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Key Points Question What are the characteristics of amyloid-related imaging abnormalities (ARIA) during aducanumab treatment in individuals with early Alzheimer disease? Findings In an integrated safety data set of 2 phase 3 clinical trials (EMERGE and ENGAGE) including 3285 participants, 425 patients (41.3%) in the combined 10 mg/kg aducanumab group (n = 1029) experienced ARIA; ARIA-edema occurred in 362 patients (35.2%), and 94 of these patients (26.0%) experienced associated symptoms (eg, headache, confusion, dizziness, and nausea). ARIA-microhemorrhage and ARIA–superficial siderosis occurred in 197 patients (19.1%) and 151 patients (14.7%), respectively. Meaning Amyloid-related imaging abnormalities occurred in approximately 40% of participants in the phase 3 studies of aducanumab, and approximately one-quarter of these patients experienced symptoms., This secondary analysis of 2 phase 3 randomized clinical trials describes the radiographic and clinical characteristics of amyloid-related imaging abnormalities that occurred in the EMERGE and ENGAGE trials., 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. Supplementary Information The online version contains supplementary material available at 10.1007/s40120-021-00273-0.

Vixotrigine is a voltage and use dependent sodium channel blocker currently under development for treatment of various neuropathic pain indications. The objective of this work was to develop a population pharmacokinetic model and assess effects of various covariates on pharmacokinetic parameters of vixotrigine. 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. 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 (Cmax) was within ± 25%. 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.

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.

Objective Analyses were conducted to determine the clinical utility of measuring JC virus (JCV) DNA in blood or urine of natalizumab-treated multiple sclerosis (MS) patients to predict the risk of progressive multifocal leukoencephalopathy (PML). Methods A total of 12,850 blood and urine samples from nearly 1,400 patients participating in natalizumab clinical trials were tested for JCV DNA using a commercially available quantitative polymerase chain reaction (qPCR) assay. A subset of these samples was also tested using a more sensitive qPCR assay developed at the National Institutes of Health (NIH). Results At the time natalizumab dosing was suspended, JCV DNA was detected in plasma by the commercial assay in 4 of 1,397 (0.3%) patients; the NIH assay confirmed these positive samples and detected JCV DNA in an additional 2 of 205 (1%) patients who tested negative with the commercial assay. None of these 6 JCV DNA positive patients developed PML. In a 48-week study testing the safety of natalizumab redosing, JCV DNA was detected in plasma of 6 of 1,094 (0.3%) patients, none of whom developed PML. Urine at baseline and week 48 was assessed in 224 patients; 58 (26%) were positive at baseline, and 55 (25%) were positive after 48 weeks of natalizumab, treatment. JCV DNA was not detected in peripheral blood mononuclear cells from any of these 1,094 patients before or after natalizumab treatment. In 5 patients who developed PML, JCV DNA was not detected in blood at any time point before symptoms first occurred. Interpretation Measuring JCV DNA in blood or urine with currently available methods is unlikely to be useful for predicting PML risk in natalizumab-treated MS patients. Ann Neurol 2010

Objectives: Report long-term safety and effectiveness of natalizumab over 240 weeks in the prospective, observational, open-label Safety of TYSABRI Re-dosing and Treatment (STRATA) Study. Methods: Patients (N = 1,094) previously enrolled in natalizumab multiple sclerosis clinical trials received natalizumab 300 mg IV every 4 weeks, up to 240 weeks. Serious adverse events, Expanded Disability Status Scale (EDSS) scores, and annualized relapse rates were analyzed. Results: At data cutoff (February 9, 2012), natalizumab exposure was 3,460 patient-years; a median of 56 (range 1–70) infusions were received. Serious adverse events, including progressive multifocal leukoencephalopathy, were consistent with natalizumab9s known profile. Upon natalizumab re-exposure, rates of anti-natalizumab antibodies and hypersensitivity reactions were 3% and 5% overall, and 40% and 24% among patients with 1 to 2 prior natalizumab doses. Patients originally randomized to placebo/another disease-modifying therapy vs natalizumab in previous studies had significantly higher EDSS scores at STRATA baseline; this difference persisted over 240 weeks. EDSS scores generally remained stable. Patients initially randomized to natalizumab had lower annualized relapse rates over 240 weeks. Conclusions: Serious adverse events were consistent with natalizumab9s known safety profile; short exposure with a gap before redosing was associated with higher incidences of anti-natalizumab antibodies and hypersensitivity reactions. Stability of EDSS scores and consistently low relapse rates over 5 years of natalizumab treatment are consistent with its known efficacy profile. Classification of evidence: This study provides Class III evidence that in patients with relapsing-remitting multiple sclerosis, natalizumab stabilizes EDSS scores, decreases relapse rates, and is associated with an increased risk of progressive multifocal leukoencephalopathy.

