William Cho

Homozygosity of the autosomal dominant Alzheimer disease presenilin 1 E280A mutation

We identified several families in Antioquia, Colombia, with early-onset Alzheimer disease (AD) due to the mendelian autosomal dominant inheritance of a PSEN1 E280A gene mutation. Extended family members were interviewed and parish baptism certificates in Antioquian municipalities examined.1 The size of these extended families (including carriers and noncarriers) approaches 5,000 individuals. Full genomes in carriers proved a single founder.2 To support an AD prevention clinical trial, we established a registry in 2010 of all family members over age 8 years.3 Since then we genotyped 3,407 family members and identified 823 (24%) carriers of the PSEN1 E280A mutation. The Comite de Bioetica de la Sede de Investigacion Universitaria, SIU Universidad de Antioquia, approved this study. All participants provided written informed consent. Despite the size of this exceptionally large family and frequent consanguinity, homozygosity at this gene locus had not been reported. The apparent absence of homozygous PSEN1 mutations led to the speculation that E280A homozygosity could be lethal. Generally, homozygous dominant mutations are more severely affected than heterozygotes in both humans and model systems.4 However, human cases in which dominant point mutations are homozygous are rare.

THE ALZHEIMER'S PREVENTION INITIATIVE

genic animal experiments suggest that we may be testing anti-Ab therapies much too late in the pathophysiological process of Alzheimer’s disease (AD). Converging data from PETamyloid imaging, cerebrospinal fluid studies, and large autopsy series suggest that approximately one-third of clinically normal older individuals harbor a substantial burden of cerebral amyloid-b. These amyloid-positive “normals” demonstrate evidence of functional and structural imaging abnormalities, elevation of CSF tau, and subtle cognitive deficits, consistent with the preclinical stages of AD, and represent an ideal population for a large secondary prevention effort to slow cognitive decline. Methods: The Alzheimer’s Disease Cooperative Study (ADCS) is proposing a placebo-controlled, 3-year trial in clinically normal older individuals with biomarker evidence of AD pathology. The primary outcome will be slowing the rate of decline on a cognitive composite, with multiple biomarkers as secondary outcomes. Eligible subjects will be clinically normal (CDR 0, MMSE 27-30), over age 70, and will have evidence of amyloid-positivity on PET amyloid imaging. The choice of treatment has not yet been finalized, but will be a monoclonal antibody with clear evidence of target engagement and adequate safety data to support a 3-year trial.Results:Analyses using available data from the Alzheimer’s Disease Neuroimaging Initiative and Australian Imaging Biomarkers Lifestyle study consistently demonstrate evidence of an increased rate of cognitive decline in amyloid-positive normals, and that approximately n1⁄4500 subjects per arm will yield adequate power to detect a 25-35% treatment-related decrease in the rate of cognitive decline. We will also include a natural history arm of 500 amyloid-negative individuals to investigate the specific pattern of “amyloid-related” decline and to develop more sensitive outcome measures to improve the efficiency of future secondary prevention trials in preclinical AD.Conclusions:TheA4 trial will provide complementary information to the prevention initiatives being planned in genetic-risk cohorts. Although amyloid-b may be only one of several pathogenic factors in the elderly population, we now have the biomarker tools and biologically active compounds to test the hypothesis that altering “upstream” amyloid burden will impact “downstream” neurodegeneration and delay or prevent cognitive decline.

ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease

Objective To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD). Methods In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimers Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73. Results The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF β-amyloid1-42 levels that correlated with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. Conclusions Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD. Clinicaltrials.gov identifier NCT 01343966. Classification of evidence This study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because <80% of enrolled patients completed the study.Objective To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD). Methods In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimers Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73. Results The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF &bgr;-amyloid1-42 levels that correlated with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. Conclusions Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD. Clinicaltrials.gov identifier NCT 01343966. Classification of evidence This study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because <80% of enrolled patients completed the study.

The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer's disease, including a placebo-treated noncarrier cohort

Autosomal‐dominant Alzheimers disease (ADAD) represents a crucial population for identifying prevention strategies that might modify disease course for cognitively unimpaired individuals at high imminent risk for developing symptoms due to Alzheimers disease (AD), that is, who have “preclinical” AD. Crenezumab is an antiamyloid monoclonal antibody that binds monomeric and aggregated forms of amyloid β, with highest affinity for oligomers; it is in development for early stages of sporadic AD and for ADAD.

