FDA To Consider Analgesic Opioid Molecule That Lessens Drug High, Addiction Risks

Steve Doberstein, PhD

A new molecular entity (NME) is being considered by the US Food and Drug Administration (FDA) for the treatment of chronic low back pain in adult patients new to opioid therapy.

Nektar Therapeutics announced the filing and acceptance for review of the company’s New Drug Application (NDA) for NTKR-181, the first analgesic opioid molecule to exhibit a low incidence of specific CNS-mediated side effects through targeted alteration of brain-entry kinetics.

The therapy—anticipated to lessen the rate of common side effects such as euophoria in such treated patients—is expected to be given a Prescription Drug User Fee Act (PDUFA) target action date of May 28, 2019.

NTKR-181, an investigational long-acting, selective full mu-opioid receptor agonist, is designed to have a lower permeability across the blood-brain barrier. This slows its entry into the brain and attenuates the dopamine release that underlies euphoria. It is being analyzed to treated lower back pain in adults.

According to Nektar, low back pain is the second most common causes of disability of adults in the US, affecting enough people to account for approximately 149 million lost work days and $100 to $200 billion in annual costs.

The NDA submission is supported by extensive clinical and nonclinical data from 15 studies, featuring 2234 patients, as well as a pair of 600-plus-patient study of adults with no prior exposure to opioid therapy—one of which assessed its safety over 52 weeks in patients with noncancer pain. Another 450 subjects participated in pharmacokinetic/pharmacodynamics studies, and an unlisted pool of recreational drug users participated in human abuse potential studies that evaluated NKTR-181’s therapeutic and supratherapeutic doses versus an oxycodone control.

In trial data presented by Nektar at the College on Problems of Dependence 80^th Annual Scientific Meeting in San Diego, CA, this June, NKTR-181 reported good tolerance in patients, particularly in comparison to oxycodone.

The pair of double-blind, randomized, crossover human abuse potential studies compared 100 mg, 200 mg, 400 mg, 600 mg, and 1200 mg oral tablet therapy to 40 mg and 60 mg oxycodone and matching placebo solution, with set wash-out periods between doses.

Researchers evaluated for abuse potential via subjective visual analog scale (VAS) ratings, ranging from 0-100 mm for Drug Liking “at this moment,” and for Drug High using the Drug Effects Questionnaire (DEQ) in both trials. Additional outcome measures included pupil diameter, pharmacokintetics, and drug safety.

Patients reported significantly lower Drug Liking and Drug High peak effects and extent at the critical first and second post-dose hours than those administered oxycodone. The 400 mg NKTR-181 dose—the only dose to be evaluated in both trials—reported consistent Drug Liking and Drug High rates across its patient populations.

Researchers concluded the therapy had a reduced risk for abuse in patients compared to oxycodone. In measuring its safety, patients administered oxycodone and 1200 mg NKTR-181 reported the majority of treatment-emergent adverse events across both studies.

In a statement regarding the data presented at the conference, Steve Doberstein, PhD, senior vice president and chief research and development officer of Nektar, said the company was privileged to share “meaningful new data” and translational research on the drug.

“The data presented show that NKTR-181 demonstrates consistently low abuse potential when we look at a range of measurements used to understand potential abuse liability of investigational medicines including the MADDERS assessment,” Doberstein said. “In addition, we demonstrated in our preclinical research that NKTR-181 has a unique neuropharmacodynamic profile with slow brain uptake and a blunted dopamine response as compared to oxycodone."