Solanezumab in- depth outcomes

BackgroundSolanezumab is a monoclonal antibody targeting soluble forms of β- amyloid protein important in the pathogenesis of Alzheimer- s disease (AD). Three previous 18- month double- blind placebo- controlled trials of low- dose solanezumab in late- onset sporadic AD found inconsistent benefits on cognitive and functional assessments. Dominantly- inherited mutation- associated AD subjects both before and after onset of symptoms form an ideal population to study potential benefits of solanezumab therapy.MethodMutation- carrying asymptomatic (CDR 0, N=41) or mildly symptomatic (CDR 0.5 - 1, N=28) patients were treated for a minimum of 4 years and up to 7 years in a double- blind 3 to 1 active versus placebo randomized clinical trial that measured disease progression by clinical, neuropsychological and biomarker evaluations. The trial was initiated with a dose of 400 mg every 4 weeks and escalated to 1600 mg when low dose trials in sporadic AD did not meet their primary endpoints. The primary cognitive outcome measure was DIAN- MCE, composed of Delayed Recall Score of the International Shopping List Test, the Delayed Recall score of the Logical Memory IIa subtest from the Wechsler Memory Scale- Revised, the Digit Symbol Substitution Test total score from the WAIS- R and the MMSE total score. Secondary outcomes included a battery of other cognitive and functional measures. The study was powered to detect delay of cognitive disease progression in the DIAN- MCE. Biomarkers include imaging modalities (volumetric MRI, FDG, amyloid and Tau PET). CSF markers included β- amyloid, Tau and PhosphoTau species. NfL was measured in both CSF and plasma. The study used a pre- specified Bayesian multivariate disease progression model, which included dynamic borrowing of control subjects from the DIAN Observational study.ResultThe topline efficacy, safety and biomarker results will be reported.ConclusionThis study provides the first test of targeting soluble abeta forms in DIAD. It addresses the efficacy of early initiation of higher doses of solanezumab targeting soluble forms of amyloid as a disease modifying therapy. While these results are specific to DIAD, they have the potential to inform the application of anti- amyloid therapy in sporadic AD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163859/1/alz038028.pd

Gantenerumab in- depth outcomes

BackgroundGantenerumab 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163780/1/alz038049.pd

Overview of dominantly inherited AD and top- line DIAN- TU results of solanezumab and gantenerumab

BackgroundAlzheimer- 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163864/1/alz041129.pd