SAN FRANCISCO, July 18, 2017 /PRNewswire/ -- Nektar
Therapeutics (NASDAQ: NKTR) announced positive topline
results from an oral Human Abuse Potential (HAP) study of NKTR-181,
a first-in-class opioid analgesic. NKTR-181 is a new chemical
entity (NCE) that is the first full mu-opioid agonist molecule
designed to provide potent pain relief without the high levels of
euphoria that can lead to abuse and addiction with standard
opioids.1 NKTR-181 is the first analgesic opioid
molecule to exhibit reduction in specific CNS-mediated side
effects, like euphoria, through the strategic alteration of
brain-entry kinetics. The U.S. Food and Drug
Administration (FDA) has granted the investigational medicine
NKTR-181 Fast Track designation for the treatment of moderate to
severe chronic pain.
The NKTR-181 HAP study was designed to confirm and assess the
relative oral abuse potential of NKTR-181 at its maximum analgesic
or therapeutic dose (400 mg) and at a supratherapeutic dose (3
times to 12 times greater than its analgesic dose range of 100 mg
to 400 mg) compared to common therapeutic doses of a Schedule II
opioid, oxycodone.
"Today's opioid abuse epidemic has created a pressing need for a
better pain medicine that does not possess the euphorigenic
qualities of conventional opioids," said Ivan Gergel, MD, Senior Vice President and Chief
Medical Officer of Nektar. "It is clear from our new study
results that NKTR-181 is highly differentiated in this respect from
oxycodone, which is a choice drug of abuse. Further, and
critically important in the context of this public health
emergency, NKTR-181's less rewarding properties and strong
analgesia are inherent to its novel molecular structure and
independent of any abuse-deterrent formulation. Many patients
do not receive adequate pain relief because they fear taking
conventional opioids, including abuse-deterrent formulations,
because of their potential for abuse and addiction. We
believe NKTR-181 is a transformational pain medicine that should
significantly advance the treatment of chronic pain and could be a
fundamental building block in the fight against prescription opioid
abuse. We are committed to bringing this new pain treatment to
patients and physicians as quickly as possible."
Opioids act on specific receptors in the brain to provide pain
relief, but they also target the dopamine reward system in the
brain to produce euphoria and other psychoactive effects, which
leads to addiction and abuse.1 Brain imaging
studies have shown that the faster a euphorigenic drug enters and
leaves the brain, the stronger are its reinforcing
effects.2 In 2014, nearly 2 million Americans either
abused or were dependent on prescription opioid pain
relievers.3 Opioid abuse is a growing epidemic in
the U.S., with one in five Americans who say they have a family
member who has been addicted to prescription
painkillers.4
"Getting very high, very fast, is a mark of conventional
high-risk, abused opioids," said Jack
Henningfield, PhD, vice president at Pinney Associates and
adjunct professor at The Johns Hopkins
University School of Medicine. "NKTR-181 represents a
meaningful advance in the treatment of pain as the first opioid
analgesic with inherent brain-entry kinetics that avoids this
addictive quality of traditional opioids. This prevents the rapid
'rush' that abusers seek during the critical period immediately
after dosing. Importantly, these properties of NKTR-181 are
inherent to its molecular structure and are not changed through
tampering or route of administration."
In March 2017, NKTR-181 completed
a Phase 3 efficacy trial (SUMMIT-07) in 610 patients with moderate
to severe chronic low back pain who were new to opioid therapy
(opioid-naïve). SUMMIT-07 evaluated four analgesic doses of
NKTR-181 (100 mg, 200 mg, 300 mg and 400 mg). Patients in the
trial achieved an average pain score reduction of over 65% (from
6.73 at screening to 2.32 at randomization) during the dose
titration period. The primary efficacy endpoint of the
study demonstrated significantly improved chronic back pain relief
with NKTR-181 compared to placebo (p=0.0019). Key secondary
endpoints of the study also achieved high statistical significance.
The study demonstrated that NKTR-181 had a favorable safety profile
and was well tolerated.
