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Introduction: Zuranolone (ZRN) is a positive allosteric modulator of both synaptic and extrasynaptic gamma-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the US and under investigation for adults with major depressive disorder (MDD). The randomised, double-blind, placebo-controlled, Phase 3 CORAL Study assessed the efficacy and safety of ZRN 50 mg vs placebo, each co-initiated with an open-label standard-of-care antidepressant (ADT). Patients who completed CORAL could roll over into open-label SHORELINE, which assessed the safety and tolerability of ZRN 50 mg and need for repeat treatment courses in adults with MDD. Objectives: To assess the safety and tolerability (primary endpoint) and need for repeat ZRN 50 mg treatment courses (secondary endpoint) in adults with MDD who previously enrolled in CORAL. Methods: CORAL enrolled adults (18–64 years) with MDD and 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥24. After completing the 6-week CORAL Study, patients who enrolled in SHORELINE could enter a 46-week observation period to assess the safety and need for 14-day repeat ZRN treatment course(s), with a total of ≤4 repeat treatment courses permitted. Patients were screened every 2 weeks with the 9-item Patient Health Questionnaire, and scores ≥10 prompted a HAMD-17 assessment within 1 week. Patients with HAMD-17 total score ≥20 were eligible for repeat ZRN course(s) ≥8 weeks after completing the prior ZRN treatment course. Results: Among the 190 patients from CORAL who rolled over into SHORELINE and received ≥1 ZRN treatment course in either study, 133 (70.0%) had received ZRN+ADT and 57 (30.0%) received placebo+ADT in CORAL. Overall, 118 rollover patients received ≥1 open-label ZRN treatment course in SHORELINE. For patients who received ≥1 ZRN treatment course in either study, 76.8% received 1 (54.2%; 103/190) or 2 (22.6%; 43/190) total ZRN treatment courses across both studies in up to 1 year in study. The most common (>5%) treatment-emergent adverse events (TEAEs) during treatment and 14 days following the last ZRN dose were somnolence (16.1% of patients), dizziness (8.5%), headache (8.5%), fatigue (7.6%), sedation (5.9%), and nausea (5.1%); study-period TEAEs (73.7%; 87/118) for the majority of patients were mild/moderate (69.5%; 82/118) in severity and occurred primarily during the treatment period (58.5%; 69/118). No signals for increased suicidal ideation/behaviour were observed. Conclusions: Safety and tolerability among rollover patients were consistent with previous studies; most of the TEAEs reported by adults with MDD who received ZRN were mild/moderate in severity. Most patients who rolled over from CORAL to SHORELINE received ≤2 total treatment courses in up to 1 year in study. Disclosure of Interest: G. Mattingly Grant / Research support from: Akili, Alkermes, Allergan (now AbbVie), Axsome, Boehringer, Janssen, Lundbeck, Medgenics, NLS-1 Pharma AG, Otsuka, Reckitt Benckiser, Roche, Sage, Sunovion, Supernus, Takeda, and Teva, Consultant of: Akili, Alkermes, Allergan (now AbbVie), Axsome, Ironshore, Intra-Cellular Therapies, Janssen, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Rhodes, Sage, Sunovion, Takeda, and Teva, Speakers bureau of: Alkermes, Allergan (now AbbVie), Ironshore, Janssen, Lundbeck, Otsuka, Sunovion, and Takeda, S. Mathew Grant / Research support from: Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, Inc., and VistaGen Therapeutics, Consultant of: Allergan (now AbbVie), Alkermes, Almatica Pharma, Axsome Therapeutics, BioXcel Therapeutics, Boehringer-Ingelheim, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Inc., Seelos Therapeutics, Signant Health, and Sunovion, S. Parikh Grant / Research support from: Aifred, Assurex, Janssen, Mensante, Sage Therapeutics, Inc., and Takeda, S. Aaronson Grant / Research support from: COMPASS Pathways and Neuronetics; has served as a consultant to Genomind, Inc., Janssen, LivaNova PLC, Neuronetics; and Sage Therapeutics, Inc., Speakers bureau of: Janssen and Sunovion Pharmaceuticals, Inc., B. Baune Speakers bureau of: Angelini, AstraZeneca, Biogen, Bristol Myers Squibb, Janssen, LivaNova, Lundbeck, Novartis, Otsuka, Pfizer, Servier, Sumitomo Pharma, Wyeth, and Boehringer-Ingelheim, A. Czysz Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., I. Nandy Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., V. Ona Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., C. Brown Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., S. Kyaga Employee of: Biogen Inc., F. Forrestal Employee of: Biogen Inc., S. Levin Employee of: Biogen Inc., J. Doherty Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., G. Mattingly: None Declared [ABSTRACT FROM AUTHOR]

