Presented at the 2012 AAPM Annual Meeting « Back

NKTR-181: A Novel, Orally Available Mu-Opioid Agonist with Reduced Rate and Extent of CNS Exposure Exhibits Comparable Analgesic Efficacy but Reduced Abuse Liability and CNS Side Effects Compared to Oxycodone

Kathleen R. Gogas, PhD, kgogas@nektar.com¹, Juergen W. Pfeiffer, MS¹, Irene Choi, PhD¹, Juli Evans¹, Dan M. McWeeney, BA¹, Phi N. Quach, BS¹, Patricia C. Trinchero¹, David V. Gauvin, PhD², Simone Fishburn, PhD³, Stephen Harrison, PhD¹, Timothy A. Riley, PhD⁴, Stephen Doberstein, PhD¹, Jennifer A. Riggs, PhD¹, (1) Nektar Therapeutics, San Francisco, California, (2) MPI Research Inc., Mattawan, Michigan, (3) Exponent, Menlo Park, California, (4) Pharmaceutical Drug Dev, Huntsville, Alabama

Introduction/Statement of the Problem: Opioid agonists are potent analgesics but also cause central side effects and are subject to abuse. NKTR-181 is a novel, orally available mu-opioid analgesic engineered using Nektar’s advanced polymer conjugate technology. NKTR-181 has a significantly reduced rate and extent of CNS exposure relative to oxycodone, is active in multiple preclinical pain models and exhibits significantly less abuse potential as assessed in rodent models of abuse liability. Objective: To compare NKTR-181 with oxycodone across analgesic, abuse liability and CNS motor tests in rodents. Methods: Drug discrimination: Rats were trained to discriminate oxycodone from vehicle. Relative effects of NKTR-181 and oxycodone were compared to these comparators. Analgesia: Mice received oral NKTR-181, oxycodone or vehicle followed 30 minutes later by 0.5% acetic acid (intraperitoneal). Writhes were counted over 20 minutes. Impairment in coordination: The impact of oral NKTR-181, oxycodone, or vehicle on the length of time rats could remain on a rotarod was measured. Results: NKTR-181 analgesic doses were 46 and 56 fold lower than those resulting in CNS side effects and abuse liability, respectively. For oxycodone, these ratios were only 12 and 7 fold, respectively. As NKTR-181 was only three fold less potent than oxycodone in analgesia assays, the primary benefit of the polymer conjugation is in reducing side effects. Conclusions: NKTR-181 is a novel orally available mu-opioid analgesic that is as efficacious as oxycodone but has lower abuse liability and CNS side-effects, giving it a markedly improved therapeutic window.

Funding: Nektar Therapeutics