Changes in Cataplexy Frequency in a Clinical Trial of Lower-Sodium Oxybate with Taper and Discontinuation of Other Anticataplectic Medications.

BACKGROUND: Lower-sodium oxybate (LXB) is an oxybate medication with the same active moiety as sodium oxybate (SXB) and a unique composition of cations, resulting in 92% less sodium. LXB was shown to improve cataplexy and excessive daytime sleepiness in people with narcolepsy in a placebo-controlled, double-blind, randomized withdrawal study (NCT03030599). Additional analyses of data from this study were conducted to explore the effects of LXB on cataplexy, including the clinical course and feasibility of transition from other anticataplectics to LXB monotherapy. OBJECTIVE: The aim of these analyses was to evaluate cataplexy frequency during initiation/optimization of LXB and taper/discontinuation of prior antidepressant/anticataplectic medications. METHODS: Eligible participants (adults aged 18-70 years with narcolepsy with cataplexy) entered the study taking SXB only (group A), SXB + other anticataplectics (group B), or anticataplectic medication other than SXB (group C), or were cataplexy-treatment naive (group D). LXB was initiated/optimized during a 12-week, open-label, optimized treatment and titration period (OLOTTP). Other anticataplectics were tapered/discontinued during weeks 3-10 of OLOTTP. A 2-week stable-dose period (SDP; during which participants took a stable dose of open-label LXB) and 2-week double-blind randomized withdrawal period (during which participants were randomized to continue LXB treatment or switch to placebo) followed OLOTTP. Treatment-emergent adverse events (TEAEs) were recorded throughout the duration of the study. RESULTS: At the beginning of OLOTTP, median weekly cataplexy attacks were lower in participants taking SXB at study entry (SXB only [2.00]; SXB + other anticataplectics [0.58]) versus participants who were taking other anticataplectics (3.50) or were anticataplectic naive (5.83). Median weekly cataplexy attacks decreased during weeks 1-2 of OLOTTP in all groups. Increased cataplexy frequency was observed in participants tapering/discontinuing other anticataplectics during weeks 3-10 and was more prominent in participants taking other anticataplectics alone compared with those taking SXB plus other anticataplectics. Cataplexy frequency decreased throughout initiation/optimization in anticataplectic-naive participants. Median number of cataplexy-free days/week at the end of SDP (study week 14) was similar in all groups (6.0, 6.1, 6.0, and 6.2 in groups A, B, C, and D, respectively). During OLOTTP and SDP, TEAEs of worsening cataplexy were reported in 0%, 47.8%, 16.7%, and 2.2% of participants in groups A, B, C, and D, respectively; most TEAEs of worsening cataplexy were reported during tapering/discontinuation of other anticataplectics. CONCLUSIONS: LXB monotherapy was effective in reducing cataplexy and increasing cataplexy-free days. These results illustrate the feasibility of switching from SXB to LXB while tapering/discontinuing other anticataplectics. TRIAL REGISTRATION: A Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy; https://clinicaltrials.gov/ct2/show/NCT03030599 ; clinicaltrials.gov identifier: NCT03030599.

People with narcolepsy are often sleepy during the day. They may also have sudden muscle weakness (known as cataplexy). Lower-sodium oxybate (LXB) is a narcolepsy medicine that is similar to sodium oxybate (SXB) but has 92% less sodium. A recent study found that treatment with LXB was better at reducing how often people with narcolepsy had sleepiness and cataplexy than no medicine at all (NCT03030599). This paper is about the first 12 weeks of that study, when all the people taking part in the study first tried LXB to check that they were being given the right amount. In people who only took LXB, cataplexy happened less often over time. Some people were already taking other medicines to treat their cataplexy (such as antidepressants), so they were asked to slowly stop those medicines while taking LXB. In those people, cataplexy happened more often at first as they stopped taking antidepressants and then less often later on. The increase in cataplexy when antidepressants were stopped was smaller in people who switched from SXB to LXB. This study shows that many people getting treatment for narcolepsy can switch to LXB without their cataplexy becoming worse.

