Background
In two phase 3 trials, elobixibat, a locally acting ileal bile acid transporter inhibitor, resolved constipation and was well tolerated in Japanese patients with chronic constipation. We ...analyzed the efficacy, safety, and impact on quality of life (QOL) of elobixibat in patients with symptomatically more severe constipation in the two phase 3 trials.
Methods
This post hoc analysis of elobixibat treatment outcomes included data from a 2‐week, randomized, placebo‐controlled, phase 3 trial (10 mg/d), and a 52‐week, open‐label trial (5‐15 mg/d) in subgroups with severe constipation defined as ≤2 spontaneous bowel movements (SBMs) and ≤3 Bristol Stool Form Scale score during the second week of the 2‐week run‐in period. We also analyzed the rates of abdominal pain, diarrhea, and QOL in subgroups according to sex, presence of constipation‐predominant irritable bowel syndrome (IBS‐C) and side effects.
Key Results
In patients with severe constipation, there was significant improvement in the 10 mg elobixibat group compared to the placebo group in change in SBMs from baseline at week 1 (primary endpoint) of the 2‐week trial. The differences between groups were reduced in patients with more severe constipation. Increasing the dose to 15 mg was effective for more severe constipation in improving the number of SBMs per week in the 52‐week trial. Overall, elobixibat was well tolerated and improved QOL scores, irrespective of gender, presence of IBS‐C or side effects.
Conclusions & Inferences
Elobixibat is effective for symptomatically severe constipation, is well tolerated and improves QOL, irrespective of potentially confounding patient characteristics.
This post hoc analysis of elobixibat treatment outcomes included data from a 2‐week, randomized, placebo‐controlled, phase 3 trial (10 mg/d) and a 52‐week, open‐label trial (5‐15 mg/d) in subgroups with severe constipation defined as ≤2 spontaneous bowel movements (SBMs) and ≤3 Bristol Stool Form Scale score during the second week of the 2‐week run‐in period. In patients with severe constipation, there was significant improvement in the 10 mg elobixibat group compared to placebo group in change in SBMs from baseline at week 1 (primary endpoint) of the 2‐week trial. Elobixibat is effective for symptomatically severe constipation, is well tolerated and improves quality of life, irrespective of potentially confounding patient characteristics.
Autosomal-dominant Alzheimer's disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using
C-Pittsburgh compound B (PiB) tracer has shown ...differences in binding between brains from ADAD and sporadic Alzheimer's disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with
H-PiB,
H-MK6240-
H-THK5117, and
H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AβPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AβPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable
H-THK5117 and
H-deprenyl brain homogenate binding was observed for AβPParc, PSEN1ΔE9, and sAD, respectively. Some differences were observed between
H-MK6240 and
H-THK5117 in ADAD. A positive correlation between
H-deprenyl and
H-THK5117 binding was observed in AβPParc, while no such correlation was found in PSEN1ΔE9 and sAD. Our study demonstrates differences in the properties of the amyloid plaques between two genetic variants of AD and sAD. Despite the lack of measurable amyloid fibrils by PiB in the AβPParc cases, high regional tau and astrocyte binding was observed. The lack of correlation between
H-deprenyl and
H-THK5117 binding in PSEN1ΔE9 and sAD in contrast of the positive correlation observed in the AβPParc cases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo.
Background and Aim
Elobixibat is a locally acting inhibitor of the ileal bile acid transporter. We compared bile acid metabolism between healthy subjects and patients with chronic constipation and ...assessed changes in the bile acid profile after elobixibat administration in the latter group.
Methods
Healthy subjects (n = 10) and patients with chronic constipation (n = 19) were assessed as inpatients for 7 days, during which they received meals containing ~60 g/day of fat. Patients with chronic constipation remained as inpatients for a further 7 days for once‐daily elobixibat administration. Assessments included concentrations of fecal and serum bile acids, serum 7α‐hydroxy‐4‐cholesten‐3‐one (C4) and fibroblast growth factor 19, and bowel movements and constipation symptoms.
Results
Fecal total and primary bile acids were significantly lower in patients with chronic constipation versus healthy subjects. Serum C4 and fibroblast growth factor 19 levels were comparable between groups. Elobixibat treatment increased fecal total and primary bile acids and decreased levels of fecal lithocholic acid and serum total as well as secondary bile acids in patients with chronic constipation. Bowel movements and other constipation‐related symptoms were also improved by elobixibat to levels almost comparable with those of healthy subjects.
Conclusions
Despite comparable C4 levels, patients with chronic constipation demonstrated decreased levels of fecal bile acids versus healthy subjects. Elobixibat treatment increased fecal bile acid excretion and reduced serum bile acid concentrations. The improvement of constipation after elobixibat treatment was associated with increased total bile acids, particularly primary bile acids.
Abstract
Bile acids have secretory, motility and antimicrobial effects in the intestine. In patients with bile acid malabsorption the amount of primary bile acids in the colon is increased compared ...to healthy controls. Deoxycholic acid is affecting the intestinal smooth muscle activity. Chenodeoxycholic acid has the highest potency to affect intestinal secretion. Litocholic acid has little effect in the lumen of intestine compared to both deoxycholic acid and chenodeoxycholic acid. There is no firm evidence that clinically relevant concentrations of bile acids induce colon cancer. Alterations in bile acid metabolism may be involved in the pathophysiology of constipation.