HAP Study Design and Objectives
HAP studies are
clinical studies that help assess the relative abuse potential of a
medicine. The NKTR-181 HAP study was a randomized,
double-blind, placebo-controlled, six-sequence crossover study
evaluating the relative oral abuse potential of NKTR-181 relative
to the Schedule II opioid oxycodone in healthy non-dependent
recreational drug users experienced in the oral abuse of opioids
who can identify drug effects that are relevant to abuse risk
assessment. Subjects (n=54) were randomized to one of six
test sequences, in each of which they received a single dose of one
of the six study drugs:
- NKTR-181 400 mg (highest efficacious dose established in the
Phase 3 efficacy trial);
- NKTR-181 600 mg (a dose of 1.5 to 6 times greater than the
efficacious dose range established in the Phase 3 efficacy
trial);
- NKTR-181 1200 mg (a supratherapeutic dose of 3 to 12 times
greater than the efficacious dose range of 100 mg to 400 mg
established in the Phase 3 efficacy trial);
- Moderate therapeutic dose of oxycodone at 40 mg
- High therapeutic dose of oxycodone at 60 mg
There was a five-day washout period between each
treatment. NKTR-181 doses and its matching placebo were
administered as oral tablets. Oxycodone HCl doses were administered
as over-encapsulated oral tablets.
The study evaluated effects that are predictive of abuse
potential with opioids for all doses in the study. The HAP
trial was powered to detect a relative peak (Emax*) drug liking
score difference between oxycodone at 60 mg and NKTR-181 at 1,200
mg. Liking was based on a subject-reported 100-point bipolar
liking/disliking visual analog scale (VAS), which is a standard
measure of abuse potential in HAP studies. Key secondary endpoints
were Area Under Effect for Drug Liking in the first 1, 2 and 3
hours after dosing as well as retrospective subject-reported
unipolar VAS ratings for Drug High and bipolar VAS ratings for Take
Drug Again.
Topline Results
Primary Endpoint of Drug Liking:
- NKTR-181 400 mg had a significantly lower rating of peak (Emax)
liking compared to oxycodone 40 mg (62.0 vs. 76.6,
p<0.0001).
- NKTR-181 400 mg had a significantly lower rating of peak (Emax)
liking compared to oxycodone 60 mg (62.0 vs. 81.5,
p<0.0001).
- NKTR-181 600 mg had a significantly lower rating of peak (Emax)
liking compared to oxycodone 40 mg (67.9 vs. 76.6,
p<0.0001).
- NKTR-181 600 mg had a significantly lower rating of peak (Emax)
liking compared to oxycodone 60 mg (67.9 vs. 81.5,
p<0.0001).
- NKTR-181 1200 mg had a significantly lower rating of peak
(Emax) drug liking compared to oxycodone 60 mg (76.7 vs. 81.5,
p=0.0071). This dose was not statistically different from oxycodone
40 mg.
The peak liking score for NKTR-181 400 mg oral tablet in this
study confirmed the same peak liking score for NKTR-181 400 mg oral
solution evaluated in the company's prior HAP study (62.0 vs
62.3**).
Secondary Endpoint of Area Under Effect (AUE) for Drug Liking
Following Dosing (0-1 Hours, 0-2 Hours, 0-3 Hours):
- NKTR-181 400 mg had significantly lower AUE for all timepoints
compared to both oxycodone 40 mg and 60 mg (p<0.0001).
- NKTR-181 600 mg had significantly lower AUE for all timepoints
compared to both oxycodone 40 mg and 60 mg (p<0.0001).
- NKTR-181 1200 mg had significantly lower AUE for all timepoints
compared to both oxycodone 40 mg and 60 mg. For AUE (0-1 Hours),
p=0.0002 and p<0.0001, respectively; for AUE 0-2 Hours, p=0.001
and p<0.0001, respectively; for AUE 0-3 Hours, p=0.0396 and
p=0.0003, respectively).
Secondary Endpoint of Drug High:
- NKTR-181 400 mg had significantly lower ratings of peak (Emax)
Drug High compared to both oxycodone 40 mg and 60 mg
(p<0.0001).
- NKTR-181 600 mg had significantly lower ratings of peak (Emax)
Drug High compared to both oxycodone 40 mg and 60 mg
(p<0.0001).
- NKTR-181 1200 mg had a significantly lower rating of peak
(Emax) Drug High compared to 60 mg oxycodone (p=0.0071).
The peak Drug High score for NKTR-181 400 mg oral tablet in this
study confirmed the peak Drug High score in the first HAP trial,
which evaluated 400 mg NKTR-181 as an oral solution (21.3 vs
22.59**).
Secondary Endpoint of Take Drug Again:
- NKTR-181 400 mg had significantly lower ratings of peak (Emax)
Take Drug Again compared to the 40 mg and 60 mg oxycodone
(p<0.0001).
