AstraZeneca Announces Top-line Phase III Results from Naloxegol Pivotal Trials In Patients With Opioid-Induced Constipation
SAN FRANCISCO, November 12, 2012, 2012 /PRNewswire/ -- AstraZeneca today announced positive top-line results from two Phase III trials and one safety extension trial in patients with non-cancer related pain and opioid-induced constipation (OIC). These Phase III KODIAC trials evaluated the safety and efficacy of naloxegol, an oral peripherally-acting, mu-opioid receptor antagonist for the treatment of OIC, a common side effect of prescription opioids.
KODIAC-04 and -05 are both multicenter, randomized,
double-blind, placebo-controlled pivotal trials of 12 weeks
duration evaluating 12.5 mg and 25 mg naloxegol administered
once-daily. The primary endpoint in both trials was percentage of
OIC responders versus placebo over 12 weeks of treatment where a
responder was defined as having at least three Spontaneous Bowel
Movements (SBM) per week, with at least one SBM per week increase
over baseline, for at least nine out of 12 weeks, and at least
three out of the last four weeks. Under the design of both trials,
statistical significance for the primary endpoint would be achieved
if at least one of the two naloxegol doses had a p-value <0.025
compared with placebo.
Analysis of the data indicates that in KODIAC-04 both naloxegol
doses (12.5 mg and 25 mg) demonstrated statistically significant
results for the primary endpoint. P-values were 0.015 and 0.001
respectively.
In KODIAC-05, the 25 mg dose demonstrated a statistically
significant result for the primary endpoint but the 12.5 mg dose
did not. P-values were 0.202 for 12.5 mg and 0.021 for 25 mg.
The analyses also showed no clinically relevant imbalances in
serious adverse events (SAEs), including externally adjudicated
major cardiovascular events, across the three treatment arms in
KODIAC-04, -05 and -07. The most common adverse events (AEs) in the
naloxegol treatment arms in both trials were abdominal pain,
diarrhea and nausea. In KODIAC-07, (the safety extension of
KODIAC-04) the occurrence of AEs and SAEs was lower than in
KODIAC-04 and -05. Among non serious adverse events, arthralgia was
the most common and was reported only in patients in the naloxegol
25 mg arm. All other common AEs were distributed similarly across
the three treatment arms. In KODIAC-04 and -05 for either naloxegol
dose, compared to placebo, there were no significant differences in
change from baseline in mean daily pain scores or mean total daily
opioid dose. A full assessment of the safety and tolerability
findings of all three studies is ongoing.
Naloxegol is part of the exclusive worldwide license agreement
announced on 21 September 2009 between AstraZeneca and Nektar
Therapeutics.
“Opioid-induced constipation is a burdensome condition which
is often overlooked, inadequately managed and can negatively impact
a patient’s quality of life,” said Martin Mackay,
President of Research and Development, AstraZeneca. “The
top-line results of the pivotal KODIAC studies provide important
new information on the safety and efficacy of naloxegol as a
potential treatment for opioid-induced constipation and we are
looking forward to advancing this programme.”
The core Phase III KODIAC programme for naloxegol is comprised of
four clinical trials which are designed to investigate the safety
and efficacy of naloxegol for the treatment of OIC in patients with
non-cancer related pain. The full data from these trials will be
submitted for presentation at future medical meetings.
The three trials reporting top-line results today include
KODIAC-04, -05, and -07. KODIAC-04 and -05 are replicate pivotal
12-week efficacy and safety trials, while KODIAC-07 is a 12-week
safety extension of KODIAC-04. After initial locking of the
database for KODIAC-05, data associated with one patient that was
previously assessed as non-retrievable was found to be retrievable.
These data were added to the database and the database was again
locked and underwent a final analysis. All three trials were
conducted in patients with non-cancer pain and documented OIC, who
require daily opioid therapy.
Enrolment is complete for the open-label, randomized, 52-week
long-term safety trial (KODIAC-08) and the trial is expected to be
completed by Q1 2013.
Naloxegol is currently considered a Schedule II controlled
substance by the US Drug Enforcement Administration (DEA) based on
structural relatedness to noroxymorphone. AstraZeneca has conducted
the studies necessary to evaluate the abuse potential and
dependence-producing properties of naloxegol in support of
obtaining decontrol. A petition for the decontrol of naloxegol was
submitted to the DEA in March 2012 and subsequently accepted for
review. Commercialisation and launch in the US will be subject to
both FDA approval and DEA schedule determination.
NOTES TO EDITORS
About Naloxegol
Naloxegol is a peripherally-acting mu-opioid receptor antagonist
being investigated for the treatment of constipation
(opioid-induced constipation or OIC) as a side effect of
prescription opioid pain medicines.
Top-line results of the Phase II study of naloxegol (formerly
NKTR-118) were previously presented at the American College of
Gastroenterology Annual Clinical Meeting and the American Academy
of Pain Management Annual Meeting. Naloxegol was developed using
Nektar’s oral small molecule polymer conjugate
technology.
About Opioid-Induced Constipation
Opioids attach to specific proteins called opioid receptors. When
the opioids attach to certain opioid receptors in the
gastrointestinal tract, constipation may occur. Opioid-induced
constipation (OIC) is a result of decreased fluid absorption and
lower gastrointestinal motility due to opioid receptor binding in
the gastrointestinal tract.
Globally, approximately 40–50% (28-35 million) patients
taking opioids for long-term pain develop constipation. About
40–50% (11-18 million) of those OIC sufferers achieve the
desired treatment outcomes with current options that include
over-the-counter and prescription laxatives.
About Nektar
Nektar Therapeutics (NASDAQ: NKTR) is a clinical-stage
biopharmaceutical company developing novel therapeutics based on
its PEGylation and advanced polymer conjugate technology platforms.
Nektar has a robust R&D pipeline of therapeutic candidates in
oncology, pain and other areas. The company is headquartered in San
Francisco, California, with additional R&D operations in
Huntsville, Alabama and Hyderabad, India. Further information about
Nektar and its drug development programs and capabilities may be
found online at www.nektar.com
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical
business with a primary focus on the discovery, development and
commercialization of prescription medicines for gastrointestinal,
cardiovascular, neuroscience, respiratory and inflammation,
oncology and infectious disease. AstraZeneca operates in over 100
countries and its innovative medicines are used by millions of
patients worldwide. For more information please visit:
www.astrazeneca.com
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Posted: November 2012