Two-Part Phase 1 Multiple-Ascending-Dose Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of TRV734 in Healthy Adults.

TRV734, an oral G-protein biased ligand at the µ-opioid receptor has demonstrated differentiated pharmacology in preclinical studies compared to unbiased ligands. First-time-in-human data suggested that TRV734 was safe and well tolerated and caused effective pain relief after single doses of 150 to 250 mg. In this study, safety and tolerability of multiple ascending doses of TRV734, and single doses of TRV734 125 mg following various administration paradigms, in healthy subjects were evaluated. In both parts of the study, TRV734 was generally well tolerated with no serious adverse events. Pharmacokinetics of TRV734 were similar when TRV734 125 mg was administered following a high-fat or standard meal. Compared to either of the fed conditions, maximum concentration and area under the plasma concentration-time curve did not change, and time to maximum concentration was 1.5 hours later when TRV734 125 mg was administered as 3 split portions over 120 minutes under fasted conditions. Split doses of TRV734 delayed time to peak decrease in pupil diameter. Following multiple-dose administration of TRV734 60 to 175 mg every 6 hours, there was a trend of slightly less-than-dose proportional increase of maximum concentration, and area under the plasma concentration-time curve and accumulation was modest. Time to maximum concentration was ≈1 to 2 hours and elimination half-life ≈1.9 to 2.5 hours. The analgesic effect of TRV734 on the cold pain test was generally dose proportional and similar to that of oxycodone 10 mg immediate release, after both the first and last doses. There was a dose-related decrease in pupil diameter following administration of TRV734 up to TRV734 125 mg every 6 hours. A favorable trend in bowel function index for TRV734 warrants continued study.

Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study.

BACKGROUND: Idiopathic hypersomnia is a central hypersomnolence disorder mainly characterised by excessive daytime sleepiness, with prolonged night-time sleep and pronounced sleep inertia. Until August, 2021, no medication had regulatory approval for the treatment of idiopathic hypersomnia. This study aimed to evaluate the safety and efficacy of lower-sodium oxybate in idiopathic hypersomnia. METHODS: This was a phase 3, multicentre (50 specialist sleep centres; six EU countries and the USA), placebo-controlled, double-blind, randomised withdrawal study. Participants (aged 18-75 years) with idiopathic hypersomnia (meeting criteria from the International Classification of Sleep Disorders, 2nd or 3rd editions) began lower-sodium oxybate treatment (oral solution once or twice nightly) in an open-label titration and optimisation period (10-14 weeks), followed by a 2-week, open-label, stable-dose period. After these open-label periods, participants were randomised (1:1) by means of an interactive web recognition system, stratified by participants' baseline medication use, to either placebo or lower-sodium oxybate (individually optimised dose; range 2·5-9·0 g/night) during a 2-week, double-blind, randomised withdrawal period. To maintain masking of treatment assignment, placebo and lower-sodium oxybate oral solutions were matched in volume, appearance, and taste. During the double-blind, randomised withdrawal period, participants and investigators were unaware of treatment assignments. The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score from the end of the stable-dose period to the end of the double-blind, randomised withdrawal period, which was assessed in the modified intention-to-treat population (defined as all participants who were randomly assigned, took at least one dose of study medication during the double blind, randomised withdrawal period, and had at least one set of post-randomisation assessments for the primary or key secondary endpoints). Adverse events were assessed in the safety population (defined as all participants who took at least one dose of study medication). This study is registered at ClinicalTrials.gov, NCT03533114, and at EU Clinical Trials, 2018-001311-79, and is complete. FINDINGS: Between Nov 27, 2018, and March 6, 2020, 154 participants were enrolled and comprised the safety population. ESS scores decreased from a mean of 15·7 (SD 3·8) at baseline to 6·1 (4·0) by the end of the stable-dose period. After the open-label periods, 115 participants were randomly assigned either placebo (n=59) or lower-sodium oxybate (n=56) and comprised the modified intention-to-treat population. During the double-blind, randomised withdrawal period, ESS scores increased (worsened) in participants randomly assigned to placebo but remained stable in those assigned to lower-sodium oxybate (least squares mean difference -6·5; 95% CI -8·0 to -5·0; p<0·0001). Treatment-emergent adverse events included nausea (34 [22%] of 154), headache (27 [18%] of 154), dizziness (19 [12%] of 154), anxiety (17 [11%] 154), and vomiting (17 [11%] 154). No deaths were reported during the study. INTERPRETATION: Lower-sodium oxybate treatment resulted in a clinically meaningful improvement in idiopathic hypersomnia symptoms, with an overall safety profile consistent with that reported for narcolepsy. Lower-sodium oxybate was approved in August, 2021, by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults. FUNDING: Jazz Pharmaceuticals.

Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy.

STUDY OBJECTIVES: Evaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB). METHODS: Adults aged 18-70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment. RESULTS: Efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (-0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (-1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%). CONCLUSIONS: Efficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB. CLINICAL TRIAL REGISTRATION: NCT03030599.

A First-in-Human Clinical Study With TRV734, an Orally Bioavailable G-Protein-Biased Ligand at the µ-Opioid Receptor.

TRV734 is an orally bioavailable G-protein-biased ligand at the µ-opioid receptor. In nonclinical studies it was potently analgesic while causing less gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. A 2-part, first-in-human study was conducted with ascending doses of TRV734 to explore its tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers. TRV734 was well tolerated over the dose range 2 to 250 mg when administered orally. Plasma TRV734 maximum concentration and area under the plasma concentration-time curve generally increased with dose, while time to maximum concentration was similar across doses (0.5-1.3 h). The half-life increased with dose from 10 mg through 150 mg (0.75-2.28 h) but was similar from 150 mg through 250 mg. Pupil constriction, confirming central nervous system µ-opioid receptor engagement, correlated with higher plasma TRV734 concentrations; the greatest reductions in pupil diameter occurring between 0 and 4 hours after dosing (-2.9 mm/h, with reduction peaking at 1 hour, and returning to baseline by 8 hours). Following administration of TRV734 125 mg under fasted or fed conditions, there was no significant difference in bioavailability when given as a solution or drug in capsule to fasted subjects. When drug in capsule was given to subjects following a high-fat meal, absorption was slowed, resulting in decreased peak concentrations, but area under the plasma concentration-time curve was not affected.

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Oliceridine.

Oliceridine is a G protein-biased ligand at the µ-opioid receptor in development for treatment of moderate to severe acute pain. A phase 1, open-label, single-dose study investigated the pharmacokinetics and safety of oliceridine 0.5 mg intravenous (IV) in subjects with end-stage renal disease (ESRD, n = 9) versus 1 mg in healthy controls (n = 8). A second phase 1, open-label, single-dose study investigated the pharmacokinetics and safety of a 0.5-mg IV dose in hepatic impairment (mild, n = 10; moderate, n = 10; severe, n = 6) versus 1 mg in healthy controls (n = 8). The controls were sex and age (±10 years) matched. In ESRD versus healthy subjects, no difference in clearance was observed between ESRD patients and subjects with normal renal function. Oliceridine clearance and AUC were not affected by hepatic impairment. Half-life (hours; GM [%CV]) increased in subjects with moderate (4.3 [44.1]) and severe (5.8 [41.2]) impairment versus mild impairment (2.6 [20.0]) and healthy subjects (2.1 [11.3]). Volume of distribution was increased with the degree of hepatic impairment. All adverse events were mild and generally consistent with the known safety profile of oliceridine. No dose adjustment is needed in patients with renal impairment or in patients with mild or moderate hepatic impairment. Initial dose reduction should be considered in severe hepatic impairment, and patients may require fewer doses of oliceridine due to the longer half-life observed in these patients.