- NKTR-181 600 mg had significantly lower ratings of peak (Emax)
Take Drug Again compared to the 40 mg and 60 mg oxycodone (p=0.0004
and p<0.0001, respectively).
- NKTR-181 1200 mg had a significantly lower rating of peak Take
Drug Again compared to 60 mg oxycodone (p=0.011).
Full data from the NKTR-181 HAP study will be presented at a
future medical meeting.
Pain is one of the most common reasons people seek medical
treatment.5 A study published in the American Pain
Society's The Journal of Pain in October 2014 estimated that 19 percent of the
U.S. population, or 39 million people, suffer from some type of
persistent pain.6 In 2015, there were nearly
22,000 deaths involving prescription opioids in the
U.S.7 The health care utilization consequences are
also significant; for every one death from prescription opioids, it
is estimated that there are 10 treatment admissions for abuse, 32
emergency room visits for misuse or abuse, 130 people who are
dependent, and 825 people who report non-medical use of these
drugs.8
Conference Call and Webcast Information
Nektar will
host a conference call and webcast presentation today, July
18, 2017 at 8:45 a.m. Eastern Daylight Time to discuss
the study results. The call can be accessed by dialing (877)
881-2183 (U.S.) or (970) 315-0453 (international), and entering
passcode 56389932. To access the live webcast, or the subsequent
archived recording, visit the Investors section of the Nektar
website at www.nektar.com. The webcast will be available for
replay on Nektar's website for two weeks following the call.
About NKTR-181
NKTR-181 is the first long-acting,
selective mu-opioid agonist designed to provide potent pain relief
without the inherent high levels of euphoria which lead to abuse
and addiction with standard opioids. The novel molecular
structure of NKTR-181 is designed to have low permeability across
the blood-brain barrier in order to slow its rate of entry into the
brain and attenuate the dopamine release that underlies
euphoria. NKTR-181 is the first opioid molecule to exhibit
reduction in specific CNS-mediated side effects, like euphoria,
through the strategic alteration of brain-entry
kinetics. In addition, NKTR-181 is designed with an
inherent 12-hour elimination half-life to enable twice-daily dosing
with continuous pain control. NKTR-181 is an investigational
medicine and has not been approved by the FDA or any other
regulatory agencies.
Current and past strategies of abuse deterrence to address the
addictive qualities of standard opioids rely on formulations
alone. However, all abuse-deterrent formulations are
pre-cursors to highly euphorigenic rapid-acting opioids, which can
liberated through tampering. The National Survey on Drug Use
and Health (NSDUH) indicated that 16.0 million people in the U.S.
reported using oxycodone products non-medically in their lifetime
in 2012.
Preclinical and clinical data show that the inherent properties
of NKTR-181 reduce its rate of entry into the brain compared to
standard mu opioids, regardless of route of
administration.9
About Nektar Therapeutics
Nektar Therapeutics is a
research-based biopharmaceutical company whose mission is to
discover and develop innovative medicines to address the unmet
medical needs of patients. Our R&D pipeline of new
investigational medicines includes treatments for cancer,
auto-immune disease and chronic pain. We leverage Nektar's
proprietary and proven chemistry platform in the discovery and
design of our new therapeutic candidates. Nektar is headquartered
in San Francisco, California, with
additional operations in Huntsville,
Alabama and Hyderabad,
India. Further information about the company and its drug
development programs and capabilities may be found online at
http://www.nektar.com.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements which can
be identified by words such as: "plan," "expect," "may," "will,"
"believe," "can," "should," "could" and similar references to
future periods. Examples of forward-looking statements include,
among others, statements we make regarding the potential
therapeutic benefit of NKTR-181 for treating patients with pain,
the potential importance of NKTR-181's development in the area of
new pain medicines, the risks of opioid abuse resulting from use of
NKTR-181, as well as from new and existing pain medicines, future
development plans for NKTR-181 (including, but not limited to,
future clinical development plans and future regulatory filings
seeking regulatory approval for NKTR-181), the potential timeframe
for commercial availability of NKTR-181, and certain other
statements regarding the prospects and potential of NKTR-181
specifically, and Nektar's business and technology platform
generally. Forward-looking statements are neither historical
facts nor assurances of future performance. Instead, they are based
only on our current beliefs, expectations and assumptions regarding
the future of our business, future plans and strategies,
anticipated events and trends, the economy and other future
conditions. Because forward-looking statements relate to the
future, they are subject to inherent uncertainties, risks and
changes in circumstances that are difficult to predict and many of
which are outside of our control. Our actual results may differ
materially from those indicated in the forward-looking statements.