Background Early intervention with an effective disease-modifying drug (DMD) offers the best chance of limiting the inflammatory process that contributes to irreversible axonal damage correlating with disability in multiple sclerosis (MS). It is equally important to ascertain fairly quickly whether patients are responding positively to the choice of therapy to allow time for either a treatment modification or a switch in treatment, a process we termed "treatment optimization". Various treatment optimization recommendations (TOR) have been proposed to help decide when a patient taking an MS DMD might be showing a sub-optimal response. We have applied the clinical scheme proposed by the Canadian TOR to the patients involved in the Prevention of Relapses and disability by Interferon Subcutaneously in MS 4-year (PRISMS-4) study, who received interferon 3-1 a treatment for 4 years, with the TOR applied retrospectively at year 1. Objective The aim of this investigation was to examine whether these TOR were able to predict which patients would go on to develop disease breakthrough (defined as any relapses or disease progression), indicative of a sub-optimal response over the ensuing 3 years of study and therefore might have benefited from a change in treatment. Results We found 39% of patients receiving therapy experienced either a medium or high level of concern of breakthrough after a year of treatment, and 89% of these patients went on to develop further breakthrough over years 2-4. Although 67% of the 61% of patients having no or low-level concern after a year of treatment also experienced further disease breakthrough, it was significantly less than the medium or high group. Conclusion This study shows that the Canadian TOR may be an important tool for early treatment optimization. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a mental health disorder that can cause disability and functional impairment that standard-of-care (SOC) antidepressant therapies (ADTs) can take weeks to treat. Zuranolone is a neuroactive steroid and positive allosteric modulator of synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors approved as an oral, once-daily, 14-day treatment course in adults with postpartum depression and under investigation in adults with MDD. The phase 3 CORAL Study (NCT04476030) evaluated the efficacy and safety of zuranolone 50 mg co-initiated with SOC ADT (zuranolone+ADT) vs placebo co-initiated with SOC ADT (placebo+ADT) in adults with MDD. Patients were randomized 1:1 to once-daily, blinded zuranolone+ADT or placebo+ADT for 14 days, then continued open-label SOC ADT for 28 more days. The primary endpoint was change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day 3. Among 425 patients in the full analysis set, CFB in HAMD-17 total score at Day 3 was significantly improved with zuranolone+ADT vs placebo+ADT (least squares mean [standard error], -8.9 [0.39] vs -7.0 [0.38]; p = 0.0004). The majority of patients receiving zuranolone+ADT that experienced treatment-emergent adverse events (TEAEs) reported mild or moderate events. The most common TEAEs present in ≥10% of patients in either zuranolone+ADT or placebo+ADT groups were somnolence, dizziness, headache, and nausea. These results demonstrate that zuranolone+ADT provided more rapid improvement in depressive symptoms compared with placebo+ADT in patients with MDD, with a safety profile consistent with previous studies. Clinical trial registration: ClinicalTrials.gov identifier: NCT04476030., (© 2023. The Author(s).)

