A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides.

BACKGROUND: Vupanorsen is a GalNAc3-conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia. OBJECTIVES: The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG). METHODS: In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg. PK parameters, PD markers (including ANGPTL3, TG, non-high-density lipoprotein cholesterol [non-HDL-C]), and safety were assessed. RESULTS: Absorption of vupanorsen was rapid (median time to maximum concentration [Tmax]: 2.0 h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80 mg] and 465.2 h [160 mg]). Exposure (area under curve [AUC] and maximum plasma concentration [Cmax]) generally increased in a greater than dose-proportional manner from 80 mg to 160 mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were - 59.7% and - 69.5% for ANGPTL3, - 41.9% and - 52.5% for TG, and - 23.2% and - 25.4% for non-HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study. CONCLUSIONS: This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04916795.

Viral SARS-CoV-2 Rebound Rates in Linked Commercial Pharmacy-Based Testing and Health Care Claims.

Background: Viral SARS-CoV-2 rebound (viral RNA rebound) is challenging to characterize in large cohorts due to the logistics of collecting frequent and regular diagnostic test results. Pharmacy-based testing data provide an opportunity to study the phenomenon in a large population, also enabling subgroup analyses. The current real-world evidence approach complements approaches focused on smaller, prospective study designs. Methods: We linked real-time reverse transcription quantitative polymerase chain reaction test data from national pharmacy-based testing to health care claims data via tokenization to calculate the cumulative incidence of viral RNA rebound within 28 days following positive test results in nirmatrelvir/ritonavir (NMV-r)-treated and untreated individuals during the Omicron era (December 2021-November 2022) and prior to the Omicron era (October 2020-November 2021). Results: Among 30 646 patients, the rate of viral RNA rebound was 3.5% (95% CI, 2.0%-5.7%) in NMV-r-treated infections as compared with 1.5% (95% CI, 1.3%-1.7%) in untreated infections during the Omicron era and 1.9% (95% CI, 1.7%-2.1%) prior to the Omicron era. Viral RNA rebound in patients who were vaccinated (n = 8151), high risk (n = 4411), or older (≥65 years, n = 4411) occurred at comparable rates to the overall cohort (range, 1.1%-4.8%). Viral rebounds to high RNA levels in NMV-r-treated infections occurred in 8% of viral rebounds as compared with 5% to 11% in untreated infections. Rates of hospitalization were comparable between patients with NMV-r-treated infections with viral RNA rebound (0%) and untreated patients with viral RNA rebound (0%-1.2%). Conclusions: Our findings suggest viral RNA rebound is rare (< 5%), with rates that were consistent with those from the EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients). Most occurrences of viral RNA rebound were associated with low viral RNA levels, and viral RNA rebound progression to severe disease was not observed.

Subphenotypes of self-reported symptoms and outcomes in long COVID: a prospective cohort study with latent class analysis.

OBJECTIVE: To characterise subphenotypes of self-reported symptoms and outcomes (SRSOs) in postacute sequelae of COVID-19 (PASC). DESIGN: Prospective, observational cohort study of subjects with PASC. SETTING: Academic tertiary centre from five clinical referral sources. PARTICIPANTS: Adults with COVID-19 ≥20 days before enrolment and presence of any new self-reported symptoms following COVID-19. EXPOSURES: We collected data on clinical variables and SRSOs via structured telephone interviews and performed standardised assessments with validated clinical numerical scales to capture psychological symptoms, neurocognitive functioning and cardiopulmonary function. We collected saliva and stool samples for quantification of SARS-CoV-2 RNA via quantitative PCR. OUTCOMES MEASURES: Description of PASC SRSOs burden and duration, derivation of distinct PASC subphenotypes via latent class analysis (LCA) and relationship with viral load. RESULTS: We analysed baseline data for 214 individuals with a study visit at a median of 197.5 days after COVID-19 diagnosis. Participants reported ever having a median of 9/16 symptoms (IQR 6-11) after acute COVID-19, with muscle-aches, dyspnoea and headache being the most common. Fatigue, cognitive impairment and dyspnoea were experienced for a longer time. Participants had a lower burden of active symptoms (median 3 (1-6)) than those ever experienced (p<0.001). Unsupervised LCA of symptoms revealed three clinically active PASC subphenotypes: a high burden constitutional symptoms (21.9%), a persistent loss/change of smell and taste (20.6%) and a minimal residual symptoms subphenotype (57.5%). Subphenotype assignments were strongly associated with self-assessments of global health, recovery and PASC impact on employment (p<0.001) as well as referral source for enrolment. Viral persistence (5.6% saliva and 1% stool samples positive) did not explain SRSOs or subphenotypes. CONCLUSIONS: We identified three distinct PASC subphenotypes. We highlight that although most symptoms progressively resolve, specific PASC subpopulations are impacted by either high burden of constitutional symptoms or persistent olfactory/gustatory dysfunction, requiring prospective identification and targeted preventive or therapeutic interventions.

Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial.

AIMS: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target. METHODS AND RESULTS: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL. The primary endpoint of this analysis was percentage change in remnant cholesterol (total cholesterol minus directly measured LDL-C minus HDL-C) and VLDL-C (directly measured) over 24 weeks. Two hundred eighty-six patients were enrolled, with a median age of 64 years and 44% female. Median baseline remnant cholesterol and VLDL-C were 42 and 31 mg/dL, respectively (reference: <30 mg/dL). Vupanorsen lowered remnant cholesterol by 42-59% at 24 weeks over placebo (P < 0.001), achieving a median level of 18 mg/dL at the highest dose. Over the same period, VLDL-C was reduced by 52-67% over placebo (P < 0.001), with a median achieved level of 2.5 mg/dL at the highest dose. The effect of vupanorsen on remnant cholesterol and VLDL-C reduction was dose-dependent and directly associated with the degree of ANGPTL3 inhibition: at 90% ANGPTL3 reduction, there was a 61% and 81% decrease in remnant cholesterol and VLDL-C, respectively. CONCLUSION: Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins.

In this randomized controlled trial of 286 participants with elevated triglycerides, treatment with vupanorsen, an ANGPTL3 inhibitor, lowered remnant cholesterol by up to 59% and VLDL cholesterol by up to 67% over placebo. The effect of the treatment was sustained throughout 24 weeks and consistent across key patient subgroups. ANGPTL3 inhibition may be a promising approach to treat patients with elevated triglycerides.

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3.

BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF). OBJECTIVE: To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes. METHODS: TRANSLATE-TIMI 70 was a randomized, placebo-controlled trial testing 7 dosing regimens of vupanorsen in 286 adults with hyperlipidemia. A total of 227 patients had HFF measured at baseline and 24 weeks and were included in this analysis. RESULTS: The median HFF at baseline was 8.5%. Vupanorsen led to dose-dependent relative increases in HFF of up to 76% at 24 weeks (p < 0.001), corresponding to an absolute increase of up to 7.0% at the highest dose (p < 0.001). Increases in HFF were numerically greater in patients who had elevated baseline HFF, body mass index, triglycerides, or diabetes. Vupanorsen also increased liver enzymes in a dose-dependent manner, and changes in HFF were moderately positively correlated with changes in aspartate transaminase (AST) (rho = 0.49, p < 0.001) and alanine transaminase (ALT) (rho = 0.50, p < 0.001). CONCLUSION: Vupanorsen, an inhibitor of ANGPTL3 protein synthesis, caused dose-dependent increases in HFF. Increases in HFF were only moderately correlated with elevations in AST and ALT, suggesting that liver enzymes are an imperfect indicator to detect increases in hepatic fat. These results highlight the need to monitor HFF in clinical trials of therapies targeting intracellular ANGPTL3 inhibition, especially those that are targeted to the liver.

A multi-purpose Japanese phase I study in the global development of vupanorsen: Randomized, placebo-controlled, single-ascending dose study in adults.

