BACKGROUND AND OBJECTIVES:Zagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD). METHODS:Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Examination score of 20-28, and intermediate levels of brain tau on PET imaging. In this double-blind study, participants were equally randomized to 1,400 mg or 5,600 mg of zagotenemab, or placebo (IV infusion every 4 weeks for 100 weeks). The primary outcome was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model. Secondary measures include mixed model repeated measures analysis of additional cognitive and functional endpoints as well as biomarkers of AD pathology. RESULTS:A total of 360 participants (mean age = 75.4 years; female = 52.8%) were randomized, and 218 completed the treatment period. Demographics and baseline characteristics were reasonably balanced among arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for the iADRS was 1.10 (0.959-1.265) for the zagotenemab low-dose group and 1.05 (0.907-1.209) for the high-dose, where a ratio less than 1 favors the treatment group. Secondary clinical endpoint measures failed to show a drug-placebo difference in favor of zagotenemab. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analyses. A dose-related increase in plasma phosphorylated tau181 and total tau was demonstrated. Zagotenemab treatment groups reported a higher incidence of adverse events (AEs) (85.1%) compared with the placebo group (74.6%). This difference was not attributable to any specific AE or category of AEs. DISCUSSION:In participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression compared with placebo. Imaging biomarker and plasma NfL findings did not show evidence of pharmacodynamic activity or disease modification. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov: NCT03518073. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression.

Background and ObjectivesZagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD).MethodsParticipants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Examination score of 20-28, and intermediate levels of brain tau on PET imaging. In this double-blind study, participants were equally randomized to 1,400 mg or 5,600 mg of zagotenemab, or placebo (IV infusion every 4 weeks for 100 weeks). The primary outcome was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model. Secondary measures include mixed model repeated measures analysis of additional cognitive and functional endpoints as well as biomarkers of AD pathology.ResultsA total of 360 participants (mean age = 75.4 years; female = 52.8%) were randomized, and 218 completed the treatment period. Demographics and baseline characteristics were reasonably balanced among arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for the iADRS was 1.10 (0.959-1.265) for the zagotenemab low-dose group and 1.05 (0.907-1.209) for the high-dose, where a ratio less than 1 favors the treatment group. Secondary clinical endpoint measures failed to show a drug-placebo difference in favor of zagotenemab. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analyses. A dose-related increase in plasma phosphorylated tau181 and total tau was demonstrated. Zagotenemab treatment groups reported a higher incidence of adverse events (AEs) (85.1%) compared with the placebo group (74.6%). This difference was not attributable to any specific AE or category of AEs.DiscussionIn participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression compared with placebo. Imaging biomarker and plasma NfL findings did not show evidence of pharmacodynamic activity or disease modification.Trial Registration InformationClinicalTrials.gov: NCT03518073.Classification of EvidenceThis study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression.

BACKGROUND:Muscle weakness is common and significantly affects persons with multiple sclerosis (PwMS), with dysfunction in upper limb (UL) muscle groups occurring in approximately 60% of PwMS. OBJECTIVE:To develop gender-specific regression-based prediction equations, with 95% confidence intervals for maximal bilateral UL isometric strength (shoulder abduction and adduction, wrist flexion and extension) and hand grip strength in PwMS. DESIGN:Cross-sectional study. SETTING:Comprehensive MS center. PARTICIPANTS:256 PwMS. INTERVENTIONS:Not Applicable. MAIN OUTCOME MEASURES:Shoulder abduction and adduction and wrist flexion and extension isometric strength (Biodex System 4 Pro Dynamometer) and hand grip strength (Jamar handheld dynamometer) were measured. Disease characteristics (disability and disease duration) and demographics (age, height, and weight) were collected. Regression-based predictive equations were generated for the UL muscle groups for each gender and limb, using age, height, weight, disability, and disease duration as covariates. Variables were compared between genders using the Mann-Whitney U test. Maximal voluntary contraction (MVC) reference values (mean ± SD) were reported based on age (<30, 30-39, 40-49, 50-59, 60-69 years) and disability (mild, moderate, severe ambulant, and severe nonambulant) for each gender and limb. RESULTS:Regression-based equations were developed for both genders' strongest and weakest limb, accounting for age, height, weight, disability, and disease duration. MVC was higher in men than women (p < .001) in all muscle groups. Overall, MVC was significantly related to age in 14, height in 5, weight in 6, disability in 14, and disease duration in none of the 20 models. CONCLUSION:This is the first study to provide regression-based prediction equations for strongest and weakest MVC of UL muscle groups and demonstrated an inverse relationship between MVC with disability and age. Regression-based reference strength values can help clinicians understand muscular strength along a spectrum of PwMS and can aid in goal setting and education for realistic outcomes.