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once-daily, 14-day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open-label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the long-term safety and efficacy of zuranolone in adults with MDD are reported., Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 20 received an initial 30-mg or 50-mg 14-day zuranolone course. HAMD-17 responders (≥ 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for ≤ 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s)., Results: As of September 2021, among patients in the 30-mg (n = 725) and 50-mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment-emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30-mg Cohort, 90.9% [448/493]; 50-mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30-mg and 50-mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received ≤ 2 total treatment courses (30-mg Cohort, 68.5% [335/489]; 50-mg Cohort, 79.5% [116/146])., Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses., Trial Registration: ClinicalTrials.gov identifier: NCT03864614., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Objective: This study assessed the efficacy and safety of a 14-day treatment course of once-daily zuranolone 50 mg, an investigational oral positive allosteric modulator of the γ-aminobutyric acid type A (GABA A ) receptor, for the treatment of major depressive disorder., Methods: Patients 18-64 years of age with severe major depressive disorder were enrolled in this randomized, double-blind, placebo-controlled trial. Patients self-administered zuranolone 50 mg or placebo once daily for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15. Safety and tolerability were assessed by incidence of adverse events., Results: Of 543 randomized patients, 534 (266 in the zuranolone group, 268 in the placebo group) constituted the full analysis set. Compared with patients in the placebo group, patients in the zuranolone group demonstrated a statistically significant improvement in depressive symptoms at day 15 (least squares mean change from baseline HAM-D score, -14.1 vs. -12.3). Numerically greater improvements in depressive symptoms for zuranolone versus placebo were observed by day 3 (least squares mean change from baseline HAM-D score, -9.8 vs. -6.8), which were sustained at all visits throughout the treatment and follow-up periods of the study (through day 42, with the difference remaining nominally significant through day 12). Two patients in each group experienced a serious adverse event; nine patients in the zuranolone group and four in the placebo group discontinued treatment due to adverse events., Conclusions: Zuranolone at 50 mg/day elicited a significantly greater improvement in depressive symptoms at day 15, with a rapid time to effect (day 3). Zuranolone was generally well tolerated, with no new safety findings compared with previously studied lower dosages. These findings support the potential of zuranolone in treating adults with major depressive disorder., Competing Interests: Dr. Clayton has received grant support from Daré Bioscience, Janssen, Otsuka, Praxis Precision Medicines, Relmada Therapeutics, and Sage Therapeutics; she has received advisory board or consulting fees from AbbVie, Brii Biosciences, Fabre-Kramer, Janssen Research and Development, MindCure Health, Mycomedica Life Sciences, Ovoca Bio, Praxis Precision Medicines, PureTech Health, Reunion Neuroscience (formerly Field Trip Health), S1 Biopharma, Sage Therapeutics, Takeda/Lundbeck, Vella Bioscience, and WCG MedAvante-ProPhase; she has received royalties from Ballantine Books/Random House, the Changes in Sexual Functioning Questionnaire, and Guilford Publications; and she holds shares/restricted stocks in Euthymics, Mediflix, and S1 Biopharma. Dr. Parikh has served as a consultant for Aifred, Assurex, Boehringer Ingelheim, Janssen, Mensante, NeonMind, Sage Therapeutics, and Takeda; he has received speaking honoraria from CANMAT and Otsuka and CME honoraria from Otsuka; he has received research grants from Assurex, the Canadian Institutes for Health Research, the Ethel and James Flinn Foundation, Janssen, Merck, the Ontario Brain Institute, Sage Therapeutics, and Takeda; and he holds shares in Mensante and NeonMind. Dr. Iosifescu has served as a consultant for Alkermes, Allergan, Angelini, Axsome, Biogen, Boehringer Ingelheim, the Centers for Psychiatric Excellence, Clexio, Jazz, Lundbeck, Neumora, Otsuka, Precision Neuroscience, Relmada, Sage Therapeutics, and Sunovion, and he has received grant support (paid to his institutions) from Alkermes, AstraZeneca, BrainsWay, LiteCure, NeoSync, Otsuka, Roche, and Shire. Ms. Forrestal and Dr. Kotecha are employees of Biogen and may hold stock. Drs. Lasser, Doherty, Jonas, and Jung are employees of Sage Therapeutics and may hold stock and/or stock options. Dr. Jonas serves as a board member for Sage Therapeutics. Dr. Kanes is currently an employee of Ancora Bio and was an employee of Sage Therapeutics at the time this trial was conducted and is a shareholder of Sage Therapeutics.

