Pharmaleads announced it has successfully completed a Phase I single ascending dose (SAD) trial in France with its oral dual ENKephalinase Inhibitor (DENKI) candidate PL265 for the treatment of neuropathic pain. The company is now preparing to start a Phase I multiple ascending dose (MAD) study with oral PL265 in the UK. Data from the MAD study is expected in 2018.

The Phase I SAD results have shown that single doses of PL265, administered orally were safe and well-tolerated. Pharmacokinetic and pharmacodynamic studies showed that PL265 was slowly transformed in plasma into its active metabolite (PL254). PL254 inhibited both of its target enzymes, aminopeptidase N (APN) and neprilysin (NEP), which are responsible for the physiological degradation of enkephalins. This inhibition was effective for more than 24 hours after single doses of 400 and 800mg of PL265, making it an ideal oral candidate for the treatment of neuropathic chronic pain.

Pharmaleads' DENKIs, are the only drugs in clinical development that can inhibit both enkephalin-degrading enzymes APN and NEP, thereby increasing the local concentration of enkephalins resulting in local and sustained pain relief without the side-effects observed with opioids. PL265 is the second DENKI to start human clinical development at Pharmaleads.

"We are pleased with the encouraging data from this first-in-human study with PL265, a DENKI which we believe is an ideal oral candidate for the treatment of neuropathic pain. Results from this study show that PL265, via its active metabolite PL254, is able to inhibit its two key targets and provide strong evidence supporting our hypothesis that DENKIs are the only drug candidates in development that harbor the analgesic properties of opiates without their side-effects," Michel Wurm, MD, Director of Corporate Development, said.

The Phase I study was a randomised, double-blind, placebo-controlled single oral dose escalation study aimed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of PL265. The study was conducted at Eurofins-Optimed Phase 1 unit in France in 32 healthy male volunteers. Four cohorts of eight subjects each were randomised 6:2 (active:placebo) to receive single doses of PL265 ranging from 100 to 800mg or matching placebo. The maximum tolerated dose was not reached, but as optimal target engagement was achieved, higher doses were not tested.