APOLLO-2: 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 Abdominoplasty.

OBJECTIVES: The clinical utility of conventional IV opioids is limited by the occurrence of opioid-related adverse events. Oliceridine is a novel G protein-biased µ-opioid receptor agonist designed to provide analgesia with an improved safety and tolerability profile. This phase III, double-blind, randomized trial (APOLLO-2 [NCT02820324]) evaluated the efficacy and safety of oliceridine for acute pain following abdominoplasty. METHODS: Patients received a loading dose of either placebo, oliceridine (1.5 mg), or morphine (4 mg), followed by demand doses via patient-controlled analgesia (0.1, 0.35, or 0.5 mg oliceridine; 1 mg morphine; or placebo) with a 6-minute lockout interval. The primary endpoint was the proportion of treatment responders over 24 hours for oliceridine regimens compared to placebo. Secondary outcomes included a predefined composite measure of respiratory safety burden (RSB, representing the cumulative duration of respiratory safety events) and the proportion of treatment responders vs. morphine. RESULTS: A total of 401 patients were treated with study medication. Effective analgesia was observed for all oliceridine regimens, with responder rates of 61.0%, 76.3%, and 70.0% for the 0.1-, 0.35-, and 0.5-mg regimens, respectively, compared with 45.7% for placebo (all P < 0.05) and 78.3% for morphine. Oliceridine 0.35- and 0.5-mg demand dose regimens were equi-analgesic to morphine using a noninferiority analysis. RSB showed a dose-dependent increase across oliceridine regimens (mean hours [standard deviation], 0.1 mg: 0.43 [1.56]; 0.35 mg: 1.48 [3.83]; 0.5 mg: 1.59 [4.26]; all comparisons not significant at P > 0.05 vs. placebo: 0.60 [2.82]). The RSB measure for morphine was 1.72 (3.86) (P < 0.05 vs. placebo). Gastrointestinal adverse events increased in a dose-dependent manner across oliceridine demand dose regimens (0.1 mg: 49.4%; 0.35 mg: 65.8%; 0.5 mg: 78.8%; vs. placebo: 47.0%; and morphine: 79.3%). In comparison to morphine, the proportion of patients experiencing nausea or vomiting was lower with the 2 equi-analgesic dose regimens of 0.35 and 0.5 mg oliceridine. CONCLUSIONS: Oliceridine is a safe and effective IV analgesic for the relief of moderate to severe acute postoperative pain in patients undergoing abdominoplasty. Since the low-dose regimen of 0.1 mg oliceridine was superior to placebo but not as effective as the morphine regimen, safety comparisons to morphine are relevant only to the 2 equi-analgesic dose groups of 0.35 and 0.5 mg, which showed a favorable safety and tolerability profile regarding respiratory and gastrointestinal adverse effects compared to morphine. These findings support that oliceridine may provide a new treatment option for patients with moderate to severe acute pain where an IV opioid is warranted.

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.