Objective: Postpartum depression (PPD) is a common perinatal complication with adverse maternal and infant outcomes. This study investigated the efficacy and safety of zuranolone, a positive allosteric modulator of synaptic and extrasynaptic GABA A receptors and neuroactive steroid, as an oral, once-daily, 14-day treatment course for patients with severe PPD., Methods: In this double-blind phase 3 trial, women with severe PPD were randomized in a 1:1 ratio to receive zuranolone 50 mg/day or placebo for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15; key secondary endpoints were change from baseline in HAM-D score at days 3, 28, and 45 and change from baseline in Clinical Global Impressions severity (CGI-S) score at day 15. Adverse events were monitored., Results: Among 196 patients randomized (zuranolone, N=98; placebo, N=98), 170 (86.7%) completed the 45-day study. Treatment with zuranolone compared with placebo resulted in statistically significant improvement in depressive symptoms at day 15 (least squares mean [LSM] change from baseline in HAM-D score, -15.6 vs. -11.6; LSM difference, -4.0, 95% CI=-6.3, -1.7); significant improvement in depressive symptoms was also reported at days 3, 28, and 45. CGI-S score at day 15 significantly improved with zuranolone compared with placebo. The most common adverse events (≥10%) with zuranolone were somnolence, dizziness, and sedation. No loss of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior were observed., Conclusions: In this trial, zuranolone demonstrated significant improvements in depressive symptoms and was generally well tolerated, supporting the potential of zuranolone as a novel, rapid-acting oral treatment for PPD., Competing Interests: Dr. Deligiannidis has served as a consultant for Brii Biosciences, Gerbera Therapeutics, GH Research, Neuroscience Software, Reunion Neuroscience, and Sage Therapeutics; she has received grants from Sage Therapeutics, awarded to Zucker Hillside Hospital/Feinstein Institutes for Medical Research (related to clinical trials of brexanolone and zuranolone), and grants from NIH and Vorso Corporation; and she has received royalties from an NIH employee invention. Dr. Meltzer-Brody has received grant funding from Janssen, awarded to the University of North Carolina Chapel Hill, grants from NIH and the Patient-Centered Outcomes Research Institute, and grants and other research funding from Sage Therapeutics, awarded to the University of North Carolina at Chapel Hill; and she has received personal fees from WebMD/Medscape. Dr. Maximos has received grants from Sage Therapeutics related to the zuranolone clinical trial; he has served as a consultant for Evofem Biosciences; and he may hold stock in Sage Therapeutics. Dr. Peeper holds stock in Sage Therapeutics. Dr. Freeman conducts research with the Massachusetts General Hospital (MGH) National Pregnancy Registry and, as an employee of MGH, works with the MGH Clinical Trials Network and Institute, which received research funding from multiple pharmaceutical companies and NIMH; current sponsors of the MGH National Pregnancy Registry include Alkermes, Eisai, Johnson & Johnson/Janssen Pharmaceuticals, Otsuka America Pharmaceutical, Sage Therapeutics, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, and Teva Pharmaceutical Industries; she is a research investigator for Sage Therapeutics; she serves on advisory boards for independent data safety and monitoring committees for Beckley Psytech, Brainify, Eliem, Everly Health, Janssen (Johnson & Johnson), Neurocrine, Novartis, Relmada, Sage Therapeutics, and Tibi Health; she has participated in Everly Health Educational activities (speaking, planning): WebMD, Medscape, Pri-Med, and Postpartum Support International; and she has received royalties from the MGH Scale and the Massachusetts General Hospital Female Reproductive Lifecycle and Hormones Questionnaire. Dr. Lasser, Dr. Bullock, Ms. Li, and Dr. Doherty are employees of Sage Therapeutics, and may hold stock and/or stock options. Dr. Rana and Dr. Garcia were employees of Sage Therapeutics at the time of the study and development of the manuscript, and may hold stock and/or stock options. Dr. Kotecha, Ms. Forrestal, and Dr. Leclair are employees of Biogen, and may hold stock.

