeletal muscle force in response to
neuronal input and delays in the onset and reductions in the degree of muscle


BENEFIT-ALS was a Phase IIb, multi-national, double-blind, randomized,
placebo-controlled, clinical trial designed to evaluate the safety,
tolerability and efficacy of tirasemtiv
in patients with ALS. BENEFIT-ALS enrolled patients in 73 centers in 8
countries. Patients enrolled in BENEFIT-ALS began treatment with
at 125 mg twice daily. Patients who tolerated this open-label treatment for
one week were randomized to receive 12 weeks of double-blind treatment with
twice-daily oral ascending doses of tirasemtiv
or placebo, beginning at 125 mg twice daily and increasing weekly up to 250
mg twice daily (or a dummy dose titration with placebo). Clinical assessments
occurred every four weeks during double-blind treatment; patients also
returned for follow-up evaluations at one and four weeks after their final
dose of double-blind study medication. The primary efficacy analysis of
BENEFIT-ALS compared the mean change from baseline in the ALS Functional
Rating Scale in its revised form (ALSFRS-R) to the average of the scores
obtained after 8 and 12 weeks of double-blind treatment on tirasemtiv
versus placebo. Secondary endpoints evaluated measures of respiratory
performance and other measures of skeletal muscle function and fatigability.

About Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that
afflicts approximately 25,000 people in the United States and a comparable
number of patients in Europe. Approximately 5,600 new cases of ALS are
diagnosed each year in the United States. The average life expectancy of an
ALS patient is approximately three to five years after diagnosis and only 10%
of patients survive for more than 10 years. Death is usually due to
respiratory failure because of diminished strength in the skeletal muscles
responsible for breathing. Few treatment options exist for these patients,
resulting in a high unmet need for new therapeutic options to address the
symptoms and modify the disease progression of this grievous illness.

About Cytokinetics

Cytokinetics is a clinical-stage biopharmaceutical company focused on the
discovery and development of novel small molecule therapeutics that modulate
muscle function for the potential treatment of serious diseases and medical
conditions. Cytokinetics' lead drug candidate from its cardiac muscle
contractility program,omecamtiv mecarbil
, is in Phase II clinical development for the potential treatment of heart
failure. Amgen Inc. holds an exclusive license worldwide to develop and
commercializeomecamtiv mecarbil
and related compounds, subject to Cytokinetics' specified development and
commercialization participation rights. Cytokinetics is independently
, a fast skeletal muscle activator, as a potential treatment for diseases and
medical conditions associated with neuromuscular dysfunction.Tirasemtiv
is the subject of a Phase II clinical trials program and has been granted
orphan drug designation and fast track status by the U.S. Food and Drug
Administration and orphan medicinal product designation by the European
Medicines Agency for the potential treatment of amyotrophic lateral sclerosis
(ALS). Cytokinetics is collaborating with Astellas Pharma Inc. to develop
CK-2127107, a skeletal muscle activator structurally distinct fromtirasemtiv
, for non-neuromuscular indications. All of these drug candidates have arisen
from Cytokinetics' muscle biology focused research activities and are
directed towards the cytoskeleton. The c...

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