Comparative efficacy of lemborexant and other insomnia treatments: a network meta-analysis.

BACKGROUND: Insomnia is a common disorder associated with a substantial burden of illness, particularly in older adults. OBJECTIVE: To compare the efficacy and safety of lemborexant with specified other insomnia treatments through a systematic literature review and network meta-analysis (NMA). METHODS: Medline and Embase were systematically searched from inception to February 2019 and updated with a targeted search of PubMed for pivotal trials in March 2021. Randomized controlled trials in adults with primary insomnia were included if they reported results following at least 1 week of treatment. Interventions of interest were specified as lemborexant, suvorexant, benzodiazepines, benzodiazepine receptor agonists (also called Z-drugs [zolpidem, eszopiclone, zaleplon, zopiclone]), trazodone, and ramelteon. Efficacy outcomes included wake after sleep onset (WASO), sleep efficiency (SE), latency to persistent sleep (LPS)/sleep onset latency (SOL), total sleep time (TST) and Insomnia Severity Index (ISI). Bayesian NMA were performed at predetermined time intervals approximating 4 weeks, 3 months, and 6 months. Safety outcomes included serious adverse events (SAEs), withdrawals due to adverse events (AEs), and specified AEs (dizziness, somnolence, and falls). Subgroup analysis was conducted in the older population. RESULTS: 45 studies were included in the NMA. At 4 weeks, lemborexant had the highest probability of being the best treatment for 3 of the 4 outcomes measured objectively by polysomnography-TST, LPS, and SE-and was ranked second to suvorexant on WASO. Eszopiclone was highly ranked for subjectively measured SOL and ISI at 4 weeks, 3 months, and 6 months. Lemborexant was rated more highly than suvorexant in subjective measures of WASO, TST, and SOL at 4 weeks (the differences were not statistically significant). No statistically significant interactions between treatment effect and older subpopulations were found, indicating that the treatment effect was similar in older and adult populations. The safety profile of lemborexant was broadly similar to the other treatments for SAEs and withdrawals due to AEs. A limitation is the age of some of the included studies (3 were published in 1990 or earlier). A further limitation is the lack of stratification of recommended doses. If the doses used in the study publications do not reflect doses used in clinical practice, this could potentially bias the results. CONCLUSIONS: Lemborexant was ranked highest of the treatments studied on 3 out of the 4 objectively measured insomnia efficacy outcomes, with a safety profile broadly similar to other insomnia treatments. DISCLOSURES: This work was funded by Eisai Inc., which was involved with all stages of the study and analysis. McElroy, O'Leary, and Adena are consultants with Datalytics Pty Ltd., which was paid by Eisai Inc. for conducting the literature review and analysis. They were not financially compensated for collaborative efforts on publication-related activities. Campbell, Tahami Monfared, and Meier are employed by Eisai Inc. This study was presented as a poster at AMCP Nexus Virtual, October 20-23, 2020 and at the AGS Virtual Annual Scientific Meeting 2021, May 13-15, 2021.

Comparison of the effect of lemborexant and other insomnia treatments on driving performance: a systematic review and meta-analysis.

Study Objectives: This systematic literature review and meta-analysis explored the impact of lemborexant and other insomnia treatments on next-day driving performance. Methods: Searches were conducted in MEDLINE and Embase on May 16, 2019, supplemented by clinical trial registries. Randomized controlled trials in healthy volunteers or people with insomnia were included if they reported a standardized on-road driving test, were published in English and included ≥1 group receiving a recommended dose of flunitrazepam, estazolam, triazolam, temazepam, brotizolam, etizolam, alprazolam, lorazepam, zolpidem, eszopiclone, zaleplon, zopiclone, trazodone, ramelteon, lemborexant, or suvorexant. Pairwise random-effects meta-analyses used the difference between each active treatment and placebo in standard deviation of lateral position (ΔSDLP). ΔSDLP of +2.4 cm, established as equivalent to a blood alcohol concentration of 0.05%, was considered clinically significant. Results: Fourteen studies were included. Clinically significant differences in ΔSDLP were shown in healthy volunteers for zopiclone (10/10 studies) and ramelteon (1/1 study), and in people with insomnia for flunitrazepam (2/3 studies). Premature test termination was reported most frequently for zopiclone (5/10 studies) and was reported in two subjects for suvorexant (1/2 studies), one for flunitrazepam (1/3 studies), and one for placebo (1/12 studies). Lemborexant had no statistically or clinically significant ΔSDLP, and no premature driving test terminations. Conclusions: Zopiclone, flunitrazepam, and ramelteon were associated with impaired driving performance, similar to driving under the influence of alcohol. Premature test termination was reported most frequently for zopiclone, and also for suvorexant, flunitrazepam and placebo. Lemborexant had no statistically or clinically significant effect on driving performance.

