Efficacy, safety, and side effects of oliceridine in acute postoperative pain, a protocol for a systematic review and meta-analysis.

This will be the first meta-analysis on the efficacy, safety, and side effects of oliceridine on postoperative pain. Our aim with this work is to evaluate the clinical utility of this relatively new substance in a broad postoperative context. Oliceridine is a new so-called bias opioid that is approved for severe pain requiring an opioid. Due to its biased agonism, it is said to have fewer side effects than conventional opioids. This systematic review and meta-analysis will analyze the efficacy, safety, and side effects of oliceridine compared to placebo or morphine in acute postoperative pain for up to 72 hours. In January 2024, an extensive search in various databases will be performed without restrictions for randomized controlled trials with at least single blinding. After data extraction, data will be pooled and meta-analytic calculations performed. A random-effects model will be used. Dichotomous data will be presented as risk ratio and continuous data as standardized mean difference. Dose-dependent side effects will be evaluated with meta-regression. Heterogeneity will be assessed via the Q statistic and prediction interval in case of a sufficient number of included studies. Publication bias will be examined using funnel plot and Duval and Tweedie's trim and fill method.

A critical review of oliceridine injection as an IV opioid analgesic for the management of severe acute pain.

INTRODUCTION: Oliceridine is a G protein-selective (biased) agonist at the µ-opioid receptor, with less recruitment of ß-arrestin-2, a signaling pathway associated with opioid-related adverse events. Nonclinical evidence showed that oliceridine elicits a rapid systemic analgesic effect while attenuating opioid-related adverse events. AREAS COVERED: Three pivotal studies in patients with moderate-to-severe acute pain, including two randomized, double-blind, placebo- and morphine-controlled efficacy studies following either orthopedic surgery-bunionectomy or plastic surgery-abdominoplasty; and an open-label safety study following a surgical procedure or due to a medical condition. EXPERT OPINION: Poorly controlled acute postoperative pain is associated with poorer recovery, longer hospitalization, increased complications, and worse healthcare outcomes. Recently, oliceridine intravenous injection was approved for use in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Introduction of this new IV opioid provides a valuable option to manage postoperative pain.

Atogepant: an emerging treatment for migraine.

INTRODUCTION: Until recently, only nonspecific and not always well-tolerated medications were available for migraine prophylaxis. Currently, specific drugs such as calcitonin gene-related peptide (CGRP) monoclonal antibodies and second-generation gepants are marketed for migraine treatment. Atogepant, an orally active small molecule, is a potent, selective antagonist of the CGRP receptor and is the only gepant authorized exclusively for episodic migraine prophylaxis in adults. AREAS COVERED: Using literature obtained from PubMed, Scopus, Web of Science, Cochrane, and ClinicalTrials.gov (up to February 13rd, 2022), the authors summarize and evaluate the available data on atogepant for the prophylaxis of episodic migraine. EXPERT OPINION: From pivotal trials, the efficacy and tolerability of atogepant in episodic migraine prophylaxis seem comparable to those of CGRP monoclonal antibodies, even if comparative studies have not been conducted. To date, limited information is available on atogepant, including the optimal dose and duration of therapy; hence, it is difficult to establish whether it could be a first-line drug for migraine prophylaxis. Furthermore, it is important to evaluate if atogepant use is associated with the risk of cardiovascular and cerebrovascular events, which could result from potent and persistent blockade of vasodilation by CGRP.

Safety and Antiviral Effects of Nebulized PC786 in a Respiratory Syncytial Virus Challenge Study.

BACKGROUND: PC786 is a nebulized nonnucleoside respiratory syncytial virus (RSV) polymerase inhibitor designed to treat RSV, which replicates in the superficial layer of epithelial cells lining the airways. METHODS: Fifty-six healthy volunteers inoculated with RSV-A (Memphis 37b) were randomly dosed with either nebulized PC786 (5 mg) or placebo, twice daily for 5 days, from either 12 hours after confirmation of RSV infection or 6 days after virus inoculation. Viral load (VL), disease severity, pharmacokinetics, and safety were assessed until discharge. RSV infection was confirmed by reverse-transcription quantitative polymerase chain reaction with any positive value (intention-to-treat infected [ITT-I] population) or RSV RNA ≥1 log10 plaque-forming unit equivalents (PFUe)/mL (specific intention-to-treat infection [ITT-IS] population) in nasal wash samples. RESULTS: In the ITT-I population, the mean VL area under the curve (AUC) was lower in the PC786 group than the placebo group (274.1 vs 406.6 log10 PFUe/mL × hour; P = .0359). PC786 showed a trend toward reduction of symptom score and mucous weight. In ITT-IS (post hoc analysis), the latter was statistically significant as well as VL AUC (P = .0126). PC786 showed an early time to maximum plasma concentration, limited systemic exposure, and long half-life and consequently a 2-fold accumulation over the 5-day dosing period. PC786 was well tolerated. CONCLUSIONS: Nebulized PC786 demonstrated a significant antiviral effect against RSV, warranting further clinical study. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT03382431; EudraCT: 2017-002563-18.

