Indication: Treatment of moderate to severe chronic low back pain
Discovered by Nektar
NKTR-181, a first-in-class opioid analgesic, 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
About Opioids and Pain Management
Pain is one of the most common reasons people seek medical treatment.2 Low back pain is the second most common cause of disability for adults in the U.S.3 Approximately 149 million work days are lost every year because of low back pain, with total costs estimated to be $100 to 200 billion a year (of which two-thirds is due to lost wages and lower productivity).4 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 persistent pain.5
Opioids are considered the most effective therapeutic option for pain. In 2016, 230 million opioid prescriptions were written in the U.S. 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.6 Brain imaging studies have shown that the faster a euphorigenic drug enters and leaves the brain, the stronger are its reinforcing effects.7 In 2014, nearly 2 million Americans either abused or were dependent on prescription opioid pain relievers.8 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.9
In 2015, there were nearly 22,000 deaths involving prescription opioids in the U.S.10 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.11
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 and sedation, 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.
Current strategies of abuse deterrence to address the addictive qualities of standard opioids rely on formulations alone. All abuse-deterrent formulations are limited in that once the opioid within the formulation is liberated through tampering, it can rapidly enter the brain and is highly euphorigenic. Preclinical 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.12
The U.S. Food and Drug Administration (FDA) has granted NKTR-181 Fast Track designation for the treatment of moderate to severe chronic pain. NKTR-181 is an investigational product and has not been approved by the FDA or any other regulatory agencies.
SUMMIT Phase 3 Program
The SUMMIT Phase 3 program includes the SUMMIT-07 efficacy study, the SUMMIT-LTS long-term safety study and a human abuse potential (HAP) study.
The SUMMIT-07 study compared twice-daily dosing of NKTR-181 tablets to placebo in the treatment of over 600 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.
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 oxycodone (40 mg and 60 mg) in 54 healthy non-dependent recreational drug users. For the primary endpoint of Drug Liking, NKTR-181 (400 mg and 600 mg) rated less likable compared to oxycodone 40 mg and 60 mg (p<0.0001), and a supratherapeutic dose of NKTR-181 (1200 mg) rated less likable than oxycodone 60 mg (p=0.0071). Key secondary endpoints of Area Under Effect (AUE) for Drug Liking (0-1 hours, 0-2 hours, 0-3 hours), Drug High and Take Drug again were also met statistical significance for all doses of NKTR-181 (1200 mg, 600 mg, 400 mg) compared to oxycodone (60 mg).
The SUMMIT Phase 3 program also includes a 52-week long term safety study (SUMMIT-LTS). SUMMIT-LTS is evaluating the long-term safety and tolerability of NKTR-181 in 638 subjects (opioid-naïve and opioid-experienced) with moderate to severe chronic low pain or chronic non-cancer pain. Information about the SUMMIT studies can be found on clinicaltrials.gov.
1Hyman, Steven E., Harvard Review of Psychiatry. 2(1):43-46, May/June 1994.
22011 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).
3Arch Intern Med 2009 February 9; 169(3): 251-258.
4World Health Organization: Priority Medicines for Europe and the World Update Report, 2013; Background Paper 6.24, Low Back Pain.
6Melnikova, I, Pain Market, Nature Reviews Drug Discovery, Volume 9, 589-90 (August 2010).
7Volkow, N., et al., Addiction: Beyond dopamine reward circuitry; PNAS, Volume 108(37), 15037-15042 (September 2011)
8Substance Abuse and Mental Health Services Administration, National Survey on Drug Use and Health, 2014.
9The 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.
10CDC. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; 2016. Available at http://wonder.cdc.gov.
