A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aß protofibril antibody.

BACKGROUND: Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aß), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia. METHODS: BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. RESULTS: A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (-0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. CONCLUSIONS: BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer's disease is underway. TRIAL REGISTRATION: Clinical Trials.gov NCT01767311 .

Erratum: Lai, R.Y.K.; Harrington, C.R.; Wischik, C.M. Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer's Disease. Biomolecules 2016, 6, 19.

The authors wish to correct their affiliations in this paper [1] as follows:[...].

Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer's Disease.

Alzheimer's disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of tau and tubulin in vitro using a system in which we can measure binding affinities for proteins alternated between solid and aqueous phases. The study reveals that a phase-shifted repeat domain fragment from the Paired Helical Filament core contains all that is required for high affinity tau-tau binding. Unlike tau-tubulin binding, tau-tau binding shows concentration-dependent enhancement in both phase directions due to an avidity effect which permits one molecule to bind to many as the concentration in the opposite phase increases. Phosphorylation of tau inhibits tau-tau binding and tau-tubulin binding to equivalent extents. Tau-tau binding is favoured over tau-tubulin binding by factors in the range 19-41-fold, irrespective of phosphorylation status. A critical requirement for tau to become aggregation-competent is prior binding to a solid-phase substrate, which induces a conformational change in the repeat domain permitting high-affinity binding to occur even if tau is phosphorylated. The endogenous species enabling this nucleation event to occur in vivo remains to be identified. The findings of the study suggest that development of disease-modifying drugs for tauopathies should not target phosphorylation, but rather should target inhibitors of tau-tau binding or inhibitors of the binding interaction with as yet unidentified endogenous polyanionic substrates required to nucleate tau assembly.

Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury.

Current treatments of neuropathic pain arising from conditions such as nerve injury/compression are only partially effective, and limited in their use by side-effects. p38 mitogen-activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. p38 inhibitors may reduce neuronal sensitisation in preclinical models of neuropathic pain, particularly where there is a substantial inflammatory component. An exploratory, multicentre, double-blind, placebo-controlled, two-period, cross-over trial was undertaken to evaluate the effect of dilmapimod (SB-681323), a selective p38 MAPK inhibitor, on neuropathic pain symptoms and signs. Fifty patients with nerve trauma, radiculopathy or carpal tunnel syndrome were randomised; 43 patients completed the study. Eligible patients received oral dilmapimod and placebo twice daily for 2 weeks, with an intervening washout period of 2-4 weeks. Subjects attended weekly for efficacy and safety assessments, which included evaluation of daily and current pain intensity using an 11-point numerical rating scale (NRS), quantitative sensory testing, allodynia and global impression of change. There was a statistically significant reduction in the primary endpoint of average daily pain score during the second week of treatment among patients treated with dilmapimod (15 mg/day) compared to placebo using NRS [0.80; 95% CI (0.28, 1.33); p=0.0034]. A similar trend for effect was seen in some secondary endpoints. Dilmapimod was well tolerated, with no clinically relevant safety findings. p38 MAPK inhibitors merit further evaluation for neuropathic pain in larger clinical trials, particularly for clinically meaningful analgesic effect size.

A multi-center randomized proof-of-concept clinical trial applying [¹8F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease.

Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD.

Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET.

UNLABELLED: The histamine H(3) receptor is implicated in the pathophysiology of several central nervous system disorders. N-methyl-6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotamide (GSK189254) is a highly potent, selective, and brain-penetrant H(3) receptor antagonist. Previous studies in the pig using PET have shown that (11)C-GSK189254 uptake in H(3)-rich regions of the brain can be blocked by the selective H(3) antagonist ciproxifan. The purpose of the present study was to evaluate (11)C-GSK189254 as a PET radioligand for human studies and to determine the dose-receptor occupancy relationship of GSK189254 in the human brain. METHODS: Dynamic PET scans were obtained in healthy subjects over 90 min after intravenous administration of approximately 370 MBq of (11)C-GSK189254. Blood samples were taken throughout the scans to derive the arterial plasma parent input function. Each subject was scanned twice, either with tracer alone (test-retest) or before and after a single oral dose of GSK189254 (10-100 microg). Data were analyzed by compartmental analysis, and regional receptor-occupancy estimates were obtained by graphical analysis of changes in the total volumes of distribution (V(T)) of the radioligand. RESULTS: (11)C-GSK189254 readily entered the brain; its regional brain distribution reflected the known distribution of H(3) receptors, with high binding in the caudate and putamen, intermediate binding in cortical regions, and low binding in the cerebellum. GSK189254 displayed a high receptor affinity, and a marked reduction in V(T) was apparent at all the doses tested. The oral dose equaling 50% occupancy of the available receptor sites (ED(50)) was estimated as 4.33 microg. Additional data on plasma pharmacokinetics after oral dosing and the plasma free fraction gave a corresponding estimate of the free concentration of GSK189254 required to occupy 50% of the available receptor sites (EC(50)) (0.011 nM). The test-retest data showed reductions in regional V(T) on the second scan in all subjects. A nonlinear compartmental analysis of this effect demonstrated that this reduction was consistent with carryover of a tracer mass dose effect with an estimated in vivo apparent dissociation constant of 0.010 nM, close to the independent estimate of the plasma EC(50). CONCLUSION: (11)C-GSK189254 can be used to quantify H(3) receptor availability in humans in vivo using PET but requires high specific activity; the possibility of tracer mass dose effects should be carefully analyzed.