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Oliceridine injection Development

In February 2016, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to 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. In January, 2018, we announced that FDA has accepted the oliceridine injection new drug application for review with a Prescription Drug User Fee Act review date of November 2, 2018.

Clinical development

APOLLO-1 and APOLLO-2 Phase 3 Studies

Two pivotal efficacy trials evaluated oliceridine injection in patients with moderate-to-severe acute pain: the APOLLO-1 study, which evaluated pain for 48 hours following bunionectomy, and the APOLLO-2 study, which evaluated pain for 24 hours following abdominoplasty. These Phase 3 trials were multicenter, randomized, double-blind, placebo- and active-controlled studies. During the study period, a loading dose of placebo, morphine (4 mg), or oliceridine injection (1.5 mg) was administered first, and then patients used a PCA button to dose themselves as often as every 6 minutes with the same study drug: 1 mg morphine or 0.1 mg, 0.35 mg, or 0.5 mg oliceridine injection. If pain control with PCA dosing was inadequate, patients could request supplemental study medication (0.75 mg oliceridine injection or 2 mg morphine, no more than once an hour). If additional pain relief was needed, patients could receive an oral nonsteroidal anti-inflammatory agent (NSAID) rescue analgesic. Placebo loading, demand, and supplemental doses were volume-matched.

All endpoints were the same in both studies. Efficacy was measured by a responder analysis, which defined a responder as a patient who experienced at least a 30% reduction in their sum of pain intensity difference at the end of the treatment period without either early discontinuation (for lack of efficacy or safety/tolerability) or use of rescue medication. Non-inferiority to morphine and superiority to morphine were key secondary endpoints. Respiratory safety events were defined as clinically relevant worsening of respiratory status, including oxygen saturation, respiratory rate, or sedation. The product of the frequency and conditional duration of these events was reported as respiratory safety burden, a key secondary endpoint. Additional measures of respiratory safety included prevalence of oxygen saturation less than 90% and prevalence of supplemental oxygen use. Measures of gastrointestinal tolerability included use of rescue antiemetics, vomiting, and spontaneously reported nausea.

In both studies, all dose regimens achieved their primary endpoint of statistically greater analgesic efficacy than placebo, as required for FDA approval.

ATHENA Phase 3 open label safety study

The ATHENA trial was a a large, Phase 3, open label safety study designed to model "real world" use in a wide spectrum of surgical and medical acute pain conditions. This study was conducted in over 40 sites including academic medical centers and community hospitals. More than 750 patients undergoing a variety of procedures including general, GI, orthopedic and plastic surgeries received oliceridine injection, including those considered at higher risk of opioid-related adverse events such as elderly patients and those with body mass index (BMI) over 30 kg/m2. Oliceridine injection was administered as a component of multimodal analgesia, and given in post-anesthesia care units by IV bolus, and on surgical/medical floors by IV bolus and/or patient-controlled analgesia (PCA).

Phase 2b trial of oliceridine injection in acute postoperative pain following abdominoplasty

A Phase 2b randomized, double-blind, placebo- and active-controlled clinical trial evaluated the efficacy, safety and tolerability of oliceridine injection in the management of moderate-to-severe acute postoperative pain after abdominoplasty surgery, utilizing on-demand dosing to reflect standard clinical practice. Two regimens of oliceridine injection were tested: 1.5 mg IV loading dose with 0.1 mg self-administered on-demand doses as often as every 6 minutes using a PCA device and 1.5 mg loading dose with 0.35 mg on-demand doses as often as every 6 minutes using a PCA device. The comparator groups were volume matched placebo and a morphine PCA regimen of 4 mg loading dose with 1 mg on-demand doses as often as every 6 minutes. Allowable rescue medications were ibuprofen or oxycodone in all groups.

Phase 2a/b trial of oliceridine injection in acute postoperative pain following bunionectomy

A Phase 2a/b multicenter, randomized, double-blind, placebo- and active-controlled, multiple dose, adaptive clinical trial evaluated the efficacy and tolerability of oliceridine injection in the management of patients undergoing a primary unilateral first-metatarsal bunionectomy surgery. Patients were randomized after surgery to receive oliceridine injection (1 mg, 2 mg, 3 mg, or 4 mg every 4 hours), morphine (4 mg every 4 hours) or placebo to manage their pain. Pain intensity was measured using validated numeric rating scales ranging from ten (most severe pain) to zero (no pain) at multiple time points up to 48 hours. Analgesic efficacy was assessed with a time-weighted average change in pain score over 48 hours.

Phase 1b

A randomized, double-blind, crossover Phase 1b experimental proof of concept trial was conducted in healthy male subjects. The aims of this trial were to characterize the analgesic activity and safety and tolerability of a single IV bolus dose of oliceridine injection 1.5, 3.0, and 4.5mg compared to a single 10 mg IV dose of morphine. We used a well-established evoked-pain model, the cold pain test, to evaluate the analgesic effects of oliceridine injection by measuring the time to hand removal, or latency, from a temperature-controlled cold water bath. Ventilatory response to hypercapnia was measured to assess effects on respiratory drive, which can be reduced by conventional opioids.

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