BACKGROUND:Cognitive impairment, difficulty performing basic activities of daily living (ADLs) and instrumental ADLs (IADLs), depression, and fatigue are common among individuals with multiple sclerosis (MS). Some associations between these symptoms are known; however, many of their relationships remain unclear. This study investigated the contributions of subjective and objective cognition, depressive symptom severity, and fatigue on ADLs and IADLs.METHODS:Participants (N = 217) were individuals with MS from a comprehensive MS center, participating in a larger study characterizing upper extremity function in MS. Outcome measures of ADL and IADL abilities were the Functional Status Index-Assistance (FSI-A) and Functional Status Index-Difficulty (FSI-D) and the Test D'évaluation Des Membres Supérieurs de Personnes Âgées (TEMPA). Predictors were objective cognition (Symbol Digit Modalities Test; SDMT), subjective cognition (Performance Scales©-Cognition; PS-C), depressive symptom severity (Center for Epidemiologic Studies Depression Scale; CES-D-10), and fatigue (Modified Fatigue Impact Scale; MFIS-5). Correlations were conducted, followed by hierarchal linear regressions. The SDMT and PS-C were entered into separate models.RESULTS:After controlling for demographics, the SDMT significantly predicted the TEMPA and FSI-A, while the PS-C predicted only the FSI-D. The CES-D-10 predicted the FSI-D even after accounting for PS-C and SDMT, while the MFIS-5 only predicted the FSI-D when the SDMT was included. Neither the CES-D-10 nor MFIS-5 significantly predicted the FSI-A or TEMPA.CONCLUSIONS:The way an individual with MS perceived their symptoms significantly contributed to their reported difficulty with functional tasks, while only their objective cognitive functioning predicted ADL and IADL performance and the level of assistance they would require.

PURPOSE:This study aimed to evaluate 1) whether having a vascular comorbidity (i.e., hypertension, hyperlipidemia, heart disease, and diabetes) was associated with self-reported issues with functional activities among persons with multiple sclerosis (MS) and 2) if certain contributing factors (i.e., disability, depression, and fatigue) might explain the observed relationships. MATERIALS AND METHODS:Participants (n = 263) completed the Functional Status Index (FSI), which assessed five domains: gross mobility, hand activities, personal care, home chores, and social/role activities. After bivariate analyses, individual linear regressions were conducted for each FSI domain, controlling for demographics. Follow-up mediation analyses were done for each of the three mediators. RESULTS:Participants with vascular comorbidities endorsed more issues on all five domains, with the demographic-adjusted associations with gross mobility (b = 0.34, p = 0.002), hand activities (b = 0.15, p = 0.006), home chores (b = 0.44, p = 0.003), and social/role activities (b = 0.32, p = 0.024) remaining significant. Disability fully mediated the effects of vascular comorbidities on these domains, with partial and full mediations observed with depression and fatigue. Diabetes emerged as a significant individual comorbidity in several models. CONCLUSIONS:Vascular comorbidities, diabetes in particular, are associated with persons with MS endorsing worse ratings on functional outcomes, with disability, depression, and fatigue explaining these associations.

Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer’s disease (AD). Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed. Clinicaltrials.gov: NCT03019536

Enhanced in-vitro killing of EMMESO-PDL1 tumor targets by PD1CD28 modification.

Alteration of tumor structure by FAP-CAR T cells in murine PDAs.

Background: There is a need to update prevalence data for multiple sclerosis (MS) in the US. The Rhode Island Multiple Sclerosis Study (RIMSS) determined prevalence of adults with MS in the state of Rhode Island (RI) over a 5-year period (2007-2013), through direct chart abstraction, a method uncommonly used in the US. Methods: Prevalence estimates for adults with MS were derived from chart abstraction from neurology practices throughout RI, including 100% of large practices, and a random sample of 50% of smaller practices. Abstracted data included medical history, physical exam findings and imaging results over the longitudinal course of clinic visits. These data were then adjudicated to determine the diagnosis and subtype of MS. Findings: The results indicated that 2,319 adults received treatment for diagnosed MS during this five-year period (1,693 women and 622 men. This corresponds to a prevalence of 279.4 per 100,000 adults. The peak prevalence for women was between ages 45-54 at 679.7/100,000, and for men between ages 55-64 at 272.9/100,000. The proportion for each subtype was: Relapsing Remitting MS, 65.2%; Secondary Progressive MS, 23.2%; Primary Progressive MS 5.1%; Progressive Type Not otherwise Specified, 4.4%; MS Not otherwise Specified, 2.2%. Interpretation: This representative sampling of RI clinics that treat people with MS generated a population prevalence for a single state that has not been previously reported. These results show that prevalence was 2.7 times greater for men then woman; and, with a higher prevalence than prior US-based population samples, supports the increasing trend of higher prevalence of MS in the US . Approximately one third of the cohort had a progressive subtype of MS. Funding Information: The Rhode Island Multiple Sclerosis Study was supported by a grant from the National Multiple Sclerosis Society (# RG 4283A2/2).Declaration of Interests: None to declare. Ethics Approval Statement: Study procedures were reviewed and approved by Institutional Review Boards at Brown University and four RI hospitals; data use agreements were provided for practices that were not covered by these hospitals.

