Nektar Therapeutics has initiated the phase II study for NKTR-118 (PEG-naloxol), an oral treatment being developed to treat opioid-induced constipation (OIC) and other clinical manifestations of opioid-induced bowel dysfunction (OBD).

The double-blind, randomised, dose-escalation trial will evaluate the efficacy, safety and tolerability of NKTR-118 in patients experiencing constipation while receiving opioid therapy.

"We are excited to begin our phase II clinical trial for oral NKTR-118 in OBD and OIC patient settings," said Hoyoung Huh, M.D., Ph.D. chief operating officer and head, PEGylation Business Unit, Nektar. "NKTR-118 represents an innovative application of our small molecule PEGylation technology to prevent drugs from entering the central nervous system."

NKTR-118 is being evaluated as an oral therapy to treat OBD and OIC,
which are serious and debilitating conditions resulting from the use of opioids for pain management. NKTR-118, which is a PEGylated form of naloxol, was designed to selectively target peripheral opioid receptors to alleviate constipation associated with opioid therapy, while reducing the drug's penetration across the blood-brain barrier (BBB) and into the central nervous system in order to preserve opioid analgesia.

The phase II trial for NKTR-118 is a multi-centre, placebo-controlled, dose-escalation trial (5 mg, 25 mg, 50 mg or 100 mg). Patients experiencing OIC will be randomised 1:1 to NKTR-118 or placebo in addition to their opioid treatment. Therapy will be administered orally once-daily (QD) over a five-week treatment period. The primary efficacy endpoint of the trial will be the increase from baseline in spontaneous bowel movements per week (SBMs per week). Additional endpoints include monitoring of other symptoms of OBD, which will include the Patient Assessment of Constipation Symptoms (PAC-SYM) outcomes tool, and other quality of life measures. Maintenance of opioid analgesic effect will be assessed by measuring changes from baseline in mean daily opioid requirements and daily pain scores. Safety and tolerability will be assessed and pharmacokinetics of the drug will be evaluated. The trial will be conducted in approximately 50 centres in North America and Europe.

NKTR-118 is an oral drug that combines Nektar's advanced small molecule PEGylation technology platform with naloxol, a derivative of the opioid-antagonist drug, naloxone. In preclinical studies, Nektar's PEGylation technology has been shown to reduce penetration of drugs across the blood-brain barrier, an important potential advance for NKTR-118 and possibly many other small molecule therapies.

The peripheral opioid antagonist NKTR-118 targets opioid receptors within the enteric nervous system, which mediate OBD, a symptom complex resulting from opioid use that encompasses constipation, bloating, abdominal cramping, and gastroesophageal reflux. Constipation is the hallmark of this syndrome, and is generally its most prominent component. Currently, there are no specific drugs approved or specifically indicated to treat OBD or OIC. NKTR-118 has been studied in two Phase 1 trials evaluating the safety, tolerability and pharmacokinetics of single and repeated dose administration of the drug.

In a proof-of-principle phase I trial, single oral doses of NKTR-118 antagonized morphine-induced delay in gastrointestinal transit time
demonstrating the potential of the drug to relieve constipation caused by opioid treatment. This effect was seen to increase in a dose-dependent fashion, reaching maximal effect at 125 mg. Further, no diminution of morphine-induced miosis, a CNS effect, was observed at single oral doses of NKTR-118 that produced a maximal effect on gastrointestinal transit time. NKTR-118 was well-tolerated and rapidly absorbed with dose proportional pharmacokinetics over single dose ranges of 8-1,000 mg.

According to IMS Health, more than 200 million prescriptions were written for opioids in 2006 in the United States, alone. Many studies indicate that a high percentage of patients receiving opioids are likely to experience significant constipation and other symptoms of OBD. Stool softeners or laxatives may be inadequate for many patients with OIC and often are associated with unwanted side effects such as bloating and cramping.

Nektar Therapeutics is a biopharmaceutical company that develops and enables differentiated therapeutics with its industry-leading PEGylation and pulmonary drug development platforms.