The Mobility Volunteer Program: Stepping into the Future of Senior-Friendly Care.

Low mobility during hospitalization is an under-recognized epidemic leading to adverse outcomes (Brown et al. 2009). The goal of the Mobility Volunteer Program (MVP) is to keep older people as active as possible while in hospital to prevent delirium and loss of strength. Maintaining or improving function from admission to discharge increases the likelihood of patients being able to return home sooner and to their prior level of functioning. The MVP is a valuable component of a multi-pronged corporate strategy to improve rates of mobilization at Sunnybrook Health Sciences Centre. We will describe the MVP and share stakeholder feedback and lessons learned.

Translational Pharmacokinetic/Pharmacodynamic Characterization and Target-Mediated Drug Disposition Modeling of an Anti-Tissue Factor Pathway Inhibitor Antibody, PF-06741086.

Tissue factor pathway inhibitor (TFPI) exhibits multiple isoforms, which are known to present in multiple locations such as plasma, endothelium, and platelets. TFPI is an endogenous negative modulator of the coagulation pathway, and therefore, neutralization of TFPI function can potentially increase coagulation activity. A human monoclonal antibody, PF-06741086, which interacts with all isoforms of TFPI is currently being tested in clinic for treating hemophilia patients with and without inhibitors. To support clinical development of PF-06741086, pharmacokinetics (PK) and pharmacodynamics of PF-06741086 were characterized in monkeys. In addition, a mechanistic model approach was used to estimate PK parameters in monkeys and simulate PK profiles in human. The results show that PF-06741086 exhibited target-mediated drug disposition and had specific effects on various hemostatic markers including diluted prothrombin time, thrombin generation, and thrombin-antithrombin complex in monkeys after administration. The model-predicted and observed human exposures were compared retrospectively, and the result indicates that the exposure prediction was reasonable within less than 2-fold deviation. This study demonstrated in vivo efficacy of PF-06741086 in monkeys and the utility of a rational mechanistic approach to describe PK for a monoclonal antibody with complex target binding.

Preclinical Pharmacokinetics, Pharmacodynamics, Tissue Distribution, and Interspecies Scaling of Recombinant Human Coagulation Factor XaI16L.

FXaI16L is a recombinant human FXa variant which is currently being evaluated in the clinic for treating intracerebral hemorrhage. The aim of our studies is to investigate overall pharmacokinetics, pharmacodynamics, and distribution of FXaI16L in preclinical species, and to understand its potential implication in human. Pharmacokinetics of FXaI16L was examined using active site probes and the results showed that FXaI16L displayed fast clearance, low volume of distribution, and a very short plasma resident time in mice, rats, and monkeys. When pharmacodynamics was examined in monkeys, concentration effects of FXaI16L on shortening of active partial prothrombin time and formation of thrombin-antithrombin complex were observed. Furthermore, biodistribution study was conducted in mice using radiolabeled FXaI16L, and showed that 125I-FXaI16L has high plasma protein binding and significant liver and kidney distribution. Human pharmacokinetic prediction for first-in-human dosing was evaluated using allometric scaling, liver blood flow, and a fixed coefficient method, and single species allometric scaling using monkey data was most predictive for human pharmacokinetics of FXaI16L.

The impact of multiple sclerosis severity on health state utility values: Evidence from Australia.

BACKGROUND: The measurement of health state utility values (HSUVs) for a representative sample of Australian people with multiple sclerosis (MS) has not previously been performed. OBJECTIVES: Our main aim was to quantify the HSUVs for different levels of disease severities in Australian people with MS. METHOD: HSUVs were calculated by employing a 'judgement-based' method that essentially creates EQ-5D-3L profiles based on WHOQOL-100 responses and then applying utility weights to each level in each dimension. A stepwise linear regression was used to evaluate the relationship between HSUVs and disease severity, classified as mild (Expanded Disability Status Scale (EDSS) levels: 0-3.5), moderate (EDSS levels: 4-6) and severe (EDSS levels: 6.5-9.5). RESULTS: Mean HSUV for all people with MS was 0.53 (95% confidence interval (CI): 0.52-0.54). Utility decreased with increasing disease severity: 0.61 (95% CI: 0.60-0.62), 0.51 (95% CI: 0.50-0.52) and 0.40 (95% CI: 0.38-0.43) for mild, moderate and severe disease, respectively. Adjusted differences in mean HSUV between the three severity groups were statistically significant. CONCLUSION: For the first time in Australia, we have quantified the impact of increasing severity of MS on health utility of people with MS. The HSUVs we have generated will be useful in further health economic analyses of interventions that slow progression of MS.

