&lt;p&gt;APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the &amp;micro;-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy&lt;/p&gt;

Viscusi, Eugene R.; Skobieranda, Franck; Soergel, David G.; Cook, Emily; Burt, David; Singla, Neil

doi:10.2147/jpr.s171013

Cited by 117 publications

(139 citation statements)

References 32 publications

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“…The findings on the lower rates of OIRD in the oliceridine cohort compared to CO cohort using IV morphine alone or combined with conventional opioids are consistent with those observed in randomized clinical phase 3 trials of patients following a bunionectomy or abdominoplasty procedure, where a reduced rate of respiratory events was reported with IV oliceridine compared with morphine [ 17 , 18 ].…”

Section: Discussionsupporting

confidence: 77%

“…Findings from the ATHENA trial demonstrated that oliceridine, administered alone or as a component of multimodal analgesia, was generally safe and well tolerated in both surgical and medical patients experiencing moderate to severe acute pain, with nausea (18%), vomiting (7%), and constipation (6%) being the most frequent AEs “probably” or “possibly” related to oliceridine [ 19 ], similar to the profile observed in the prior phase 3 controlled trials [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 84%

“…A sample size target of 250 patients within each cohort was selected based on a projected respiratory depression probability of 14.5% for the CO cohort vs. 7.25% for the oliceridine group. The projected event rates were calculated using data from the phase 2b and phase 3 clinical trials with oliceridine [ 15 , 17 , 18 ]. This sample size calculation also incorporated an 80% power, an alpha of 0.05 (one-sided), and a missing data rate of 10%.…”

Section: Methodsmentioning

confidence: 99%

“…Nonclinical studies and initial clinical trials reported effective, rapid analgesia, with a low incidence of adverse events, with data suggesting less reduction in respiratory drive with oliceridine than morphine [ 12 – 16 ]. In randomized, controlled pivotal phase 3 trials involving hard tissue and soft tissue models of surgical pain, oliceridine IV exhibited a lower incidence of respiratory safety events and gastrointestinal adverse events compared to morphine at doses achieving comparable pain relief [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis

Bergese

Berkowitz

Rider

et al. 2020

Pain Research and Management

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Background. Oliceridine, an investigational IV opioid, is a first-in-class G-protein selective agonist at the μ-opioid receptor. The G-protein selectivity results in potent analgesia with less recruitment of β-arrestin, a signaling pathway associated with opioid-related adverse events (ORAEs). In randomized controlled studies in both hard and soft tissue models yielding surgical pain, oliceridine provided effective analgesia with a potential for an improved safety and tolerability profile at equianalgesic doses to morphine. The phase 3, open-label, single-arm, multicenter ATHENA trial demonstrated the safety, tolerability, and effectiveness of oliceridine in moderate to severe acute pain in a broad range of patients undergoing surgery or with painful medical conditions warranting use of an IV opioid. This retrospective, observational chart review study compared respiratory depression events associated with oliceridine administration as found in the ATHENA trial to a control cohort treated with conventional opioids. Methods. Patients at 18 years of age or older, who underwent colorectal, orthopedic, cardiothoracic, bariatric, or general surgeries between June 2015 and May 2017 in 11 sites participating in the ATHENA trial who received postoperative analgesia either with IV oliceridine or with IV conventional opioids (e.g., morphine alone or in combination with other opioids) (CO cohort); and had a hospital stay >48 hours, were included in this retrospective analysis. Data from the ATHENA trial was used for the oliceridine cohort; and additional baseline characteristics were collected from medical charts. Data from medical charts were collected for all CO cohort patients. The two cohorts were balanced using an inverse probability weighting method. The primary outcome was the incidence of operationally defined opioid-induced respiratory depression (OIRD) in the two cohorts. Secondary outcomes included between-group comparison of the incidence of OIRD events among a subset of high-risk patients. Results. OIRD was significantly less in the oliceridine cohort compared to the CO cohort (8.0% vs. 30.7%; odds ratio: 0.139) (95% confidence interval [CI] 0.09–0.22; P < 0.0001 ). Likewise, the incidence of OIRD was lower among high-risk patients in the oliceridine cohort (9.1% vs. 34.7%; odds ratio: 0.136) (95% CI [0.09–0.22]; P < 0.0001 ) compared to the CO cohort. Conclusion. In this retrospective chart review study, patients receiving IV oliceridine for moderate to severe acute pain demonstrated a lower incidence of treatment emergent OIRD compared to patients who were treated with IV morphine either alone or with concomitant administration of other opioids.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis

Bergese

Berkowitz

Rider

et al. 2020

Pain Research and Management

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“…These clinical results suggest that oliceridine promotes effective, rapid analgesia in patients with postoperative pain, with acceptable safety/tolerability profiles and a potentially wider therapeutic window than morphine [ 48 ]. Moreover, favorable analgesia over respiratory depression has been reported for oliceridine, but not morphine in a recent study that reanalyzed data obtained from healthy volunteers and postoperative patients [ 49 ] Finally, the analgesic effectiveness and favorable safety/tolerability profiles of oliceridine regarding respiratory and gastrointestinal adverse effects compared to morphine have been confirmed in different Phase III studies [ 50 , 51 , 52 ]. In October 2018, the FDA Advisory Committee voted 8 against and 7 in favor of the approval of oliceridine for the management of moderate to severe acute pain.…”

Section: Pharmacological Studies—are Mu-receptor Agonists Biased Tmentioning

confidence: 99%

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

et al. 2020

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Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.

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Discovery of Biased Mu‐Opioid Receptor Agonists for the Treatment of Pain

Ma¹,

Li²,

Tong³

et al. 2019

ChemMedChem

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G protein‐biased mu‐opioid receptor (MOR) agonists have been developed as promising new potent analgesic drugs with fewer adverse side effects than standard MOR agonists. PZM21 represents a unique chemotype unrelated to known opioids, which makes it a desirable lead for modification to find analgesics with new chemical entities. In the present study, we synthesized and tested novel PZM21 derivatives as potent biased MOR agonists by introducing a benzodioxolane group to replace the hydroxybenzene of PZM21. The new compounds displayed more potent analgesic activities in vivo and greater bias toward G protein signaling in vitro than did PZM21. These results suggest that the benzodioxolane group is essential for the maintenance of bias. Compounds 7 i ((S)‐1‐(3‐(benzo[d][1,3]dioxol‐4‐yl)‐2‐(dimethylamino)propyl)‐3‐phenethylurea) and 7 j ((S)‐1‐(3‐(benzo[d][1,3]dioxol‐4‐yl)‐2‐(dimethylamino)propyl)‐3‐benzylurea) could serve as new leads for further modifications to find novel biased MOR agonists with greater G protein signaling potency and less β‐arrestin‐2 recruitment.

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<p>APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the µ-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy</p>

Cited by 117 publications

References 32 publications

Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis

Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

Discovery of Biased Mu‐Opioid Receptor Agonists for the Treatment of Pain

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