Positive Topline Results for First-in-Class, Low-Abuse-Potential Opioid  

Megan Brooks

July 18, 2017

Nektar Therapeutics has announced positive topline results from an oral human abuse potential (HAP) study of NKTR-181, a first-in-class opioid analgesic for chronic pain that reportedly carries significantly less abuse potential than oxycodone.

"NKTR-181 is a new chemical entity 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 company said in a news release.

NKTR-181 is the first analgesic molecule to show a reduction in specific central nervous system–mediated side effects, such as euphoria, through the alteration of brain-entry kinetics, the company said.

NKTR-181 has been granted fast-track designation from the US Food and Drug Administration for the treatment of moderate to severe chronic pain.

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 oxycodone in healthy nondependent recreational drug users who are experienced in the oral abuse of opioids and can identify drug effects that are relevant to abuse risk assessment.

Fifty-four participants were randomly assigned to one of six test sequences. In each of which they received a single dose of one of the six study drugs (NKTR-181 at a dose of 400, 600, or 1200 mg or oxycodone at 40 or 60 mg). There was a 5-day washout period between the treatments.

At all doses, NKTR-181 had a significantly lower rating of peak "liking" compared with oxycodone. Liking was based on a participants-reported 100-point bipolar liking/disliking visual analog scale, which is a standard measure of abuse potential in HAP studies.

"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," Ivan Gergel, MD, senior vice president and chief medical officer of Nektar, said in the release.

"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," added Dr Gergel.

"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," said Dr Gergel.

"Getting very high, very fast, is a mark of conventional high-risk, abused opioids," Jack Henningfield, PhD, vice president at Pinney Associates and adjunct professor at The Johns Hopkins University School of Medicine in Baltimore, Maryland, said in the release.

"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," Dr Henningfield added.

In March 2017, the company reported results of the first phase 3 efficacy trial (SUMMIT-07) of NKTR-181 in 610 opioid-naive patients with moderate to severe chronic low back pain.

The trial tested 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, measured by a subjective pain reduction scale, of more than 65% during the dose titration period.

Patients were then randomly assigned in a double-blind fashion to either continue NKTR-181 or switch to placebo for 12 weeks. The primary efficacy endpoint of the study showed significantly improved chronic back pain relief with NKTR-181 compared with placebo (P = .0019), the company reported. Key secondary endpoints of the study also achieved high statistical significance. NKTR-181 had a favorable safety profile and was well tolerated.

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