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).

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no approved disease-modifying therapy (DMT). In this review, we summarize the various past approaches taken in an attempt to find treatments capable of altering the longterm course for individuals with AD, including: translating epidemiological observations into potential treatment options; seeking a single-treatment approach across the continuum of AD severity; utilizing biomarkers for assessing target engagement; using biomarkers as early surrogates of clinical efficacy; and enriching study populations to demonstrate adequate placebo decline during the limited duration of clinical trials. Although targeting the amyloid-β (Aβ) pathway has been central to the search for an effective DMT, to date, trials of anti-Aβ monoclonal antibodies have failed to consistently demonstrate significant clinical efficacy. Key learnings from these anti-Aβ trials, as well as the trials that came before them, have shifted the focus within clinical development programs to identifying target populations thought most likely to benefit from treatments (i.e., individuals at an earlier stage of disease). Other learnings include strategies to increase the likelihood of showing measurable improvements within the clinical trial setting by better predicting decline in placebo participants, as well as developing measures to quantify the needed treatment exposure (e.g., higher doses). Given the complexity associated with AD pathology and progression, treatments targeting non-amyloid AD pathologies in combination with anti-amyloid therapies may offer an alternative for the successful development of DMTs.

There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer’s disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer’s Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential.

The termination of many clinical trials of amyloid-targeting therapies for the treatment of Alzheimer’s disease (AD) has had a major impact on the AD clinical research enterprise. However, positive signals in recent studies have reinvigorated support for the amyloid hypothesis and amyloid-targeting strategies. In December 2019, the EU-US Clinical Trials on Alzheimer’s Disease (CTAD) Task Force met to share learnings from these studies in order to inform future trials and promote the development of effective AD treatments. Critical factors that have emerged in studies of anti-amyloid monoclonal antibody therapies include developing a better understanding of the specific amyloid species targeted by different antibodies, advancing our insight into the mechanism by which those antibodies may reduce pathology, implementing more comprehensive repertoires of biomarkers into trials, and identifying appropriate doses. Studies suggest that Amyloid-Related Imaging Abnormalities – effusion type (ARIA-E) are a manageable safety concern and that caution should be exercised before terminating studies based on interim analyses. The Task Force concluded that opportunities for developing effective treatments include developing new biomarkers, intervening in early stages of disease, and use of combination therapies.

BACKGROUND: The Clinical Dementia Rating–Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population. OBJECTIVE: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD. SETTING: Data were gathered as part of a two-year clinical trial. PARTICIPANTS: Patients had biomarker confirmed prodromal AD. MEASUREMENTS: Clinical Dementia Rating (CDR), Functional Activities Questionnaire (FAQ), Alzheimer’s Disease Assessment Scale – Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR [words]). Assessments were conducted at least every 24 weeks. RESULTS: For the CDR-SB, test-retest reliability was good (intra-class correlation coefficient [ICC]=0.83); internal consistency was 0.65 at baseline but above 0.8 at later assessments. Relationships between the CDR-SB and other measures were as expected (higher correlations with more closely related constructs), and the CDR-SB differentiated between patients with different severities of dementia (-2.9 points difference between CDR-Global Score 0.5 and 1, P<.0001). Floor and ceiling effects on the CDR-SB total score were minimal; however, at baseline there were ceiling effects in the personal care domain. Further detail is provided on the psychometric properties of ADAS-Cog, MMSE, FCSRT-IR and FAQ in this population. CONCLUSION: The psychometric properties of the CDR-SB are adequate in prodromal AD and continued use is warranted in clinical trials. However, there remains scope for improvement in the assessment of functional constructs and development of novel measures should continue.

Previous findings from the positron emission tomography (PET) substudy of the SCarlet RoAD and Marguerite RoAD open-label extension (OLE) showed gantenerumab doses up to 1200 mg every 4 weeks administered subcutaneously resulted in robust beta-amyloid (Aβ) plaque removal over 24 months in people with prodromal-to-moderate Alzheimer’s disease (AD). In this 36-month update, we demonstrate continued reduction, with mean (standard error) centiloid values at 36 months of -4.3 (7.5), 0.8 (6.7), and 4.7 (8.0) in the SCarlet RoAD (double-blind pooled placebo and active groups), Marguerite RoAD double-blind placebo, and Marguerite RoAD double-blind active groups respectively, representing a change of -57.0 (10.3), -90.3 (9.0), and -74.9 (10.5) centiloids respectively. These results demonstrate that prolonged gantenerumab treatment, at doses up to 1200 mg, reduces amyloid plaque levels below the amyloid positivity threshold. The ongoing GRADUATE Phase III trials will evaluate potential clinical benefits associated with gantenerumab-induced amyloid-lowering in people with early (prodromal-to-mild) AD.

The EU/US/CTAD Task Force, an international collaboration of AD investigators from industry and academia, met in Barcelona, Spain, on November 4th, 2015, to explore existing and planned patient registries and other clinical trial infrastructure meant to expedite recruitment of large numbers of participants into clinical trials and improve their productivity. The Task Force identified a number of approaches currently being tested around the world, including the use of predictive algorithms to identify individuals likely to have prodromal or preclinical AD, the establishment of clinical trial networks to streamline trials, and reforming the informed consent process to make it less burdensome to both investigators and trial participants. Multi-national systems such as the European Prevention of Alzheimer’s Dementia (EPAD) and the Global Alzheimer’s Platform (GAP) offer value for sponsors, trial sites, and patients by optimizing efforts to find effective disease-modifying and symptomatic treatments.

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