PURPOSE: Oliceridine is a novel G protein-biased µ-opioid receptor agonist designed to provide intravenous (IV) analgesia with a lower risk of opioid-related adverse events (ORAEs) than conventional opioids. PATIENTS AND METHODS: APOLLO-1 (NCT02815709) was a phase III, double-blind, randomized trial in patients with moderate-to-severe pain following bunionectomy. Patients received a loading dose of either placebo, oliceridine (1.5 mg), or morphine (4 mg), followed by demand doses via patient-controlled analgesia (0.1, 0.35, or 0.5 mg oliceridine, 1 mg morphine, or placebo). The primary endpoint compared the proportion of treatment responders through 48 hours for oliceridine regimens and placebo. Secondary outcomes included a composite measure of respiratory safety burden (RSB, representing the cumulative duration of respiratory safety events) and the proportion of treatment responders vs morphine. RESULTS: Effective analgesia was observed for all oliceridine regimens, with responder rates of 50%, 62%, and 65.8% in the 0.1 mg, 0.35 mg, and 0.5 mg regimens, respectively (all P<0.0001 vs placebo [15.2%]; 0.35 mg and 0.5 mg non-inferior to morphine). RSB showed a dose-dependent increase across oliceridine regimens (mean hours [SD]: 0.1 mg: 0.04 [0.33]; 0.35 mg: 0.28 [1.11]; 0.5 mg: 0.8 [3.33]; placebo: 0 [0]), but none were statistically different from morphine (1.1 [3.03]). Gastrointestinal adverse events also increased in a dose-dependent manner in oliceridine regimens (0.1 mg: 40.8%; 0.35 mg: 59.5%; 0.5 mg: 70.9%; placebo: 24.1%; morphine: 72.4%). The odds ratio for rescue antiemetic use was significantly lower for oliceridine regimens compared to morphine (P<0.05). CONCLUSION: Oliceridine is a novel and effective IV analgesic providing rapid analgesia for the relief of moderate-to-severe acute postoperative pain compared to placebo. Additionally, it has a favorable safety and tolerability profile with regard to respiratory and gastrointestinal adverse effects compared to morphine, and may provide a new treatment option for patients with moderate-to-severe postoperative pain where an IV opioid is required.

Oliceridine, a Novel G Protein-Biased Ligand at the µ-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. II: Simulation of Potential Phase 3 Study Designs Using a Pharmacokinetic/Pharmacodynamic Model.

Oliceridine is a novel G protein-biased ligand at the µ-opioid receptor that differentially activates G protein coupling while mitigating ß-arrestin recruitment. Unlike morphine, oliceridine has no known active metabolites; therefore, analgesic efficacy is predictably linked to its concentration in the plasma. Oliceridine is primarily hepatically metabolized by CYP3A4 and CYP2D6. Using a pharmacokinetic/pharmacodynamic model relating oliceridine plasma concentrations to its effect on pain intensity as measured by numeric pain-rating scale (NPRS) scores, we have simulated potential dosing regimens using both fixed-dose regimens and as-needed (prn) dosing regimens in which various doses of oliceridine were administered if NPRS scores indicated moderate to severe pain (≥4 on a 0-10 scale). In addition, regimens in which oliceridine was self-administered via a patient-controlled analgesia device were also simulated. The simulated population included 10% CYP2D6 poor metabolizers (PM). The simulation results suggest that oliceridine doses of 1-3 mg prn should be effective in reducing NPRS scores relative to placebo. The simulations also revealed that a 1-mg "supplemental dose" given 0.25 hour after the loading dose would decrease NPRS scores further in almost one-third of patients. In addition, if oliceridine is administered prn, a longer interval between doses is observed in simulated PM patients, consistent with their reduced oliceridine clearance. Because this longer average dosing interval is predicted to decrease oliceridine exposure in PM patients, the need to know the patient's CYP2D6 genotype for dosing is effectively obviated.

Oliceridine (TRV130), a Novel G Protein-Biased Ligand at the µ-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model.

Conventional opioids bind to µ-opioid receptors and activate 2 downstream signaling pathways: G-protein coupling, linked to analgesia, and ß-arrestin recruitment, linked to opioid-related adverse effects and limiting efficacy. Oliceridine (TRV130) is a novel G protein-biased ligand at the µ-opioid receptor that differentially activates G-protein coupling while mitigating ß-arrestin recruitment. Using data derived from both phase 1 studies in healthy volunteers as well as data from a phase 2 study examining the efficacy of oliceridine for the treatment of postbunionectomy pain, we have developed a population pharmacokinetic/pharmacodynamic model linking the pharmacokinetics of oliceridine to its effect on pain, as measured by the Numeric Pain Rating Scale score. Phase 1 data consisted of 145 subjects (88% male, 12% female), who received single doses of oliceridine ranging between 0.15 and 7 mg, as well as multiple doses ranging from 0.4 to 4.5 mg every 4-6 hours. Sixteen of these subjects were CYP2D6 poor metabolizers, who have lower oliceridine clearance than extensive metabolizers. Approximately 265 subjects (10% male, 90% female) came from the phase 2 study, in which they received active doses ranging from 0.5 to 4 mg every 3-4 hours. The final model was a 3-compartment model that included covariates of body weight, sex, and CYP2D6 status. The PD model was an indirect response model linked to plasma oliceridine concentrations and included the placebo pain response over the 48-hour treatment period. The EC50 for oliceridine on pain relief was estimated as 10.1 ng/mL (95%CI, 8.4-12.1 ng/mL). Model qualification showed that the model robustly reproduced the original data.