11Centers for Disease Control and Prevention. Policy Impact: Prescription Painkiller Overdoses. 2011 https://www.cdc.gov/drugoverdose/pdf/policyimpact-prescriptionpainkillerod-a.pdf#page=5
- Clinical Pain Advisor: Mu-Opioid Analgesic in Phase III Offers Hope for the Management of Chronic Pain Without Addictive Side Effects
- MIT Technology Review: Opioids without Addiction
- Medscape Medical News: Novel Opioid May Deter Abuse Through Slow-Acting Analgesia
- BioCentury: BioCentury: BioCentury features Phase 1 NKTR-181 data in the Bernstein Report on BioBusiness
Current Medical Research and Opinion
- Manuscript: Assessment of potentially abuse-related events in two phase 3 studies of NKTR-181, a novel opioid analgesic, using the MADDERS® system (Misuse, Abuse, and Diversion Drug Event Reporting System)
PAIN: The Journal of the International Association for the Study of Pain
- Manuscript: Summit-07: A randomized trial of NKTR-181, a new molecular entity, full mu-opioid receptor agonist for chronic low-back pain
2018 Society for Neuroscience Annual Meeting
- Poster 478.09: “NKTR-181: Relationship Between Mu-Opioid Receptor Binding Kinetics and In Vivo Pharmacodynamics”
American Association of Nurse Practitioners 2018 National Conference
- Abuse Potential of NKTR-181 in Recreational Opioid Users: Results from a Randomized, Double-Blind Crossover Oral Study
- Efficacy, Safety, and Tolerability of NKTR-181 in Patients With Moderate to Severe Chronic Low-Back Pain: A Phase 3 Study
80th Annual Scientific Meeting of the College on Problems of Drug Dependence (CPDD)
- Abstract 335: Neuropharmacodynamic Profile of NKTR-181: Correlation to Low Abuse Potential
- Abstract 76: Assessment of Drug Abuse-Related Events with MADDERS in SUMMIT-07: A Phase-3 Study of NKTR-181 in Patients with Moderate to Severe Chronic Low-Back Pain
- Abstract: 168: NKTR-181 demonstrates low abuse potential in recreational opioid users in two double-blind, randomized crossover human abuse potential studies
2018 American Academy of Pain Medicine 34th Annual Meeting
- Poster 233: Efficacy, safety, and tolerability of NKTR-181 in patients with moderate to severe chronic low-back pain: A Phase 3 study.
- Poster 246: Opioid withdrawal findings from a phase 3 study of NKTR-181 in subjects with moderate to severe chronic low-back pain.
American College of Neuropsychopharmacology 56th Annual Meeting, Palm Springs, CA
- Poster T166: Abuse Potential of NKTR-181 in Recreational Opioid Users: Results From a Randomized, Double-Blind Crossover Oral Study, Ge, X., et al.
- Poster 38: Measuring Withdrawal in a Phase 3 Study of a New Analgesic, NKTR-181, in Subjects With Moderate to Severe Chronic Low-Back Pain
- Poster 41: Efficacy, Safety, and Tolerability of NKTR-181 in Patients With Moderate to Severe Chronic Low-Back Pain: A Phase 3 Study
Pain Medicine - March 2017
- Original Research Article: Human Abuse Potential of the New Opioid Analgesic Molecule NKTR-181 Compared with Oxycodone
IASP 26th Annual World Congress on Pain
- Poster L00055: NKTR-181, a novel mu opioid analgesic with inherently low abuse potential and efficacy in multiple preclinical models of pain
2016 American Academy of Pain Management Annual Meeting
2013 College on Problems of Drug Dependence (CPDD) Annual Meeting
- Poster: Abuse Potential Assessment of Novel Opioid Analgesic NKTR-181: Implications for Labeling and Scheduling
2012 American Association of Pharmaceutical Scientists Annual Meeting
2012 American College of Clinical Pharmacology Annual Meeting
- Poster: New Oral Opioid Analgesic NKTR-181: Bioequivalence between Tablet and Aqueous Solution and Lack of Food Effect
