An interim exploratory proteomics biomarker analysis of a phase 2 clinical trial to assess the impact of CT1812 in Alzheimer's disease.

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer's disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Aß) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in participants with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from 18 participants in an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau, and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812.

Randomized, Placebo Controlled Trial of NPT088, A Phage-Derived, Amyloid-Targeted Treatment for Alzheimer's Disease.

The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer's disease. Previous studies showed that NPT088 treatment reduced ß-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer's disease. Patients were treated with 4 dose levels of NPT088 for 6 months to evaluate its safety and tolerability. Exploratory measurements included measurement of change in ß-amyloid plaque and tau burden utilizing Positron Emission Tomography imaging as well as measures of Alzheimer's disease symptoms. At endpoint NPT088 was generally safe and well-tolerated with the most prominent finding being infusion reactions in a minority of patients. No effect of NPT088 on brain plaques, tau aggregates or Alzheimer's disease symptoms was observed.

EU/US/CTAD Task Force: Lessons Learned from Recent and Current Alzheimer's Prevention Trials.

At a meeting of the EU/US/Clinical Trials in Alzheimer's Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.

Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study.

This study was designed to evaluate whether subjects with amyloid beta (Aß) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aß pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aß+) or negative (Aß-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aß+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aß+ MCI subjects demonstrated greater worsening compared with Aß- subjects on the ADAS-Cog over 36 months (5.66 ± 1.47 vs -0.71 ± 1.09, P = 0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P < 0.05). Similar to MCI subjects, Aß+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aß+ AD patients showed greater declines in verbal fluency and the MMSE (P < 0.05). Aß+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aß+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aß+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aß- subjects do.

Association between illness progression measures and total cost in Alzheimer's disease.

OBJECTIVE: To compare the associations between dependence and clinical measures of cognition, function and behaviour and total care cost using data from a longitudinal study in Alzheimer's disease (AD). DESIGN: Longitudinal, observational study. SETTING: Community-dwelling subjects. PARTICIPANTS: Male and female subjects between 50 and 85 years of age with mild to moderate AD. INTERVENTION: None. MEASUREMENTS: Subject dependence was assessed using the Dependence Scale (DS), cognition (ADAS-Cog, MMSE), function (DAD), behaviour (NPI) and resource utilization with the Resource Utilization in Dementia Questionnaire. RESULTS: The repeated measures models confirmed a significant association between the DS and total care cost indicating an increase in cost with increasing dependence. A 1-unit increase in DS score was associated with a 28.60% increase in total care cost. Model 2 indicated that a one point change in MMSE, DAD and NPI is associated with 5.29%, 2.32% and 1.71% increase in total cost, respectively. Model 3 indicated that a one point change in ADAS-Cog, DAD and NPI is associated with a 1.74%, 2.42%and 1.62% increase in total cost, respectively. CONCLUSION: Strategies which prevent deterioration in clinical measures or delay dependence should result in total cost savings. The quantitative relationships observed should assist in the economic assessment of interventions which effect cognition, function, behaviour and dependence.

MR imaging features of amyloid-related imaging abnormalities.

BACKGROUND AND PURPOSE: AD is one of the few leading causes of death without a disease-modifying drug; however, hopeful agents are in various phases of development. MR imaging abnormalities, collectively referred to as amyloid-related imaging abnormalities, have been reported for several agents that target cerebral Aß burden. ARIA includes ARIA-E, parenchymal or sulcal hyperintensities on FLAIR indicative of parenchymal edema or sulcal effusions, and ARIA-H, hypointense regions on gradient recalled-echo/T2* indicative of hemosiderin deposition. This report describes imaging characteristics of ARIA-E and ARIA-H identified during studies of bapineuzumab, a humanized monoclonal antibody against Aß. MATERIALS AND METHODS: Two neuroradiologists with knowledge of imaging changes reflective of ARIA reviewed MR imaging scans from 210 bapineuzumab-treated patients derived from 3 phase 2 studies. Each central reader interpreted the studies independently, and discrepancies were resolved by consensus. The inter-reader κ was 0.76, with 94% agreement between neuroradiologists regarding the presence or absence of ARIA-E in individual patients. RESULTS: Thirty-six patients were identified with incident ARIA-E (17.1%, 36/210) and 26 with incident ARIA-H (12.4%, 26/210); of those with incident ARIA-H, 24 had incident microhemorrhages and 2 had incident large superficial hemosiderin deposits. CONCLUSIONS: In 49% of cases of ARIA-E, there was the associated appearance of ARIA-H. In treated patients without ARIA-E, the risk for incident blood products was 4%. This association between ARIA-E and ARIA-H may suggest a common pathophysiologic mechanism. Familiarity with ARIA should permit radiologists and clinicians to recognize and communicate ARIA findings more reliably for optimal patient management.

2012: A watershed year for Alzheimer's disease research.

