INTRODUCTION:TRAILBLAZER-ALZ 6 (NCT05738486) is a multicenter, double-blind, ongoing phase 3b study in early symptomatic Alzheimer's disease. METHODS:Participants (n = 843) were randomized 1:1:1:1 (standard + three alternative donanemab dosing arms). Primary outcome was relative risk reduction (RRR) of amyloid-related imaging abnormalities with edema/effusions (ARIA-E) at 24 weeks assessed with Bayesian logistic regression. Amyloid plaque levels by positron emission tomography and serum donanemab pharmacokinetics were measured. RESULTS:ARIA-E frequencies for standard, modified titration, dose skipping, and Cmax arms were 23.7%, 13.7%, 18.6%, and 18.3%, respectively, at 24 weeks and similar at 52 weeks: 24.2%, 15.6%, 18.6%, and 18.8%, respectively. Modified titration met the 24-week primary outcome with 94% probability of achieving ≥ 20% RRR versus the standard arm. Modified titration also had significantly lower ARIA-E severity, but similar cumulative exposure and mean amyloid reduction compared to the standard arm. DISCUSSION:Gradual up-titration of dose significantly reduced ARIA-E risk while demonstrating comparable pharmacokinetics/pharmacodynamics compared to standard dosing. HIGHLIGHTS:In TRAILBLAZER-ALZ 6, the amyloid-related imaging abnormalities-edema/effusions (ARIA-E) frequency was 13.7% in the modified titration arm compared to 23.7% in the standard arm at week 24. The modified titration arm met the primary endpoint of ARIA-E relative risk reduction at 24 weeks versus the standard arm. The modified titration versus standard arm at week 24 had comparable non-ARIA-E related safety profile, amyloid reduction, plasma phosphorylated tau217 reduction, cumulative exposure, and pharmacokinetics. Data at week 52 were consistent with week 24 results.

The TRAILBLAZER-ALZ 6 study (NCT05738486) evaluated the effect of different donanemab dosing regimens on amyloid-related imaging abnormalities with edema/sulcal effusions (ARIA-E). The modified titration arm met the primary outcome and significantly reduced ARIA-E frequency compared with the standard dosing while maintaining a similar pharmacodynamic effect on amyloid reduction at 24 weeks. Primary outcome and 52-week data were previously published. Completed study results at 76 weeks are reported here. ARIA-E frequencies were 15.6 % and 24.2 % in the modified titration and standard arms, respectively. ARIA-E radiographic severity was significantly lower (p = 0.015) with modified titration than with standard dosing. Additionally, symptomatic ARIA-E frequency was lower with modified titration versus standard dosing (2.8 % vs 4.8 %). The frequency of serious adverse events was comparable between the modified titration and standard dosing arms. A more gradual titration of donanemab dosing significantly reduced ARIA-E risk versus standard dosing. CLINICALTRIALS.GOV: NCT05738486.

Amyloid-related imaging abnormalities (ARIA) are the major adverse event associated with amyloid-targeting immunotherapy. Identifying clinical features and individual risk factors for ARIA could facilitate effective prediction and prevention strategies. To characterize ARIA in participants treated with donanemab. These prespecified and post hoc exploratory analyses use data from the placebo-controlled portions of the TRAILBLAZER-ALZ and ALZ 2 randomized clinical trials, conducted from December 2017 to December 2020 and from June 2020 to April 2023, respectively. Additional analyses are included from a stand-alone open-label addendum conducted from August 2021 through August 2023. Participants in the placebo-controlled trials and the open-label addendum aged 60 to 85 years with early symptomatic Alzheimer disease and elevated amyloid levels were included. The placebo-controlled trials, but not the addendum, had tau inclusion criteria. Placebo-controlled trial participants were randomized 1:1 to receive placebo or donanemab, and all open-label participants received donanemab. Donanemab was administered every 4 weeks for up to 72 weeks. The primary outcomes were the frequency, radiographic severity, seriousness, symptoms, timing relative to donanemab treatment, and risk factors for ARIA. Across 3030 total participants (placebo-controlled trials: 999 placebo participants, 984 donanemab participants; open-label addendum: 1047 donanemab participants), mean (SD) age was approximately 73.7 (6.0) years and 1684 participants (55.6%) were female. Frequencies of ARIA–edema/effusions (ARIA-E) and ARIA–microhemorrhages and hemosiderin deposition (ARIA-H) were higher with donanemab (24.4% and 31.3% in placebo-controlled trials, respectively; 19.8% and 27.2% in open-label addendum, respectively) than with placebo (1.9% and 13.0%, respectively). ARIA-E was mostly mild or moderate in severity. Serious ARIA-E was reported in 1.5% and symptomatic ARIA-E in 5.8% of donanemab-treated participants in the placebo-controlled trials. Symptoms most frequently reported with ARIA-E were headache and confusional state. In 58.3% of donanemab-treated participants with ARIA-E, the first event occurred by the third infusion (approximately month 3). Risk analysis demonstrated independent associations between ARIA-E and 6 baseline variables, including increased risk with APOE ε4 allele number, greater number of microhemorrhages, presence of cortical superficial siderosis, higher amyloid plaque, and elevated mean arterial pressure, and decreased risk with antihypertensive use. ARIA is an adverse event associated with donanemab treatment that requires safety monitoring. Individual ARIA risk can be assessed by APOE ε4 status and baseline imaging findings. ClinicalTrials.gov Identifiers: NCT03367403 and NCT04437511

