Baudler, Monika

AbstractBackgroundAnti‐amyloid monoclonal antibody therapies for AD have documented plaque removal on amyloid PET scans. We evaluate the findings for amyloid PET, tau PET, FDG PET and volumetric MRI over the course the open label extension (OLE) for the DIAN‐TU gantenerumab treatment, compared to the last imaging obtained prior to the OLE (to evaluate for potential rebound effects) and in comparison to longitudinal imaging in the DIAN Observational study.MethodThis double‐blind, phase 2/3 trial (2012‐2019), followed by open‐label extension (OLE), investigated varying gantenerumab doses up to 1500 mg SQ q2 weeks [NCT NCT01760005]. We report long‐term amyloid‐plaque removal by PET and findings for metabolic FDG PET and tau PET, and additionally changes of atrophy on volumetric MRI. Imaging measures were secondary outcome analyses. Comparison is made between the treatment cohort and controls (DB placebo participants who didn’t enter OLE, plus external controls from the DIAN OBS). Estimated years to onset was included as a covariate. The gap period of ∼1 year is specifically analyzed to estimate any “rebound” effect on amyloid or tau accumulation or neurodegeneration. Volumetric MRI measures include hippocampal volumes, lateral ventricular volumes, and white matter hyperintensities.ResultIn participants who were asymptomatic at baseline and treated with gantenerumab (n = 53), amyloid‐plaque removal measured by PIB‐PET in Centiloids was dose‐dependent. Few participants had reached completely negative levels (below 24). No statistical significance was found for FDG PET, tau PET, or volumetric MRI, including hippocampal volumes. Impact of the gap period of ∼1 year (gap in treatment) on the rate of amyloid accumulation compared to the rate of accumulation predicted in observational studies of this cohort is under evaluation, as are the other imaging measures.ConclusionWhile no overall effect was observed in the total group for non‐amyloid measures, results suggest dose dependent clearance of amyloid plaque in asymptomatic DIAD mutation carriers following long‐term, high‐dose gantenerumab. The potential “rebound effect” of elevated amyloid accumulation for participants for whom there was a significant gap in therapy between the trial and the OLE is under evaluation and will be presented, as will the variables for FDG PET, tau PET, and volumetric MRI.

AbstractBackgroundAlzheimer’s disease (AD) prevention trials aim to intervene prior to significant neuronal loss, brain damage, and symptom onset to delay or slow cognitive decline. In dominantly inherited AD (DIAD), mutation carriers develop symptomatic AD at predictable ages with near 100% penetrance. In 2012, the Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial (DIAN‐TU APT) platform launched a double‐blind, randomized, placebo‐controlled, parallel group trial of two anti‐amyloid‐beta monoclonal antibodies with two different antigenic targets, gantenerumab and solanezumab (NCT01760005). The DIAN‐TU scientific development, implementation of the first AD prevention trial, trial challenges and opportunities, including dose escalation, and top‐line results will be presented.MethodDIAN was established in 2008 in response to a call from the National Institute of Aging to establish a network to study DIAD and enable future clinical trials. Successive breakthroughs in understanding disease processes enabled the launch of the DIAN‐TU adaptive prevention trial, a global adaptive platform trial supporting testing multiple drugs in parallel. The DIAN‐TU partners include patients and families at risk for DIAD, global academic researchers, the NIH, Alzheimer’s Association, philanthropic supporters, the DIAN‐TU Pharma Consortium, and pharmaceutical companies with drugs being tested. Important milestones include developing a platform to enable a comprehensive efficient treatment trial for this rare population, adding tau PET as part of AMP AD, adapting dosing mid‐trial and extending the original biomarker trial to continue randomized dosing to test a cognitive endpoint until the last patient reaches 4 years, developing a disease progression statistical model and inclusion of DIAN observational data to increase the power to determine drug effects.ResultThe primary and key secondary outcomes of the DIAN‐TU trial will be presented for each therapy in the context of targeting amyloid‐beta at pre‐clinical and clinically symptomatic stages of disease.ConclusionThese results inform about AD hypotheses, timing of treatment and the prospect of slowing, or preventing AD in DIAD and sporadic AD.

AbstractBackgroundGantenerumab is a humanized anti‐amyloid‐beta monoclonal antibody in clinical development for the treatment of several stages of Alzheimer disease (AD). Gantenerumab was evaluated in a phase 2/3 clinical trial program designed to evaluate its efficacy in autosomal dominant AD based on a combination of clinical and biomarker evidence.MethodThe study enrolled both mutation carriers (n=69 with 3:1 randomization of treatment (n=52) vs placebo (n=17)) and non‐carriers (n=28, all on placebo) from 15 years before to 10 years after the expected age of onset inclusive. Patients were both asymptomatic (CDR 0 and MMSE >25) and symptomatic (CDR 0.5‐1 and MMSE >16). There were 41 asymptomatic and 28 symptomatic mutation carriers. The initial dose of gantenerumab was 225 mg monthly administered subcutaneously. The dose was titrated to 1200 mg/month following a protocol amendment based on the increased amyloid lowering seen at higher doses in the gantenerumab program in symptomatic AD. The treatment duration was a minimum of 4 years (range 48‐80 months). The primary outcome was change from baseline in the DIAN‐TU multivariate cognitive endpoint. Secondary clinical outcomes included the DIAN‐TU cognitive composite, Cogstate multivariate cognitive endpoint, CDR SB, and time to CDR progression of >0.5 points. Change from baseline in amyloid PET was the primary biomarker outcome. Other biomarker outcomes included MRI, tau PET, CSF amyloid, tau and phosphotau, and CSF and plasma neurofilament light (NfL). Safety outcomes including ARIA were compared between drug and placebo groups.ResultWe will report change from baseline on the DIAN‐TU multivariate cognitive endpoint, DIAN‐TU cognitive composite, CDR‐SB and other secondary efficacy endpoints. We expect significant lowering on amyloid PET with PIB and florbetapir based on the results from recent anti‐amyloid antibodies, including Gantenerumab, in sporadic AD. We will also present the results of change in other key imaging and fluid biomarkers. The frequency, duration, and severity of ARIA will be reported and compared with studies in sporadic AD.ConclusionThis clinical trial was designed to inform future for ADAD and will provide new insights on the role of amyloid reduction in both pre‐symptomatic and clinical AD.