Despite negative topline phase 3 clinical trial results for bapineuzumab and solanezumab in mild to moderate AD, findings from these trials and recent advances suggest renewed optimism for anti-amyloid therapies. Aß immunotherapy has now demonstrated its ability to engage CNS Aß and modify downstream CNS biomarkers in bapineuzumab treated patients, and to show likely cognitive benefits in mild patients treated with solanezumab. The current availability of potent BACE inhibitors provides additional opportunities to test the value of reducing Aß in the clinic. Trial enhancements, such as selecting and enriching for early stage AD, treating participants longer and using more sensitive composite endpoints may further improve our chances of demonstrating clinical efficacy and securing beneficial treatments for patients.

Is there a rationale for including only patients already being treated with acetylcholinesterase inhibitors in a prodromal AD trial?

Prodromal AD clinical trial methodology is advancing rapidly. It is now possible to more accurately identify MCI patients with underlying AD pathology at an earlier stage of the disease through the use of amyloid imaging and CSF biomarkers. Measurement of decline in these early stage clinical trials using continuous clinical and cognitive outcome measures is conceptually more appealing and adds greater efficiency compared to the classical outcome of "conversion" to dementia used in prior MCI clinical trials. Nevertheless, the fact that many prodromal AD patients who are likely to be recruited to these early stage studies are not taking acetylcholinesterase inhibitors at the time of enrollment, but are poised to start taking them over a multi-year period of follow-up, is a potential confound that needs to be addressed.

Alzheimer's disease therapeutic trials: EU/US Task Force report on recruitment, retention, and methodology.

While we may not be able to find a cure for Alzheimer's disease (AD) in the near future, several drugs presently in trials have shown promise as possible modifiers of disease progression. However, we may not be able to demonstrate efficacy due to issues of recruitment, retention, site-to-site variability, and other methodological issues. It is thus incumbent on the scientific community to find solutions to these problems, particularly as the field moves toward preventing illness or treating the disease in its prodromal stages, where these methodological issues will become even more critical. We need to better understand why participants agree or refuse to enter drug trials, and why both primary care physicians and Alzheimer's specialists agree or refuse to involve their patients. We also need to quantify the impact of requiring imaging studies, extensive questionnaires, cognitive testing, and lumbar punctures on recruitment and retention. With these concerns in mind, an international task force meeting of experts from academia and industry in the United States, European Union, and Japan in San Diego, California on November 2, 2011 to focus on recruitment, retention and other methodological issues related to clinical trials for AD. Based on the recommendations of this Task force meeting, this Perspectives article critically reflects on the most critical and timely methodological issues related to recruitment and retention in prevention and therapeutic trials in AD, which are paralleled by a paradigm shift in the diagnostic conceptualization of this disease, as reflected by recently new proposed diagnostic criteria involving preclinical stages of the disease.

Report of the task force on designing clinical trials in early (predementia) AD.

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

Seeing with new eyes: finding a path to early intervention trials in Alzheimer's disease.

The clinical course of Alzheimer's Disease (AD) and other degenerative disorders affecting cognition can be visualized as a progression from normal cognition through the syndrome of Mild Cognitive Impairment (MCI) to dementia. The use of biomarker data can supplement clinical characterization and identification of MCI and dementia pathologies. Clinical staging algorithms that use both clinical and biomarker information can assist in the early identification of AD patients. A comprehensive outcome measure such as the Clinical Dementia Rating Sum of Boxes (CDR-SB), which has components that assess both cognitive and functional domains in parallel deserves consideration as a primary outcome measure for early AD clinical trials.

A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease.

BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta (Abeta) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study in mild to moderate AD. METHODS: The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale-Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline. RESULTS: No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study "completers" and APOE epsilon4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms. CONCLUSIONS: Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE epsilon4 carrier status. CLASSIFICATION OF EVIDENCE: Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.

Idebenone treatment fails to slow cognitive decline in Alzheimer's disease.

OBJECTIVE: To determine the effect of idebenone on the rate of decline in Alzheimer's disease (AD). METHODS: A 1-year, multicenter, double-blind, placebo-controlled, randomized trial was conducted. Subjects were over age 50 with a diagnosis of probable AD and had Mini-Mental State Examination (MMSE) scores between 12 and 25. Subjects were treated with idebenone 120, 240, or 360 mg tid, each of which was compared with placebo. Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive Subcomponent (ADAS-Cog) and a Clinical Global Impression of Change (CGIC). Secondary outcome measures included measurements of activities of daily living, the Behavioral Pathology in Alzheimer's Disease Rating Scale, and the MMSE. RESULTS: Five hundred thirty-six subjects were enrolled and randomized to the four groups. Except for a slight difference in age, there were no differences in patient characteristics at baseline. For the primary outcome measures, there were no significant overall differences between the treatment groups in the prespecified four-group design. In an exploratory two-group analysis comparing all three treated groups combined with placebo, drug-treated patients performed better on the ADAS-Cog in both the intent-to-treat (ITT) and completers analyses. There were no differences in the CGIC scores for the ITT or completers analyses in either the four-group or the two-group analyses. There were no overall differences on any of the secondary outcome measures in any of the analyses. CONCLUSION: Idebenone failed to slow cognitive decline in AD that was of sufficient magnitude to be clinically significant.