Preclinical discovery and development of oliceridine (Olinvyk®) for the treatment of post-operative pain.

INTRODUCTION: Opioids acting at the MOP (mu:µ) receptor produce analgesia but also side effects. There is debate suggesting opioid receptors produce analgesia via G-protein and side-effects via ß-arrestin-2 pathways. Opioids targeting G-proteins over the arrestins (bias) offer potential therapeutic advantages. Oliceridine is a putative MOP, G-protein biased agonist. AREAS COVERED: Oliceridine is selective for MOP receptors with greater activity at G-proteins over arrestins. A substantial body of evidence now points to a simpler pharmacological descriptor of partial agonist. Preclinical in vivo data indicates a robust antinociceptive response of shorter duration than morphine. Apollo trials (Phase-III RCT-bunionectomy/abdominoplasty) describe good analgesic efficacy that was non-inferior to morphine with good tolerability and side-effect profile. There is evidence for an improved respiratory safety profile. Oliceridine is approved by the FDA. EXPERT OPINION: Oliceridine will be an important addition to the clinical armamentarium for use for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Respiratory advantage and the possibility of reduced abuse potential are possible advantages over the use of traditional opioids. Based on a number of excellent, highly detailed studies, oliceridine should be described as a partial agonist; this 'label' does not matter.

Atogepant: First Approval.

Atogepant (Qulipta™) is an orally administered, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist being developed by AbbVie for the prophylaxis of migraine. In September 2021, atogepant was approved in the USA for the preventive treatment of episodic migraine in adults. The drug is also in phase 3 clinical development for the preventive treatment of migraine in various other countries. This article summarizes the milestones in the development of atogepant leading to this first approval for the preventive treatment of episodic migraine in adults.

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa.

BACKGROUND: The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether-lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa. METHODS: This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether-lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial. RESULTS: Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether-lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether-lumefantrine. Cipargamin was well tolerated with no safety concerns. CONCLUSIONS: This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin. Trial registration ClinicalTrials.gov number: NCT03334747 (7 Nov 2017), other study ID CKAE609A2202.

Safety evaluation of oliceridine for the management of postoperative moderate-to-severe acute pain.

INTRODUCTION: Opioids for managing postoperative pain are associated with side effects including opioid-induced respiratory depression (OIRD) and gastrointestinal complications. Opioids induce analgesia via G-protein signaling, while adverse effects are mediated by the ß-arrestin pathway. Oliceridine is a biased ligand that preferentially activates G-protein signaling over ß-arrestin, theoretically reducing adverse effects. Oliceridine has been approved by the Food and Drug Administration to treat acute pain severe enough to require intravenous opioid analgesics. AREAS COVERED: Preclinical and clinical trials demonstrate the analgesic efficacy of oliceridine. Available evidence suggests that oliceridine may have a lower risk of OIRD and gastrointestinal complications compared to conventional opioids. EXPERT OPINION: The analgesic efficacy of oliceridine has been evaluated in several clinical trials. However, safety data were obtained from an open-label observational study and studies assessing adverse effects as secondary outcomes, as post-hoc analyses, or from retrospective studies. These may be affected by gaps in detecting adverse events, heterogeneity in the original studies, and the limitations of retrospective studies. Prospective trials examining the safety of oliceridine versus conventional opioids are needed. Studies are also needed to assess the safety and efficacy of oliceridine in obstetric and pediatric populations, and in the context of multimodal analgesia and Enhanced Recovery after Surgery protocols.

Atogepant for the Preventive Treatment of Migraine.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine. METHODS: In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D). RESULTS: A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group. CONCLUSIONS: Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).

A Single Supratherapeutic Dose of Atogepant Does Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized, Single-Dose, Phase 1 Crossover Trial.

Atogepant is a selective, oral calcitonin gene-related peptide receptor antagonist in development for preventive treatment of migraine. This randomized, double-blind, phase 1 crossover study evaluated the cardiac repolarization effect of a single supratherapeutic (300 mg) atogepant dose vs placebo in healthy adults. Moxifloxacin 400 mg was the open-label active control. The primary end point was a change from baseline in Fridericia-corrected QT intervals (ΔQTcF). Sixty participants were randomized to atogepant 300 mg, placebo, and moxifloxacin; 59 (98.3%) completed all interventions. Assay sensitivity was confirmed: lower 90% confidence interval limit for QTcF interval change from baseline (ΔΔQTcF) for moxifloxacin was >5 millisecond vs placebo at prespecified 2-, 3-, and 4-hour time points. Following single-dose atogepant 300 mg, mean atogepant ΔΔQTcF and upper 90% confidence interval limits were lower than the 10-millisecond threshold at all time points. Atogepant mean peak plasma concentration was 3197 ng/mL, area under the concentration-time curve from time 0 to time t was 16 640 ng • h/mL, area under the concentration-time curve from time 0 to 24 hours was 16 607 ng • h/mL, and median time to peak plasma concentration was 2.1 hours. The incidence of adverse events was low; no serious adverse events or elevations of liver enzymes were reported. Overall, a single supratherapeutic dose of atogepant was safe and did not impact cardiac repolarization in healthy participants.

