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.
The US Food and Drug Administration (FDA) has granted the investigational medicine NKTR-181 Fast Track designation for the treatment of moderate to severe chronic pain.
Gold Coast Research medical director and clinical investigator Martin Hale said: "The data from this efficacy study are extremely important because they demonstrate that NKTR-181 produces strong analgesia in patients suffering from chronic pain while NKTR-181 has also demonstrated significantly lower abuse potential than oxycodone in a human abuse potential study.
"While standard opioid analgesics, including abuse-deterrent formulations, have been the most effective way to treat chronic pain, they are associated with serious safety concerns and many opioid-naïve patients fear taking them because of the potential for abuse and addiction.
“The data for NKTR-181 suggest that it is a transformational pain medicine that could fundamentally change how we treat patients with chronic pain conditions."
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).
The clinical trial met the primary efficacy endpoint of the study in demonstrating significantly improved chronic back pain relief with NKTR-181 compared to placebo (p=0.0019). Key secondary endpoints of the study were also met with high statistical significance.
Pain is one of the most common reasons people seek medical treatment. Low back pain is the second most common cause of disability for adults in the US.
Approximately 149 million work days are lost every year because of low back pain, with total costs estimated to be $100 to 200bn a year (of which two-thirds is due to lost wages and lower productivity).
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.
The Phase 3 SUMMIT-07 study used an enriched-enrollment randomized withdrawal (EERW) trial design in patients with moderate to severe chronic low back pain. The trial included an open-label titration period in which patients were titrated to a tolerated, effective dose of NKTR-181 (100 mg to 400 mg twice-daily).
Following this open-label titration period, patients entered a double-blind, placebo-controlled treatment period in which they were randomized 1:1 to either continue to receive the tolerated, effective dose of NKTR-181 or to receive matching placebo (i.e. active drug was withdrawn) for a period of 12 weeks.
During the open-label titration period of the trial in which patients were titrated to a tolerated, effective dose of NKTR-181, average pain scores dropped by 65% (from 6.73 at screening to 2.32 at randomization, n=610).
The primary endpoint of the study was mean change in the weekly average pain score in the double-blind randomized treatment period from baseline (end of open-label titration period) to week 12 (end of double-blind randomized treatment period).
Primary and key sensitivity analyses:
- During the double-blind randomized treatment period of the trial, average pain scores increased more in the placebo arm versus NKTR-181 at week 12 from randomization baseline (1.46, placebo versus 0.92, NKTR-181, p=0.0019, n=610).
- 83% of patients completed the 12-week double-blind randomized treatment period and for these study completers, average pain scores increased more in the placebo arm versus NKTR-181 at week 12 from baseline (1.25, placebo versus 0.56, NKTR-181, p < 0.0001, n=504).
Key secondary endpoints:
- A statistically significant proportion of patients on NKTR-181 experienced pain reductions greater than 30% compared to placebo (71.2% versus 57.1%; p=0.0003).
- A statistically significant proportion of patients on NKTR-181 experienced pain reductions greater than 50% compared to placebo (51.1% versus 37.9%; p=0.001).
- A statistically significant proportion of patients on NKTR-181 reported their general overall status and quality of life as "improved" or "very much improved" compared to placebo as assessed by the Patient's Global Impression of Change (PGIC) of pain medication questionnaire (51.5% versus 33.2%; p < 0.0001).
The study also demonstrated that NKTR-181 had a favorable safety profile and was well tolerated. During the double-blind randomized treatment period, the most commonly reported adverse events for patients ( > 5%) were nausea (10.4%) and constipation (8.7%) in the NKTR-181 arm as compared to nausea (6.0%) and constipation (3.0%) in the placebo arm.
Patients randomized to NKTR-181 as compared to placebo reported more favorable sleep outcomes as measured by the validated Medical Outcomes Study (MOS) Sleep Scale, which captures debilitating aspects of sleep most strongly associated with chronic pain. Patients reported better overall quality of sleep with less sleep problems on NKTR-181 versus placebo. There were no differences in daytime sleepiness on NKTR-181 versus placebo.
Full data from the SUMMIT-07 study will be presented at a medical meeting in the second half of 2017.
Nektar Therapeutics president and CEO Howard W. Robin said: "As a new molecule, NKTR-181 has a highly differentiated profile with the potential to be one of the most important advancements in pain medicine.
"Given the seriousness of the current opioid epidemic in the U.S. and the significant number of people battling chronic pain, we are committed to bringing this new molecule to patients and physicians as quickly as possible."
In March 2017, results from a separate human abuse potential trial of NKTR-181 were published in the American Academy of Pain Medicine's journal of Pain Medicine. The human abuse potential study assessed the relative abuse potential of a range of therapeutic doses of NKTR-181 (100 mg to 400 mg), the same dose range evaluated in the Phase 3 SUMMIT-07 efficacy trial.
All doses of NKTR-181 tested for abuse potential were rated similarly to placebo in "drug liking" and "feeling high" scores and had highly statistically significant lower "drug liking" scores and reduced "feeling high" scores as compared to 40 mg oxycodone (p < 0.0001). In addition, all doses of NKTR-181 also scored lower on sleepiness when compared to 40 mg oxycodone (p < 0.0001).
Jack Henningfield, Ph.D., Adjunct Professor of Behavioral Biology in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine and Head of Health Policy and Abuse Liability at Pinney & Associates in Bethesda said: "It is clear that there is a pressing societal need for better and safer analgesics.
"In the human abuse potential study, even the highest analgesic dose of NKTR-181 was barely distinguishable from placebo with respect to both drug-liking and feeling high and these effects were modest compared to those produced by oxycodone.
“Drug-liking and feeling high are two of the most important metrics that help us understand the abuse potential of a medicine. Importantly, as NKTR-181 is a new chemical entity, the properties of NKTR-181 are inherent to its molecular structure and independent of any abuse-deterrent formulation.
“Today's reported efficacy and safety results, along with the human abuse potential data published this past week in Pain Medicine, suggest NKTR-181 may be a major advance towards safer opioid therapy for the treatment of moderate to severe chronic pain."