Background Donanemab significantly slowed clinical progression in participants with early symptomatic Alzheimer’s disease (AD) during the 76-week placebo-controlled period of TRAILBLAZER-ALZ 2. Methods Participants who completed the placebo-controlled period were eligible for the 78-week, double-blind, long-term extension (LTE). Early-start participants were randomized to donanemab in the placebo-controlled period. Delayed-start participants (randomized to placebo) started donanemab in the LTE. Participants who met amyloid treatment course completion criteria were switched to placebo. An external control cohort comprised participants from the AD Neuroimaging Initiative (ADNI). Results At 3 years, donanemab slowed disease progression on the Clinical Dementia Rating Scale (CDR)-Sum of Boxes (CDR-SB) in early-start participants versus a weighted ADNI control (-1.2 points; 95 % confidence interval [CI], -1.7, -0.7). Seventy-six weeks after initiating donanemab, delayed-start participants also demonstrated slower CDR-SB progression versus a weighted ADNI control (-0.8 points; 95 % CI, -1.3, -0.3). Participants who completed treatment by 52 weeks demonstrated similar slowing of CDR-SB progression at 3 years. Compared with delayed-start participants, early-start participants demonstrated a significantly lower risk of disease progression on the CDR-Global over 3 years (hazard ratio=0.73; p < 0.001). In both groups, >75 % of participants assessed by positron emission tomography 76 weeks after starting donanemab achieved amyloid clearance (<24.1 Centiloids). The addition of LTE data to prior modeling predicted a median reaccumulation rate of 2.4 Centiloids/year. No new safety signals were observed compared to the established donanemab safety profile. Conclusions Over 3 years, donanemab-treated participants with early symptomatic AD demonstrated increasing clinical benefits and a consistent safety profile, with limited-duration dosing. Trial registration ClinicalTrials.gov identifier NCT04437511

