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Oliceridine Development

In February 2016, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to intravenous oliceridine for the management of moderate-to-severe acute pain. Breakthrough Therapy designation is granted by the FDA to new therapies intended to treat serious conditions and for which preliminary clinical evidence indicates that the drug may demonstrate substantial clinical improvement over available therapies. Breakthrough Therapy designation provides the opportunity for more frequent interactions with the FDA, including more intensive FDA guidance on preparing an efficient drug development program and eligibility for rolling review and priority review.

Phase 3 development program

The oliceridine Phase 3 program includes two pivotal efficacy trials evaluating moderate-to-severe acute pain: the APOLLO-1 study will evaluate pain for 48 hours following bunionectomy, and the APOLLO-2 study will evaluate pain for 24 hours following abdominoplasty. In each trial, patients will be randomized to receive placebo, morphine, or one of three regimens of oliceridine by patient-controlled analgesia (PCA) for the management of their post-operative pain. Each study will enroll approximately 375 patients, allocated equally across study arms. The primary endpoint for both APOLLO studies will be a responder analysis comparing active treatment arms to placebo. Secondary endpoints in both APOLLO studies will include comparisons of oliceridine efficacy, safety, and tolerability to morphine. A respiratory safety endpoint will measure prevalence and duration of hypoventilation.

In addition to the pivotal efficacy studies, the open-label ATHENA-1 safety study, initiated in January 2016, is enrolling patients experiencing pain as a result of either a medical diagnosis or surgery. In this study, patients may receive oliceridine as-needed either as an intermittent bolus or via PCA device, with doses and durations appropriate to manage their pain. This study will support a safety database expected to include at least 1,100 patients exposed to oliceridine across the development program. The safety database is intended to include a sufficient number of patients with higher exposures and longer durations of oliceridine therapy to adequately characterize oliceridine safety and tolerability.

Both APOLLO-1 and APOLLO-2 studies are expected to start in the second quarter of this year; the company expects to report top-line data from these studies in the first quarter of 2017 and to file an NDA for oliceridine in the second half of 2017.

Phase 2b abdominoplasty PCA study:

This was a randomized, double-blind, placebo- and active-controlled Phase 2b trial of oliceridine in moderate-to-severe acute postoperative pain after abdominoplasty surgery. Two regimens of oliceridine were tested: the first consisted of a 1.5 mg intravenous loading dose with 0.1 mg self-administered on-demand doses as often as every 6 minutes using a patient controlled analgesia (PCA) device; the second consisted of a 1.5 mg loading dose with 0.35 mg on-demand doses using a PCA device. A commonly used morphine PCA regimen was also tested, consisting of a 4 mg loading dose with 1 mg on-demand doses. Placebo was administered as a loading dose and on-demand doses that were volume-matched to the active regimens.

Oliceridine demonstrated statistically significant pain reduction compared to placebo and comparable efficacy to morphine. Oliceridine provided rapid reduction in average pain scores, consistent with the previous Phase 2 trial where oliceridine showed more rapid onset of meaningful pain relief than morphine. Rescue analgesic use was similar for both oliceridine and morphine, and less than half the rate of rescue analgesic use for placebo. In this study, the oliceridine groups had a significantly lower prevalence (percentage of patients) of hypoventilation events (a measure of respiratory safety), nausea, and vomiting than the morphine group. Adverse events associated with oliceridine were largely opioid-related; the most frequently reported events were nausea, vomiting, hypoventilation and headache. Opioid-related AEs were generally less frequent in the oliceridine groups compared to morphine. No drug-related serious adverse events were reported in the study.

Phase 2 a/b bunionectomy fixed dose study:

This trial evaluated oliceridine in postoperative pain following bunionectomy surgery. At doses of 2 mg and 3 mg of oliceridine administered every three hours, the trial achieved its primary endpoint of statistically greater pain reduction than placebo for 48 hours. The 3 mg dose of oliceridine also showed statistically superior analgesic efficacy over the 48-hour trial period compared to 4 mg of morphine administered every four hours. Additionally, in the first three hours of dosing, when pain was most severe, the 1 mg, 2 mg and 3 mg doses of oliceridine demonstrated superior analgesic efficacy in the trial compared to placebo, and the 2 mg and 3 mg doses of oliceridine demonstrated superior analgesic efficacy compared to 4 mg of morphine. Trends in respiratory depression for oliceridine were no worse than morphine, consistent with our earlier studies, and there were no serious adverse events reported in the trial, suggesting that oliceridine can safely achieve superior efficacy to morphine. Over the 48-hour trial period, the tolerability of oliceridine at doses of 2 mg and 3 mg administered every three hours was similar to that of 4 mg of morphine administered every four hours. Full results from this study were published in the leading journal Pain.

Poster: Oliceridine Phase 2 bunionectomy trial

Phase 1b proof-of-concept study summary:

This trial evaluated 3 doses of oliceridine compared to both placebo and i.v. morphine to evaluate safety, tolerability, pharmacokinetics, and a range of pharmacodynamic responses using experimental medicine methods in healthy volunteers. In the study, oliceridine was generally well tolerated and produced greater analgesia compared to morphine, with less reduction in respiratory drive, less vomiting, and less severe nausea. Data from this study was presented as a poster at the 2014 American Pain Society meeting and full data were published in the leading journal Pain.

This trial evaluated 3 doses of oliceridine compared to both placebo and i.v. morphine to evaluate safety, tolerability, pharmacokinetics, and a range of pharmacodynamic responses using experimental medicine methods in healthy volunteers. In the study, oliceridine was generally well tolerated and produced greater analgesia compared to morphine, with less reduction in respiratory drive, less vomiting, and less severe nausea. Data from this study was presented as a poster at the 2014 American Pain Society meeting.

Article: Oliceridine Phase 1b full results

Phase 1 first-time-in-human study:

This was a multi-part single ascending dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of oliceridine in healthy adult males. Single doses of oliceridine or placebo were delivered by infusion to 64 individuals. Oliceridine was generally well-tolerated in the study, and showed pharmacodynamic effects that were consistent with its preclinical profile. Summary data from the study was presented as a poster at the 2013 American Academy of Neurology meeting, and full data was published in the Journal of Clinical Pharmacology.

Article: Oliceridine FTIH study

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