BACKGROUND:The Multiple Sclerosis Resiliency Scale (MSRS) was designed to assess factors connected to resilience when facing MS-related challenges. Although the MSRS has demonstrated good internal consistency and construct validity, its test-retest reliability has yet to be established. Identifying the minimal detectable change (MDC) of the scale will also improve its utility as an outcome measure for resilience-based interventions. This study aimed to determine the test-retest reliability and MDC of the MSRS.METHODS:Participants were 62 persons with MS who completed the MSRS twice, with a mean ± SD of 16.60 ± 3.97 days (range, 14-30 days) between assessments. Test-retest reliability was evaluated using a 2-way, random-effects, single-measurement intraclass correlation coefficient (ICC), with agreement between time 1 and time 2 visualized with a Bland-Altman plot. The MDC was calculated using the standard error of measurement with a 95% CI.RESULTS:At time 1, the mean ± SD MSRS score was 77.19 ± 11.97 (range, 45.83-97.00); at time 2, the mean ± SD score was 76.38 ± 12.75 (range, 46-98). The MSRS total score had good test-retest reliability (ICC = 0.88), with the subscale ICCs ranging from 0.77 (MS Peer Support) to 0.93 (Spirituality). The MDC for the total score was 11.95.CONCLUSIONS:These findings suggest that the MSRS has good test-retest reliability and that persons with MS with a difference of 12 points or more between assessments have experienced a reliable change. The results support the utility of the MSRS as a potential outcome measure for MS-related resilience.

Background: Dysfunction in upper limb (UL) function has been reported as an important indicator for disease progression in persons with multiple sclerosis (PwMS), thus a relevant outcome in clinical trials. However, standard assessment of UL function is limited to Nine-Hole Peg Test (NHPT) which assesses fine dexterity. This study aimed to deeply endophenotype UL involvement in PwMS and identify the most accurate set of measures needed to capture the complexity of UL dysfunction in the activities of daily living (ADL). Methods: 257 PwMS underwent an extensive UL assessment using standardized measures of grip strength and endurance, coordination, vibratory and tactile sensation, dexterity, capacity and functionality. Limitation in ADL was defined from an objective perspective using a timed test (Test d' Evaluation de la performance des Membres Superieurs des Personnes Agees: TEMPA) and from a subjective perspective using a questionnaire (Disabilities of the Arm, Shoulder and Hand: DASH). Disease severity subgroups were compared utilizing the Kruskal-Wallis test and frequencies determined the prevalence of abnormal UL for each measure. The Jonckheere-Terpstra test compared tested variables with disease severity. Then Receiver operating characteristic (ROC) curve analysis was used to test the accuracy of each tested variable in defining abnormality in the TEMPA and DASH. Cut-off scores were calculated using the Youden index. The predictive value of various tests over TEMPA and DASH were tested using a linear regression analysis. Results: UL dysfunction was highly prevalent in all the modalities tested, even in participants with no/mild disability. Box and Block Test (BBT), finger-nose test (FNT), and NHPT were independently selected with ROC analyses as the most accurate measures in detecting abnormalities in TEMPA and DASH. In multivariate regression models, BBT and FNT, and NHPT all contributed to predicting TEMPA (adj. R-2 0.795, P < 0.001), while only BBT and FNT predicted DASH. Conclusions: UL dysfunction is highly prevalent in PwMS, even when global disability is mild. BBT and FNT are time-efficient and cost-effective measures that complement the NHPT for more precise monitoring of PwMS at all disease stages.

