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Background Amyloid PET imaging enables the in vivo visualization and quantification of amyloid-beta deposits in the brain. In research and clinical settings, it is further used to monitor amyloid-beta burden as well as the biological response to disease-modifying therapies. Amyloid-beta targeting monoclonal antibodies (mAbs) such as lecanemab and donanemab were designed to reduce brain amyloid-beta burden. If the PET tracer and the mAbs would bind to the same site, the PET signal may be impacted in patients undergoing therapy. Binding interaction studies were conducted to verify the reliability of PET readouts in this setting. The aim of this study was to investigate whether lecanemab or donanemab interfere with the binding of the amyloid PET tracer florbetaben to aggregated amyloid-beta deposits in vitro. Methods Human Alzheimer’s disease (AD) brain tissue from various sources was used to assess potential interactions between florbetaben and lecanemab or donanemab. Three complementary approaches were used to confirm target binding and to study potential interactions: (1) competitive immunohistochemistry (IHC), (2) competitive autoradiography (ARG), and (3) ligand binding assays (LBA). Results Across all three sets of experiments, no evidence of competition or inhibition of florbetaben binding to amyloid-beta deposits by lecanemab or donanemab was observed. Autoradiography demonstrated robust tracer binding to amyloid-beta plaques that was unaffected by incubation with excess antibody. Similarly, IHC and LBA experiments confirmed that florbetaben and the tested mAbs target distinct binding sites on amyloid-beta aggregates. Conclusions These results demonstrate that neither lecanemab nor donanemab interfere with florbetaben binding to amyloid-beta plaques in vitro, further validating its use in this setting. While the current data are limited to in-vitro experiments, they further support the use of florbetaben PET for monitoring amyloid-beta changes during treatment with amyloid-beta targeting therapies.

INTRODUCTION The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid‐related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ‐801/valiltramiprosate, an oral brain‐penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. METHODS This Phase 3 randomized, double‐blind, placebo‐controlled, 78‐week study of ALZ‐801 administered as 265 mg twice per day tablets, enrolled 50‐ to 80‐year‐old homozygotes with Mini‐Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating–Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug–placebo difference on the Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating–Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. RESULTS The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. DISCUSSION APOLLOE4 is the first disease‐modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ‐801 has the potential to be the first effective and safe anti‐amyloid treatment for the high‐risk APOE ε4/ε4 population. Highlights The APOLLOE4 Phase 3, placebo‐controlled, 78‐week study is designed to evaluate the efficacy and safety of ALZ‐801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype. The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini‐Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD). The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating–Sum of Boxes, Amsterdam‐Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes. The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA). At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%). Study results will become available in the second half of 2024 and, if positive, ALZ‐801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

Lecanemab is an anti-amyloid monoclonal antibody demonstrated to slow cognitive decline in early Alzheimer's disease (AD) in clinical trials. In August 2024, it was approved in the UK for the treatment of AD patients with mild cognitive impairment or early dementia who are apolipoprotein E4 heterozygotes or non-carriers. Here, we present a clinical snapshot of the first 26 patients treated with lecanemab in a real-world UK setting. Our findings offer early insights into the novel use of anti-amyloid therapy in clinical practice, marking a new era in AD treatment. Patients referred to Re:Cognition Health, London, underwent screening to confirm AD diagnosis and eligibility for lecanemab. Lecanemab infusions commenced in November 2024. Collected data includes patient demographics, disease and treatment characteristics, and adverse events (AE). Patient experience was evaluated using the standardised Quality of Life in Alzheimer's Disease (Qol-AD) patient/caregiver survey. 41 AD patients were referred for anti-amyloid therapy, of whom 26 consented and were eligible to receive lecanemab. The mean cohort age was 72 years with 69% patients being female (Table 1). Most patients (81%) had university-level education. All patients had confirmed amyloid biomarker status, verified during or prior to screening via neuroimaging or lumbar puncture. The mean (standard deviation) time from diagnosis to first infusion was 26.2 (22.4) months, while screening to infusion time was 1.3 (1.3) months. A total of 49 AEs were reported in 20 patients (76.9%), with non-amyloid-related imaging abnormalities (ARIA) AEs comprising 91.8% of all events (Table 2). The most frequently reported AEs included infection (24.4%), infusion-related reactions (11.1%), headache (4.4%), confusion (4.4%) and vertigo (4.4%). ARIA was observed in 4 patients (8.2%), all of whom had pre-existing ARIA at baseline. No serious AEs were reported. Results from the ongoing QoL-AD survey show that patients felt better since initiating lecanemab treatment. This report presents the first real-world experience of lecanemab treatment for AD patients in the UK. Our findings demonstrate feasibility of anti-amyloid therapy in clinical practice, manageable safety profile and early indications of positive patient-reported outcomes. These insights can inform service development and support clinical uptake of novel disease-modifying therapies.