- Poster: Mixed-Effects PK/PD Analysis of NKTR-181, a New Oral Opioid Analgesic in Healthy Subjects
2012 American Academy of Pain Medicine 28th Annual Meeting
- Poster: NKTR-181: An Orally Available Mu-Opioid Agonist with Slow Rate of Uptake into the CNS, Exhibits Comparable Analgesic Efficacy with Reduced Abuse Liability and CNS Mediated Side Effects Compared to Oxycodone
- Poster: Multiple Dose Pharmacokinetics and Pharmacodynamics of the New Oral Opioid Analgesic NKTR-181
2011 American Academy of Pain Management 22nd Annual Meeting
- Poster: Pharmacokinetics and Pharmacodynamics of Oral NKTR-181, a Novel Opioid Analgesic: Results of a Single Ascending Dose Phase 1 Study
- Poster: NKTR-181: A Novel Opioid Analgesic That Exhibits Reduced Abuse Potential and Maintains Full Analgesic Activity Following Repeat Dosing in Preclinical Rodent Models
2011 Society for Toxicology 50th Annual Meeting & ToxExpo
- Poster: NKTR-181, a Novel Polymer Conjugated Opioid Agonist, Demonstrates Reduced Toxicity and CNS Side Effects Relative to Oxycodone
2010 Society for Neuroscience 40th Annual Meeting
- Poster: NKTR-181: A novel opioid analgesic with slowed CNS entry shows reduced abuse liability and CNS side effects
- Poster: Controlling the rate of entry to the CNS by polymer conjugation
American Society of Anesthesiologists (ASA) Annual Meeting - Anesthesiology 2010
- Abstract #A509: NKTR-181, a Novel Opioid Analgesic with Slow Entry into CNS and Markedly Reduced CNS Side Effects
5th Annual Frontiers of Clinical Investigation Symposium - Pain 2010: From Bench to Bedside
- July 30, 2018: Nektar Therapeutics Announces New Drug Application for NKTR-181 Accepted for Review by FDA
- June 14, 2018: New Data for NKTR-181, a First-in-Class Investigational Opioid to Treat Chronic Low Back Pain in Adult Patients New to Opioid Therapy, Presented at College on Problems of Drug Dependence 80th Annual Scientific Meeting
- May 31, 2018: Nektar Therapeutics Announces Submission of a New Drug Application to the U.S. FDA for NKTR-181, a First-in-Class Investigational Opioid to Treat Chronic Low Back Pain in Adult Patients New to Opioid Therapy
- September 6, 2017: Nektar Therapeutics Presents Clinical Data from Phase 3 SUMMIT-07 Study of NKTR-181, a First-in-Class Investigational Opioid to Treat Chronic Pain, at 2017 PAINWeek®
- July 18, 2017: Nektar Announces Topline Data from Human Abuse Potential Study for NKTR-181, a First-in-Class Investigational Opioid to Treat Chronic Pain
- March 20, 2017: NKTR-181 Meets Primary and Secondary Endpoints in Phase 3 SUMMIT-07 Study in Chronic Pain
- February 25, 2015: Nektar Announces Start of Phase 3 SUMMIT-07 Study of NKTR-181 in Patients with Chronic Low Back Pain
- September 26, 2013: Nektar Announces Preliminary Topline Results from Phase 2 Efficacy Study for NKTR-181 in Chronic Pain Patients with Osteoarthritis of the Knee
- June 19, 2013: Nektar Therapeutics Presents Positive Data from Human Abuse Liability Study for NKTR-181, a First-in-Class Investigational Opioid to Treat Chronic Pain, at 2013 Annual Meeting of The College on Problems of Drug Dependence
- July 24, 2012: Nektar Announces Start of Enrollment in Phase 2 Study of NKTR-181, a Novel Opioid Analgesic Molecule, for Treatment of Chronic Pain
- February 27, 2012: Nektar Presents Positive Proof-of-Concept Clinical Data for Its New Opioid Molecule, NKTR-181, at American Academy of Pain Medicine's 28th Annual Meeting
- December 13, 2011: Nektar Announces Positive Clinical Data from Second Phase 1 Clinical Study of NKTR-181, a Novel Opioid Analgesic Molecule to Treat Chronic Pain