Vupanorsen (PF-07285557) is a second-generation tri-N-acetyl galactosamine (GalNAc3 )-antisense oligonucleotide targeted to angiopoietin-like 3 (ANGPTL3) mRNA, shown to reduce lipids and apolipoproteins in subjects with dyslipidemia. To aid bringing innovative drugs to global patients efficiently, a multi-purpose Japanese phase I study was conducted, with integrated development approaches agreed by the Pharmaceuticals and Medical Devices Agency (PMDA). This randomized, double-blind, placebo-controlled, single-ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of vupanorsen administered subcutaneously to Japanese adults (20-65 years) with elevated triglycerides (TG). Participants were randomized (1:1:1) to vupanorsen (80:160 mg) or placebo (N = 4 each). Vupanorsen 160 mg was a first-in-human (FIH) dose level. Vupanorsen was well-tolerated with no treatment-related adverse events reported for either dose. Absorption into the systemic circulation was rapid with median time to maximum concentration (Tmax ) of 3.5 and 2.0 h, for vupanorsen 80 and 160 mg, respectively. Following maximum concentration (Cmax ), vupanorsen underwent multiphasic decline characterized by a relatively fast initial distribution phase followed by slower terminal elimination phase, with elimination half-life (t1/2 ) of 397 and 499 h (80, 160 mg), respectively. Area under the concentration-time curve (AUC) and Cmax increased in a greater than dose-proportional manner. Pharmacodynamic markers (ANGPTL3, TG, and other key lipids) were reduced with vupanorsen versus placebo. Vupanorsen was safe and well-tolerated in healthy Japanese participants with elevated TG. This study provided FIH data for vupanorsen 160 mg. Moreover, the SAD study in Japanese participants fulfilled PMDA bridging requirements, and with the totality of global vupanorsen data, supported the PMDA waiver for a local phase II dose-finding study. ClinicalTrials.gov: NCT04459767.

Clinical Meaningfulness of Response to Tanezumab in Patients with Chronic Low Back Pain: Analysis From a 56-Week, Randomized, Placebo- and Tramadol-Controlled, Phase 3 Trial.

INTRODUCTION: A recent phase 3, randomized, placebo- and tramadol-controlled trial (56-week treatment/24-week safety follow-up) demonstrated efficacy of tanezumab 10 mg in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics. Here, we report on the clinical meaningfulness of treatment response in this study, focused on secondary measures of pain, interference with daily functions, overall disease status, and satisfaction with treatment. METHODS: Patients received placebo (up to week 16; n = 406), subcutaneously administered (SC) tanezumab 5 mg (every 8 weeks; n = 407), SC tanezumab 10 mg (every 8 weeks; n = 407), or orally administered tramadol prolonged-release (100-300 mg/day; n = 605) for 56 weeks. Patient's global assessment of low back pain (PGA-LBP), Brief Pain Inventory-short form (BPI-sf), Treatment Satisfaction Questionnaire for Medication (TSQM), and modified Patient-Reported Treatment Impact (mPRTI) were assessed at weeks 16 and 56. RESULTS: At week 16, significant (p < 0.05) improvements over placebo were evident with tanezumab for the PGA-LBP (10 mg) and most BPI-sf (both doses), TSQM (both doses), and mPRTI (both doses) items assessed. Improvements over baseline persisted for the PGA-LBP and BPI-sf at week 56. However, the magnitude of improvements was modestly lower at week 56 relative to week 16. Tramadol did not improve PGA-LBP or BPI-sf scores versus placebo at week 16. Most differences between tanezumab and tramadol at week 56 did not reach the level of statistical significance for all endpoints. CONCLUSIONS: The totality of the evidence as captured by measures of pain, interference with daily function, patient overall assessment of disease status, and satisfaction with treatment demonstrates the clinically meaningful benefit of tanezumab for some patients with CLBP compared with placebo. CLINICALTRIALS: gov: NCT02528253.

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

BACKGROUND: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. METHODS: Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3. RESULTS: Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P<0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P<0.001). The effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship' and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P<0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%). CONCLUSIONS: Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04516291.

Tanezumab for chronic low back pain: a randomized, double-blind, placebo- and active-controlled, phase 3 study of efficacy and safety.

