Aims

Methods

Results

Conclusions

Aims

Methods

Results

Conclusions

Aims

We investigated the effect of aducanumab treatment on plasma p-tau¹⁸¹ levels via prespecified subgroup analyses from the Phase 3 trials EMERGE (NCT02484547) and ENGAGE (NCT02477800).

Methods

In the Phase 3 studies of aducanumab, participants were randomized (1:1:1) to receive high-dose aducanumab, low-dose aducanumab, or placebo monthly over 18 months. Plasma samples were obtained from all participants. Plasma p-tau¹⁸¹ levels were assessed in those participants with samples at Baseline and Week 78.

Subgroup analyses of plasma p-tau¹⁸¹ levels were conducted for factors that included age (≤64, 65 to 74, or ≥75 years), sex (male or female), ApoE ε4 status (carrier or noncarrier), baseline clinical stage (MCI due to AD or mild AD dementia) and use of AD symptomatic medications at baseline (yes or no).

Results

A total of 870 participants in EMERGE and 945 participants in ENGAGE were included in this analysis. A reduction in plasma p-tau¹⁸¹ levels in high-dose and low-dose aducanumab groups compared with placebo was observed across subgroups in both EMERGE and ENGAGE. Results were consistent with overall plasma p-tau¹⁸¹ results from the studies, in which aducanumab significantly lowered plasma p-tau¹⁸¹ levels in a dose and time- dependent manner. A greater treatment response with respect to plasma p-tau¹⁸¹ levels was consistently observed in individuals who were ≥75 years old at baseline and in ApoE ε4 noncarriers.

Conclusions

Plasma p-tau¹⁸¹ levels are a biomarker of Alzheimer’s disease pathology. Subgroup analysis revealed a consistent reduction in plasma p-tau¹⁸¹ levels in participants treated with aducanumab across all subgroups investigated.

Aims

Twenty-eight patients from our memory clinic were initially randomized to participate in the Biogen ENGAGE study, which tested the effects of Aducanumab® in patients with mild cognitive impairment and mild dementia due to Alzheimer’s disease. After study discontinuation, 15 patients agreed to participate in an exploratory follow-up study (Clinical-trials-ID: NCT02686554) to analyze the long-term effects of Aducanumab® on CSF p(181)tau, amyloid-β ratio and cognition.

Methods

Lumbar punctures and neuropsychological assessments were performed before inclusion in the ENGAGE study, as part of the diagnostic workup at our memory clinic, and in the context of the current follow-up study, overall representing a time-span of approximately two years. Treatment response was analyzed by examining changes in CSF p(181)tau concentration and in Clinical Dementia Rating Scale (CDR) and Mini-Mental State Examination (MMSE) ratings over time. Based on a median split analysis of p(181)tau, eight patients were classified as responders, showing an average reduction of 27pg/ml and seven patients as non-responders, showing merely an average reduction of 2pg/ml.

Results

The groups showed differences in their CSF biomarker profiles, with responders showing more signs of neurodegeneration (t-tau: 592pg/ml, p(181)tau: 99pg/ml), compared to non-responders (t-tau: 442pg/ml, p(181)tau: 74pg/ml) and a more significant reduction in the amyloid-ß ratio (0.046 vs. 0.054). Clinical assessments indicated a slower cognitive decline in the responder group (▲CDR -1.3, ▲MMSE -1.9), compared to the non-responder group (▲CDR -4.6, ▲MMSE -5.0).

Conclusions

Although this was an exploratory study, our data suggests that biomarker profiles may be an important criterion for identifying individuals who will benefit from Aducanumab®.

Aims

Patient/caregiver perceptions about drug administration as well as the monitoring required during treatment with a novel therapy may provide insights into real-world treatment experience, including patient outcomes and adherence. These insights are increasingly important to researchers, clinicians, payers and regulators. Subcutaneous gantenerumab, a fully human anti-amyloid beta (Aβ) monoclonal antibody with high affinity for aggregated Aβ, is in development as a potential disease-modifying therapy for Alzheimer’s disease (AD), including 2 Phase III double-blind studies (GRADUATE 1 [NCT03444870]; GRADUATE 2 [NCT03443973]) and an open-label extension phase of these studies (POST-GRADUATE [NCT04374253]). A non-interventional, interview-based survey was recently initiated to elicit treatment-associated experiences from participants and caregivers involved in these pivotal trials of gantenerumab for early (prodromal-to-mild dementia) AD. The primary objective of these surveys is to identify facilitators and barriers to treatment with gantenerumab; this information may inform the development of real-world strategies to decrease treatment burden, if approved.

Methods

Participants in the GRADUATE studies and their caregivers will each be asked to join a separate, one-time, 60-minute semi-structured interview, up to 8 weeks after their final study visit or date of early withdrawal/discontinuation from a GRADUATE study. Input from an expert advisory board and pilot interviews with persons living with AD and their caregivers informed development of interview guides.

Results

Transcribed interviews will undergo qualitative analysis to identify common themes. This study is anticipated to conclude in 2022.

Conclusions

In-depth interviews will help characterize the experience of treatment with gantenerumab and inform its potential real-world use.