Background Lecanemab is an anti‐amyloid monoclonal antibody demonstrated to slow cognitive decline in early Alzheimer’s disease (AD) in clinical trials. In August 2024, it was approved in the UK for the treatment of AD patients with mild cognitive impairment or early dementia who are apolipoprotein E4 heterozygotes or non‐carriers. Here, we present a clinical snapshot of the first 26 patients treated with lecanemab in a real‐world UK setting. Our findings offer early insights into the novel use of anti‐amyloid therapy in clinical practice, marking a new era in AD treatment. Method Patients referred to Re:Cognition Health, London, underwent screening to confirm AD diagnosis and eligibility for lecanemab. Lecanemab infusions commenced in November 2024. Collected data includes patient demographics, disease and treatment characteristics, and adverse events (AE). Patient experience was evaluated using the standardised Quality of Life in Alzheimer's Disease (Qol‐AD) patient/caregiver survey. Result 41 AD patients were referred for anti‐amyloid therapy, of whom 26 consented and were eligible to receive lecanemab. The mean cohort age was 72 years with 69% patients being female (Table 1). Most patients (81%) had university‐level education. All patients had confirmed amyloid biomarker status, verified during or prior to screening via neuroimaging or lumbar puncture. The mean (standard deviation) time from diagnosis to first infusion was 26.2 (22.4) months, while screening to infusion time was 1.3 (1.3) months. A total of 49 AEs were reported in 20 patients (76.9%), with non‐amyloid‐related imaging abnormalities (ARIA) AEs comprising 91.8% of all events (Table 2). The most frequently reported AEs included infection (24.4%), infusion‐related reactions (11.1%), headache (4.4%), confusion (4.4%) and vertigo (4.4%). ARIA was observed in 4 patients (8.2%), all of whom had pre‐existing ARIA at baseline. No serious AEs were reported. Results from the ongoing QoL‐AD survey show that patients felt better since initiating lecanemab treatment. Conclusion This report presents the first real‐world experience of lecanemab treatment for AD patients in the UK. Our findings demonstrate feasibility of anti‐amyloid therapy in clinical practice, manageable safety profile and early indications of positive patient‐reported outcomes. These insights can inform service development and support clinical uptake of novel disease‐modifying therapies.

Valiltramiprosate/ALZ-801, an oral inhibitor of amyloid oligomer formation, was evaluated in a Phase 3 trial in APOE4/4 homozygotes with Early AD, with main results presented at this meeting (Power et al, 2025). APOE4 is a risk factor for cerebral amlyloid angiopathy (CAA) and ARIA. Tramiprosate (active agent in ALZ-801) had shown no ARIA-E in prior studies, allowing the APOLLOE4 trial to include subjects with any number of microhemorrhages (MH) and several siderosis lesions at screening MRI. This 78-week placebo-controlled trial enrolled 325 homozygotes who received placebo or 265 mg BID. Anti-coagulants were exclusionary. In addition to adverse event (AE) assessments, MRIs were performed every 26 weeks and evaluated by Clario Inc. for occurrence of ARIA with edema and/or microhemorrhage/siderosis (ARIA-E, ARIA-H). Safety population (N =325) was 51% females, 89% Caucasian, mean age 68 years, MMSE 25.6, with MCI vs. Mild AD (39% vs 61%); 298 had screening MRI (149/arm provided ≥1 post-dose MRI). At baseline, 32% had >1 MH (placebo, 32%, active, 31%); 11% in placebo and 8% in active arm had siderosis (maximum 4 and 5 lesions, respectively); and 5% in each arm had ≥ 10 MH. New ARIA-E occurred during the study in 5 subjects in each arm (3%) and new macrohemorrhages in 2 subjects/arm. Increase in MH from low to high category (0, 1-4, 5-9, ≥10 MH) was seen in 14% placebo and 9% active arm. Radiographic ARIA were all mild except 1 severe (placebo) and 1 moderate (active); all were without symptoms. AEs with incidence >5% and >2x placebo rate were nausea (26%), weight decrease (14%), decreased appetite and vomiting (10% each); with lower incidence of headache, falls and dizziness in active arm. APOLLOE4 enrolled homozygotes with a high CAA burden who would be ineligibile for amyloid antibody treatments. Valiltramiprosate overall safety was favorable and consistent with prior studies. ARIA-E incidence was similar to placebo, and ARIA-H was lower than placebo with no symptomatic ARIA events over 78 weeks of treatment. Coupled with promising efficacy in MCI subjects, valiltramiprosate can provide a favorable benefit-risk profile for the high-risk APOE4/4 patients with unmet treatment need.