ABSTRACT: This randomized, double-blind, phase 3 study (56-week treatment; 24-week follow-up) assessed tanezumab in patients with chronic low back pain and history of inadequate response to standard-of-care analgesics (NCT02528253). Patients received placebo, subcutaneous tanezumab (5 or 10 mg every 8 weeks), or oral tramadol prolonged-release (100-300 mg/day). Primary endpoint was change in low back pain intensity (LBPI) at week 16 for tanezumab vs placebo. Key secondary endpoints were proportion of patients with ≥50% decrease in LBPI at week 16, change in Roland Morris Disability Questionnaire at week 16, and change in LBPI at week 2 for tanezumab vs placebo. Adverse events and joint safety were assessed through weeks 56 and 80, respectively. Tanezumab 10 mg met the primary endpoint by significantly improving LBPI at week 16 vs placebo; least squares (LS) mean (95% CI) difference = -0.40 (-0.76 to -0.04; P = 0.0281). Tanezumab 10 mg significantly improved all key secondary endpoints. Tanezumab 5 mg did not meet the primary endpoint (LS mean [95% CI] treatment difference vs placebo = -0.30 [-0.66 to 0.07; P = 0.1117]), preventing formal testing of key secondary endpoints for this dose. The proportion of patients with ≥50% improvement in LBPI at week 16 was 37.4% in the placebo group, 43.3% in the tanezumab 5 mg group (Odds ratio [95% CI] vs placebo = 1.28 [0.97 to 1.70; P = 0.0846]), and 46.3% in the tanezumab 10 mg group (Odds ratio [95% CI] vs placebo = 1.45 [1.09 to 1.91; P = 0.0101]). Prespecified joint safety events were more frequent with tanezumab 10 mg (2.6%) than tanezumab 5 mg (1.0%), tramadol (0.2%), or placebo (0%). Seven patients, all in the tanezumab 10 mg group (1.4%), underwent total joint replacement. In conclusion, tanezumab 10 mg significantly improved pain and function vs placebo in patients with difficult-to-treat chronic low back pain. Tanezumab was associated with a low rate of joint safety events, some requiring joint replacement.

Abuse Potential Study of ALO-02 (Extended-Release Oxycodone Surrounding Sequestered Naltrexone) Compared with Immediate-Release Oxycodone Administered Orally to Nondependent Recreational Opioid Users.

Objective: To evaluate the abuse potential of ALO-02, an abuse-deterrent formulation comprising pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride. Design: Randomized, double-blind, placebo-/active-controlled, 6-way crossover study, with naloxone challenge, drug discrimination, and treatment phases. Subjects: Nondependent, recreational opioid users. Methods: Oral administration of crushed and intact ALO-02, crushed immediate-release (IR) oxycodone, and placebo. Primary endpoints were Drug Liking and High measured on visual analog scales and reported as maximum effect (E max ) and area-under-the-effect-curve from 0 to 2 hours (AUE 0-2h ). Other pharmacodynamic, pharmacokinetic and safety assessments were included. Results: Drug Liking and High (E max ) for crushed oxycodone IR 40 mg were significantly higher compared with placebo, confirming study validity ( P < 0.0001). Drug Liking and High (E max, AUE 0-2h ) for crushed ALO-02 (40 mg/4.8 mg and 60 mg/7.2 mg) were significantly lower compared to corresponding doses of crushed oxycodone IR (40 and 60 mg; P < 0.0001). Likewise, Drug Liking and High (E max and AUE 0-2h ) for intact ALO-02 60 mg/7.2 mg were significantly lower compared with crushed oxycodone IR 60 mg ( P < 0.0001). Secondary pharmacodynamic endpoints and plasma concentrations of oxycodone and naltrexone were consistent with these results. Fewer participants experienced adverse events (AEs) after ALO-02 (crushed or intact: 71.1-91.9%) compared with crushed oxycodone IR (100%). Most common AEs following crushed ALO-02 and oxycodone IR were euphoric mood, pruritus, somnolence, and dizziness. Conclusions: The results suggest that ALO-02 (crushed or intact) has lower abuse potential than crushed oxycodone IR when administered orally in nondependent, recreational opioid users.

Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

ALO-02 is an abuse-deterrent formulation consisting of capsules filled with pellets of extended-release oxycodone surrounding sequestered naltrexone. This randomized, double-blind, placebo-/active-controlled, 4-way crossover study examined the abuse potential of crushed ALO-02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4-way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO-02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate-release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax ) and effect occurring over 2 hours postdose (AUE0-2 h ). Crushed ALO-02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax , 60.5 vs 92.8; AUE0-2 h , 105.4 vs 160.0, respectively) and High (Emax , 25.2 vs 86.9; AUE0-2 h , 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO-02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO-02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research.

A randomized double-blind, placebo-controlled efficacy and safety study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) for moderate-to-severe chronic low back pain treatment.

