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Nektar Announces Topline Data from Human Abuse Potential Study for NKTR-181, a First-in-Class Investigational Opioid to Treat Chronic Pain

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...