A randomized, Phase IIb study investigating oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (µ-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty.

BACKGROUND: Oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (µ-GPS) modulator, was designed to improve the therapeutic window of conventional opioids by activating G-protein signaling while causing low ß-arrestin recruitment to the µ receptor. This randomized, double-blind, patient-controlled analgesia Phase IIb study was conducted to investigate the efficacy, safety, and tolerability of oliceridine compared with morphine and placebo in patients with moderate to severe pain following abdominoplasty (NCT02335294; oliceridine is an investigational agent not yet approved by the US Food and Drug Administration). METHODS: Patients were randomized to receive postoperative regimens of intravenous oliceridine (loading/patient-controlled demand doses [mg/mg]: 1.5/0.10 [regimen A]; 1.5/0.35 [regimen B]), morphine (4.0/1.0), or placebo with treatment initiated within 4 hours of surgery and continued as needed for 24 hours. RESULTS: Two hundred patients were treated (n=39, n=39, n=83, and n=39 in the oliceridine regimen A, oliceridine regimen B, morphine, and placebo groups, respectively). Patients were predominantly female (n=198 [99%]) and had a mean age of 38.2 years, weight of 71.2 kg, and baseline pain score of 7.7 (on 11-point numeric pain rating scale). Patients receiving the oliceridine regimens had reductions in average pain scores (model-based change in time-weighted average versus placebo over 24 hours) of 2.3 and 2.1 points, respectively (P=0.0001 and P=0.0005 versus placebo); patients receiving morphine had a similar reduction (2.1 points; P<0.0001 versus placebo). A lower prevalence of adverse events (AEs) related to nausea, vomiting, and respiratory function was observed with the oliceridine regimens than with morphine (P<0.05). Other AEs with oliceridine were generally dose-related and similar in nature to those observed with conventional opioids; no serious AEs were reported with oliceridine. CONCLUSION: These results suggest that oliceridine may provide effective, rapid analgesia in patients with moderate to severe postoperative pain, with an acceptable safety/tolerability profile and potentially wider therapeutic window than morphine.

A randomized, phase 2 study investigating TRV130, a biased ligand of the µ-opioid receptor, for the intravenous treatment of acute pain.

Efficacy of conventional opioids can be limited by adverse events (AEs). TRV130 is a structurally novel biased ligand of the µ-opioid receptor that activates G protein signaling with little ß-arrestin recruitment. In this phase 2, randomized, placebo- and active-controlled study, we investigated the efficacy and tolerability of TRV130 in acute pain after bunionectomy. We used an adaptive study design in which 144 patients experiencing moderate-to-severe acute pain after bunionectomy were randomized to receive double-blind TRV130, placebo, or morphine in a pilot phase. After pilot phase analysis, 195 patients were randomized to receive double-dummy TRV130 0.5, 1, 2, or 3 mg every 3 hours (q3h); placebo; or morphine 4 mg q4h intravenously. The primary end point was the time-weighted average change in numeric rating scale pain intensity over the 48-hour treatment period. Secondary end points included stopwatch and categorical assessments of pain relief. Safety and tolerability were also assessed. TRV130 2 and 3 mg q3h, and morphine 4 mg q4h produced statistically greater mean reductions in pain intensity than placebo over 48 hours (P < 0.005). TRV130 at 2 and 3 mg produced significantly greater categorical pain relief than morphine (P < 0.005) after the first dose, with meaningful pain relief occurring in under 5 minutes. TRV130 produced no serious AEs, with tolerability similar to morphine. These results demonstrate that TRV130 rapidly produces profound analgesia in moderate-to-severe acute pain, suggesting that G-protein-biased µ-opioid receptor activation is a promising target for development of novel analgesics.

