Now in Phase III Trials:
An investigational agent designed to improve conventional opioid pharmacology has demonstrated efficacy and safety, as well as faster onset of action, in a pair of pivotal trials.
Compared with placebo, patients receiving IV oliceridine (Olinvo, Trevena), a G protein-biased ligand (GPBL) at the mu-opioid receptor, experienced superior relief following bunionectomy or abdominoplasty. Oliceridine also showed favorable trends in respiratory safety and upper gastrointestinal tolerability compared with morphine. According to investigators, these findings support the potential for oliceridine to widen the therapeutic window between rapid, effective analgesia and opioid-related adverse events.
“In APOLLO-1 and APOLLO-2 [trials], all doses of oliceridine met the primary end point, demonstrating superior efficacy compared with placebo,” said Eugene Viscusi, MD, professor of anesthesiology and director of acute pain management at Sidney Kimmel Medical College of Thomas Jefferson University, in Philadelphia. Dr. Viscusi is also a member of the advisory board of Anesthesiology News.
Efficacy in Hard and Soft Tissue Pain Models
“Moreover, when compared with morphine, oliceridine demonstrated comparable efficacy with overall faster onset and a significant trend toward fewer treatment-emergent adverse events. Oliceridine has now shown relevance in established soft and hard tissue models of acute pain, and is one step closer to FDA approval.”
As Dr. Viscusi reported at the 2017 annual spring meeting of the American Society of Regional Anesthesia and Pain Medicine (abstracts 3681 and 3682), conventional opioids bind to mu receptors and nonselectively activate a number of signaling pathways, including the G protein pathway, associated with analgesia, and the beta-arrestin pathway, associated with opioid-related adverse events and inhibition of G protein–mediated analgesia.
“There’s very good evidence that a lot of the side effects associated with opioids, such as respiratory depression and nausea, are related to the beta-arrestin pathway,” Dr. Viscusi said.
Based on the work of Drs. Robert Lefkowitz and Brian Kobilka, who shared the 2012 Nobel Prize in chemistry, oliceridine is a novel mu-GPBL modulator that spares some portion of the beta-arrestin pathway.
“If it works,” Dr. Viscusi said, “the result will be an opioid with an improved side effect profile.”
As standard drug development requires both a hard or bony tissue model and a soft tissue model for approval, investigators tested oliceridine on bunionectomy and abdominoplasty patients.
APOLLO Trials Show Safety, Efficacy
In APOLLO-1, a Phase III, multicenter, double-blind, placebo- and active-controlled study, 389 patients experiencing moderate to severe pain following bunionectomy were randomly assigned to one of five treatment regimens: IV oliceridine (1.5 mg loading dose; 0.1, 0.35 or 0.5 mg demand doses), volume-matched placebo, or morphine (4 mg loading dose; 1 mg demand doses). Treatment was administered as needed by a patient-controlled analgesia (PCA) device with a six-minute lockout for 48 hours. Etodolac was available as necessary for rescue analgesia, the authors said.
Investigators then measured pain intensity using the 11-point Numeric Pain Rating Scale (NPRS) and the categorical pain relief scale (none, a little, some, a lot, complete) at baseline and designated follow-up time points.
As Dr. Viscusi reported, the primary end point of APOLLO-1 was the proportion of responders in each oliceridine group paired with placebo that achieved 30% or greater reduction in time-weighted average pain score at 48 hours, and the study found that all oliceridine regimens were superior to placebo in this regard, from 0 to 48 hours (P<0.0001 for all comparisons). In addition, Dr. Viscusi said, post hoc analysis showed that oliceridine regimens involving 0.35 and 0.5 mg were noninferior to morphine in terms of the percentage of treatment responders at study end point (P<0.01 for both comparisons).
According to Dr. Viscusi, however, oliceridine is distinguished by rapid onset of action. Analysis of treatment responders over the hour of treatment showed a much faster response than with morphine.
“The onset of efficacy is much faster than morphine, which is critical when you’re trying to get patients comfortable,” Dr. Viscusi pointed out. “We’ve shown that oliceridine establishes a quick response.”
Although none of the arms reached statistical significance, investigators also observed a consistent trend toward lower respiratory burden in patients receiving oliceridine. All oliceridineregimens had lower percentages of patients with oxygen saturation less than 90% and patients requiring supplemental oxygen, although only the regimen involving 0.1 mg was statistically significant.
As Dr. Viscusi reported, the use of antiemetics was also significantly lower in all oliceridineregimens compared with morphine, and the regimen with 0.1 mg exhibited a significantly lower frequency of nausea and vomiting.
He added that oliceridine was generally well tolerated, with no serious adverse events and few discontinuations due to adverse events. “As with any opioid, there are still going to be adverse events, but reports were definitely lower for the most part.”
APOLLO-2, the soft tissue study, followed a similar model, with 401 patients experiencing moderate to severe pain following abdominoplexy randomly assigned to one of five treatment regimens. The major difference in this study, Dr. Viscusi explained, was a 24-hour time point instead of 48 hours.
“Outcomes were similarly positive,” he said. “Compared to placebo, all oliceridine regimens demonstrated superior efficacy from 0 to 24 hours.”
Compared with morphine, although only the regimen with 0.35 mg demonstrated noninferiority, a faster onset of action was again observed across all groups. Similar trends were seen for respiratory burden, oxygen saturation and use of antiemetics, Dr. Viscusi said.
Regarding treatment-emergent adverse events, Robert S. Weller, MD, professor of anesthesiology and section head of the Acute Pain Service at Wake Forest Baptist Medical Center, in Winston-Salem, N.C., speculated that oliceridine may become less selective at higher doses.
“This is often true of many selective agents,” said Dr. Viscusi, who noted that the 0.35 mg dose of oliceridine appears to be the “sweet spot” in both trials.