Nektar Therapeutics has reported positive clinical data for NKTR-181, its new oral opioid analgesic molecule.

NKTR-181 is a novel mu-opioid agonist molecule, which was designed to have a slow rate of entry into the brain to reduce the attractiveness of the molecule as a target of abuse and to reduce its CNS-mediated side effects.

The phase I, randomized, 60-patient study evaluated the pharmacokinetics, harmacodynamics and safety of oral doses of NKTR-181 in four cohorts as compared to placebo over an eight-day treatment period in healthy subjects. Using pupil constriction as a measure of the onset of central opioid effect, the study showed that NKTR-181 enters the brain slowly and produces centrally-mediated opioid effects that are dose-dependent and statistically meaningful (P<0.001) following twice-daily oral doses of 200-400mg. Further, NKTR-181 enters the CNS from the plasma at a rate approximately 10 times slower than historical published rates for oxycodone. The slow rate may reduce the euphoria and other CNS side effects associated with rapid CNS uptake of current standard opioid therapies.

“By slowing the rate of entry into the brain, NKTR-181 is designed to have less euphoria, sedation and respiratory depression than traditional opioid compounds. Individuals with a higher risk of abusing opioids prefer rapid onset of euphoria, which means NKTR-181 should be less attractive as a drug of abuse,” said Lynn R. Webster, M.D., medical director of Lifetree Clinical Research.

Data showed positive analgesic properties of NKTR-181, which produced dose-dependent analgesic responses in two separate models of pain used to measure central and peripheral analgesic activity in healthy subjects. In a cold-pressor test pain model measuring latency-to-hand-removal (LHR), the 200mg dose of NKTR-181 given twice-daily over the eight-day dosing period demonstrated the extent and duration of analgesic effect of NKTR-181 administration. Results show a significant analgesic effect as compared to placebo (P<0.01, n=12) over the entire dosing period.

In addition, a model of induced UVB injury was also used to demonstrate the extent and duration of analgesic effect produced by NKTR-181. Results show that NKTR-181 has both centrally-mediated and peripherally-mediated analgesic effects. In this model, data was presented on NKTR-181 at doses of 300mg and 400mg demonstrating its significant analgesic and anti-hyperalgesic effect (measured as change from baseline) following mechanical and thermal stimulation, with p-values of P<0.009 and P<0.03, respectively (n=12).

NKTR-181 is currently being prepared for phase II development in chronic pain patients in mid-2012.