Little is known about neuropsychological status changes in multiple sclerosis (MS) patients experiencing a relapse. The Symbol Digit Modalities Test (SDMT) and MS Neuropsychological Screening Questionnaire (MSNQ) are brief measures of cognitive performance and self-reported status, respectively. We retrospectively identified relapses in subjects participating in the 48-week open-label, safety-extension study of natalizumab (STRATA) to determine if changes in cognitive ability occurred during acute relapses. SDMT and MSNQ were administered prior to infusions. We analyzed SDMT and MSNQ scores pre- and post-relapse in 53 MS patients with relapses (cases) and 115 MS patients without relapses (controls) matched on age, gender, baseline SDMT and time from study initiation. ANOVA and GLM were used to compare cases versus controls overall, and stratified by EDSS cerebral functional status (cFS) scores. SDMT change pre- to post-relapse in cases was significantly lower than difference between similar time points in controls (p = 0.003). When comparing visit 2 (two visits pre-relapse) to visit 1 (first visit post-relapse), MSNQ change was significantly different between cases and controls (p = 0.012). For cFS ≤ 1, the change in SDMT was significantly different between cases and controls but not for cFS ≥ 2. These results confirm the involvement of cognitive function during some MS relapses suggesting the SDMT or MSNQ can be used to identify transitory neuropsychological status changes and cognitive relapses.

Analyses were conducted to determine the clinical utility of measuring JC virus (JCV) DNA in blood or urine of natalizumab-treated multiple sclerosis (MS) patients to predict the risk of progressive multifocal leukoencephalopathy (PML).A total of 12,850 blood and urine samples from nearly 1,400 patients participating in natalizumab clinical trials were tested for JCV DNA using a commercially available quantitative polymerase chain reaction (qPCR) assay. A subset of these samples was also tested using a more sensitive qPCR assay developed at the National Institutes of Health (NIH).At the time natalizumab dosing was suspended, JCV DNA was detected in plasma by the commercial assay in 4 of 1,397 (0.3%) patients; the NIH assay confirmed these positive samples and detected JCV DNA in an additional 2 of 205 (1%) patients who tested negative with the commercial assay. None of these 6 JCV DNA positive patients developed PML. In a 48-week study testing the safety of natalizumab redosing, JCV DNA was detected in plasma of 6 of 1,094 (0.3%) patients, none of whom developed PML. Urine at baseline and week 48 was assessed in 224 patients; 58 (26%) were positive at baseline, and 55 (25%) were positive after 48 weeks of natalizumab, treatment. JCV DNA was not detected in peripheral blood mononuclear cells from any of these 1,094 patients before or after natalizumab treatment. In 5 patients who developed PML, JCV DNA was not detected in blood at any time point before symptoms first occurred.Measuring JCV DNA in blood or urine with currently available methods is unlikely to be useful for predicting PML risk in natalizumab-treated MS patients.

Age (years) Mean ± SD 44.0 ± 7.1 42.3 ± 7.2 0.387* Gender N (%) female 35 (66.0%) 75 (65.2%) 0.917 EDSS prior to relapse Median (range) 3.0 (1.0–7.5) 2.5 (0.0–7.0) 0.717 Cerebral FS prior to relapse Median (range) 0.0 (0.0–2.0) 0.0 (0.0–2.0) 0.777 SDMT 2 visits prior to relapse Mean ± SD 52.3 ± 11.6 52.5 ± 11.3 0.937* SDMT 1 visit prior to relapse Mean ± SD 53.6 ± 10.9 53.4 ± 11.6 0.658* MSNQ 1 visit prior to relapse Mean ± SD 15.0 ± 11.2 13.0 ± 10.8 0.112* MSNQ 2 visits prior to relapse Mean ± SD 14.1 ± 10.6 13.3 ± 11.0 0.666* Corticosteroid treatment N (%) 37 (56.9%) N/A