Evaluation of an Adaptive Maximizing Design Study Based on Clinical Utility Versus Morphine for TRV130 Proof-of-Concept and Dose-Regimen Finding in Patients With Postoperative Pain After Bunionectomy.

BACKGROUND: Conventional opioids provide powerful analgesia but also produce efficacy-limiting adverse effects, limiting their clinical utility (CU). TRV130 is being evaluated to determine whether CU can be expanded by way of increased efficacy, decreased adverse effects, or some combination thereof. METHODS: This phase 2 study of TRV130 blends traditional objectives with novel design features aimed toward the specific strategic goal of optimizing the attributes of TRV130 efficacy and tolerability compared with the conventional opioid, morphine. The adaptive maximizing design (AMD) was developed to maximize assignment of future patients to doses that demonstrate maximum balance between efficacy and tolerability (ie, CU) assessed via a CU function. RESULTS: Our evaluation of the AMD performance characteristics reveals that the AMD has a strong capacity to estimate the TRV130 dose-regimens with maximum CU, assign more patients to the TRV130 dose-regimens with maximum CU, and, conversely, assign fewer patients to doses away from the those with maximum or near-maximum CU. CONCLUSIONS: Based on this evaluation of performance characteristics of the AMD versus a traditional study design, the AMD was selected for this proof-of-concept and dose-regimen finding study of TRV130.

Biased agonism of the µ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers.

Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating µ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus -7.3, -7.6, and -9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.

Dupilumab in persistent asthma with elevated eosinophil levels.

BACKGROUND: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels. METHODS: We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)-associated biomarkers and safety and tolerability were also evaluated. RESULTS: A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo. CONCLUSIONS: In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.).

Efficacy and tolerability of coadministration of rizatriptan and acetaminophen vs rizatriptan or acetaminophen alone for acute migraine treatment.

OBJECTIVE: To evaluate the efficacy and tolerability of coadministration of rizatriptan and acetaminophen in the acute treatment of migraine. BACKGROUND: Rizatriptan is a selective 5-HT1B/1D agonist approved for the acute treatment of migraine. Acetaminophen has been studied for acute migraine treatment. In consideration of the prominent central and peripheral mechanisms in migraine, the use of "multi-mechanism therapy" is gaining momentum in the treatment of acute migraine attacks. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled trial conducted at 10 centers. Eligible patients with migraine according to International Headache Society criteria treated a single migraine attack of moderate or severe intensity within 4 h from pain onset. Patients were randomized into 1 of 4 groups (rizatriptan 10 mg + acetaminophen 1000 mg [RA], rizatriptan alone [R], acetaminophen alone [A], and placebo [P]). There were 3 co-primary hypotheses tested sequentially for 2-h pain relief: (1) RA would be superior to P; (2) if the first was fulfilled, RA would be superior to A; and (3) if the first 2 were fulfilled, RA would be superior to R. RESULTS: Of 173 patients who treated a migraine, 123 patients (71.5%) achieved pain relief within 2 h. RA (90%) was significantly better than P (46%) and A (70%), but only numerically better than R (77%) for 2-h pain relief. No significant differences were seen between the active treatment groups in adverse events. CONCLUSION: Rizatriptan coadministered with acetaminophen achieved 2 of the 3 primary hypotheses, proving superior to both acetaminophen and placebo for 2-h pain relief, but failing to achieve superiority to rizatriptan alone. RA was as well tolerated as each of the individual agents.