Cara Therapeutics, Inc. (Nasdaq:CARA), a biopharmaceutical company
focused on developing and commercializing new chemical entities
designed to alleviate pain and pruritus by selectively targeting
peripheral kappa opioid receptors, today announced summary results
from its Phase 1 safety trial showing that I.V. CR845 did not
significantly differ from placebo across three quantitative
measures of respiratory drive in healthy individuals. Respiratory
depression remains the most life-threatening side effect of
traditional, centrally acting, opioid analgesics, the most commonly
used drug class for current treatment of postoperative pain in the
United States.
“We are very pleased that I.V. CR845
demonstrated no significant alteration in any measure of
respiratory drive, even at doses five-fold greater than the
projected therapeutic dose,” said Joseph Stauffer, D.O., M.B.A.,
Chief Medical Officer of Cara Therapeutics. “These data further
underscore the overall clinical safety profile of CR845 for use in
postoperative pain management and continue to differentiate it from
traditional mu opioids.”
“There remains a clear unmet need for effective
analgesic agents that lack the risk of serious, potentially fatal
respiratory depression that is inherent in current opioids,” said
Christopher Wu, M.D., Department of Anesthesiology and Critical
Care, Johns Hopkins University. “The ability to administer I.V.
CR845 without any direct effect on respiratory function is a
significant advantage in the acute post-surgical care setting where
patients are already at heightened risk of respiratory depression.
CR845’s profile also aligns with the most recent standard of care
guidelines for postoperative pain, which call for minimizing
opioid-related side effects.”
Respiratory Safety Phase 1 Trial Design
and Results
The Phase 1 trial was a randomized,
double-blind, placebo-controlled, three-way crossover trial of two
doses of I.V. CR845 (1.0 ug/kg, and 5.0 ug/kg) versus placebo on
three measures of respiratory drive in 15 healthy volunteers. Each
subject was randomized to one of three treatment sequences and was
administered I.V. bolus placebo, CR845 (1.0 ug/kg) and CR845 (5.0
ug/kg) on sequential 24-hour periods, with CR845 at 5.0 ug/kg
representing a projected five-fold supra-therapeutic dose. After
each administration, and continuing through four hours post-dosing,
end-tidal CO2 (ETCO2), oxygen saturation (SpO2) and respiratory
rate were continuously monitored. The primary safety endpoints
were: a >10 mmHg sustained (>30 seconds duration) increase in
ETCO2 above baseline or to >50 mmHg, and a sustained reduction
in SpO2 to <92 percent.
Mean ETC02 pre-dosing ranged from 36.1 ± 3.9 to
37.8 ± 2.9 mmHg across treatment groups. At one hour
post-administration, ETC02 values for placebo, CR845 1.0 ug/kg and
CR845 5.0 ug/kg treatment groups were numerically and statistically
equivalent at 38.1 ± 2.8, 38.1 ± 3.1, and 38.3 ± 2.9 mmHg,
respectively. Pre-treatment levels of SpO2 ranged from 98.3 percent
± 1.2 to 98.9 percent ± 1.0 and were measured at 97.8 percent ±
1.2, 98.2 percent ± 1.5 and 97.9 percent ± 1.0 for placebo, CR845
1.0 ug/kg and CR845 5.0 ug/kg treatment groups respectively, at one
hour post-treatment. There were no statistically significant
differences in any respiratory measures between groups throughout
the four-hour observation period and no individual patient met the
threshold for a respiratory safety event.
All reported treatment-emergent adverse events
were previously reported with CR845 administration and were mild,
resolving without intervention.
An oral presentation of this dataset will be
part of the Journal Anesthesiology Symposium on Sunday, October 22,
2017 at the American Society of Anesthesiology (ASA) Annual Meeting
in Boston, MA.
About Respiratory
Depression
Respiratory depression is the most
life-threatening side effect of conventional opioids, which act
primarily at the mu opioid receptor subtype. Mu opioid receptors
are present in high amounts in brainstem areas that control
respiration, similar to midbrain and spinal areas that regulate
pain perception. A wide variety of factors are involved in
determining the effects of mu opioids on breathing, with high
potency and speed of onset being well known risk factors, in
addition to the presence of sedating medications, the site of
surgery and surgical technique used, the presence of underlying
disease, and the patient’s age, sex, genetics, and hormonal status,
as well as arousal and pain, which can vary substantially between
patients. Although death rates from opioid-induced respiratory
arrest have declined in many hospitals due to more aggressive
patient monitoring, it remains the leading concern of
anesthesiologists and pain specialists (1). However, such
monitoring is generally not available when patients are discharged
home with powerful opioids, and the increasingly high rate of
deaths associated with both opioid use and misuse is presently
considered a national health crisis.