OBJECTIVE:To characterize amyloid-related imaging abnormalities (ARIA) risk associated with donanemab, a novel amyloid-targeting therapy (ATT). BACKGROUND:ARIA is an important safety concern associated with the class of ATTs. Identifying patient characteristics, comorbidities, concomitant medications, and modifiable factors potentially contributing to ARIA risk is paramount to inform use of ATTs in clinical practice. DESIGN/METHODS:This post-hoc exploratory analysis evaluated data from 2031 donanemab-exposed participants in the phase 2 TRAILBLAZER-ALZ study (NCT03367403), the phase 3 TRAILBLAZER-ALZ2 study (NCT04437511), and the open-label TRAILBLAZER-ALZ2 addendum. TRAILBLAZER-ALZ and TRAILBLAZER-ALZ2 participants had mild cognitive impairment or mild dementia due to Alzheimer's disease with amyloid and tau pathology (via PET). Addendum enrollment required PET evidence of amyloid, but participants without tau pathology were eligible. Participants received donanemab every 4 weeks for up to 72 weeks and stopped treatment if amyloid PET-based completion criteria were met. Hypothesis-generating penalized regression and decision tree-based models were employed to identify variables associated with ARIA-edema and effusions (ARIA-E). RESULTS:In TRAILBLAZER-ALZ, TRAILBLAZER-ALZ2, and the addendum, respectively, ARIA-E occurred in 36/131 (27.5%), 205/853 (24.0%), and 207/1047 (19.8%) of donanemab-treated participants. Most events were transient and asymptomatic. Baseline factors most strongly and independently associated with increased ARIA-E frequency included APOE ɛ4/ɛ4 genetic presence, higher number of microhemorrhages, presence of cortical superficial siderosis, higher mean arterial pressure, and greater amyloid burden. Antihypertensive medication use was associated with decreased ARIA-E frequency. Within APOE ɛ4 genotypes (non-carrier, heterozygous, homozygous), ARIA-E frequency increased with higher number of microhemorrhages and presence of cortical superficial siderosis on baseline MRI. CONCLUSIONS:Baseline variables associated with ARIA-E frequency were identified through post-hoc exploratory analysis of donanemab clinical datasets. Genotyping and baseline MRI may represent the most informative methods to assess potential ARIA risk in practice. This analysis is hypothesis-generating for future validation work across the class of ATTs and may yield modifiable factors. Disclosure: Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Greenberg has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Washington University/IQVIA. Dr. Greenberg has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer. Dr. Greenberg has received research support from National Institutes of Health. Dr. Greenberg has received publishing royalties from a publication relating to health care. Dr. Battioui has received personal compensation for serving as an employee of Eli Lilly and Company. Dr. Battioui has stock in Eli Lilly. Ming Lu has received personal compensation for serving as an employee of Eli Lilly and Company. Ming Lu has received stock or an ownership interest from Eli Lilly and Company. Dr. Biffi has nothing to disclose. Paul Ardayfio has received personal compensation for serving as an employee of Eli Lilly and Co.. Paul Ardayfio has received stock or an ownership interest from Eli Lilly and Co.. Dr. Zimmer has received personal compensation for serving as an employee of Eli Lilly & Company. Dr. Zimmer has stock in Eli Lilly & Company. Dr. Evans has received personal compensation for serving as an employee of Eli Lilly & Company. Dr. Evans has received stock or an ownership interest from Eli Lilly & Company. Mrs. Wang has received personal compensation for serving as an employee of Eli Lilly and company. Dr. Monkul Nery has received personal compensation for serving as an employee of Eli Lilly And Company. An immediate family member of Dr. Monkul Nery has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Karuna Therapeutics. The institution of an immediate family member of Dr. Monkul Nery has received research support from Boehringer-Ingelheim. The institution of an immediate family member of Dr. Monkul Nery has received research support from Compass Therapeutics. The institution of an immediate family member of Dr. Monkul Nery has received research support from Recognify Life Sciences. The institution of an immediate family member of Dr. Monkul Nery has received research support from Neurocrin Biosciences. Scott W. Andersen, 19156 has received personal compensation for serving as an employee of Eli Lilly. Scott W. Andersen, 19156 has stock in Eli Lilly. Scott W. Andersen, 19156 has received personal compensation in the range of $100,000-$499,999 for serving as a Statistician with Eli Lilly. Dr. Collins has received personal compensation for serving as an employee of Eli Lilly and Company. Dr. Collins has stock in Eli Lilly and Company. An immediate family member of Dr. Brooks has received personal compensation for serving as an employee of Indiana Hospital Association. Dr. Brooks has received stock or an ownership interest from Eli Lilly and Company. Dr. Sims has received personal compensation for serving as an employee of Eli Lilly and Company. Dr. Sims has stock in Eli Lilly and Company.

Importance:Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective:To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants:From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions:In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures:Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results:Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance:This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration:ClinicalTrials.gov Identifier: NCT04623242.

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: 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

INTRODUCTION:Solanezumab is a monoclonal antibody that binds to the mid-domain of soluble amyloid β peptide. This meta-analysis evaluated the effect of low-dose solanezumab on clinical progression in three phase 3 studies.METHODS:The population comprised patients aged ≥55 years with Alzheimer's disease (AD) with mild dementia, randomized to 400 mg solanezumab or placebo every 4 weeks for 80 weeks. Frequentist mixed-model repeated-measures (MMRM) and Bayesian disease progression model (DPM) longitudinal analyses were conducted.RESULTS:Pooled MMRM analyses showed a statistically significant effect of solanezumab across cognitive and functional outcome measures. DPM results were generally consistent with MMRM results, ranging from 15% to 30% slowing of clinical progression.DISCUSSION:These analyses suggest low-dose solanezumab slows clinical progression of AD with mild dementia. The ongoing A4 solanezumab study in participants with preclinical AD will ascertain the effect of a higher dose of solanezumab in an earlier disease stage.HIGHLIGHTS:Individual EXPEDITION studies were negative but suggest low-dose solanezumab had an effect in slowing the clinical progression of Alzheimer's disease (AD) with mild dementia. At 80 weeks, mixed-model repeated-measures analyses showed numeric reductions in measures of clinical decline in solanezumab-treated arms compared with placebo across almost every outcome measure, and statistical significance in multiple outcome measures in each study. Pooled analyses suggest a high probability that low-dose solanezumab has at least some effect on slowing the clinical progression of AD with mild dementia. Across cognitive and functional outcome measures, estimates from disease progression model analyses range from 15% to 30% slowing of decline with low-dose solanezumab in AD with mild dementia.

