FOLLOWING THE LIVE DISCUSSION, THE RECORDING WILL BE AVAILABLE IN THE ON-DEMAND SECTION OF THE AUDITORIUM.
To evaluate treatment effects of anti-amyloid antibody Gantenerumab on neuroimaging outcomes in individuals carrying autosomal dominant mutations in PSEN1, PSEN2, APP genes enrolled in the DIAN-TU
Participants were randomized into drug (n=52) or placebo arms (n=40) and received up to 48 months of drug treatment. Longitudinal structural MRI, [11C]-Pittsburgh Compound B (PiB) PET, and [18F]-fluorodeoxyglucose (FDG) PET imaging data were processed using FreeSurfer and the PET Unified Pipeline (PUP) and analyzed using linear mixed effects models. Models estimated the longitudinal effects of Gantenerumab treatment on imaging outcomes of the DIAN-TU trial.
Treatment significantly reduced the longitudinal increase of mean cortical PiB PET signal (β = -.06, SE = .01, t = -5.83, p < .0001), but did not affect the additional imaging endpoints of precuneus FDG (β = -.01, SE = .005, t = -1.579, p = .118) or precuneus thickness (β = .003, SE = .007, t = 0.388, p = .69). Estimated effects on PiB PET varied regionally in a pattern distinct from baseline PiB PET levels (Figure 1).
Gantenerumab successfully lowered levels of beta-amyloid as indexed by PiB PET imaging. The regional pattern of drug effects suggest clearance is not solely driven by baseline levels of pathology. The observed pattern may be influenced by Gantenerumab having a differential impact on diffuse versus dense-core beta-amyloid plaques or variability in blood brain barrier permeability that may lead to differential local concentration of the drug.
Donanemab is an antibody targeting a modified form of Aβ called N3pG. This study aimed to assess the potential treatment effects of donanemab on disease progression in individuals with early symptomatic Alzheimer’s Disease (AD).
TRAILBLAZER-ALZ (NCT03367403) was a randomized, placebo-controlled, double-blind, multi-center Phase 2 study assessing the safety, tolerability and efficacy of donanemab in patients with early symptomatic AD. The trial enrolled 272 patients, selected based on cognitive assessments in conjunction with amyloid and tau positron emission tomography (PET). The primary efficacy endpoint was change from baseline to 76 weeks in the Integrated AD Rating Scale (iADRS), a composite tool combining the AD Assessment Scale-Cognitive subscale (ADAS-Cog13) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL) for function. Secondary endpoints included changes in CDR-SB, ADAS-Cog13, ADCS-iADL, MMSE, amyloid PET, tau PET, and volumetric MRI.
Donanemab significantly slowed the clinical decline compared to placebo on the primary outcome, iADRS, by 32%. On average, patients who received donanemab showed an 84 centiloid reduction of amyloid plaque at 76 weeks. In the donanemab treatment group, amyloid-related imaging abnormalities – edema (ARIA-E) occurred in 27% of treated participants. Secondary and exploratory outcome measures will be presented.
To evaluate preliminary findings for BAN2401, a humanized IgG1 monoclonal antibody that selectively binds Aβ protofibrils, to evaluate the longitudinal amyloid positron emission tomography (PET) findings in subjects who participated in the Core amyloid imaging subgroup.
A total of 39 subjects who participated in the Core imaging subgroup are evaluated in the Open Label Extension (OLE) imaging subgroup (Core allocation: placebo:10; 10 mg/kg monthly:19; 10 mg/kg biweekly:10). All subjects received 10 mg/kg biweekly for up to 12 months in the OLE. All subjects were amyloid positive at baseline in the core study based on PET visual read. Piecewise regression analyses were conducted on amyloid PET standard uptake value ratio (SUVr) over the 18-month core period, at baseline of the OLE, and over 12 months during the OLE.
Reductions were dependent on Core treatment assignment and PET SUVr at OLE baseline, with model-estimated slope for change from baseline SUVr of -0.026 in Core placebo-treated subjects, compared to -0.004 in Core 10 mg/kg biweekly-treated subjects over the 12-month OLE. Change from core baseline point estimate SUVr values for Core placebo-treated subjects were 0.05022, -0.027, -0.104, and -257 at OLE baseline, 3, 6, and 12 months, respectively, in the OLE. Point estimate SUVr values for Core BAN2401-treated subjects changed less relative to OLE baseline over the 12-month OLE.
Results from this preliminary analysis suggest that 10 mg/kg biweekly BAN2401 elicits rapid reduction of brain amyloid that is apparent as early as 3 months of treatment.