Lecanemab Clarity AD: Quality-of-Life Results from a Randomized, Double-Blind Phase 3 Trial in Early Alzheimer's Disease.

BACKGROUND: Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to amyloid-beta protein protofibrils. In phase 3 development, lecanemab has been shown to reduce markers of amyloid in early Alzheimer's disease and reduce decline on clinical endpoints of cognition and function at 18 months. OBJECTIVES: To describe the health-related quality-of-life (HRQoL) results from Clarity AD which were exploratory outcomes in this trial. DESIGN: Clarity AD was an 18-month, multi-center, double-blind, phase 3 trial. SETTING: Early Alzheimer's disease. PARTICIPANTS: Individuals 50-90 years of age with a diagnosis of mild cognitive impairment or mild dementia due to Alzheimer's disease and positron emission tomography or cerebrospinal fluid evidence of cerebral amyloid accumulation. INTERVENTION: Placebo or lecanemab 10-mg/kg IV biweekly. MEASUREMENTS: HRQoL was measured at baseline and every 6 months using the European Quality of Life-5 Dimensions (EQ-5D-5L; by subject) and Quality of Life in AD (QOL-AD; by subject and proxy). Study partner burden was measured using the Zarit Burden Interview (ZBI). RESULTS: A total of 1795 participants were enrolled (lecanemab:898; placebo:897). At month 18, adjusted mean change from baseline in EQ-5D-5L and QOL-AD by subject showed 49% and 56% less decline, respectively. QOL-AD rated by study partner as proxy resulted in 23% less decline. ZBI adjusted mean change from baseline at 18 months resulted in 38% less increase of care partner burden. Individual HRQoL test items and dimensions also showed lecanemab benefit. CONCLUSIONS: Lecanemab was associated with a relative preservation of HRQoL and less increase in caregiver burden, with consistent benefits seen across different quality of life scales and within scale subdomains. These benefits provide valuable patient reported outcomes which, together with previously reported benefits of lecanemab across multiple measures of cognition, function, disease progression, and biomarkers, demonstrate that lecanemab treatment may offer meaningful benefits to patients, care partners, and society.

Amyloid and APOE Status of Screened Subjects in the Elenbecestat MissionAD Phase 3 Program.

BACKGROUND/OBJECTIVES: Elenbecestat, an oral BACE-1 inhibitor that has been shown to reduce Aß levels in cerebrospinal fluid, was investigated in two global phase 3 studies in early AD. Here we report on differences observed in characteristics of APOE ε4 and amyloid positive subjects in the large screening cohort. DESIGN: Screening was performed in 5 sequential tiers over a maximum of 80 days, as part of placebo controlled, double blind phase 3 studies. SETTING: Subjects were evaluated at sites in 7 regions (29 countries). PARTICIPANTS: Overall, 9758 subjects were screened. INTERVENTION: All screened subjects that were eligible received either placebo or 50 mg QID elenbecestat post randomisation. MEASUREMENTS: Gender, disease staging, APOE ε4 status, amyloid status, amyloid positron emission tomography (PET) standard uptake value ratio (SUVr) and amyloid PET Centiloid (CL) values were determined for screened subjects; by country and region. RESULTS: In this program, 44% of subjects were APOE ε4 positive. Frequency of females was similar in both APOE ε4 positive and negative groups. However, early mild AD subjects were slightly higher in the APOE ε4 positive group compared with the APOE ε4 negative group. 56% of subjects were amyloid positive. The mean age in the amyloid positive group was slightly higher than the amyloid negative group. The gender distribution was similar between amyloid groups. A lower number of mild cognitive impairment was observed in the amyloid positive group along with a higher number of early mild AD. APOE ε4 positive subjects were higher in amyloid positive group compared to the amyloid negative group. China had the lowest APOE ε4 and amyloid positivity rates with Western Europe and Oceania performing best. Subjects received florbetapir, florbetaben or flutemetamol amyloid PET tracer. Amyloid negative and positive subjects CL values were normally distributed around their respective means of 1.5 CL and 83 CL. However, there was an appreciable overlap in the 20-40 CL range. CONCLUSIONS: In this large cohort of cognitively impaired subjects, subject demographics characteristics were comparable regardless of APOE genotype or amyloid positivity. APOE ε4 positivity and amyloid positivity varied by country and by geographical region.