The objective of this multicenter, double-blind, placebo-controlled, randomized withdrawal study was to evaluate the efficacy and safety of ALO-02, an abuse-deterrent formulation containing pellets of extended-release oxycodone hydrochloride (HCl) surrounding sequestered naltrexone HCl, compared with placebo in the treatment of moderate-to-severe chronic low back pain. An open-label titration period in which all patients received ALO-02 was followed by a double-blind treatment period where patients meeting treatment response criteria were randomized to either a fixed dose of ALO-02 or placebo. Daily average low back pain was assessed using an 11-point numeric rating scale (NRS)-Pain. Of the 663 patients screened, 410 received ALO-02 during the open-label conversion and titration period and 281 patients were randomized to the double-blind treatment period (n = 134, placebo; n = 147, ALO-02). Change in the mean NRS-Pain score from randomization baseline to the final 2 weeks of the treatment period was significantly different favoring ALO-02 compared with placebo (P = 0.0114). Forty-four percent of patients treated with placebo and 57.5% of patients treated with ALO-02 reported ≥30% improvement in weekly average NRS-Pain scores from screening to the final 2 weeks of the treatment period (P = 0.0248). In the double-blind treatment period, 56.8% of patients in the ALO-02 group and 56.0% of patients in the placebo group experienced a treatment-emergent adverse event (TEAE). The most common treatment-related TEAEs for ALO-02 during the treatment period were nausea, vomiting, and constipation, consistent with opioid therapy. ALO-02 has been demonstrated to provide significant reduction of pain in patients with chronic low back pain and has a safety profile similar to other opioids.

Effects of ethanol on the pharmacokinetics of extended-release oxycodone with sequestered naltrexone (ALO-02).

BACKGROUND AND OBJECTIVES: ALO-02 capsules, intended to deter abuse, contain pellets of extended-release oxycodone hydrochloride (HCl), an opioid agonist, surrounding sequestered naltrexone HCl, an opioid antagonist. The objective of this study was to determine the effects of administration of ALO-02 with 20 or 40 % ethanol on the pharmacokinetics of oxycodone. METHODS: This was an open-label, single-dose, randomized, three-way crossover study in 18 healthy fasting adults administered ALO-02 20/2.4 mg (oxycodone/naltrexone) with water, 20 % ethanol, or 40 % ethanol, each under naltrexone block. RESULTS: Median time to maximum concentration was 12 h postdose when ALO-02 was administered with water or 20 % ethanol and decreased to 8 h postdose with 40 % ethanol. Geometric mean area under the plasma concentration-time curve (AUC) from time zero extrapolated to infinity (AUC∞) and maximum concentration (Cmax) values were similar for ALO-02 administered with water or 20 % ethanol, and increased by about 13 and 37 %, respectively, for ALO-02 administered with 40 % ethanol versus water. The 90 % confidence intervals (CIs) for AUC∞ and Cmax ratios of ALO-02 with 20 % ethanol versus water were within 80-125 %; upper 90 % CIs were >125 % for ALO-02 with 40 % ethanol versus water. The most common adverse events were mild-to-moderate vomiting, nausea, headache, and somnolence. Incidence of adverse events increased for ALO-02 given with ethanol versus water. CONCLUSIONS: Oxycodone exposures (Cmax) were unaffected when ALO-02 was administered with 20 % ethanol but Cmax increased by 37 % with 40 % ethanol versus water. ALO-02 administered with ethanol under naltrexone block was generally well tolerated.

Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain.

OBJECTIVE: Evaluate efficacy and safety of tanezumab, a humanized monoclonal antibody against nerve growth factor, in neuropathic pain. DESIGN: Two randomized controlled trials. SUBJECTS: Patients with pain due to diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN). METHODS: In the DPN study, patients received subcutaneous tanezumab 20 mg or placebo on Day 1 and Week 8. Evaluations included change from baseline in average DPN pain (primary endpoint), Patient's Global Assessment of DPN, and safety (including neuropathy assessments). Due to a partial clinical hold limiting enrollment and treatment duration, the prespecified landmark analysis was modified post hoc from Week 16 to Week 8. In the PHN study, patients received intravenous tanezumab 50 µg/kg, tanezumab 200 µg/kg, or placebo on Day 1. Evaluations included change from baseline in average daily pain (primary endpoint), Brief Pain Inventory-short form, Patient's Global Assessment of pain from PHN, and safety. RESULTS: Mean DPN pain reduction from baseline to Week 8 was greater with tanezumab vs placebo (P = 0.009); differences in Patient's Global Assessment of DPN were not significant (P > 0.05). Neither tanezumab dose resulted in significant differences vs placebo in efficacy in PHN (P > 0.05), although tanezumab 200 µg/kg provided some benefit. Neuropathy assessments showed no meaningful changes. CONCLUSIONS: Tanezumab provided effective pain reduction in DPN. In PHN, only the highest tanezumab dose reduced pain; treatment differences were not significant. No new safety concerns were observed despite preexisting neuropathy.