The value of pre-screening in the alzheimer’s prevention initiative (api) autosomal dominant alzheimer’s disease trial

The Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) trial evaluates the anti-amyloid-β antibody crenezumab in cognitively unimpaired persons who, based on genetic background and age, are at high imminent risk of clinical progression, and provides a powerful test of the amyloid hypothesis. The Neurosciences Group of Antioquia implemented a pre-screening process with the goals of decreasing screen failures and identifying participants most likely to adhere to trial requirements of the API ADAD trial in cognitively unimpaired members of Presenilin1 E280A mutation kindreds. The pre-screening failure rate was 48.2%: the primary reason was expected inability to comply with the protocol, chiefly due to work requirements. More carriers compared to non-carriers, and more males compared to females, failed prescreening. Carriers with illiteracy or learning/comprehension difficulties failed pre-screening more than non-carriers. With the Colombian API Registry and our prescreening efforts, we randomized 169 30-60 year-old cognitively unimpaired carriers and 83 non-carriers who agreed to participate in the trial for at least 60 months. Our findings suggest multiple benefits of implementing a pre-screening process for enrolling prevention trials in ADAD.

A PUBLIC RESOURCE OF BASELINE DATA FROM THE API AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE COLOMBIA TRIAL

Side effects and adverse events were more frequent in antipsychotic users vs non users (p1⁄40.0000). Inappropriate use of antipsychotics according to the 2015 Beers Criteria was found in 9.3% out of the cases. Conclusions:Antipsychotics should be avoided for BPSD unless non-pharmacologic options have failed, or the patient is threatening self-harm or harm to others. In order to use these drugs appropriately, we should ask why the patient is taking the drug, whether it was appropriate initially, and whether it is still needed. A 25%-50% dose reduction is suggested every 1-2 weeks. Further details on this topic are strongly recommended.

Adherence/Retention Alzheimer's Prevention Initiative Colombia Plan

The Alzheimers Prevention Initiative Colombia Trial is a collaborative project involving the Neurosciences Group of Antioquia, Genentech/Roche, and the Banner Alzheimers Institute, studying whether crenezumab can delay or prevent the clinical onset of Alzheimers disease in cognitively unimpaired individuals who carry the PSEN1 E280A mutation. In an effort to optimize participant compliance and adherence and maintain interest in the trial for its duration, the Neurosciences Group of Antioquia developed an “Adherence/Retention Plan.” This plan identifies potential barriers to trial adherence related to characteristics of the participants and study partners, protocol design, sponsors, investigators, environmental factors, and characteristics of this population in general and identifies potential solutions to these barriers.

SAFETY AND TOLERABILITY OF CRENEZUMAB IN MILD-TO-MODERATE AD PATIENTS TREATED WITH ESCALATING DOSES FOR UP TO 25 MONTHS

O2-17-06 SAFETYAND TOLERABILITY OF CRENEZUMAB IN MILD-TO-MODERATE AD PATIENTS TREATEDWITH ESCALATING DOSES FOR UP TO 25 MONTHS Veronica Asnaghi, Helen Lin, Nan Hu, Jillian Smith, William Cho, Susanne Ostrowitzki, F. Hoffmann-La Roche AG, Basel, Switzerland; Genentech, Inc., South San Francisco, CA, USA; F. Hoffmann-La Roche, Welwyn Garden City, United Kingdom; Genentech, Inc, South San Francisco, CA, USA. Contact e-mail: lin.helen@gene.com

The Colombian Alzheimer's Prevention Initiative (API) Registry

The Colombian Alzheimers Prevention Initiative (API) Registry is a collaborative project among the Neurosciences Group of Antioquia, the Banner Alzheimers Institute, and Genentech. The main goal is to provide a source of interested research participants and data to support the API‐Colombia Autosomal Dominant Alzheimers Disease Trial and help find treatments to delay or prevent the clinical onset of Alzheimers disease.

THE IMPACT OF CENTRAL RATING REVIEW PROGRAMS ON ADAS-COG ERROR VARIANCE

D4010 tablets. For multiple ascending dose evaluation, the once daily doses of SUVN-D4010 tablets were administered for 14 days. SUVN-D4010 was quantified in plasma and urine using a validated LC-MS/MS method. Safety was evaluated based on assessments of adverse events, physical examinations, laboratory tests, vital signs, orthostatic vital signs, 12-lead ECGs and continuous telemetry. Results: SUVN-D4010 was well tolerated in healthy male subjects and there were no clinically relevant or serious adverse events reported. During single ascending dose studies, the absorption of SUVN-D4010 is rapid and exposures (Cmaxand AUC) were dose proportional at the tested doses. During multiple ascending dose studies, SUVN-D4010 has shown a favorable pharmacokinetic profile. SUVN-D4010 achieved the projected efficacy concentrations and attained steady state on day 3 in the tested population. Conclusions: SUVN-D4010 has favorable safety and pharmacokinetic profile following single and multiple administration for 14 days in healthymale subjects. SUVN-D4010 exposures were dose proportional following single or multiple oral administrations. SUVN-D4010 achieved the projected efficacy concentrations and attained steady state on day 3 upon multiple administrations. SUVN-D4010 is well tolerated with adequate plasma exposure for efficacy and favorable pharmacokinetics suitable for once a day oral administration. Long term non-clinical safety studies are in progress and Phase II proof-of-concept studies is being planned.