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OLINVO™ (oliceridine injection) Development

In February 2016, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to OLINVO™ (oliceridine injection) 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

In February 2017, we announced top-line results from two Phase 3 pivotal efficacy trials evaluating OLINVO in moderate-to-severe acute pain. The APOLLO-1 study evaluated pain for 48 hours following bunionectomy, and the APOLLO-2 study evaluated pain for 24 hours following abdominoplasty. In each trial, patients were randomized to receive placebo, morphine, or one of three regimens of OLINVO by patient-controlled analgesia (PCA) device for the management of their post-operative pain.

Each OLINVO regimen began with a 1.5 mg IV bolus loading dose, followed by patient-administered doses of 0.1 mg, 0.35 mg, or 0.5 mg as often as every 6 minutes, with supplemental 0.75 mg clinician-administered bolus doses available as often as every hour. Morphine was administered as a commonly used regimen consisting of a 4 mg IV bolus loading dose, followed by patient-administered dosing of 1 mg as often as every 6 minutes, with supplemental 2 mg clinician-administered bolus doses available as often as every hour.

Results of APOLLO-1 (bunionectomy) and APOLLO-2 (abdominoplasty)

Primary endpoint – efficacy vs. placebo

  • All three OLINVO regimens (0.1 mg, 0.35 mg, and 0.5 mg on-demand doses) achieved the primary endpoint in both studies, with statistically superior responder rates compared to placebo at 48 hours in the APOLLO-1 hard tissue trial (p<0.0001 for each regimen, adjusted for multiplicity), and at 24 hours in the APOLLO-2 soft tissue trial (adjusted p<0.05 for the 0.1 mg regimen; adjusted p<0.001 for the 0.35 mg and 0.5 mg regimens).

Secondary and exploratory endpoints: comparisons of efficacy, safety, and tolerability vs. IV morphine

  • OLINVO demonstrated rapid onset with efficacy superior to morphine in early time points for the 0.35 mg and 0.5 mg regimens in both studies (p<0.05 at 10 through 30 minutes post-dose in APOLLO-1, and p<0.05 at 10 minutes in APOLLO-2).
  • The 0.35 mg OLINVO regimen showed comparable pain relief to the morphine regimen over the full dosing period (48 hours in APOLLO-1, 24 hours in APOLLO-2). Patients receiving this regimen in APOLLO-1 administered themselves 49 ± 27 mg of cumulative dose, versus 68 ± 50 mg for the morphine regimen. Patients receiving this regimen in APOLLO-2 administered themselves 21 ± 13 mg of cumulative dose, versus 40 ± 28 mg for the morphine regimen. In both trials, this OLINVO regimen was associated with less frequent adverse events including nausea, vomiting, rescue antiemetic use, respiratory safety events, oxygen desaturation, and use of supplemental oxygen (p<0.05 for antiemetic use and respiratory safety events in APOLLO-1, p<0.05 for vomiting in APOLLO-2).
  • The 0.1 mg OLINVO regimen showed significantly lower rates of nausea, vomiting, rescue antiemetic use, respiratory safety events, oxygen desaturation, and use of supplemental oxygen than morphine in both trials (p<0.05 for all), but did not achieve non-inferiority to morphine for analgesic efficacy. In both trials, the 0.5 mg OLINVO regimen showed efficacy comparable to morphine, and rates of gastrointestinal and respiratory events were consistently numerically lower but not statistically different from morphine.

In both studies, OLINVO was generally safe and well-tolerated. The most common drug-related adverse events were nausea, vomiting, headache, and dizziness.

To complement the APOLLO pivotal efficacy studies, the open-label ATHENA 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 OLINVO 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 OLINVO 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 OLINVO safety and tolerability. As of February 15, 2017, this trial has enrolled and treated over 400 patients, and is on track to support a New Drug Application filing in the fourth quarter of 2017.

In February 2017, we also announced results from several recently-completed clinical pharmacology and pharmacokinetics studies, which suggest that OLINVO may offer potentially safer dosing in hard-to-treat patients.

  • A renal impairment study found no evidence of altered pharmacokinetics or accumulation in patients with renal failure, both of which occur with morphine and hydromorphone.
  • Preclinical and clinical studies have found no evidence of active metabolites, which for other opioids can cause variable and delayed adverse events.

If approved, OLINVO is expected to be a Schedule II controlled substance.

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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