Valiltramiprosate (ALZ-801) is an oral inhibitor of amyloid oligomer formation. Tramiprosate (active agent in ALZ-801) had shown promising efficacy signals with favorable safety in ∼1300 APOE4 carriers with AD, with no observed ARIA-E. This trial evaluated Valiltramiprosate in APOE4/4 homozygotes with Early AD. This 78-week double-blind, placebo-controlled, two-arm trial that randomized 325 homozygotes (162 to placebo, 163 to 265 mg BID), stratified by MCI (MMSE 27-30) or Mild AD (MMSE 22-26). MRI (1.5/3 Tesla) were conducted every 26 weeks and analyzed by Clario Inc. The clinical outcomes were ADAS-Cog13 (primary), CDR-SB (key secondary) and DAD (disability assessment for dementia, secondary). Hippocampal volume (HV) was the main imaging outcome. MMRM was the primary analysis model. Safety population (N =325) was 51% females, 90% Caucasian, mean age 68 years, MMSE 25.6, 39% with MCI (MMSE 27-30) and 30% with baseline microhemorrhages and/or siderosis. In the full analysis set (N =320), the placebo-adjusted least-square mean (LSM) difference in change from baseline (CBL) on ADAS-Cog13 favored drug non-significantly (delta=-0.50; p =0.61, 11% vs placebo CBL); CDR-SB and DAD numerically favored drug by 23% and 29%, but HV favored drug significantly (74 mm , nominal p =0.017, 18% less atrophy). Prespecified Mild AD showed small nonsignificant clinical effects favoring placebo, but showed numerical benefit on HV (51mm , 12% p = 0.115). In prespecified MCI, all outcomes favored drug (nominal p -values): ADAS-Cog13= -2.14 (p =0.041; 52%); CDR-SB= -0.65 (p =0.053, 104%); DAD= 6.09 (p =0.016, 96%); and HV= 108 mm (p = 0.004, 26% less atrophy). Nausea (mostly mild) was the most common adverse event; incidence of ARIA-E was the same as placebo. In the overall population, ADAS-Cog13 did not achieve significance, but the hippocampus showed significant 18% slowing of atrophy. The pre-specified Mild group showed trends to HV atrophy slowing that did not translate to clinical benefits. The pre-specified MCI group showed significant 28% HV atrophy slowing with meaningful cognitive and functional benefits and positive trends on several secondary clinical outcomes. Overall safety was favorable with no increased ARIA. In the high-risk APOE4/4 population, this positive benefit-risk profile supports valiltramiprosate's potential as an oral disease-modifying treatment for APOE4/4 homozygotes with MCI.