Therefore, you should not rely on any of these forward-looking
statements. Important factors that could cause our actual results
to differ materially from those indicated in the forward-looking
statements include, among others: (i) challenges and uncertainties
inherent in pharmaceutical research and development, including the
uncertainty of future clinical and regulatory success, where the
risk of failure remains high and failure can unexpectedly occur at
any stage prior to regulatory approval due to lack of sufficient
efficacy, safety considerations or other factors; (ii) the
regulatory pathway to review and approve NKTR-181 for use in
patients, even with a Fast Track designation by the FDA, is subject
to substantial uncertainty; (iii) regulations concerning and
controlling the access to opioid-based pharmaceuticals are strict
and there is no guarantee which scheduling category will apply to
NKTR-181 if regulatory approval is achieved; (iv) the partnering
process for NKTR-181 is at an early stage and there is therefore
substantial uncertainty as to the timing and terms of a potential
partnership, or the success of our partnering efforts; (v) drug
manufacturing challenges which can delay or render unavailable
sufficient supplies of NKTR-181; (vi) changing standards of care
and new regulations (including, but not limited to, standards and
regulations related to health care cost containment) can affect the
use NKTR-181 and commercial success following a regulatory
approval; (vii) Nektar's patent applications for NKTR-181 may not
issue in one or more jurisdictions, patents that have issued may
not be enforceable, or additional intellectual property licenses
from third parties may be required in the future; (viii) the
outcome of any existing or future intellectual property or other
litigation related to Nektar's proprietary product candidates,
including, without limitation, NKTR-181, is unpredictable and could
have a material adverse effect on our business; and (ix) certain
other important risks and uncertainties set forth in Nektar's
Quarterly Report on Form 10-Q for the quarter ended March 31, 2017 filed with the Securities and
Exchange Commission on May 10, 2017.
Any forward-looking statement made by us in this press release is
based only on information currently available to us and speaks only
as of the date on which it is made. We undertake no obligation to
update any forward-looking statement, whether written or oral, that
may be made from time to time, whether as a result of new
information, future developments or otherwise.
Contact:
For Investors:
Jennifer Ruddock of Nektar
Therapeutics
415-482-5585
Jodi Sievers of Nektar
Therapeutics
415-482-5593
For Media:
Dan Budwick
1AB Media
973.271.6085
* Emax equal to Maximum Effect (at all
timepoints)
** Webster et al.; Human Abuse Potential of
the New Opioid Analgesic Molecule NKTR-181 Compared with
Oxycodone. Pain Med 2017 pnw344. doi:
10.1093/pm/pnw344
1. Melnikova, I, Pain Market, Nature Reviews Drug Discovery,
Volume 9, 589-90 (August 2010).
2. Volkow, N., et al., Addiction: Beyond dopamine reward
circuitry; PNAS, Volume 108(37), 15037-15042 (September 2011)
3. Substance Abuse and Mental Health Services Administration,
National Survey on Drug Use and Health, 2014.
4. The Washington Post/Kaiser Family Foundation Survey of
Long-Term Prescription Painkiller Users and Their Household
Members: http://kff.org/other/report/the-washington-post-kaiser-family-foundation-survey-of-long-term-prescription-painkiller-users-and-their-household-members.
5. 2011 National Academy of Sciences. Relieving Pain in America:
A Blueprint for Transforming Prevention, Care, Education and
Research, 2010 Decision Resources, and Harstall, C. How prevalent
is chronic pain? Pain Clinical Updates X, 1-4 (2003).
6
http://americanpainsociety.org/about-us/press-room/persistent-pain-incidence-news-release.
7. CDC. Wide-ranging online data for epidemiologic research
(WONDER). Atlanta, GA: CDC,
National Center for Health Statistics; 2016. Available
at http://wonder.cdc.gov.
8. Centers for Disease Control and Prevention. Policy Impact:
Prescription Painkiller Overdoses. 2011
https://www.cdc.gov/drugoverdose/pdf/policyimpact-prescriptionpainkillerod-a.pdf#page=5
9. 2010 Society of Neuroscience Annual Meeting
(Nov 13-17, #HHH11).
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