Positive results have been reported from a phase 3 efficacy study of NKTR-181 (Nektar Therapeutics), the first full mu-opioid agonist molecule designed to provide pain relief without the high levels of euphoria that can lead to abuse and addiction with standard opioids. The FDA has awarded a fast track designation to NKTR-181 for the treatment of patients with moderate-to-severe chronic pain.
The molecular structure of NKTR-181 is designed to have low permeability across the blood–brain barrier in order to slow its rate of entry into the brain, thereby attenuating the dopamine release that underlies euphoria. NKTR-181 is the first opioid molecule to reduce specific central nervous system–mediated adverse events, such as euphoria, through the strategic alteration of brain-entry kinetics, according to its developer. NKTR-181 is an investigational product and has not been approved by the FDA or any other regulatory agency.
The SUMMIT-07 trial enrolled opioid-naïve patients 18 to 75 years of age who had moderate-to-severe nonneuropathic chronic low back pain for at least six months. The study included an open-label dose-titration phase followed by a 12-week, randomized, double-blind, placebo-controlled treatment period.
During the open-label titration period, study participants with pain scores of between 5 and 9 on the Numeric Rating Scale (NRS) of 0 to 10 were titrated on NKTR-181 tablets (100 mg to 400 mg twice daily) until they experienced an adequate and sustained pain response (i.e., a drop of at least two points and a pain score below 4 on the NRS).
Patients who achieved this goal were then randomly assigned to continue treatment with their analgesic dose of NKTR-181 or to receive placebo (i.e., the active drug was withdrawn) during the 12-week double-blind treatment period. A total of 610 patients were enrolled into the double-blind treatment phase. The study’s primary outcome was worsening of pain in the placebo arm compared with the active-treatment arm for patients who achieved substantial analgesic responses with NKTR-181. The primary efficacy endpoint was a change in pain, as measured by the change in the patient’s weekly pain score from baseline to week 12 of the treatment period.
During the open-label titration period, in which patients were titrated to a tolerated, effective dose of NKTR-181, average pain scores dropped by 65% (from 6.73 at screening to 2.32 at randomization).
During the double-blind, randomized treatment phase, average pain scores increased more in the placebo arm than in the NKTR-181 arm at week 12 (1.46 for placebo vs. 0.92 for NKTR-181; P = 0.0019). Most of the patients (83%) completed the randomized treatment period, and among these study completers, average pain scores increased more in the placebo arm compared with the NKTR-181 arm at week 12 (1.25 for placebo vs. 0.56 for NKTR-181; P < 0.0001).
Key secondary findings included:
- Significantly more patients treated with NKTR-181 experienced pain reductions of greater than 30% compared with those given placebo (71% vs. 57%, respectively; P = 0.0003).
- Significantly more patients treated with NKTR-181 experienced pain reductions of greater than 50% compared with those given placebo (51% vs. 38%; P = 0.001).
- Significantly more patients treated with NKTR-181 reported their general overall health status and quality of life as “improved” or “very much improved” compared with those given placebo, as assessed by the Patient's Global Impression of Change (PGIC) questionnaire (52% vs. 33%; P < 0.0001).
During the double-blind treatment period, nausea (10%) and constipation (9%) were the most common adverse events associated with NKTR-181.
Source: Nektar Therapeutics; March 20, 2017.