Effect of food on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended release formulation of oxycodone with sequestered naltrexone.

WHAT IS KNOWN AND OBJECTIVE: ALO-02 is being developed as an abuse-deterrent formulation of extended-release oxycodone hydrochloride with naltrexone hydrochloride sequestered in the core of pellets contained in capsules. The primary objective of this study was to assess the effects of administration of ALO-02 capsule whole under fed conditions or sprinkling the pellets from ALO-02 capsule on applesauce under fasting conditions on the pharmacokinetics (PK) of oxycodone, naltrexone and 6-ß-naltrexol compared with ALO-02 capsule administered whole under fasting conditions. The plasma naltrexone and 6-ß-naltrexol concentrations were used to assess the sequestration of naltrexone in the ALO-02 formulation. The secondary objective was to evaluate the safety and tolerability of single 40 mg doses of ALO-02 in healthy volunteers. METHODS: This was an IRB-approved, open-label, single-dose, randomized, 3-period crossover study in 24 healthy adult volunteers, aged 18-55 years. Each subject was assigned to receive single 40 mg doses of ALO-02 administered whole (intact capsule) under fasting conditions, administered whole under fed conditions (high-fat breakfast ∼ 950 calories), or sprinkling the contents of the ALO-02 capsule (pellets) over applesauce and swallowing the dose without chewing under fasting conditions. Each treatment was separated by a 7-day washout interval. Plasma samples were analyzed just before dosing through 48 hours postdose for oxycodone, and through 120 hours postdose for naltrexone and its major metabolite, 6-ß-naltrexol. Pharmacokinetic parameters included maximum plasma concentration [Cmax ], area under the plasma concentration-time profile from time 0 to infinity [AUCinf ] and to the last quantifiable concentration [AUClast ], time to Cmax [Tmax ], and terminal half life [t1/2 ]. Adverse events, vital signs, and laboratory parameters were monitored for safety assessment. RESULTS: The t1/2 and Tmax values for oxycodone were similar for all 3 treatments. There was a lack of effect of food (whole capsule, fed vs. fasted) or of sprinkling on applesauce (pellets vs. whole capsule, fasted) on oxycodone bioavailability. The Test/Reference ratios of adjusted geometric means for oxycodone AUCinf , AUClast , and Cmax were 99.2%, 100%, and 107%, respectively, for the effect of food; and 101%, 101%, and 97.5%, respectively, for the effect of sprinkling on applesauce. The 90% confidence intervals contained entirely within the bioequivalence limits of 80% to 125% for each comparison. Naltrexone remained sequestered during each treatment, based on the sporadic and low measurable plasma concentrations of naltrexone and 6-ß-naltrexol. Single doses of ALO-02 40 mg were well tolerated, and adverse events were mild, with no apparent difference in frequency for all 3 treatments. WHAT IS NEW AND CONCLUSION: Results indicate that ALO-02 can be administered without regard to food. Also, the contents of ALO-02 can be sprinkled over applesauce and consumed without chewing as an alternative treatment option by subjects with difficulty swallowing. Naltrexone remained sequestered in the ALO-02 formulation under all 3 treatments.

Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain.

