New phase I clinical trial results for NKTR-118 (oral PEG-naloxol) were presented by Nektar Therapeutics this week at the Annual Meeting of the American Pain Society (APS) in Tampa, Florida.

In this multiple-dose phase I study, oral NKTR-118 was shown to have substantial oral bioavailability with rapid absorption and an extended half-life that is up to ten times the known half-life of unPEGylated naloxone.

NKTR-118 is Nektar's proprietary peripheral opioid antagonist candidate currently in a phase II trial in patients with opioid-induced bowel dysfunction (OBD), including opioid-induced constipation. Nektar's advanced small molecule PEGylation technology has been shown to reduce NKTR-118's penetration across the blood-brain barrier, an important potential advance for this and many other potential therapies.

"For the first time, it has now been shown that Nektar's proprietary PEGylation technology can be used to enhance oral bioavailability for a small molecule drug," said Timothy A. Riley, Ph.D., vice president of PEGylation Research at Nektar. "In addition, this PEGylated drug exhibited an exceptionally long half-life of eleven hours, enabling a once-daily dosing regimen for NKTR-118 as an oral therapy".

NKTR-118 was also shown to be safe and generally well-tolerated at doses up to 250 mg twice daily, with no serious or severe adverse events. The pharmacokinetics of NKTR-118 was dose-proportional and the observed terminal half-life of the drug was approximately eleven hours, independent of dose. This compares to a known half-life of between 45 and 100 minutes for naloxone. At all dose levels, NKTR-118 was rapidly absorbed after oral administration, as evidenced by a steep increase of plasma NKTR-118 concentration.

Plasma concentrations of NKTR-118-glucuronide were approximately 100-fold less than plasma NKTR-118 concentrations. Studies have shown that the bioavailability of oral naloxone is limited by first-pass metabolism of naloxone.

"The prevalence and impact of opioid-bowel dysfunction among chronic pain patients are underestimated today," said Sunil J. Panchal, MD, President of the National Institute of Pain and the Coalition for Pain Education (COPE) Foundation. "The condition can have a serious deleterious impact on a patient's quality of life and can also limit chronic pain management treatments. There is a clear need for an oral therapy that targets the underlying cause of OBD while preserving the desired analgesic effects of opioid treatment".

Oral NKTR-118 is currently in a phase II study to evaluate the efficacy, safety and tolerability of once-daily doses in patients with opioid-induced constipation (OIC). The investigational drug combines Nektar's advanced small molecule PEGylation technology platform with naloxol, a derivative of the opioid-antagonist drug, naloxone.