(1) Safe use of opioids in hospitals. Sentinel Event Alert, 2012
Aug 8;(49):1-5
https://www.jointcommission.org/assets/1/18/SEA_49_opioids_8_2_12_final.pdf
About the Ongoing CLIN3001 Postoperative
Pain Trial
The CLIN3001 Phase 3 trial is a multi-center,
randomized, double-blind, placebo-controlled, parallel-group
adaptive design trial with repeated doses of I.V. CR845 or placebo
administered both prior to and following abdominal surgery in male
and female patients. The trial is enrolling up to 450 patients at
30 clinical sites within the U.S. Two doses of I.V. CR845 (1.0, and
0.5 ug/kg I.V.) are being compared to placebo. The primary
efficacy measure is the Change in Pain Intensity over the 24-hour
post-operative period (AUC-24) using the patient-reported Numeric
Rating Scale (NRS) score collected at pre-specified time points
through 24 hours. Postoperative nausea and vomiting (PONV) will be
evaluated as a secondary efficacy measure.
An interim conditional power assessment at
approximately 65 percent patient recruitment completion will read
out in the second quarter of 2017.
About CR845
CR845 is a peripherally acting kappa opioid
receptor agonist currently in development for the treatment of
acute and chronic pain and pruritus. In multiple randomized,
double-blind, placebo-controlled Phase 2 trials in patients
undergoing laparoscopic hysterectomy or bunionectomy procedures,
I.V. CR845 treatment resulted in statistically significant
reductions in pain intensity and opioid-related side effects. In
more than 1200 subjects dosed to date, CR845 was observed to be
well-tolerated, without incurring the dysphoric and psychotomimetic
side effects that have been reported with centrally acting
(CNS-active) kappa opioid receptor agonists, and lacking the
respiratory depression and abuse liability of mu opioid receptor
agonists. Top-line data from a Phase 2b trial of Oral CR845 in
chronic pain associated with osteoarthritis are expected in the
second quarter of 2017.
About Cara Therapeutics
Cara Therapeutics is a clinical-stage
biopharmaceutical company focused on developing and commercializing
new chemical entities designed to alleviate pain and pruritus by
selectively targeting peripheral kappa opioid receptors. Cara is
developing a novel and proprietary class of product candidates, led
by CR845, that target the body's peripheral nervous system and have
demonstrated initial efficacy in patients with moderate-to-severe
pain without inducing many of the undesirable side effects
typically associated with currently available pain
therapeutics.
Forward-looking Statements
Statements contained in this press release
regarding matters that are not historical facts are
"forward-looking statements" within the meaning of the Private
Securities Litigation Reform Act of 1995. Examples of these
forward-looking statements include statements concerning the
expected timing of the read out of the planned interim conditional
power assessment of the ongoing CLIN3001 postoperative pain trial
of I.V. CR845 and the expected timing of the release of top-line
data from the ongoing Phase 2b trial of Oral CR845 in chronic pain
associated with osteoarthritis Because such statements are subject
to risks and uncertainties, actual results may differ materially
from those expressed or implied by such forward-looking statements.
Risks are described more fully in Cara’s filings with the
Securities and Exchange Commission, including the "Risk Factors"
section of Cara’s Annual Report on Form 10-K for the year ended
December 31, 2016 and its other documents subsequently filed with
or furnished to the Securities and Exchange Commission. All
forward-looking statements contained in this press release speak
only as of the date on which they were made. Except to the extent
required by law, Cara undertakes no obligation to update such
statements to reflect events that occur or circumstances that exist
after the date on which they were made.
MEDIA CONTACT:
Annie Starr
6 Degrees
973-415-8838
astarr@6degreespr.com
INVESTOR CONTACT:
Michael Schaffzin
Stern Investor Relations, Inc.
212-362-1200
michael@sternir.com
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