Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

INTRODUCTION: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aß) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. METHODS: Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 µg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aß positron emission tomography (PET) scans at 18 to 24 months. RESULTS: CAD106 induced measurable serum Aß immunoglobulin G titers in 41/42 participants, slower rates of Aß plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic). DISCUSSION: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aß active immunotherapies in individuals at risk for AD. HIGHLIGHTS: This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies.

INTRODUCTION: The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. METHODS: Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE) Îµ4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. RESULTS: Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up. DISCUSSION: In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. HIGHLIGHTS: This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.

Rationale for the selection of dual primary endpoints in prevention studies of cognitively unimpaired individuals at genetic risk for developing symptoms of Alzheimer's disease.

BACKGROUND: There is a critical need for novel primary endpoints designed to detect early and subtle changes in cognition in clinical trials targeting the asymptomatic (preclinical) phase of Alzheimer's disease (AD). The Alzheimer's Prevention Initiative (API) Generation Program, conducted in cognitively unimpaired individuals at risk of developing AD (e.g., enriched by the apolipoprotein E (APOE) genotype), used a novel dual primary endpoints approach, whereby demonstration of treatment effect in one of the two endpoints is sufficient for trial success. The two primary endpoints were (1) time to event (TTE)-with an event defined as a diagnosis of mild cognitive impairment (MCI) due to AD and/or dementia due to AD-and (2) change from baseline to month 60 in the API Preclinical Composite Cognitive (APCC) test score. METHODS: Historical observational data from three sources were used to fit models to describe the TTE and the longitudinal APCC decline, both in people who do and do not progress to MCI or dementia due to AD. Clinical endpoints were simulated based on the TTE and APCC models to assess the performance of the dual endpoints versus each of the two single endpoints, with the selected treatment effect ranging from a hazard ratio (HR) of 0.60 (40% risk reduction) to 1 (no effect). RESULTS: A Weibull model was selected for TTE, and power and linear models were selected to describe the APCC score for progressors and non-progressors, respectively. Derived effect sizes in terms of reduction of the APCC change from baseline to year 5 were low (0.186 for HR = 0.67). The power for the APCC alone was consistently lower compared to the power of TTE alone (58% [APCC] vs 84% [TTE] for HR = 0.67). Also, the overall power was higher for the 80%/20% distribution (82%) of the family-wise type 1 error rate (alpha) between TTE and APCC compared to 20%/80% (74%). CONCLUSIONS: Dual endpoints including TTE and a measure of cognitive decline perform better than the cognitive decline measure as a single primary endpoint in a cognitively unimpaired population at risk of AD (based on the APOE genotype). Clinical trials in this population, however, need to be large, include older age, and have a long follow-up period of at least 5 years to be able to detect treatment effects.

The Alzheimer's Prevention Initiative Composite Cognitive Test: a practical measure for tracking cognitive decline in preclinical Alzheimer's disease.

BACKGROUND: There is growing interest in identifying sensitive composite cognitive tests to serve as primary endpoints in preclinical Alzheimer's disease (AD) treatment trials. We reported previously a composite cognitive test score sensitive to tracking preclinical AD decline up to 5 years prior to clinical diagnosis. Here we expand upon and refine this work, empirically deriving a composite cognitive test score sensitive to tracking preclinical AD decline up to 11 years prior to diagnosis and suitable for use as a primary endpoint in a preclinical AD trial. METHODS: This study used a longitudinal approach to maximize sensitivity to tracking progressive cognitive decline in people who progressed to the clinical stages of AD (n = 868) compared to those who remained cognitively unimpaired during the same time period (n = 989), thereby correcting for normal aging and practice effects. Specifically, we developed the Alzheimer's Prevention Initiative Preclinical Composite Cognitive test (APCC) to measure very early longitudinal cognitive decline in older adults with preclinical AD. Data from three cohorts from Rush University were analyzed using a partial least squares (PLS) regression model to identify optimal composites within different time periods prior to diagnosis, up to 11 years prior to diagnosis. The mean-to-standard deviation ratio (MSDRs) is an indicator of sensitivity to change and was used to inform the final calculation of the composite score. RESULTS: The optimal composite, the APCC, is calculated: 0.26*Symbol Digit Modalities + 2.24*MMSE Orientation to Time + 2.14*MMSE Orientation to Place + 0.53*Logical Memory Delayed Recall + 1.36* Word List-Delayed Recall + 0.68*Judgment of Line Orientation + 1.39*Raven's Progressive Matrices Matrices (subset of 9 items from A and B). The MSDR of the APCC in a population of preclinical AD individuals who eventually progress to cognitive impairment, compared to those who remained cognitively unimpaired during the same time period, was - 1.10 over 1 year. CONCLUSIONS: The APCC is an empirically derived composite cognitive test score with high face validity that is sensitive to preclinical AD decline up to 11 years prior to diagnosis of the clinical stages of AD. The components of the APCC are supported by theoretical understanding of cognitive decline that occurs during preclinical AD. The APCC was used as a primary outcome in the API Generation Program trials.