Intradermal delivery of recombinant vaccinia virus vector DIs induces gut-mucosal immunity.

Antigen-specific mucosal immunity is generally induced by the stimulation of inductive mucosal sites. In this study, we found that the replication-deficient vaccinia virus vector, DIs, generates antigen-specific mucosal immunity and systemic responses. Following intradermal injection of recombinant DIs expressing simian immunodeficiency virus gag (rDIsSIVgag), we observed increased levels of SIV p27-specific IgA and IgG antibodies in faecal extracts and plasma samples, and antibody-forming cells in the intestinal mucosa and spleen of C57BL/6 mice. Antibodies against p27 were not detected in nasal washes, saliva, and vaginal washes. The enhanced mucosal and systemic immunity persisted for 1 year of observation. Induction of Gag-specific IFN-gamma spot-forming CD8(+) T cells in the spleen, small intestinal intraepithelial lymphocytes, and submandibular lymph nodes was observed in the intradermally injected mice. Heat-inactivated rDIsSIVgag rarely induced antigen-specific humoral and T-helper immunity. Moreover, rDIsSIVgag was detected in MHC class II IA antigen-positive (IA(+)) cells at the injection site. Consequently, intradermal delivery of rDIs effectively induces antigen-specific humoral and cellular immunity in gut-mucosal tissues of mice. Our data suggest that intradermal injection of an rDIs vaccine may be useful against mucosally transmitted pathogens.

Mucosal administration of completely non-replicative vaccinia virus recombinant Dairen I strain elicits effective mucosal and systemic immunity.

We studied the immunogenicity of completely replication-deficient vaccinia virus Dairen I strain recombinant encoding simian immunodeficiency virus (SIV) gag/pol (rDIs) in both mucosal and systemic compartments. When administered either intranasally or intragastrically, rDIs elicited enhanced levels of both SIV Gag p27-specific IgA antibodies and specific plasma antibodies, and the enhanced immunity persisted for the 1-year of observation by intranasal immunization. Increases were observed in antigen-specific IgA antibody-forming cells (AFC) in intestinal mucosal tissues and in IgG AFC in spleens. Furthermore, induction of type 1 and 2 helper cytokines in CD4+ spleen T cells and of CD8+ IFN-gamma spot-forming cells in mucosal tissues was observed in the intranasally immunized mice. Moreover, not even high-dose rDIs generated an SIV gene signal in the brain tissues of immunized mice. These findings suggest that mucosal immunization with the DIs recombinant hold promise as a safe mucosal vector.

Zinc-induced activation of the human cytomegalovirus major immediate-early promoter is mediated by metallothionein and nuclear factor-kappaB.

We previously reported that major immediate-early promoter (MIEP) activity was regulated by intercellular zinc levels. In this report, we elucidate the mechanisms involved in this phenomenon. In luciferase reporter assays, zinc-induced activation of MIEP (-735/+62) was decreased with deletion of the promoter in stages, and MIEP (-117/+62) did not respond to zinc. The time course of the activity of MIEP responding to diethylenetriamine pentaacetic acid and zinc was not parallel with metallothionein (MT) promoter, which contains metal responsive elements. SV40 promoter that contains AP-1 binding sites, a candidate for the zinc-responsive motif in the MIEP, was not affected by zinc under our conditions. The activation of MIEP (-735/+62) by zinc was prevented with NF-kappaB decoy. When three kappaB motifs from the enhancer in the MIEP were inserted in the front of the zinc-nonresponsive MIEP (-117/+62), it became responsive to zinc. Moreover, overexpression of MT up-regulates the DNA binding of NF-kappaB and NF-kappaB-induced activation of transcription. These findings strongly suggest that MT and NF-kappaB act as mediator/regulator in zinc-induced activation of MIEP.

