New Publication Shows Respiratory Decline Correlated With Disease Progression in People Living With ALS
November 30 2017 - 7:30AM
Retrospective Analyses of Clinical Trials
in ALS Shows Faster Rate of Decline in Slow Vital
Capacity Strongly Predicts Increased Risk of Future Clinical
Events
Cytokinetics, Incorporated (Nasdaq:CYTK) today announced the
publication of retrospective analyses of data from controlled
trials of patients with ALS, showing that the rate of decline in
SVC strongly predicted meaningful clinical events, including time
to respiratory insufficiency and death in patients with ALS. The
publication, titled “Association Between Decline in Slow Vital
Capacity and Respiratory Insufficiency, Use of Assisted
Ventilation, Tracheostomy, or Death in Patients With Amyotrophic
Lateral Sclerosis,” was published in the Journal of the American
Medical Association (JAMA) Neurology.
“These results suggest that respiratory function
is an important prognostic indicator of clinical progression in
people with ALS and adds to a growing body of literature on this
correlation,” said Fady I. Malik, MD, PhD, Cytokinetics’ Executive
Vice President of Research & Development. “Vital capacity is a
key measure used by clinicians to measure disease progression
during routine clinic visits and this analysis reinforces its use
to guide critical clinical management decisions.”
In this retrospective analysis, placebo data
from each of EMPOWER, the Phase 3 clinical trial of dexpramipexole
in ALS, BENEFIT-ALS, the Phase 2 clinical trial of tirasemtiv in
ALS, and the Pooled Resource Open-Access ALS Clinical Trials
(PRO-ACT) database were analyzed to investigate the natural history
of respiratory function decline in patients with ALS, as measured
by SVC. Additionally, data from EMPOWER were used to assess the
relationship between SVC and respiratory-related clinical events. A
total of 893 patients with ALS were included in the analysis, and
were on average 56.7 years old, with an SVC of 90.4 percent
predicted at baseline; 65.5 percent were male and 20.3 percent had
bulbar-onset ALS.
The average slope of SVC decline was -2.73
percent/month in EMPOWER, -2.74 percent/month in BENEFIT-ALS, and
-2.90 percent/month in PRO-ACT. In EMPOWER, two clinically relevant
subgroups were associated with a faster rate of SVC decline:
patients 65 years of age and older (‑3.6 percent per month;
p=0.005) and patients with a baseline ALSFRS-R score ≤39 (-3.1
percent per month, p=0.001). Statistically significant correlations
were observed between change from baseline in percent predicted SVC
and other respiratory measures including change from baseline in
SNIP (r=0.38, p<0.001), and change from baseline in the
individual items of the respiratory domain of the ALSFRS-R
including dyspnea (r=0.23, p<0.001), orthopnea (r=0.23,
p<0.001), and respiratory insufficiency (r=0.26, p<0.001).
Additionally, a Cox proportional hazards regression model of time
to clinical events showed that slowing the rate of SVC decline by
1.5 percentage points per month in the first six months reduced the
risk of decline in any of the three ALSFRS-R respiratory subdomains
or death by 19 percent, first onset of respiratory insufficiency or
death by 22 percent, tracheostomy or death by 23 percent, and death
by 23 percent (all p<0.001). The results of these analyses
suggest that the rate of decline in SVC in patients with ALS
correlates with the risk of clinically meaningful events, such as
respiratory insufficiency or death in patients.
About ALS
ALS is a progressive neurodegenerative disease
that afflicts approximately 30,000 people in the United States and
a comparable number of patients in Europe. Approximately 6,000 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 approximately 10 percent 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 therapies to
address functional deficits and disease progression.
About Vital Capacity and Disease
Progression in ALS
Vital capacity is a measure used in the
management of ALS to assess the strength of respiratory muscles
and, as a predictor of disease progression and survival, is used in
clinical practice to make intervention decisions. Vital capacity
can be measured as slow vital capacity (SVC) or forced vital
capacity (FVC). SVC may be easier to perform in patients with
bulbar and advanced disease. Vital capacity measures the amount of
air expelled from the lungs after a maximum inhalation and is used
to assess the strength of the skeletal muscles responsible for
breathing (e.g., the diaphragm). Vital capacity is often expressed
in terms of the percentage of the normal value predicted for the
individual patient’s sex, age, and height; i.e., percent predicted
vital capacity. Percent predicted vital capacity declines an
average of 2-3 percentage points per month in patients with ALS and
is the most frequently monitored measure of respiratory function to
measure disease progression. Vital capacity is also used to inform
critical clinical decisions, such as initiation of non-invasive
ventilation, feeding tube placement and palliative care.
About Cytokinetics
Cytokinetics is a late-stage
biopharmaceutical company focused on discovering, developing and
commercializing first-in-class muscle activators as potential
treatments for debilitating diseases in which muscle performance is
compromised and/or declining. As a leader in muscle biology and the
mechanics of muscle performance, the company is developing small
molecule drug candidates specifically engineered to increase muscle
function and contractility. Cytokinetics is collaborating
with Amgen Inc. (“Amgen”) to develop omecamtiv
mecarbil, a novel cardiac muscle activator. Omecamtiv
mecarbil is the subject of GALACTIC-HF, an international Phase
3 clinical trial in patients with heart
failure. Amgen holds an exclusive worldwide license to
develop and commercialize omecamtiv mecarbil with a
sublicense held by Servier for commercialization
in Europe and certain other countries. Cytokinetics
is collaborating with Astellas Pharma Inc. (“Astellas”)
to develop CK-2127107, a next-generation FSTA. CK-2127107 has been
granted orphan drug designation by the FDA for the
potential treatment of SMA. CK-2127107 is the subject of three
ongoing Phase 2 clinical trials enrolling patients with spinal
muscular atrophy, chronic obstructive pulmonary disease and ALS.
Astellas is also conducting a Phase 1b clinical trial of CK-2127107
in elderly adults with limited mobility. Astellas holds an
exclusive worldwide license to develop and commercialize
CK-2127107. Licenses held by Amgen and Astellas are
subject to Cytokinetics' specified co-development and
co-commercialization rights. For additional information
about Cytokinetics, visit www.cytokinetics.com.
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