Once-daily liraglutide (1.2 mg) compared with twice-daily exenatide (10 µg) in the treatment of type 2 diabetes patients: An indirect treatment comparison meta-analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists provide effective hyperglycemia management in patients with type 2 diabetes. In a randomized head-to-head trial, liraglutide 1.8 mg q.d. led to greater reductions in HbA1c than exenatide 10 µg b.i.d. There are no direct comparisons of liraglutide 1.2 mg q.d. and exenatide b.i.d.; therefore, in the present study, an indirect comparison and meta-analysis were undertaken. METHODS: A systematic literature search was performed for randomized controlled trials of liraglutide 1.2 mg q.d. or exenatide b.i.d. with HbA1c as an outcome and ≥25 subjects. Key data were extracted and analyzed. A random-effects model was used to incorporate heterogeneity between studies. RESULTS: Three liraglutide 1.2 mg q.d. (n = 1060) and 10 exenatide b.i.d. (n = 2609) placebo-controlled studies were identified, allowing indirect comparison with placebo as the common arm. Baseline characteristics were mean age ~55 years, disease duration ~7 years, HbA1c ~8%, and body mass index ~32 kg/m2 . Compared with exenatide b.i.d., liraglutide 1.2 mg was associated with significantly greater reductions from baseline in HbA1c (-0.29%; 95% confidence interval [CI] -0.53, -0.05) and fasting plasma glucose (-0.92 mmol/L; 95% CI -1.43, -0.41), with shorter duration of nausea (3 vs 14 days; P = 0.002) and fewer withdrawals (odds ratio 0.34; 95% CI 0.22, 0.52). The incidence of adverse events (including nausea) and withdrawals because of adverse events were similar between treatments. CONCLUSIONS: Liraglutide 1.2 mg provided a significantly greater reduction in HbA1c than exenatide 10 µg b.i.d. The significantly shorter duration of nausea with liraglutide than exenatide may be appreciated by patients.

Bioanalytical platform comparison using a generic human IgG PK assay format.

A comparison of four different ligand-binding assay technology platforms (ELISA, Meso Scale Discovery®, Gyros® and AlphaLISA®) was conducted using quantitative assays for the measurement of a human IgG1 monoclonal antibody (MAb) in rat serum. The assays used common reagents for Fc-specific measurement to determine total levels of a human IgG MAb drug analyte, and all were fully optimized for use on each platform. Mock MAb study samples were prepared and analyzed using all platforms to assess assay performance. Assay parameters such as sensitivity, dynamic range, minimum required dilution and sample volume as well as other considerations such as per-run cost, technology availability, requisite equipment and necessary reagent modifications were evaluated toward the determination of a default go-to assay platform for monoclonal antibody biotherapeutics in this laboratory. Based primarily on superior assay performance, Meso Scale Discovery and Gyros were selected from the four technologies evaluated as our default platforms for non-regulated (discovery) study support. As an adjunct, immunoaffinity LC-MS/MS was explored as an alternate platform for generic Fc quantitation and was found to perform similarly to the ligand-binding assays.

The economic impact of multiple sclerosis in Australia in 2010.

BACKGROUND: Multiple sclerosis (MS) has a major impact on health and is a substantial burden on patients and society. We estimated the annual costs of MS in Australia from individual and societal perspectives using data from the Australian MS Longitudinal Study (AMSLS) and prevalence figures from 2010. METHODS: Direct and indirect costs were estimated from a subsample of 712 AMSLS subjects who completed baseline and follow-up economic impact surveys. All costs are in 2010 Australian dollars (AUD). RESULTS: Annual costs per person with MS were AUD48,945 (95% CI: 45,138 to 52,752). Total costs were AUD1.042 (0.9707 to 1.1227) billion based on a prevalence of 21,283. The largest component was indirect costs due to loss of productivity (48%). Costs increased with increasing disability: AUD36,369, AUD58,890 and AUD65,305 per patient per year for mild, moderate and severe disability, respectively. Total costs of MS to Australian society have increased 58% between 2005 and 2010. CONCLUSIONS: This study confirms that MS imposes a substantial burden on Australian society, particularly impacting on productivity. The burden increases with worsening disability associated with the disease. Investment in interventions that slow progression, as well as resources, services and environments that assist people with MS to retain employment, is supported.