Cellular zinc status regulates cytomegalovirus major immediate-early promoter.

Diethylenetriaminepenta-acetic acid (DTPA) inhibits human cytomegalovirus (CMV) replication in vitro, although the mechanism has remained unclear. The present study shows that DTPA inhibits CMV major immediate-early (MIE) promoter activity in a luciferase reporter assay, whereas its enhancer-less promoter was not affected. The inhibitory effect of DTPA on CMV MIE promoter activity was abrogated by stoichiometric amounts of cations in the following (decreasing) order, Zn(2+)>Co(2+)>Ni(2+)>Cu(2+)>Fe(3+)>Fe(2+), but not by Mn(2+). These cations bind to DTPA and may limit the zinc-chelating capability. In the absence of DTPA, exogenous zinc activated CMV MIE promoter activity in a dose-dependent manner, but not its enhancer-less promoter. The intracellular metallothionein content of DTPA- and cation-treated cultures was significantly correlated with CMV MIE promoter activity. DTPA may inhibit CMV replication by regulating CMV MIE promoter activity through controlling the availability of cellular zinc. Since the CMV MIE promoter has no consensus sequence for a metal responsive element, a novel mechanism for metal-regulated transcription may be involved in this process.

Two metallothioneins in the fresh-water fish, crucian carp (Carassius cuvieri): cDNA cloning and assignment of their expression isoforms.

Two metallothionein cDNAs (MT-A and MT-B) in the fresh-water fish crucian carp (Carassius cuvieri Temminck et Schlegel) were cloned. Sequence analysis of both cDNAs gave the structure of a coding region corresponding to 60 amino acid residues. The homology of their deduced amino acid sequences was completely conserved at the positions of the cysteine residue, but a significant difference existed in the size of their 3'-untranslated regions (130 base pairs for MT-A and 280 base pairs for MT-B). Direct amino acid sequencing of the MT-II isoform purified by HPLC was accomplished for up to 30 residues and its sequence was identical to that deduced from MT-B cDNA. This is the first case in vertebrates that N-terminal methionine in crucian carp MT-II was not blocked. By northern blot analysis, basal and cadmium chloride- or dexamethasone-induced MT-B (MT-II) mRNAs were detected time dependently after treatment. On the other hand, the expression of MT-A mRNA was extremely low. These results indicate that the MT isoform II in crucian carp is coded by the MT-B gene, and that the MT-B-dominant expression of mRNA in crucian carp may be due to the difference in the 3'-untranslated regions of MT mRNAs.

Requirement for cooperative interaction of interleukin-6 responsive element type 2 and glucocorticoid responsive element in the synergistic activation of mouse metallothionein-I gene by interleukin-6 and glucocorticoid.

Metallothionein (MT)-inducing activity of interleukin (IL)-6 depends on the presence of glucocorticoid in hepatic cells. The synergistic action of IL-6 and glucocorticoid was observed in the transcriptional activation of the mouse MT (mMT)-I gene. We found that a 281-bp promoter was sufficient for IL-6 and glucocorticoid stimulation. Our inspection of this region revealed the putative type 1 and 2 IL-6 responsive elements (REs). Functional analyses of these regions were performed using luciferase reporter constructs, and it was observed that the type 2 IL-6RE exerted the major response to the IL-6 signal. The transcriptional factor binding to type 1 IL-6RE, nuclear factor-IL-6, hardly contributed to the activation of the mMT-I promoter by IL-6 and glucocorticoid. A glucocorticoid responsive element (GRE) was also required for the synergistic activation by IL-6 and glucocorticoid. Interestingly, this synergism was not observed when the type 2 IL-6RE and the GRE were kept apart. Therefore, the synergistic activation of the mMT-I gene by IL-6 and glucocorticoid may require not only that signal transducers and activators 3 (Stat3) and the glucocorticoid receptor (GR) bind to their respective responsive elements, but also that Stat3 and the GR physically interact with one another.