Importance: The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment with aducanumab, an amyloid-β (Aβ)-targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia., Objective: To describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE., Design, Setting, and Participants: Secondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment with placebo among participants at 348 sites across 20 countries. Enrollment occurred from August 2015 to July 2018, and the trials were terminated early (March 21, 2019) based on a futility analysis. The combined studies consisted of a total of 3285 participants with Alzheimer disease who received 1 or more doses of placebo (n = 1087) or aducanumab (n = 2198; 2752 total person-years of exposure) during the placebo-controlled period. Primary data analyses were performed from November 2019 to July 2020, with additional analyses performed through July 2021., Interventions: Participants were randomly assigned 1:1:1 to high-dose or low-dose intravenous aducanumab or placebo once every 4 weeks. Dose titration was used as a risk-minimization strategy., Main Outcomes and Measures: Brain magnetic resonance imaging was used to monitor patients for ARIA; associated symptoms were reported as adverse events., Results: Of 3285 included participants, the mean (SD) age was 70.4 (7.45) years; 1706 participants (52%) were female, 2661 (81%) had mild cognitive impairment due to Alzheimer disease, and 1777 (54%) used symptomatic medications for Alzheimer disease. A total of 764 participants from EMERGE and 709 participants from ENGAGE were categorized as withdrawn before study completion, most often owing to early termination of the study by the sponsor. Unless otherwise specified, all results represent analyses from the 10-mg/kg group. During the placebo-controlled period, 425 of 1029 patients (41.3%) experienced ARIA, with serious cases occurring in 14 patients (1.4%). ARIA-edema (ARIA-E) was the most common adverse event (362 of 1029 [35.2%]), and 263 initial events (72.7%) occurred within the first 8 doses of aducanumab; 94 participants (26.0%) with an event exhibited symptoms. Common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H were headache (48 [46.6%]), confusion (15 [14.6%]), dizziness (11 [10.7%]), and nausea (8 [7.8%]). Incidence of ARIA-E was highest in aducanumab-treated participants who were apolipoprotein E ε4 allele carriers. Most events (479 of 488 [98.2%]) among those with ARIA-E resolved radiographically; 404 of 488 (82.8%) resolved within 16 weeks. In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (apolipoprotein E ε4 carriers: 16 of 742 [2.2%]; noncarriers, 13 of 334 [3.9%]). ARIA-microhemorrhage and ARIA-superficial siderosis occurred in 197 participants (19.1%) and 151 participants (14.7%), respectively., Conclusions and Relevance: In this integrated safety data set from EMERGE and ENGAGE, the most common adverse event in the 10-mg/kg group was ARIA-E, which occurred in 362 of the 1029 patients (35.2%) in the 10-mg/kg group with at least 1 postbaseline MRI scan, with 94 patients (26.0%) experiencing associated symptoms. The most common associated symptom was headache., Trial Registrations: ClinicalTrials.gov Identifiers: NCT02484547, NCT02477800.

Introduction: Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease that places a substantial burden on patients and caregivers. Aducanumab is the first AD therapy approved by the US Food and Drug Administration to reduce a defining pathophysiological feature of the disease, brain amyloid plaques. In the phase 3 clinical trial EMERGE (NCT02484547), aducanumab reduced clinical decline in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia and confirmed amyloid pathology., Methods: We used a Markov modeling approach to predict the long-term clinical benefits of aducanumab for patients with early AD based on EMERGE efficacy data. In the model, patients could transition between AD severity levels (MCI due to AD; mild, moderate, and severe AD dementia) and care settings (community vs. institution) or transition to death. The intervention was aducanumab added to standard of care (SOC), and the comparator was SOC alone. Data sources for base-case and scenario analyses included EMERGE, published National Alzheimer's Coordinating Center analyses, and other published literature., Results: Per patient over a lifetime horizon, aducanumab treatment corresponded to 0.65 incremental patient quality-adjusted life-years (QALYs) and 0.09 fewer caregiver QALYs lost compared with patients treated with SOC. Aducanumab treatment translated to a lower lifetime probability of transitioning to AD dementia, a lower lifetime probability of transitioning to institutionalization (25.2% vs. 29.4%), delays in the median time to transition to AD dementia (7.50 vs. 4.92 years from MCI to moderate AD dementia or worse), and an incremental median time in the community of 1.32 years compared with SOC., Conclusion: The model predicted long-term benefits of aducanumab treatment in patients with MCI due to AD and mild AD dementia and their caregivers. The predicted outcomes provide a foundation for healthcare decision-makers and policymakers to understand the potential clinical and socioeconomic value of aducanumab., (© 2021. The Author(s).)

