Eisai (United States)

BackgroundSingle analyte blood‐based biomarkers such as p‐tau181 and p‐tau217 are promising biomarkers for identifying Alzheimer's disease (AD) pathology. However, multi‐analyte blood‐based biomarker panels are needed to further improve the detection, differential diagnosis, and screening of AD and to predict disease progression and assess response to therapy. The Alamar NULISASeq CNS Disease Panel (“NULISASeq”) simultaneously profiles 120 proteins associated with neurodegeneration, synaptic, and inflammatory pathways to support these goals. Multiplexed panels also maximize the potential of precious clinical trial biospecimens while also providing the sensitivity required to measure low abundant analytes.MethodsPlasma samples were collected during screening from a Phase 3 program for elenbecestat (MissionAD) in early AD and analyzed using NULISASeq. Data normalization was performed using the vendor protocol to form NULISA Protein Quantification (NPQ) units, used for statistical analysis. Analysis of Variance (ANOVA) was used to determine statistical significance of the difference in each target protein level between amyloid+ and amyloid‐ subjects as determined by PET visual read. p‐values were adjusted for multiplicity. Cohen's D was calculated to show the effect size of difference in target protein levels. The correlation of overlapping target protein levels between NULISASeq and other assays was evaluated.ResultsA total of 124 subjects were included in the statistical analysis (74 amyloid+ and 50 amyloid‐). Statistical significance was observed in 7 plasma proteins (GFAP, MAPT, NEFH, SNAP25, pTau‐181, pTau‐217, pTau‐231) between amyloid+ and amyloid‐ subjects. pTau‐217 showed the largest effect size. In predicting amyloid status, using pTau‐217 alone also resulted in the highest AUC (0.87). Combining these proteins did not result in much improvement in prediction. NULISASeq protein levels of common ATN biomarkers showed high correlation with that of other assays in both plasma and CSF.ConclusionTargeted multiplexed panels such as NULISASeq quantifies multiple analytes in a single run thereby reducing the amount of precious input material and the time required for analysis. This offers advantage over fluid and neuroimaging‐based measurements tailored to singular targets. We have demonstrated the utility of a multiplexed panel for reliable detection of amyloid status as well as highlighted the potential of discovering novel biomarkers associated with AD.

Aims Intravenous (IV) lecanemab is approved for the treatment of patients with early Alzheimer’s disease (AD); a subcutaneous (SC) option may offer additional benefits. We assessed the overall value of SC treatments, and direct/indirect outcomes associated with IV and SC lecanemab. Methods and materials For the narrative review, PubMed was searched (February 2025) for studies comparing patient preferences for IV/SC treatment administration published between 2015–2025. Study eligibility was determined using patient, intervention, comparator, outcomes, and study criteria. For the decision-analytic model, a Markov model was developed with four lecanemab treatment scenarios. Scenarios one to three included IV initiation (10 mg/kg biweekly) to month 18, followed by either IV initiation continued (10 mg/kg biweekly), SC maintenance (250 mg weekly) or IV maintenance (10 mg/kg every 4 weeks). Scenario four included SC initiation (500 mg weekly) for an 18-month period, followed by SC maintenance (250 mg weekly). Outcomes were administration time/frequency; patient, caregiver, and healthcare professional time; and caregiver productivity loss. Results Forty-three publications reported patient treatment preferences. Most (88.4%) reported that patients preferred SC over IV. Key reasons for this were time savings (n = 13/43 studies; 30.2%), convenience (n = 11/43; 25.6%), and treatment frequency (n = 12/43; 27.9%). Two studies (n = 2/43; 4.7%) reported an IV preference over SC; for three studies (n = 3/43; 7.0%), treatment preference was driven by administration frequency. Decision-analytic modeling of lecanemab treatment scenarios revealed that IV initiation to IV maintenance had the lowest number of administrations, whereas SC initiation to SC maintenance had the lowest number of treatment hours and caregiver productivity losses. Limitations Caution must be taken when generalizing these results for all AD patients. Conclusions SC treatments show value as a therapeutic option. IV and SC lecanemab availability may offer benefits to patients, caregivers, and society, and improve shared decision making.