Single-Dose Pharmacokinetics and Safety of Atogepant in Adults With Hepatic Impairment: Results From an Open-Label, Phase 1 Trial.

Atogepant is a selective oral calcitonin gene-related peptide receptor antagonist in development for migraine prevention. Here, we report the pharmacokinetics (PK) and safety of single-dose 60 mg atogepant in participants with severe, moderate, or mild hepatic impairment and matched participants with normal hepatic function from an open-label, parallel-group, single-dose phase 1 trial. Thirty-two participants aged 45 to 72 years were enrolled, which included 8 each with severe, moderate, mild, or no hepatic impairment. All participants completed the study. Atogepant was rapidly absorbed (median time to maximum plasma concentration, ∼2 hours) with an apparent terminal elimination half-life of ∼11 hours. Compared with participants with normal hepatic function, the change in maximum plasma concentrations of atogepant were -4%, -12%, and +9% in participants with severe, moderate, or mild hepatic impairment, respectively. Overall systemic exposures to atogepant were 15% to 38% higher in participants with hepatic impairment compared with those with normal hepatic function, but these differences are not expected to be clinically relevant given the established safety profile of atogepant. Only 1 adverse event was reported: mild rhinorrhea in a participant with moderate hepatic impairment. Overall, atogepant was safe and not associated with any clinically relevant change in PK in participants with severe, moderate, or mild hepatic impairment.

Atogepant Is Not Associated With Clinically Meaningful Alanine Aminotransferase Elevations in Healthy Adults.

Atogepant is a potent, selective, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once-daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double-blind, placebo-controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty-four participants aged 23-55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well-tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half-life of ~ 11 hours, and no evidence of accumulation after once-daily dosing. Overall, atogepant at a high oral dose is safe and well-tolerated in healthy participants with no clinically meaningful elevations in ALT.

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

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 ß-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.

The G Protein Signal-Biased Compound TRV130; Structures, Its Site of Action and Clinical Studies.

Opioid agonists elicit their analgesic action mainly via µ opioid receptors; however, their use is limited because of adverse events including constipation and respiratory depression. It has been shown that analgesic action is transduced by the G protein-mediated pathway whereas adverse events are by the ß-arrestin-mediated pathway through µ opioid receptor signaling. The first new-generation opioid TRV130, which preferentially activates G protein- but not ß-arrestin-mediated signal, was constructed and developed to reduce adverse events. TRV130 and other G protein-biased compounds tend to elicit desirable analgesic action with less adverse effects. In clinical trials, the intravenous TRV130 (oliceridine) was evaluated in Phase I, II and III clinical studies. Here we review the discovery and synthesis of TRV130, its main action as a novel analgesic having less adverse events, its up-to-date status in clinical trials, and additional concerns about TRV130 as demonstrated in the literature.

Oliceridine: First Approval.

Oliceridine (Olinvyk™, Trevena, Inc.) is a novel µ opioid agonist that was recently approved in the USA for use in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Unlike opioid agonists currently in use, the interaction of oliceridine with the opioid receptor is selective to the G protein pathway, with low potency for ß-arrestin recruitment, which may lead to fewer opioid-related adverse events. This article summarizes the milestones in the development of oliceridine leading to this first approval.

Anesthetic and Analgesic Drug Products Advisory Committee Activity and Decisions in the Opioid-crisis Era.

The United States Food and Drug Administration is tasked with ensuring the efficacy and safety of medications marketed in the United States. One of their primary responsibilities is to approve the entry of new drugs into the marketplace, based on the drug's perceived benefit-risk relationship. The Anesthetic and Analgesic Drug Product Advisory Committee is composed of experts in anesthesiology, pain management, and biostatistics, as well as consumer and industry representatives, who meet several times annually to review new anesthetic-related drugs, those seeking new indications, and nearly every opioid-related application for approval. The following report describes noteworthy activities of this committee since 2017, as it has grappled, along with the Food and Drug Administration, to balance the benefit-risk relationships for individual patients along with the overarching public health implications of bringing additional opioids to market. All anesthesia advisory committee meetings since 2017 will be described, and six will be highlighted, each with representative considerations for potential new opioid formulations or local anesthetics.