A multicenter, randomized, placebo controlled, multiple-dose, safety and pharmacokinetic study of AIT-082 (Neotrofin) in mild Alzheimer's disease patients.

A phase 1, randomized, double-blind, placebo-controlled, dose escalation study of the purine derivative, AIT-082 (Neotrofin, NeoTherapeutics) was conducted in mild Alzheimer's disease (AD) patients to evaluate multiple-dose safety, tolerability, and pharmacokinetics. Possible short-term effects of AIT-082 on cognition and memory were preliminarily investigated. AIT-082 is currently being developed as a potential treatment for Alzheimer's disease and other neurological disorders. Pre-clinical studies indicate that AIT-082 has memory enhancing properties, stimulates neuritogenesis and the production of neurotrophic factors. Patients received an oral dose of AIT-082 or placebo daily for one week. Thirty-six AD patients were divided into three dose cohorts; each dose cohort consisted of twelve patients with 8 patients randomized to AIT-082 and 4 to placebo. The 3 doses of AIT-082 evaluated in this study were 100 mg/day, 500 mg/day, and 2,000 mg/day. There were no serious adverse events at any dose and the drug was well tolerated without significant side effects. AIT-082 was orally and rapidly absorbed, resulting in peak serum concentrations within 2 hours with an elimination half-life of approximately 20 hours. Higher doses resulted in corresponding increases in peak concentrations and areas under the curve (AUC). There was an approximate 2-fold accumulation in AIT-082 with daily dosing (as reflected by the AUC) at steady state. There were no significant differences by treatment arm on the clinical or neuropsychological evaluations. AIT-082 was rapidly absorbed by the oral route with a half-life suitable for dosing once or twice daily. No problems with tolerability or safety were found. AIT-082 appears suitable for testing in larger clinical trials for the treatment of AD and other neurologic disorders.

Treatment of Alzheimer's disease: rationale and strategies.

This article reviews the rationale and provides a progress update regarding the major treatment strategies being developed for the prevention and treatment of Alzheimer's disease. Various therapeutic areas are discussed, including acetylcholinesterase inhibitors and other cholinergic agents, antioxidants, anti-inflammatory drugs, hormone replacement therapy, antiamyloid treatment, and neurotrophic agents.

Prevalence of symptoms on the CERAD behavior rating scale for dementia in normal elderly subjects and Alzheimer's disease patients.

The authors sought to define "abnormal" levels for total scores on the CERAD Behavioral Rating Scale for Dementia (BRSD) and for 37 BRSD items by comparing 242 patients with Alzheimer's disease (AD) and 64 normal elderly control subjects (NEC). BRSD total scores for NEC ranged as high as 52 (out of a maximum 167), and although item prevalence rates were higher for AD patients, not all of these differences were significant. Many symptoms were observed in < or = 10% of AD subjects. Lower Mini-Mental State Examination scores were not consistently associated with lower or higher levels of endorsement across all items. Over 6 and 12 months, endorsement rates were relatively stable for both groups. The authors conclude that assessment of behavior in long-term studies will be needed to quantify "abnormal" levels, and that item-level BRSD information could be important in clinical trials.

Treatment of agitation in AD: a randomized, placebo-controlled clinical trial.

BACKGROUND: Treatment of agitation is a crucial problem in the care of patients with AD. Although antipsychotic and antidepressant medications and behavior management techniques (BMT) have each been used to treat agitation, clinical trials of these treatments have been characterized by small sample sizes and uncontrolled treatment designs. OBJECTIVE: To compare haloperidol, trazodone, and BMT with placebo in the treatment of agitation in AD outpatients. METHODS: A total of 149 patients with AD and their caregivers participated in a randomized, placebo-controlled, multicenter trial. Blind assessment was conducted at baseline and after 16 weeks of treatment. The three active treatments were haloperidol, trazodone, and BMT. The Alzheimer's Disease Cooperative Study Clinical Global Impression of Change was the primary outcome measure. Secondary outcomes included patient agitation, cognition, and function, and caregiver burden. RESULTS: Thirty-four percent of subjects improved relative to baseline. No significant differences on outcome were obtained between haloperidol (mean dose, 1.8 mg/d), trazodone (mean dose, 200 mg/d), BMT, or placebo. Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the BMT arm. No other significant difference in adverse events was seen. Symptoms did not respond differentially to the different treatments. CONCLUSIONS: Comparable modest reductions in agitation occurred in patients receiving haloperidol, trazodone, BMT, and placebo. More effective pharmacologic, nonpharmacologic, and combination treatments are needed.