Variability in cognitive decline in preclinical Alzheimer's disease (AD) presents a significant challenge in evaluating treatment effects in clinical trials. This study developed models to forecast cognitive progression and assessed their potential to improve the precision of treatment effect estimates in future trials. Data were from the Phase III Anti-Amyloid Treatment trial of Solanezumab in amyloid-positive asymptomatic preclinical AD. Due to no significant cognitive decline differences between groups, the Solanezumab arm (n=549) was used for training, and the placebo arm (n=559) for validation. Cognitive decline was assessed as 24-week changes in Preclinical Alzheimer's Cognitive Composite (PACC) score over 216 weeks. A predictive model for PACC decline was developed using demographics, APOE ε4 status, and baseline clinical assessments (PACC composite score, its components, and CDR-SB), employing Stochastic Gradient Boosting. The added value of amyloid PET Centiloid (CL), plasma pTau217 (electrochemiluminescence assay), MRI morphometrics, and tau PET measures (375-participant substudy) were evaluated. Model performance was optimized via cross-validation and validated in the placebo group. The impact of baseline PACC decline predictions as an Alzheimer's Prognostic Covariate (APC) on treatment effect assessments was evaluated in trial simulations. A model with demographics, CL, and clinical assessments explained 16% of PACC decline at week 216 (R²=0.16), improving over CL or clinical assessments alone (p<0.05). Adding MRI increased R² to 0.23 (p<0.05); replacing CL with plasma pTau217 or tau PET raised it to 0.25 and 0.42, respectively. Without tau PET in the model, key baseline predictors were pTau217, CL, PACC, MMSE, inferior temporal area, and entorhinal volume. When tau PET was included, it became the strongest predictor, with fusiform, inferior temporal, and supramarginal regions being the most predictive. Simulations showed baseline prediction of PACC decline as APC can reduce treatment effect variance by 20.3%, increase power from 80% to 88%, or reduce sample size by 21.5%. Incorporating tau PET further reduces variance by 37%, increases power to 94%, and decreases sample size by 35%. Baseline tau PET was the strongest predictor of PACC decline. Using baseline-predicted PACC decline as APC can enhance treatment effect estimates and trial efficiency in preclinical AD.

Lecanemab is a humanized IgG1 monoclonal antibody with high affinity to Aβ soluble protofibrils. In two clinical studies (phase 2 and phase 3 Clarity AD) in early AD, lecanemab substantially reduced amyloid PET and slowed clinical decline on multiple measures of cognition and function, including CDR-SB at 18 months. Herein, we present the rationale for continued lecanemab dosing with a weekly 360 mg subcutaneous formulation beyond the initial 18-month treatment, utilizing semi-mechanistic models and simulations correlating lecanemab exposure with amyloid PET, plasma biomarkers, and clinical outcomes. Models describing the relationship between serum lecanemab exposure, amyloid PET, and CDR-SB have been previously described. Individual post-hoc model estimates for pharmacokinetics, PET, and CDR parameters were obtained from Clarity AD subjects who received lecanemab and were used to simulate change in amyloid PET, CDR-SB, and biomarkers (Ab42/40 ratio, ptau181, and GFAP) over 4 years. Simulations were conducted to evaluate the effect of lecanemab after continuous every 2-week treatment or after transitioning to 360 mg subcutaneous weekly dosing at 18 months. Models included data for 110 months from the lecanemab phase 2 study and 54 months of continuous lecanemab biweekly dosing from Clarity AD. Continued lecanemab treatment with 360 mg subcutaneous dosing resulted in a similar additional reduction of amyloid PET over 4 years of treatment as continued intravenous lecanemab. There were no differences in clinical outcomes (e.g. CDR-SB) between continued biweekly intravenous doses and 360 mg subcutaneous maintenance dose regimens. The 360 mg subcutaneous formulation weekly dosing maintains plasma biomarker (Aβ42/40, GFAP, p-tau181) at levels consistent with inhibition of AD pathology and neuroinflammation. Similar effects were observed across all assessments. Maintenance subcutaneous lecanemab dosing will reduce the burden for subjects and their caregivers associated with lecanemab administration while still maintaining the efficacy observed with lecanemab biweekly treatment. Modeling indicates that maintenance therapy with subcutaneous lecanemab prevents biomarker re-accumulation and has no significant meaningful impact on amyloid or meaningful impact on disease progression compared to the intravenous regimen. A subcutaneous formulation has the potential to improve the lecanemab safety profile with a more patient friendly and convenient route of administration.

