Data from Phase 3 COUGH-1 and COUGH-2 Trials
Presented at the Virtual European Respiratory Society (ERS)
International Congress 2020
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, has announced the results from two pivotal Phase 3 trials
(COUGH-1 and COUGH-2) evaluating the efficacy and safety of
gefapixant (MK-7264), an investigational, orally administered,
selective P2X3 receptor antagonist, for the potential treatment of
refractory or unexplained chronic cough. COUGH-1 and COUGH-2 are
the first companion Phase 3 trials ever conducted in patients with
refractory chronic cough, a cough that persists despite appropriate
treatment of underlying conditions, or unexplained chronic cough, a
cough where the underlying cause cannot be identified despite a
thorough evaluation. In these studies, adult patients treated with
gefapixant 45 mg twice daily demonstrated a statistically
significant reduction in 24-hour cough frequency (measured
objectively, as coughs per hour, using 24-hour sound recordings)
versus placebo at 12 weeks (COUGH-1) (18.45% reduction relative to
placebo, 95% CI [-32.92, -0.86; p=0.041]) and 24 weeks (COUGH-2)
(14.64% reduction relative to placebo, 95% CI [-26.07, -1.43;
p=0.031]). The gefapixant 15 mg twice daily treatment arms did not
meet the primary efficacy endpoint in either Phase 3 study.
“It is estimated that between 5 and 10% of adults globally
suffer from chronic cough. A subset of these patients have
refractory or unexplained chronic cough and appear more sensitive
to various triggers that do not typically cause cough in healthy
subjects. These include everyday things such as talking, laughing,
a change in air temperature or exposure to aerosols or food odors,
and to date treatment options are extremely limited for these
patients,” said Dr. Lorcan McGarvey, Clinical Professor,
Wellcome-Wolfson Institute of Experimental Medicine, School of
Medicine, Dentistry and Biomedical Sciences, Queen’s University
Belfast. “Given the significant unmet need for these patients, we
are strongly encouraged by the findings of COUGH-1 and COUGH-2 and
the potential for a new therapeutic option for patients who are
struggling with the burden of this disease, often for many years
without relief.”
“COUGH-1 and COUGH-2 are the first companion Phase 3 trials in
refractory or unexplained chronic cough, underscoring Merck’s
commitment to fully researching the potential for gefapixant in
this patient population,” said Dr. Roy Baynes, senior vice
president and head of global clinical development, chief medical
officer, Merck Research Laboratories. “Both trials met the primary
endpoint at the 45 mg twice daily dosage, significantly reducing
cough frequency in these patients, and we are grateful for the
opportunity to share these data with the scientific community.”
These results were presented at the virtual European Respiratory
Society (ERS) International Congress 2020 (abstract #3800). Merck
plans to share data from COUGH-1 and COUGH-2 with regulatory
authorities worldwide.
Study design and additional data from COUGH-1 and
COUGH-2
COUGH-1 (NCT03449134) and COUGH-2 (NCT03449147) are
international Phase 3, randomized, double-blind,
placebo-controlled, studies to evaluate the efficacy and safety of
gefapixant in reducing cough frequency in adult participants with
refractory or unexplained chronic cough. A total of 2,044
participants (75% female, mean age 58 years, mean cough duration 11
years) were treated in COUGH-1 (n=730) and COUGH-2 (n=1,314). In
both studies, patients were randomized to one of three groups:
gefapixant 45 mg twice daily, gefapixant 15 mg twice daily, or
placebo. Participants remained on their assigned treatment at
randomization throughout both studies. The primary efficacy
outcomes measure for COUGH-1 and COUGH-2 were 24-hour cough
frequency at Week 12, and 24-hour cough frequency at week 24,
respectively, measured using an ambulatory digital audio recording
device. Secondary endpoints in both trials included awake coughs
per hour and percentage of participants with a greater than
1.3-point increase from baseline in the Leicester Cough
Questionnaire (LCQ) total score. COUGH-1 had a 12-week treatment
period and a 40-week extension period, while COUGH-2 had a 24-week
treatment period and a 28-week extension period. Primary safety
outcomes include the percentage of patients experiencing greater
than one adverse event (AE) during treatment and follow up, and the
percentage of patients discontinuing treatment because of adverse
events.
In COUGH-1 and COUGH-2, treatment with gefapixant 45 mg twice
daily resulted in a significant reduction in objectively measured
24-hour cough frequency in participants with refractory or
unexplained chronic cough. In these studies, on average,
participants receiving gefapixant 45 mg twice daily in the COUGH-1
trial experienced a 62% reduction in cough frequency, and in the
COUGH-2 trial experienced a 63% reduction in cough frequency,
compared with baseline.