A novel method for calculating prevalence of multiple sclerosis in Australia.

OBJECTIVES: The purpose of this study was to determine the prevalence of multiple sclerosis (MS) in Australia in 2010 using a novel method based on Australia-wide prescription data for MS-specific disease modifying agents. The results obtained were validated against two other prevalence estimates. METHODS: We obtained the total number of scripts for medications that were used exclusively for the treatment of MS written in Australia for the period January-December 2010. The percentage of MS patients using medications (42-55%) was taken from state-specific surveys of MS Society clients. To estimate prevalence we divided the annual number of scripts dispensed by 12 and adjusted for penetration of medications by state. RESULTS: The prevalence of MS in Australia in 2010 calculated using the prescription method was 21,283 people (95.5/100,000). This compared to 21,200 people (95.2/100,000) obtained from the Australian Bureau of Statistics (ABS) Survey of Disability, Ageing and Carers (SDAC) survey of 2009 and 20,471 people (91.9/100,000) using MS Society client numbers. Prevalence increased with increasing latitude, with the prevalence for Tasmania over seven times that of the Northern Territory. Results were sensitive to the percentage of people with MS being treated. CONCLUSIONS: Calculation of prevalence of MS using nation-wide prescription data is a novel method that generates results similar to other potentially more resource-intensive methods.

Pharmacokinetic, biodistribution, and biophysical profiles of TNF nanobodies conjugated to linear or branched poly(ethylene glycol).

Covalent attachment of poly(ethylene glycol) (PEG) to therapeutic proteins has been used to prolong in vivo exposure of therapeutic proteins. We have examined pharmacokinetic, biodistribution, and biophysical profiles of three different tumor necrosis factor alpha (TNF) Nanobody-40 kDa PEG conjugates: linear 1 × 40 KDa, branched 2 × 20 kDa, and 4 × 10 kDa conjugates. In accord with earlier reports, the superior PK profile was observed for the branched versus linear PEG conjugates, while all three conjugates had similar potency in a cell-based assay. Our results also indicate that (i) a superior PK profile of branched versus linear PEGs is likely to hold across species, (ii) for a given PEG size, the extent of PEG branching affects the PK profile, and (iii) tissue penetration may differ between linear and branched PEG conjugates in a tissue-specific manner. Biophysical analysis (R(g)/R(h) ratio) demonstrated that among the three protein-PEG conjugates the linear PEG conjugate had the most extended time-average conformation and the most exposed surface charges. We hypothesized that these biophysical characteristics of the linear PEG conjugate accounts for relatively less optimal masking of sites involved in elimination of the PEGylated Nanobodies (e.g., intracellular uptake and proteolysis), leading to lower in vivo exposure compared to the branched PEG conjugates. However, additional studies are needed to test this hypothesis.

Cost-effectiveness of colorectal cancer screening: comparison of community-based flexible sigmoidoscopy with fecal occult blood testing and colonoscopy.

BACKGROUND AND AIMS: To determine the cost-effectiveness of screening for colorectal cancer using flexible sigmoidoscopy once every 10 years, compared with annual and biennial rehydrated Hemoccult fecal occult blood testing and colonoscopy once every 10 years, or no screening. METHODS: A Markov model was developed in order to simulate the progression of a cohort of asymptomatic, average-risk individuals aged 55-64 years who were moving through a defined series of states towards death. The main outcome measures were: cases of colorectal cancer averted, colorectal cancer deaths averted, and cost per life-year saved. RESULTS: Colonoscopy averted the greatest number of cases of colorectal cancer (35%), followed by flexible sigmoidoscopy (25%), and annual (24%) and biennial (14%) fecal occult blood testing. Colonoscopy averted the greatest number of deaths from colorectal cancer (31%), followed by annual fecal occult blood testing (29%), flexible sigmoidoscopy (21%) and biennial fecal occult blood testing (19%). Flexible sigmoidoscopy was the most efficient in terms of cost per life-year saved (16,801 Australian dollars), followed by colonoscopy (19,285 Australian dollars), biennial (41,183 Australian dollars), and annual (46,900 Australian dollars) fecal occult blood testing. CONCLUSIONS: Flexible sigmoidoscopy and colonoscopy are cost-effective strategies for reducing the disease burden of colorectal cancer.