Background ALZ‐801/valiltramiprosate, an oral small molecule inhibitor of amyloid oligomer formation, is being evaluated in a Phase 3 trial in APOE4/4 Early AD subjects (APOLLOE4). Topline results are expected in 3Q 2024. APOE4 is a major risk factor for Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) with a gene‐dose effect. APOE4/4 subjects with CAA are at higher risk of amyloid related imaging abnormalities (ARIA) with anti‐amyloid antibodies, including ARIA‐E (effusion/edema) and ARIA‐H [lobar microhemorrhages (MH), macrohemorrhages, and superficial siderosis (SS)]. APOE4 carriers are also at higher risk of hyperlipidemia and cardiovascular disease (CVD). Baseline prevalence of CAA and CVD risk factors were analyzed. Method This Phase 3 trial (NCT04770220) enrolled 325 APOE4/4 Early AD subjects (MMSE ≥22, 50‐80 years); 313 had baseline MRIs with central readings. Subjects with MH and SS were enrolled; ARIA‐E was exclusionary. Subjects with CAA (>4 MH, any siderosis, any macrohemorrhage) were compared to rest of population. Result Study population was 51% female, age 69 years, MMSE 26, 65%/MCI, 82% Caucasians. CAA group included 47/313 subjects (15%) of study, was mostly male (70% vs 45%), older (71 vs. 68 years, p = 0.004), more advanced (MMSE 25 vs 26, p = 0.018; ADAS‐cog 27 vs. 23, p = 0.002) with more severe deep WMD (p = 0.015). Both groups had similar prevalence of hypertension, diabetes, obesity, hyperlipidemia, and statin use but with higher coronary artery disease prevalence (17% vs. 8%, p = 0.049) and anti‐platelets use (38% vs 22%, p = 0.026) in the CAA group. No anticoagulants were allowed. Conclusion ALZ‐801 showed no ARIA‐E in prior AD studies allowing its evaluation in the high‐risk APOE4/4 homozygotes. This pivotal APOLLOE4 Phase 3 trial of ALZ‐801 enrolled homozygous APOE4/4 subjects with higher CAA burden than anti‐amyloid antibody trials. The APOE4/4 CAA subjects were older with more advanced AD and higher rates of CAD and antiplatelets use than non‐CAA subjects, which may increase brain edema and microhemorrhage risk, requiring heightened vigilance with anti‐amyloid antibodies. If this Phase 3 trial is positive, ALZ‐801 could become a potentially safer alternative to anti‐amyloid antibodies for this population. The Phase 3 results are expected in 3Q 2024.

Valiltramiprosate (ALZ-801), an oral inhibitor of amyloid oligomer formation, was evaluated in a Phase 3 trial in APOE4/4 homozygotes with Early AD (Abushakra, 2024); the topline results being presented at this meeting (Power, 2025). While the primary clinical endpoint was not significant, hippocampal volume (HV, main imaging outcome) showed significant slowing of atrophy. This 78-week placebo-controlled study randomized 325 homozygotes (placebo, 265 mg BID), stratified by MCI/Mild AD. ADAS-Cog13 and CDR-SB were the primary and key secondary outcomes respectively, and DAD (disability assessment for dementia) was a secondary outcome. HV was the main imaging outcome, cortical thickness and whole brain volume (CT, WBV) were secondary. Analyses by disease stage were pre-specified using baseline severity as covariate in the MMRM model; drug-effect correlations utilized Spearman's correlations. The pre-specified MCI subgroup (MMSE 27-30) included 125 subjects (58 placebo, 67 active); with balanced baseline characteristics except for cholinesterase-inhibitors (placebo 31%, active 19%). Imaging population included 54 placebo, 62 active subjects. The MCI subgroup vs placebo showed positive effects on ADAS-cog/DAD (nominal p <0.05), trend on CDR-SB (p =0.053) with significant slowing of HV, CT and WBV atrophy vs placebo (26%, p =0.004; 35% p < 0.0001; 22%, p =0.027). In the active arm, change in HV correlated significantly with change in ADAS-Cog13 (r=-0.40, p <0.005), CDR-SB (r=-0.45, p <0.005), and DAD (r=0.33, p =0.018). For CT, the correlations were also significant: ADAS-Cog13 (r=-0.34, p =0.015), CDR-SB (r=-0.49, p < 0.005), and DAD (r=0.40, p <0.005). WBV treatment effect also correlated with the clinical outcomes (p ≤ 0.01). These strong correlations between structural preservation and clinical benefits of valiltramiprosate at the MCI stage support its efficacy and are consistent with its proposed mechanism of inhibiting amyloid oligomer formation, thereby potentially protecting neurons from synaptic dysfunction and neurodegeneration. Given the accelerated neurodegeneration in APOE4/4 patients, these findings suggest that intervention at the early stages of AD when neuronal reserve is higher, may be critical for valiltramiprosate to exert meaningful clinical effects alongside preservation of brain structure and volume.