Alzheimer's Prevention Initiative Generation Program: Development of an APOE genetic counseling and disclosure process in the context of clinical trials.

INTRODUCTION: As the number of Alzheimer's disease (AD) prevention studies grows, many individuals will need to learn their genetic and/or biomarker risk for the disease to determine trial eligibility. An alternative to traditional models of genetic counseling and disclosure is needed to provide comprehensive standardized counseling and disclosure of apolipoprotein E (APOE) results efficiently, safely, and effectively in the context of AD prevention trials. METHODS: A multidisciplinary Genetic Testing, Counseling, and Disclosure Committee was established and charged with operationalizing the Alzheimer's Prevention Initiative (API) Genetic Counseling and Disclosure Process for use in the API Generation Program trials. The objective was to provide consistent information to research participants before and during the APOE counseling and disclosure session using standardized educational and session materials. RESULTS: The Genetic Testing, Counseling, and Disclosure Committee created a process consisting of eight components: requirements of APOE testing and reports, psychological readiness assessment, determination of AD risk estimates, guidance for identifying providers of disclosure, predisclosure education, APOE counseling and disclosure session materials, APOE counseling and disclosure session flow, and assessing APOE disclosure impact. DISCUSSION: The API Genetic Counseling and Disclosure Process provides a framework for large-scale disclosure of APOE genotype results to study participants and serves as a model for disclosure of biomarker results. The process provides education to participants about the meaning and implication(s) of their APOE results while also incorporating a comprehensive assessment of disclosure impact. Data assessing participant safety and psychological well-being before and after APOE disclosure are still being collected and will be presented in a future publication.

The Alzheimer's Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) pathology, including the accumulation of amyloid beta (Aß) species and tau pathology, begins decades before the onset of cognitive impairment. This long preclinical period provides an opportunity for clinical trials designed to prevent or delay the onset of cognitive impairment due to AD. Under the umbrella of the Alzheimer's Prevention Initiative Generation Program, therapies targeting Aß, including CNP520 (umibecestat), a ß-site-amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor, and CAD106, an active Aß immunotherapy, are in clinical development in preclinical AD. METHODS: The Alzheimer's Prevention Initiative Generation Program comprises two pivotal (phase 2/3) studies that assess the efficacy and safety of umibecestat and CAD106 in cognitively unimpaired individuals with high risk for developing symptoms of AD based on their age (60-75 years), APOE4 genotype, and, for heterozygotes (APOE ε2/ε4 or ε3/ε4), elevated brain amyloid. Approximately, 3500 individuals will be enrolled in either Generation Study 1 (randomized to cohort 1 [CAD106 injection or placebo, 5:3] or cohort 2 [oral umibecestat 50 mg or placebo, 3:2]) or Generation Study 2 (randomized to oral umibecestat 50 mg and 15 mg, or placebo [2:1:2]). Participants receive treatment for at least 60 months and up to a maximum of 96 months. Primary outcomes include time to event, with event defined as diagnosis of mild cognitive impairment due to AD and/or dementia due to AD, and the Alzheimer's Prevention Initiative preclinical composite cognitive test battery. Secondary endpoints include the Clinical Dementia Rating Sum of Boxes, Repeatable Battery for the Assessment of Neuropsychological Status total score, Everyday Cognition Scale, biomarkers, and brain imaging. DISCUSSION: The Generation Program is designed to assess the efficacy, safety, and biomarker effects of the two treatments in individuals at high risk for AD. It may also provide a plausible test of the amyloid hypothesis and further accelerate the evaluation of AD prevention therapies.

Active Aß immunotherapy CAD106 in Alzheimer's disease: A phase 2b study.