COUGH-1 (Week 12)
COUGH-2 (Week 24)
Placebo
Gefapixant
15 mg
Gefapixant 45 mg
Placebo
Gefapixant
15 mg
Gefapixant
45 mg
Efficacy
N included in Analysis
222
227
217
419
415
409
Baseline Geometric Mean 24-Hr Cough
Frequency (coughs/hr)
22.83
19.86
18.24
19.48
19.35
18.55
Geometric Mean 24-Hr Cough Frequency at
Primary Timepoint
10.33
9.66
7.05
8.34
8.10
6.83
Estimated Relative Reduction (%) (95%
Cl) vs Placebo*
--
1.58
(-16.12, 23.01)
p=0.872
-18.45
(-32.92, -0.86)
p=0.041
--
-1.14
(-14.27, 14.02)
p=0.875
-14.64
(-26.07, -1.43)
p=0.031
*Estimated relative reduction (%) vs
placebo was estimated by 1OO*(exp(diff) -1), where diff was the
difference provided by the analysis of the log transformed
variable.
The secondary endpoints in COUGH-1 and COUGH-2 support the
primary observation of the studies. Awake cough frequency results
were generally similar to the 24-hour cough frequency outcome,
reaching statistical significance in the 45 mg twice daily group in
COUGH-2 (15.79% estimated relative reduction, 95% CI [-27.27,
-2.50; p=0.022]) and trending towards significance in COUGH-1
(17.68% estimated relative reduction, 95% CI [-32.57, 0.50;
p=0.056]). Significantly more participants in the gefapixant 45 mg
twice daily group at week 24 demonstrated a clinically important
improvement in cough-related quality of life, with an odds ratio of
1.41 (p=0.042) compared with placebo. Of the participants in the 45
mg group, 77.1% experienced a clinically important level of
improvement in their quality of life related to cough, as measured
using the LCQ.
The safety and tolerability profile of gefapixant was consistent
with that reported in previous studies. The incidence of serious
AEs was similar between treatments (<4%). Discontinuations due
to AEs were more frequent in the 45 mg group (15% in COUGH-1 and
20% in COUGH-2) compared to the 15 mg (3% in COUGH-1 and 8% in
COUGH-2) and placebo groups (3% and 5%, respectively).
Taste-related AEs occurred at higher incidence in the 45 mg group
(58.0% in COUGH-1 and 68.6% in COUGH-2) compared to the 15 mg
(10.7% in COUGH-1 and 19.5% in COUGH-2) and placebo (3.3% in
COUGH-1 and 8.3% in COUGH-2) groups. The majority of taste-related
AEs were mild to moderate.
About Gefapixant
Gefapixant is an investigational, orally administered, selective
P2X3 receptor antagonist, for the potential treatment of refractory
or unexplained chronic cough. P2X3 receptors are one of the
receptor types found on sensory nerve fibers, predominantly C
fibers, in the airway lining. Chemical stimuli, including adenosine
triphosphate (ATP), can be released from airway lining cells due to
processes including airway inflammation, irritation, and mechanical
stress/injury. Binding of extracellular ATP to P2X3 receptors on C
fibers in the airway can be sensed as a signal of potential damage,
creating an action potential, which may initiate coughing. Blockade
of extracellular ATP binding to P2X3 receptors is thought to reduce
sensory C fiber activation and subsequently, coughing.
About Chronic Cough
The prevalence of chronic cough (a cough lasting more than 8
weeks) is estimated at 5-10% of the general adult population
globally. In a subset of these cases, patients either do not
respond to treatment of underlying conditions (such as asthma or
gastroesophageal reflux), known as refractory chronic cough (RCC),
or they have no identifiable underlying condition despite a
thorough evaluation, known as unexplained chronic cough (UCC).
There are currently no approved therapies for the treatment of RCC
or UCC.
About Merck
For more than 125 years, Merck, known as MSD outside of the
United States and Canada, has been inventing for life, bringing
forward medicines and vaccines for many of the world’s most
challenging diseases in pursuit of our mission to save and improve
lives. We demonstrate our commitment to patients and population
health by increasing access to health care through far-reaching
policies, programs and partnerships. Today, Merck continues to be
at the forefront of research to prevent and treat diseases that
threaten people and animals – including cancer, infectious diseases
such as HIV and Ebola, and emerging animal diseases – as we aspire
to be the premier research-intensive biopharmaceutical company in
the world. For more information, visit www.merck.com and connect
with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
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