Valiltramiprosate/ALZ-801, an oral inhibitor of amyloid oligomer formation, was evaluated in a Phase 3 trial in APOE4/4 subjects with Early AD. While the study did not meet its primary clinical endpoint, volumetric MRI (vMRI) showed significant brain atrophy slowing. The pre-specified MCI subgroup showed positive effects on both clinical and vMRI outcomes. Amyloid oligomers are hypothesized to cause synaptic dysfunction and axonal damage, leading to microstructural changes and volume loss. The effects of valiltramiprosate on microstructural tissue changes in grey/white matter (GM, WM) were investigated using mean water diffusivity (MD) on diffusion MRI (dMRI-MD). This study enrolled 325 APOE4/4 homozygotes (162 placebo, 163 valiltramirposate) stratified by MCI/Mild AD. The ADAS-Cog13/CDR-SB were primary/key secondary outcomes; hippocampal volume and cortical thickness (HV, CT) were main/secondary vMRI outcomes, respectively. dMRI from 1.5/3 Tesla scanners were centrally analyzed by Clario Inc. (lower MD indicates tissue preservation). MMRM was primary analysis; Pearson's correlations were conducted. The clinical/vMRI datasets included 320/290 subjects respectively; dMRI included 206 subjects (84 MCI, 122 Mild AD). In the overall population, valiltramiprosate effects on MD compared to placebo showed positive trends (p <0.1) on cingulate/occipital cortex and caudate/striatum, and significant WM effects (corpus callosum genu [GCC] p <0.001; fornix p =0.007). Mild AD showed positive trends on occipital cortex and significant WM effects (GCC p =0.005; fornix p =0.019). MCI showed significant effects in cingulate (p =0.031) and WM (GCC/whole CC: p =0.003/0.013) and fornix (p =0.032). In MCI active arm, dMRI effects correlated significantly with clinical and volumetric effects. Frontal cortex MD correlated significantly with ADAS-Cog13/CDR-SB (p < 0.05) and HV and CT (both p =0.002). WM-GCC diffusivity correlations to HV (p =0.03) and CT were significant (p =0.006). Consistent with valiltramiprosate's effects on brain volumes, its effects on microstructural integrity were most prominent in the MCI subgroup that showed lower diffusivity in the cingulate cortex and major hippocampal outflow tracts. This microstructural preservation correlated significantly with preservation of HV/CT and with clinical benefits. These findings support valiltramiprosate's proposed mechanism: inhibiting oligomer formation may directly protect synapses/axons from damage, thus slowing neurodegeneration at a microstructural level and contributing to macrostructural preservation of brain volumes and clinical benefit.

Background Valiltramiprosate (ALZ‐801), an oral inhibitor of amyloid oligomer formation, was evaluated in a Phase 3 trial in APOE4/4 homozygotes with Early AD (Abushakra, 2024); the topline results being presented at this meeting (Power, 2025). While the primary clinical endpoint was not significant, hippocampal volume (HV, main imaging outcome) showed significant slowing of atrophy. Method This 78‐week placebo‐controlled study randomized 325 homozygotes (placebo, 265 mg BID), stratified by MCI/Mild AD. ADAS‐Cog13 and CDR‐SB were the primary and key secondary outcomes respectively, and DAD (disability assessment for dementia) was a secondary outcome. HV was the main imaging outcome, cortical thickness and whole brain volume (CT, WBV) were secondary. Analyses by disease stage were pre‐specified using baseline severity as covariate in the MMRM model; drug‐effect correlations utilized Spearman’s correlations. Result The pre‐specified MCI subgroup (MMSE 27‐30) included 125 subjects (58 placebo, 67 active); with balanced baseline characteristics except for cholinesterase‐inhibitors (placebo 31%, active 19%). Imaging population included 54 placebo, 62 active subjects. The MCI subgroup vs placebo showed positive effects on ADAS‐cog/DAD (nominal p <0.05), trend on CDR‐SB (p =0.053) with significant slowing of HV, CT and WBV atrophy vs placebo (26%, p =0.004; 35% p < 0.0001; 22%, p =0.027). In the active arm, change in HV correlated significantly with change in ADAS‐Cog13 (r=‐0.40, p <0.005), CDR‐SB (r=‐0.45, p <0.005), and DAD (r=0.33, p =0.018). For CT, the correlations were also significant: ADAS‐Cog13 (r=‐0.34, p =0.015), CDR‐SB (r=‐0.49, p < 0.005), and DAD (r=0.40, p <0.005). WBV treatment effect also correlated with the clinical outcomes (p ≤ 0.01). Conclusion These strong correlations between structural preservation and clinical benefits of valiltramiprosate at the MCI stage support its efficacy and are consistent with its proposed mechanism of inhibiting amyloid oligomer formation, thereby potentially protecting neurons from synaptic dysfunction and neurodegeneration. Given the accelerated neurodegeneration in APOE4/4 patients, these findings suggest that intervention at the early stages of AD when neuronal reserve is higher, may be critical for valiltramiprosate to exert meaningful clinical effects alongside preservation of brain structure and volume.