Aims

The anti-amyloid beta (Aβ) monoclonal antibody gantenerumab is in late-phase clinical development for early (prodromal-to-mild) Alzheimer’s disease (AD). Here we describe an upcoming Phase III multicentre, randomised, parallel-group, double-blind, placebo-controlled secondary prevention study (SKYLINE), evaluating the efficacy and safety of subcutaneous gantenerumab in participants at risk for or at the earliest stages of AD.

Methods

SKYLINE will enrol ~1,200 cognitively unimpaired participants (Clinical Dementia Rating Global Score=0 and Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index ≥80), aged 60–80, with confirmed Aβ pathology (cerebrospinal fluid [CSF] or positron emission tomography [PET]). Screening includes an optional exploratory blood-based biomarker (BBBM) pre-screening to predict Aβ positivity. Participants will be randomised 1:1 to 211 weeks subcutaneous gantenerumab (titrated to 1,020 mg monthly dosage) or placebo treatment administered weekly or every other week. Any participant confirmed as progressing to mild cognitive impairment or AD dementia during the study will undergo a blinded post-progression dose escalation, during which participants on placebo switch to gantenerumab. All parties will remain blinded to the assigned treatment at randomization.

Results

The primary endpoint is change from baseline to Year 4 in the Preclinical Alzheimer’s Cognitive Composite-5 score. Secondary and exploratory objectives include further efficacy assessments (e.g., clinical progression), safety (e.g., adverse events, amyloid-related imaging abnormalities), pharmacodynamic biomarkers (Aβ/Tau PET, CSF, BBBM), pharmacokinetics, and identification of additional biomarkers.

Conclusions

SKYLINE will be the first secondary prevention study of subcutaneous gantenerumab in cognitively unimpaired participants at risk for or at the earliest stages of AD.

Aims

Amyloid immunotherapy received clinical validation with monoclonal antibodies (mAb) targeting pathologic forms of Abeta. Vaccines present a more attractive strategy for treatment/prevention of AD, including in Down Syndrome (AD-DS). ACI-24 is a liposomal vaccine that incorporates Abeta 1-15 peptide in a β-sheet conformation, creating efficient B-cell crosslinking and antibody production. In 3 trials, ACI-24 was shown to be safe and well tolerated. Immunogenicity and pharmacodynamic data demonstrated target engagement. The optimized ACI-24 was developed adding a non-Abeta, universal T-cell help for an optimal antibody production.

Methods

Optimized ACI-24 was generated using the SupraAntigen^® platform. Studies in mice and monkeys were conducted and sera/plasma used to measure titers against Abeta1-42, pyroGlu-Abeta3-42 and oligomers. Epitope mapping, immunohistochemistry on AD brains and a human tissue cross-reactivity study were performed.

Results

Immunization of mice/monkeys with optimized ACI-24 induced potent antigen-specific IgGs, with titers in the range of therapeutic mAbs. The antibody response matured to higher affinity IgGs and an increase of IgGs recognizing neurotoxic species including pyroGlu-Abeta3-42 and oligomers. Vaccine induced a spectrum of antibodies recognizing the N-terminal, including the truncated pathological species. Immunized sera labeled Abeta plaques, without an off-target binding.

Conclusions

Optimized ACI-24 vaccination generates IgGs with a broader N-terminal Abeta recognition than clinically tested mAbs or vaccines. This unique binding profile, including pyroGlu-Abeta3-42 and oligomers combines the targets of mAbs (aducanumab, donanemab) and the potential of enhancing plaque reduction. These data support fast progression of optimized ACI-24 into clinics as a disease modifying treatment for AD-DS and AD.

Aims

To evaluate the PK of donanemab, an IgG1 antibody targeting N3pG (a modified form of beta amyloid present only in brain plaques), and the effect of donanemab on amyloid plaque levels.

Methods

Analyses included participants with symptomatic AD (mild cognitive impairment or mild-to-moderate AD) in the combined population from a phase 1 study (N=61; NCT02624778) and a phase 2 study (TRAILBLAZER-ALZ; N=256; NCT03367403). Dose- and exposure-response relationships were characterized relative to amyloid plaque lowering, measured by florbetapir F18 positron emission tomography. Individual PK parameter estimates were used to develop an indirect response model investigating the potential association between exposure and amyloid plaque reduction.

Results

Donanemab had a median terminal elimination half-life of 11.4 days. Clearance of donanemab was increased by body weight and antidrug antibody (ADA) titer, but not age, sex, race, creatinine clearance, or apolipoprotein E4 gene carrier status. Reductions in amyloid plaque levels were associated with maintaining median serum donanemab concentrations over 4.43 µg/mL (95% confidence interval 0.96─10.4). Although donanemab clearance increased with increasing ADA titer, most participants (over 80%) maintained concentrations above the efficacy threshold. Higher baseline amyloid plaque levels were associated with fewer participants achieving plaque levels below 11 Centiloid. In covariate analyses, no factor (including ADA status) was found to have a statistically significant impact on the effect of donanemab on amyloid plaque levels.

Conclusions

Donanemab exposure was associated with reduced amyloid plaque levels. While donanemab exposure was influenced by body weight and ADA titer, these factors did not meaningfully impact reductions in amyloid plaque levels.