A noncontrolled, randomized, multicenter study (NCT00924664) evaluated long-term safety and effectiveness of tanezumab in patients with chronic low back pain following a randomized placebo- and active-controlled parent study that evaluated analgesic efficacy. Patients were randomized to tanezumab 10mg (n=321) or 20mg (n=527) administered at 8-week intervals via 3 intravenous injections followed by 4 subcutaneous injections. Effectiveness analyses included change from parent study baseline in Brief Pain Inventory Short Form, Roland Morris Disability Questionnaire, and Patient's Global Assessment of low back pain. Safety assessments included adverse event documentation, physical/neurological examinations, and laboratory tests. Mean treatment duration during the extension study was 194 and 202 days with tanezumab 10 and 20mg, respectively. Both tanezumab doses provided similar and sustained improvements in all effectiveness outcomes. The most frequently reported adverse events were arthralgia, paresthesia, and hypoesthesia. Adverse events initially described as osteonecrosis were reported in 6 patients (tanezumab 10mg, n=2; tanezumab 20mg, n=4); 9 additional patients (tanezumab 10mg, n=7; tanezumab 20mg, n=2) underwent total joint replacement (TJR). A blinded, independent adjudication committee reviewed all 6 patients with reported osteonecrosis and 4 of the 9 patients undergoing TJR. Adjudication outcomes were osteonecrosis (n=0), worsening osteoarthritis (n=5; 1 rapidly progressive), and another diagnosis or indeterminate (n=5). Tanezumab 10mg had better tolerability than tanezumab 20mg, and may represent an effective long-term treatment for chronic low back pain.

Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain.

Tanezumab is a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for chronic pain. This phase IIB study investigated the efficacy and safety of tanezumab for chronic low back pain vs placebo and naproxen. Patients (N=1347) received intravenous tanezumab (5, 10, or 20mg every 8weeks), naproxen (500mg twice daily), or placebo. The primary efficacy end point was mean change in daily average low back pain intensity (LBPI) from baseline to week 16. Secondary end points included mean change from baseline to week 16 in the Roland Morris Disability Questionnaire and Patient's Global Assessment (PGA) of low back pain. Tanezumab 10 and 20mg had similar efficacy profiles and significantly improved LBPI, Roland Morris Disability Questionnaire, and PGA scores vs both placebo and naproxen (P⩽.05). Tanezumab 5mg provided improvement of PGA scores vs placebo (P⩽.05), and naproxen resulted in significant improvement of LBPI vs placebo (P⩽.05). Adverse event incidence was comparable across tanezumab doses but higher than with placebo or naproxen. Arthralgia, pain in extremity, headache, and paresthesia were the most commonly reported adverse events by tanezumab-treated patients. The most frequently reported adverse events resulting in discontinuation of tanezumab treatment were arthralgia and paresthesia; the highest frequency was observed with tanezumab 20mg (both 1.4%). Serious adverse event incidence was similar across treatments. In conclusion, tanezumab provided significantly greater improvement in pain, function, and global scores vs placebo and naproxen in patients with chronic low back pain.

Efficacy and safety of tanezumab in the treatment of chronic low back pain.

Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti-nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 µg/kg plus oral placebo (n=88), intravenous placebo plus oral naproxen 500 mg twice a day (n=88), or intravenous placebo plus oral placebo (n=41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ≥30% or ≥50% reduction in aLBPI, Roland-Morris Disability Questionnaire and Brief Pain Inventory-short form scores, Patients' Global Assessment of LBP, Patients' Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P=0.004) and placebo (P<0.001). Greater proportions of patients reported ≥30% and ≥50% reduction in aLBPI with tanezumab vs naproxen (P≤0.013) and placebo (P<0.001), and greater improvements in Roland-Morris Disability Questionnaire (P<0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab-treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients.

Bioavailability of amlodipine besylate/atorvastatin calcium combination tablet.

The bioequivalence of combination tablets containing amlodipine besylate/atorvastatin calcium with coadministered matching doses of amlodipine besylate and atorvastatin calcium tablets was investigated in randomized, 2-way crossover studies in healthy volunteers (N = 126). Subjects received a single dose of the amlodipine/atorvastatin tablet or coadministered matching doses of amlodipine and atorvastatin at the highest (10/80 mg; n = 62) and lowest (5/10 mg; n = 64) dose strengths. Atorvastatin geometric mean ratios for maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) for the highest and lowest dose strengths were 94.1 and 98.8, and 104.5 and 103.8, respectively. Amlodipine geometric mean ratios for C(max) and AUC for the highest and lowest dose strengths were 100.8 and 103.4, and 100 and 102.7, respectively. The 90% confidence intervals for all comparisons were within 80% to 125%, demonstrating bioequivalence for amlodipine and atorvastatin at both dose strengths. Use of amlodipine/atorvastatin combination tablets may provide a more integrated approach to treatment of cardiovascular risk.