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer’s disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. Methods: The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey’s post hoc test and clinical data used summary statistics. Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aβ1–40 and 0.228±0.244 nM for Aβ1–42 in PDAPP neuronal cultures. In dogs, CSF Aβ1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ1–42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

BACKGROUND:Backward walking (BW) interventions have improved gait and balance in persons with stroke, cerebral palsy, and Parkinson disease but have not been studied in persons with multiple sclerosis (MS). We examined the feasibility of a BW intervention and how it affected strength, balance, and gait vs forward walking (FW) in persons with MS.METHODS:Sixteen persons with MS with a Patient-Determined Disease Steps (PDDS) scale score of 3 to 5 (gait impairment-late cane) were randomized to the FW (n = 8) or BW (n = 8) group. Participants did 30 minutes of FW or BW on a treadmill 3 times per week for 8 weeks (24 visits). Enrollment, adherence rate, and safety were tracked. The Timed Up and Go test, Six-Spot Step Test, single-leg stance, and abbreviated Activities-specific Balance Confidence scale were used to measure balance. Hip and knee flexion and extension strength (isometric peak torque), gait speed, and spatiotemporal gait parameters were measured. A 2×2 factorial multivariate analysis of covariance was used to examine changes in strength, balance, and gait, with the PDDS scale score as the covariate.RESULTS:Treatment adherence rate was 99.7%, with no safety concerns. After controlling for baseline differences in disability (PDDS scale score; P = .041), the BW group improved dominant hip flexion strength preintervention to postintervention compared with the FW group (F 1,13 = 9.03; P = .010). No other significant differences were seen between groups.CONCLUSIONS:This was the first study to look at BW as an intervention in persons with MS. Based on its feasibility, safety, and significant finding, BW should be studied in a larger, definitive trial in the future.

Accumulation of amyloid-β (Aβ) peptide in amyloid plaques is a pathological hallmark of Alzheimer’s disease (AD). Reduction of Aβ could slow the progression of AD. Donanemab is an antibody specific for the N-terminal pyroglutamate Aβ epitope that is only present in mature brain amyloid plaques. In the TRAILBLAZER-ALZ study, 67.8% (n=61) of donanemab-treated participants became amyloid negative by 76 weeks. Here we further characterize amyloid reduction after donanemab treatment. Participants (placebo N=84, donanemab N=69) that completed 4 florbetapir scans in TRAILBLAZER-ALZ were analyzed for amyloid reduction rate, measured in centiloids (CL). Donanemab dosing was 700mg every 4 weeks (Q4W) for the first 3 doses, then 1400mg Q4W, for up to 76 weeks. Planned blinded dose reduction evaluations occurred at 24 and 52 weeks creating three periods of time between florbetapir scans: baseline-24wk, 24wk-52wk, or 52wk-76wk. ANOVA were performed to compare baseline parameters. At 24wk, 15 participants in the donanemab group were assigned to 700mg dose and 19 were assigned to placebo. At 52wk, 10 participants were assigned to 700mg dose and 8 were assigned to placebo. In the 17 participants that remained on 1400mg donanemab until the end of the trial, amyloid reduction rate decreased during baseline-24wk, 24wk-52wk, and 52wk-76wk (mean (SD): -2.7(1.5), -1.0 (0.7), and -0.5 (0.5) CL/wk, respectively). At the end of the trial, 5 out of 17 participants that remained in the 1400mg group became amyloid negative. In the 15 participants that were assigned to 700mg at 24wk, plaque lowering rate decreased from an average of -3.0 (1.2) CL/wk over the first 24wk to an average of -0.4 (0.4) CL/wk over 24wk-52wk. At the end of the trial, 13 participants assigned to 700mg donanemab Q4W at 24wk became amyloid negative. Patients that received placebo at 24wk-76wk (n=19) or 52wk-76wk (n=19), had no re-accumulation (mean (SD): 0.0 (0.1) CL/wk and -0.1 (0.2) CL/wk, respectively). Participants that stayed on 1400mg until study end had higher baseline amyloid (p=0.0000) and tau (p=0.0488) and were younger (p=0.0472) than those assigned to 700mg or placebo at 24wk. Donanemab treatment reduced amyloid plaques and resulted in no re-accumulation of amyloid over 1 year.

Background: LY3202626 is a small molecule inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-β (Aβ)1–40 and Aβ1–42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer’s disease (AD). Objective: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia. Methods: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. Results: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. Conclusion: LY3202626 tested at doses generating 70–90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.

BACKGROUND:A hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for the treatment of early Alzheimer's disease.METHODS:We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog13), the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET.RESULTS:A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab.CONCLUSIONS:In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.).