As species distribution models, and similar techniques, have emerged in marine ecology, a vast array of predictor variables have been created and diverse methodologies have been applied. Marine fish are vital food resources worldwide, yet identifying the most suitable methodology and predictors to characterize spatial habitat associations, and the subsequent distributions, often remains ambiguous. Our objectives were to identify knowledge gaps in fish guilds, identify research themes, and to determine how data sources, statistics, and predictor variables differ among fish guilds. Data were obtained from an international literature search of peer-reviewed articles (2007-2018; n = 225) and research themes were determined based on abstracts. We tested for differences in data sources and modeling techniques using multinomial regressions and used a linear discriminant analysis to distinguish differences in predictors among fish guilds. Our results show predictive studies increased over time, but studies of forage fish, sharks, coral reef fish, and other fish guilds remain sparse. Research themes emphasized habitat suitability and distribution shifts, but also addressed abundance, occurrence, stock assessment, and biomass. Methodologies differed by fish guilds based on data limitations and research theme. The most frequent predictors overall were depth and temperature, but most fish guilds were distinguished by their own set of predictors that focused on their specific life history and ecology. A one-size-fits-all approach is not suitable for predicting marine fish distributions. However, given the paucity of studies for some fish guilds, researchers would benefit from utilizing predictors and methods derived from more commonly studied fish when similar habitat requirements are expected. Overall, the findings provide a guide for determining predictor variables to test and identifies novel opportunities to apply non-spatial knowledge and mechanisms to models., Competing Interests: The authors have declared that no competing interests exist. CSS-Inc., provided support in the form of salary for BP under NOAA contract no. GS-00F-217CA, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The affiliation to CSS-Inc., does not alter our adherence to PLoS One policies on sharing data and materials.

Background: Vixotrigine is a voltage and use dependent sodium channel blocker currently under development for treatment of various neuropathic pain indications., Objective: The objective of this work was to develop a population pharmacokinetic model and assess effects of various covariates on pharmacokinetic parameters of vixotrigine., Method: Plasma concentration-time data from 12 Phase 1 or 2 studies were included in the analyses. The data were obtained following administration of single or multiple doses of vixotrigine in healthy volunteers and patients. One- and two-compartment pharmacokinetic models were evaluated as base structural pharmacokinetic models. The inclusion of selected covariates was assessed using a stepwise backward elimination approach (α = 0.001) once the base/full model was developed. The predictive ability of the model was evaluated using a visual predictive check (VPC). The final model was used to evaluate effect of covariates on exposure of vixotrigine., Results: A total of 10,263 pharmacokinetic samples collected from 465 subjects were included in the analyses. The pharmacokinetics of vixotrigine was adequately described by a two-compartment model with two transit absorption compartments and first-order elimination. Predictability of the model was also established by VPC. The final model included covariates of age, weight and carbamazepine co-administration on clearance, weight on central volume of distribution, food on absorption rate constant and formulation and Japanese race on bioavailability. None of the covariates identified had a clinically relevant effect, as impact on area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) was within ± 25%., Conclusion: The model characterizes the pharmacokinetics of vixotrigine well, and the exposure of vixotrigine was comparable between healthy subjects and patients. None of the covariates evaluated have a clinically relevant impact on the pharmacokinetics of vixotrigine.

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses., Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181., Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred., Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components., Funding: Biogen., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Natalizumab is an immunomodulatory drug approved for the treatment of multiple sclerosis. This randomized, multicenter, open-label study evaluated natalizumab's effects on immunization responses to a recall antigen (tetanus toxoid [TT]) and a neoantigen (keyhole limpet hemocyanin [KLH]) in patients with relapsing forms of multiple sclerosis (MS). Natalizumab-naive relapsing MS patients were randomized (1:1; n=30 per group) to receive TT and KLH immunizations either without natalizumab treatment (control) or after 6 months of natalizumab treatment (natalizumab group). An adequate response to immunization was defined as an increase to at least twofold in specific serum immunoglobulin G (IgG) 28 days after the first immunization. All evaluable patients achieved protective levels of anti-TT IgG antibodies, and the proportion of responders to this recall antigen, as well as to primary immunization with KLH, was similar in the presence and absence of natalizumab. This indicates that natalizumab treatment does not appear to affect responses to primary or secondary immunization in a clinically meaningful way., (Copyright © 2014 Elsevier B.V. All rights reserved.)