At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

A Variational Bayesian inference method for parametric imaging of PET data.

In dynamic Positron Emission Tomography (PET) studies, compartmental models provide the richest information on the tracer kinetics of the tissue. Inverting such models at the voxel level is however quite challenging due to the low signal-to-noise ratio of the time activity curves. In this study, we propose the use of a Variational Bayesian (VB) approach to efficiently solve this issue and thus obtain robust quantitative parametric maps. VB was adapted to the non-uniform noise distribution of PET data. Moreover, we propose a novel hierarchical scheme to define the model parameter priors directly from the images in case such information are not available from the literature, as often happens with new PET tracers. VB was initially tested on synthetic data generated using compartmental models of increasing complexity, providing accurate (%bias<2%±2%, root mean square error<15%±5%) parameter estimates. When applied to real data on a paradigmatic set of PET tracers (L-[1-11C]leucine, [11C]WAY100635 and [18F]FDG), VB was able to generate reliable parametric maps even in presence of high noise in the data (unreliable estimates<11%±5%).

The role of psychopathology and suicidal intention in predicting suicide risk: a longitudinal study.

OBJECTIVE: In this study, we describe psychological symptoms, any relationship with suicidal intention in a sample of subjects recently attempting suicide and the predictive value of this association in later completed suicide. METHODS: An assessment was made of 467 suicidological consultations carried out by the Suicidology Unit of the Department of Neurology and Psychiatry, University of Padua, on 421 patients admitted to hospital following attempted suicide in the 5-year period 1990-1994. Suicidal intention was appraised by the Intent Score Scale (ISS). Suicide mortality was assessed after a mean follow-up period of 3.5 years. RESULTS: Psychiatric evaluation was completely negative in only 8% of cases. The most commonly identified symptom was depressed mood (79% of cases, 22% severe depression), followed by anxiety (43% of cases, 32% severe anxiety). From the study, it emerged that psychopathology seemed to influence suicidal intent, where this was characterized by severe depression. Anxiety and other symptoms appeared to have a secondary role. Assessments of suicidal intent showed that intention heightened as the number of symptoms increased. The symptom 'anxiety' did not prove to have a significant bearing on assessment of the seriousness of suicidal intention, whereas severely depressed mood did. The total number of subsequent suicide victims was 5.5%. During consultation relating to the index parasuicide, these subjects did not manifest a discriminate psychopathological profile (the only distinguishing characteristic was anxiety, which was less frequently identified in suicide victims), but did present a more positive personal and family psychiatric history. CONCLUSIONS: In subjects who had recently attempted suicide, the psychopathological profile appeared to be related to suicidal intent, where this was characterized by severe depression. Anxiety and other symptoms seemed to have a secondary role. Nonetheless, both total scores and subscores should be taken into consideration when assessing suicidal intention through the ISS. The psychopathological profile and ISS score following attempted suicide do not appear to permit prediction, in the medium to long term, of subsequent completed suicide.