Zagotenemab (LY3303560), a humanized monoclonal antibody targeting extracellular aggregated tau, is currently in development as a potential disease modifying treatment for early symptomatic Alzheimer’s disease (AD). The PERISCOPE‐ALZ study (Phase 2, NCT03518073) of zagotenemab implements tau PET for classifying AD pathological stage based on the NIA‐AA guidelines (Jack CR, Jr., Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535‐62) and serves as a key eligibility criterion. Here we summarize the study’s screening and baseline characteristics.

The Mixed Model for Repeated Measures (MMRM) is the most frequently used statistical analysis for clinical trial endpoints in Alzheimer’s disease (AD) but has the limitation of not efficiently leveraging data from intermediate time points due to the flexibility in the mean structure. In the TRAILBLAZER‐ALZ trial, donanemab, a humanized IgG1 antibody specifically targeting brain amyloid plaque, slowed disease progression in individuals with early symptomatic AD. The aim of this presentation is to apply different statistical models to clinical scale data gathered from this trial, as consistent conclusions following multiple methods would strengthen confidence in the results.

BACKGROUND:Pain is a common and often debilitating symptom in persons with multiple sclerosis (MS). Besides interfering with daily functioning, pain in MS is associated with higher levels of depression and anxiety. Although cognitive behavioral therapy (CBT) for pain has been found to be an effective treatment in other populations, there has been a dearth of research in persons with MS.METHODS:Persons with MS with at least moderate pain severity (N = 20) were randomly assigned to one of two groups: CBT plus standard care or MS-related education plus standard care, each of which met for 12 sessions. Changes in pain severity, pain interference, and depressive symptom severity from baseline to 15-week follow-up were assessed using a 2×2 factorial design. Participants also rated their satisfaction with their treatment and accomplishment of personally meaningful behavioral goals.RESULTS:Both treatment groups rated their treatment satisfaction as very high and their behavioral goals as largely met, although only the CBT plus standard care group's mean goal accomplishment ratings represented significant improvement. Although there were no significant differences between groups after treatment on the three primary outcomes, there was an overall improvement over time for pain severity, pain interference, and depressive symptom severity.CONCLUSIONS:Cognitive behavioral therapy or education-based programs may be helpful adjunctive treatments for persons with MS experiencing pain.

AbstractBackgroundTo date, regional patterns of the longitudinal tau accumulation in Alzheimer’s Disease (AD) have been examined in very few studies with limited sample sizes. We combined data from three phase 2 or 3 interventional trials to illustrate regional patterns of longitudinal flortaucipir accumulation.MethodEXPEDITION3 (NCT01900665), NAVIGATE‐AD (NCT02791191) and AMARANTH (NCT02245737) were double‐blind, placebo‐controlled multi‐center trials that enrolled amyloid‐positive patients with early or mild AD dementia. Longitudinal changes for flortaucipir were examined for N=208 placebo participants who underwent 8‐16 month follow‐up (scheduled or early discontinuation) flortaucipir scans. Flortaucipir scans were pooled across the three trials and divided into four stages corresponding to very low, low, medium, and high baseline global neocortical tau SUVR using pre‐determined cut‐points (Pontecorvo et al, 2019). A stage‐wise annualized percent change (APC) and mean‐standard deviation (SD) ratio (MSDR) of longitudinal tau accumulation were examined for 17 Automated Anatomical Labeling (AAL) atlas‐based bilateral cortical regions and a composite neocortical region of interest (ROI).ResultOur analysis suggested a dependence of the regional longitudinal tau accumulation profile on the global baseline tau burden at a group level. In the lowest baseline SUVR group (N=36), minimal accumulation was observed in the composite ROI (APC=0.04%, MSDR=0.01) and the inferior temporal region (APC=1.00%, MSDR=0.41) showed the strongest tau signal increase. At low (N=42) and medium (N=63) baseline levels, we found a relatively wide‐spread and spatially uniform accumulation with an APC of 2‐3% in the majority of the cortical regions and composite ROI. For patients with a high global baseline burden (N=67), tau increased in all considered frontal regions (APC ≥ 3.95%, MSDR>0.42) which exceeded accumulations in the composite ROI (APC=2.82%, MSDR=0.32).ConclusionFor the amyloid positive early‐to‐mild AD population, we found different cross‐sectional tau deposition and different regional longitudinal profiles across four baseline tau stages. Performing tau‐based screening might enroll more pathologically homogeneous populations in interventional trials and permit utilization of optimal measures of tau change as outcomes.