INTRODUCTION: This randomized, double-blind, placebo-controlled, 90-week study assessed safety, tolerability, and immunogenicity of CAD106 with/without adjuvant in patients with mild Alzheimer's disease. METHODS: One hundred twenty-one patients received up to seven intramuscular injections of CAD106 (150 µg or 450 µg) or placebo ± adjuvant over 60 weeks. An amyloid positron emission tomography (PET) substudy was also conducted. RESULTS: CAD106 induced strong serological responses (amyloid-beta [Aß]-Immunoglobuline G[IgG]) in 55.1% (150 µg) and 81.1% (450 µg) of patients (strong serological responders [SSRs]). Serious adverse events (SAEs) were reported in 24.5% (95% confidence interval [CI] 16.7-33.8) of the patients in the active treatment group and in 6.7% (95% CI 0.2-31.9) in the placebo group. Three of the SAEs were classified as possibly related to study drug by the investigators. No evidence of central nervous system inflammation was found. Amyloid-related imaging abnormalities (ARIAs) occurred in six cases, all of them were strong serological responders. None of the ARIAs were symptomatic. Serum Aß-IgG titer area under the curves correlated negatively with amyloid PET standardized uptake value ratio percentage change from baseline to week 78 within the CAD106-treated patients (r = -0.84, P = .0004). Decrease in cortical gray-matter volume from baseline to week 78 was larger in SSRs than in controls (P = .0077). DISCUSSION: Repeated CAD106 administration was generally well tolerated. CAD106 450 µg with alum adjuvant demonstrated the best balance between antibody response and tolerability.

Long-term treatment with active Aß immunotherapy with CAD106 in mild Alzheimer's disease.

INTRODUCTION: CAD106 is designed to stimulate amyloid-ß (Aß)-specific antibody responses while avoiding T-cell autoimmune responses. The CAD106 first-in-human study demonstrated a favorable safety profile and promising antibody response. We investigated long-term safety, tolerability and antibody response after repeated CAD106 injections. METHODS: Two phase IIa, 52-week, multicenter, randomized, double-blind, placebo-controlled core studies (2201; 2202) and two 66-week open-label extension studies (2201E; 2202E) were conducted in patients with mild Alzheimer's disease (AD) aged 40 to 85 years. Patients were randomized to receive 150µg CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 µg CAD106; subcutaneous, 2201E1; intramuscular, 2202E1). Our primary objective was to evaluate the safety and tolerability of repeated injections, including monitoring cerebral magnetic resonance imaging scans, adverse events (AEs) and serious AEs (SAEs). Further objectives were to assess Aß-specific antibody response in serum and Aß-specific T-cell response (core only). Comparable Aß-immunoglobulin G (IgG) exposure across studies supported pooled immune response assessments. RESULTS: Fifty-eight patients were randomized (CAD106, n = 47; placebo, n = 11). Baseline demographics and characteristics were balanced. Forty-five patients entered extension studies. AEs occurred in 74.5% of CAD106-treated patients versus 63.6% of placebo-treated patients (core), and 82.2% experienced AEs during extension studies. Most AEs were mild to moderate in severity, were not study medication-related and did not require discontinuation. SAEs occurred in 19.1% of CAD106-treated patients and 36.4% of placebo-treated patients (core). One patient (CAD106-treated; 2201) reported a possibly study drug-related SAE of intracerebral hemorrhage. Four patients met criteria for amyloid-related imaging abnormalities (ARIA) corresponding to microhemorrhages: one was CAD106-treated (2201), one placebo-treated (2202) and two open-label CAD106-treated. No ARIA corresponded to vasogenic edema. Two patients discontinued extension studies because of SAEs (rectal neoplasm and rapid AD progression, respectively). Thirty CAD106-treated patients (63.8%) were serological responders. Sustained Aß-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Aß1-6 nor Aß1-42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier. CONCLUSIONS: No unexpected safety findings or Aß-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Aß-specific antibody titers and prolonged time to decline indicate antibody exposure may increase with additional injections. CAD106 may be a valuable therapeutic option in AD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00733863, registered 8 August 2008; NCT00795418, registered 10 November 2008; NCT00956410, registered 10 August 2009; NCT01023685, registered 1 December 2009.

Active immunotherapy options for Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia and a major contributor to disability and dependency among older people. AD pathogenesis is associated with the accumulation of amyloid-beta protein (Aß) and/or hyperphosphorylated tau protein in the brain. At present, current therapies provide temporary symptomatic benefit, but do not treat the underlying disease. Recent research has thus focused on investigating the molecular and cellular pathways and processes involved in AD pathogenesis to support the development of effective disease-modifying agents. In accordance with the existing Aß-cascade hypothesis for AD pathogenesis, immunotherapy has been the most extensively studied approach in Aß-targeted therapy. Both passive and active immunotherapies have been shown to effectively reduce Aß accumulation and prevent downstream pathology in preclinical models. Following AN1792, second-generation active immunotherapies have shown promising results in terms of antibody response and safety. Comparatively, tau immunotherapy is not as advanced, but preclinical data support its development into clinical trials. Results from active amyloid-based immunotherapy studies in preclinical models indicate that intervention appears to be more effective in early stages of amyloid accumulation, highlighting the importance of diagnosing AD as early as possible and undertaking clinical trials at this stage. This strategy, combined with improving our understanding of the complex AD pathogenesis, is imperative to the successful development of these disease-modifying agents. This paper will review the active immunotherapies currently in development, including the benefits and challenges associated with this approach.