INTRODUCTION:Apolipoprotein E (APOE) ε4 may interact with response to amyloid-targeting therapies. METHODS:Aggregate data from trials enrolling participants with amyloid-positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. RESULTS:Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non-carriers. Carrier and non-carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) were -0.30 (-0.478, -0.106) and -0.20 (-0.435, 0.042) and AD Assessment Scale-Cognitive subscale (ADAS-Cog) values were -1.01 (-1.577, -0.456) and -0.80 (-1.627, 0.018), respectively. Decline in the APOE ε4 non-carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. DISCUSSION:We hypothesize that APOE ε4 carriers have same or better response than non-carriers to amyloid-targeting therapies and similar or less disease progression with placebo in amyloid-positive trials. HIGHLIGHTS:Amyloid-targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers. Clinical decline is the same/slightly faster in amyloid-positive APOE ε4 non-carriers. Prevalence of non-carriers in trial populations could impact outcomes.

This post hoc analysis of the randomized clinical trial, Study of LY3002813 in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ), investigates if amyloid reduction from donanemab treatment is associated with slowing of tau pathology and clinical decline in individuals with early symptomatic Alzheimer disease.

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.

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

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.).

Abstract Introduction Lanabecestat, a beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) inhibitor, was investigated as a potential Alzheimer's disease (AD)‐modifying treatment. As previously reported, amyloid beta (Aβ) neuritic plaque burden reduction did not result in clinical benefit. Lanabecestat's effects on neuroimaging biomarkers and correlations between neuroimaging biomarkers and efficacy measures are reported. Methods AMARANTH and DAYBREAK‐ALZ were 104‐ and 78‐week, multicenter, randomized, double‐blind, placebo‐controlled studies of lanabecestat in early symptomatic AD (AMARANTH) and mild AD dementia (DAYBREAK‐ALZ). Patients randomly (1:1:1) received placebo, lanabecestat 20 mg, or lanabecestat 50 mg daily (AMARANTH, n = 2218; DAYBREAK‐ALZ, n = 1722). Florbetapir positron emission tomography (PET), fluorodeoxyglucose (FDG) PET, flortaucipir PET, and volumetric magnetic resonance imaging (MRI) were used to measure Aβ neuritic plaque burden, cerebral metabolism, aggregated tau neurofibrillary tangles, and brain volume, respectively. Additionally, florbetapir perfusion scans were performed in DAYBREAK‐ALZ. Efficacy measures included 13‐item Alzheimer's Disease Assessment Scale–Cognitive Subscale, Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, Clinical Dementia Rating–Sum of Boxes, Functional Activities Questionnaire, and Mini‐Mental State Examination. These studies stopped early due to futility. Results Despite previously observed annualized reduction in Aβ neuritic plaque burden, there were no treatment differences in annualized change of aggregated tau neurofibrillary tangle burden (AMARANTH, n = 284; DAYBREAK‐ALZ, n = 70), cerebral metabolism (AMARANTH, n = 260; DAYBREAK‐ALZ, n = 38) and perfusion (DAYBREAK‐ALZ, n = 213). Greater brain volume reduction (AMARANTH, n = 1697 [whole brain]; DAYBREAK‐ALZ, n = 650 [whole brain]) occurred on lanabecestat compared to placebo. Higher baseline aggregated tau neurofibrillary tangle burden, lower cerebral metabolism, and lower brain volumes correlated with poorer baseline efficacy scores and greater clinical worsening. Lower baseline cerebral perfusion correlated with poorer baseline efficacy scores. Reduction in cerebral metabolism or whole brain volume correlated with clinical worsening, regardless of treatment assignment. Discussion Tau pathology and cerebral metabolism assessments showed no evidence of lanabecestat slowing pathophysiologic progression of AD. Lanabecestat exposure was associated with brain volume reductions. Correlations between imaging measures and cognitive assessments may aid future study design.

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.