Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis

Abstract

BackgroundWe previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer’s disease (AD).MethodsA subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-β plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale.ResultsSixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-β plaque levels below the amyloid-β positivity threshold.ConclusionResults from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit.Trial registrationClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).

Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

“…Abbreviations: IV intravenous, SC subcutaneous, NS not significant, ADAS-cog Alzheimer's Disease Assessment Scale-cognitive subscale, CDR-SB Clinical Dementia Rating-Sum of Boxes, ARIA-E amyloid-related imaging abnormalities with effusion or edema Assessment of amyloid oligomer selectivity: relative binding activity for soluble oligomers and protofibrils was measured by Biacore surface plasmon resonance. BAN2401 showed differential binding (K D ) at 1.32 nM versus aducanumab 138 nM [10]; gantenerumab displays comparable affinity for oligomers and fibrils, and about 10× lower affinity for monomers [12]; ALZ-801/tramiprosate fully inhibits the formation of oligomer in the brain at target clinical dose [15] Data sources: aducanumab phase 3 studies [11,19] Gantenerumab, in phase 3 studies in prodromal and early AD, showed no clinical efficacy at 225 mg and 1200 mg doses administered monthly by subcutaneous (SC) injection, while significant effects on CSF p-tau and total tau (t-tau, marker of neuronal injury) were reported [13,20,22]. A recently completed study in familial AD, led by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), enrolled approximately 50 subjects into each of placebo, solanezumab, and gantenerumab arms for 4 years of treatment [21,27].…”

Zinc Therapy in Early Alzheimer’s Disease: Safety and Potential Therapeutic Efficacy

“…The Interventional study Dominantly Inherited Alzheimer Network (DIAN)-TU was a phase 2/3 clinical trial assessing cognitive efficacy of two monoclonal antibodies against Aβ in individuals with mutations causing dominantly inherited AD. Despite the marked reduction of Aβ plaques achievable by these biologic drugs [55], the study missed the primary endpoint based on cognitive testing in early 2020 [56], suggesting that Aβ accumulation, the pathological hallmark of AD, is not necessarily the unique factor influencing cognitive decline in AD [57]. As a matter to the fact, abnormal amyloid deposition exists in 20-40% of non-demented individuals [58,59].…”

Predicting future rates of tau accumulation on PET

“…Recent disease modifying Alzheimer’s therapeutic trials have targeted amyloid. Many of these trials have enrolled participants who have either preclinical or early Alzheimer’s disease ( Sperling et al , 2014 ; Sevigny et al , 2016 ; Klein et al , 2019 ). Eligibility screening is a multi-step process.…”

“…If clinical criteria are met, potential participants then undergo biomarker testing to determine that they are in the biological Alzheimer’s continuum which in recent trials has required an abnormal amyloid PET scan or CSF test ( Cummings et al , 2019 b ). The early Alzheimer’s group may include individuals who meet clinical criteria for mild cognitive impairment (MCI) or mild dementia and in addition have abnormal biomarkers ( Sevigny et al , 2016 ; Cummings et al , 2019 b ; Klein et al , 2019 ). Currently validated tests for amyloidosis are either expensive (PET) or invasive (CSF).…”