Nektar Therapeutics (NKTR)

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NKTR-118 Shows Substantial Oral Bioavailability and Extended Half-Life in Phase 1 Clinical Data Presented at American Pain Society Meeting
Wednesday May 7, 9:00 am ET

SAN CARLOS, Calif., May 7 /PRNewswire-FirstCall/ -- New Phase 1 clinical trial results for NKTR-118 (oral PEG-naloxol) were presented by Nektar Therapeutics (Nasdaq: NKTR - News) this week at the Annual Meeting of the American Pain Society (APS) in Tampa, Florida. In this multiple-dose Phase 1 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 2 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 were 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.(1) 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.(1)

"The prevalence and impact of opioid-bowel dysfunction among chronic pain patients are underestimated today," said Sunil J. Panchal, M.D., 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."

About the Phase 1 Clinical Trial

The primary objective of this Phase 1 multi-dose, double-blind, randomized, placebo-controlled study was to evaluate the safety and tolerability of multiple doses of oral NKTR-118 in healthy human subjects not receiving opioid therapy. A total of 32 subjects enrolled in the trial. The secondary objective of the trial was to evaluate the pharmacokinetics of oral NKTR-118 and its metabolite (NKTR-118 glucuronide) following twice-daily oral administration for seven days. Escalating doses up to 250 mg twice daily were studied. Subjects were randomized 3:1 to NKTR-118 or placebo twice daily (every 12 hours) for seven days, with a single dose on the eighth day.

Prior Clinical Study Results for NKTR-118

Nektar previously presented results from a proof-of-principle, single-dose Phase 1 study at the American College of Clinical Pharmacology Meeting (ACCP) conference in September of 2007. In this proof-of-principle study, single oral doses of NKTR-118 antagonized morphine-induced delay in gastrointestinal transit time demonstrating the potential of the drug to relieve constipation. Further, no diminution of morphine-induced miosis, a CNS effect, was observed at single oral doses of NKTR-118 of 125 mg or less. In addition, NKTR-118 at single doses up to 1,000 mg was well-tolerated. The drug was rapidly absorbed with dose-proportional pharmacokinetics over the 8-1,000 mg dose range.

Data Presentations for NKTR-118

The poster presentation made this week at the APS Meeting, as well previous data presentations for NKTR-118, can be found on Nektar's website at http://www.nektar.com/wt/page/nktr118_media

APS Poster #210: "Results from a Phase 1, Double-Blind, Randomized, Placebo-Controlled, Multiple-Dose Study Evaluating the Safety, Tolerability and Pharmacokinetics of Oral Doses of NKTR-118 (PEG-Naloxol)"
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