Results from a phase I, double-blind, randomized, placebo-controlled, multiple-dose study evaluating the safety, tolerability, and pharmacokinetics of oral doses of NKTR-118

Oral NKTR-118 is a novel derivative of the opioid antagonist naloxone that is PEGylated to impede its crossing the blood brain barrier. It is being developed to treat opioid-induced constipation (OIC) and other manifestations of opioid-induced bowel dysfunction (OBD) while preserving the central analgesic effect of opioids. This phase 1 double-blind, randomized, placebo-controlled, multiple-dose trial evaluated safety, tolerability, and pharmacokinetics of oral NKTR-118 in healthy subjects. Subjects (N=32) were assigned to one of 4 cohorts (25-mg, 60-mg, 125-mg, or 250-mg doses). Subjects were randomized 3:1 to oral NKTR-118 or placebo twice daily for 7 days (with a single dose on the eighth day). In general, adverse event (AE) rates were similar in placebo and NKTR-118 groups. There were no serious or severe AEs or premature study discontinuations. The vast majority of AEs were of mild intensity. AEs deemed possibly drug-related that occurred more frequently in treated subjects than the placebo group included flatulence (29% vs 13%) and myalgia (17% vs 0%). There were no dose-dependent, drug-related AEs, with the possible exception of dizziness (placebo: 25%, 125 mg: 33%, 250 mg: 50%); one subject in the 250-mg group experienced transient orthostatic dizziness. No clinically significant drug-related laboratory toxicities or electrocardiographic changes were observed. NKTR-118 was rapidly absorbed and steady state was achieved in most subjects after a few doses. Pharmacokinetics were linear (dose-proportional) and the observed terminal NKTR-118 half-life was approximately 11 hours, independent of dose. Results from this study confirm that oral NKTR-118 is safe and generally well tolerated at doses up to 250 mg twice daily. This rapidly absorbed molecule with a relatively long half-life merits further investigation as a potential treatment for OIC and other manifestations of OBD.

Sponsored by Nektar Therapeutics.