BackgroundA subcutaneous formulation of the anti‐amyloid antibody lecanemab is being developed to improve patient convenience and safety. Herein, we will give an update on the early development history of subcutaneous lecanemab, including establishing the bioavailability and bioequivalence of a lecanemab subcutaneous formulation relative to the intravenous formulation.MethodsTwo single‐dose phase 1 clinical trials in healthy adult participants were performed. The first study was a randomized, parallel‐group study in 60 participants evaluating the absolute bioavailability and pharmacokinetic profile of lecanemab when administered subcutaneously in a 700 mg fixed dose compared to 10 mg/kg of intravenous lecanemab. The second study was a randomized, parallel‐group study in 160 participants to establish the bioequivalence of 720 mg subcutaneous lecanemab when administered by vial compared to autoinjector. Concentrations of lecanemab in serum were measured for 50 days, and noncompartmental PK parameters were calculated. Exposure‐response modeling was conducted to predict efficacy for subcutaneous formulations.ResultsIn the bioavailability study (subcutaneous:29; intravenous:30 subjects), mild/moderate injection site reactions were experienced by 6 (20.7%) subjects who received subcutaneous lecanemab, whereas grade 1 and 2 infusion‐related reactions were experienced by 10 (33.3%) subjects who receive intravenous lecanemab. The absolute bioavailability of subcutaneous vial was 49.7% (90% CI: 43.5, 56.8). In the bioequivalence study (vial/syringe:80; autoinjector: 80 subjects), the mean Cmax for vial/syringe (53.7 μg/mL) was lower than the mean Cmax for the autoinjector (67.4 μg/mL). The mean AUC(0‐t) and AUC(0‐inf) were lower for vial/syringe (17,100 and 17,500 ug·h/mL, respectively) compared to the autoinjector (20,600 and 20,900 ug·h/mL, respectively). The half‐life of lecanemab was approximately 7 days in both treatment groups. Autoinjector administration resulted in approximately 25% higher Cmax and 20% higher AUC compared to administration with vial/syringe. The upper 90% CI of the difference in geometric means were outside the standard reference of 125%, therefore bioequivalence of the autoinjector and vial/syringe administrations was not demonstrated. However, based on these results, exposure‐response models predicted similar amyloid plaque lowering and efficacy for intravenous, subcutaneous vial and autoinjector.ConclusionsSubcutaneous injection of lecanemab using a vial or autoinjector yielded comparable average steady‐state concentrations to intravenous administration of lecanemab in healthy patients.

BackgroundPreviously, we proposed disease staging using the Lawton‐Brody Instrumental Activities of Daily Living Scale (IADL) in patients with mild cognitive impairment (MCI) or Alzheimer's dementia (AD), using a crosswalk against the Mini‐Mental State Examination (MMSE). This study aimed to estimate disease trajectory based on proposed IADL Alzheimer's stage cut‐off scores.MethodPatients with MCI or AD who had an IADL administered between 2016–2024 were identified from the US Veteran's Affairs Healthcare System administrative database. IADL cut‐offs were derived in four ways: descriptive values, and least squares (LS) means from linear, categorical, and repeated measures analysis; this study used linear LS means, grouped as >5.4, 4.7‐5.4, 4.1‐<4.7, 2.7‐<4.1, <2.7 for normal, MCI, mild, moderate, and severe stages, respectively. IADL scores were analyzed using mixed effects statistical modeling with patient's state of residence (reflecting care location) as a random effect, controlling for demographics. Disease stage transition over time was estimated, allowing nonlinear trends and interactions with initial diagnosis of MCI vs AD.ResultOur sample (N = 90,114) had a mean age of 80.2 years (97.5% men, 14.1% Black, and 17.0% Hispanic). MCI patients (n = 54,569) had a mean age of 79.2 years (97.4% men, 14.5% Black, and 13.1% Hispanic); AD patients (n = 35,545) were aged 81.7 years (97.7% men, 13.4% Black, and 22.9% Hispanic). Acetylcholinesterase inhibitors and/or memantine was used in 28% of patients overall, and in 23.6% and 34.9% of patients with MCI and AD, respectively. In the MCI group, estimated transition times were 5.2 years from MCI to mild, 2.9 years from mild to moderate, and 4.8 years from moderate AD to severe stages, based on the IADL cut‐offs. In the AD group, estimated transition times were 3.5 years from mild to moderate, and 5.3 years form moderate to severe stages.ConclusionFunctional deterioration appeared to progress to severe stage within 9 years for AD and within 13 years for MCI. Polynomial growth curves may tend to skew transition times at more advanced stages; however, trajectory estimations provide an alternative measure of disease progression with IADL, a broadly used assessment in clinical practice, to assess functional decline corresponding to cognitive deterioration.