Abstract Introduction Amyloid imaging has been integrated into diagnostic criteria for Alzheimer's disease (AD). How amyloid tracers binding differ for different tracer structures and amyloid-β ...aggregates in autosomal dominant AD (ADAD) and sporadic AD is unclear. Methods Binding properties of different amyloid tracers were examined in brain homogenates from six ADAD with APPswe , PS1 M146V , and PS1 EΔ9 mutations, 13 sporadic AD, and 14 control cases. Results3 H-PIB,3 H-florbetaben,3 H-AZD2184, and BTA-1 shared a high- and a varying low-affinity binding site in the frontal cortex of sporadic AD. AZD2184 detected another binding site (affinity 33 nM) in the frontal cortex of ADAD. The3 H-AZD2184 and3 H-PIB binding were significantly higher in the striatum of ADAD compared to sporadic AD and control. Polyphenol resveratrol showed strongest inhibition on3 H-AZD84 binding followed by3 H-florbetaben and minimal on3 H-PIB. Discussion This study implies amyloid tracers of different structures detect different sites on amyloid-β fibrils or conformations.
The aim of this study was to compare the binding properties of several tau positron emission tomography tracers-THK5117, THK5351, T807 (also known as AV1451; flortaucipir), and PBB3-head to head in ...the same human brain tissue.
Binding assays were performed to compare the regional distribution of
H-THK5117 and
H-THK5351 in postmortem tissue from three Alzheimer's disease (AD) cases and three control subjects in frontal and temporal cortices as well as in the hippocampus. Competition binding assays between THK5351, THK5117, PBB3, and T807, as well as off-target binding of THK5117 and T807 toward monoamine oxidase B (MAO-B), were performed using binding assays in brain homogenates and autoradiography of three AD cases.
Regional binding of
H-THK5117 and
H-THK5351 was similar, except in the temporal cortex, which showed higher
H-THK5117 binding. Saturation studies demonstrated two binding sites for
H-THK5351 (K
= 5.6 nM, B
= 76 pmol/g; K
= 1 nM, B
= 40 pmol/g). Competition studies in the hippocampus between
H-THK5351 and unlabeled THK5351, THK5117, and T807 revealed super-high-affinity sites for all three tracers (THK5351 K
= 0.1 pM; THK5117 K
= 0.3 pM; T807 K
= 0.2 pM) and an additional high-affinity site (THK5351 K
= 16 nM; THK5117 K
= 20 nM; T807 K
= 78nM).
F-T807,
C-THK5351, and
C-PBB3 autoradiography of large frozen sections from three AD brains showed similar regional binding for the three tracers, with lower binding intensity for
C-PBB3. Unlabeled THK5351 and T807 displaced
C-THK5351 to a similar extent and a lower extent, respectively, compared with
C-PBB3. Competition with the MAO-B inhibitor
H-L-deprenyl was observed for THK5117 and T807 in the hippocampus (THK5117 K
= 286 nM; T807 K
= 227 nM) and the putamen (THK5117 K
= 148 nM; T807 K
= 135 nM).
H-THK5351 binding was displaced using autoradiography competition with unlabeled THK5351 and T807 in cortical areas by 70-80% and 60-77%, respectively, in the basal ganglia, whereas unlabeled deprenyl displaced
H-THK5351 binding by 40% in the frontal cortex and 50% in the basal ganglia.
THK5351, THK5117, and T807 seem to target similar binding sites, but with different affinities, whereas PBB3 seems to target its own binding site. Both THK5117 and T807 demonstrated off-target binding in the hippocampus and putamen with a ten times lower binding affinity to the MAO-B inhibitor deprenyl compared with
H-THK5351.
The accumulation of pathological misfolded tau is a feature common to a collective of neurodegenerative disorders known as tauopathies, of which Alzheimer's disease (AD) is the most common. Related ...tauopathies include progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), Down's syndrome (DS), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Investigation of the role of tau pathology in the onset and progression of these disorders is now possible due the recent advent of tau-specific ligands for use with positron emission tomography (PET), including first- (e.g.,
FTHK5317,
FTHK5351,
FAV1451, and
CPBB3) and second-generation compounds namely
FMK-6240,
FRO-948 (previously referred to as
FRO69558948),
FPI-2620,
FGTP1,
FPM-PBB3, and
FJNJ64349311 (
FJNJ311) and its derivative
FJNJ-067). In this review we describe and discuss findings from in vitro and in vivo studies using both initial and new tau ligands, including their relation to biomarkers for amyloid-β and neurodegeneration, and cognitive findings. Lastly, methodological considerations for the quantification of in vivo ligand binding are addressed, along with potential future applications of tau PET, including therapeutic trials.
A subset of patients with constipation has reduced colonic bile acid concentrations, which are associated with slow colonic transit. In a previous study, elobixibat, a locally acting ileal bile acid ...transporter inhibitor, accelerated colonic transit in Japanese patients with functional constipation. In this study, we aimed to determine the efficacy of elobixibat for short-term treatment of chronic constipation, and safety, patient satisfaction, and quality of life with long-term treatment.
We did two phase 3 studies of patients aged 20-80 years in Japan with at least 6 months of chronic constipation, who satisfied Rome III criteria for functional constipation, including fewer than three spontaneous bowel movements per week. The first trial, including patients enrolled at 16 clinics, was a 2-week, randomised, double-blind, placebo-controlled study in which (after a 2-week run-in period) patients were randomly assigned (1:1) to either elobixibat 10 mg/day for 2 weeks or placebo. Randomisation was done with permuted block method (block size six) without stratification. Masking to treatment allocation was achieved with identical appearances of elobixibat and placebo, which were supplied in sealed, opaque containers. Group assignment was concealed from patients, investigators, and analysts. The second trial, including patients enrolled at 34 clinics or hospitals, was an open-label, 1-year study in which all patients received elobixibat; participants could titrate the dose to 5 mg/day or 15 mg/day, or maintain the 10 mg/day dose. In both studies, participants took the study drug as an oral tablet once per day before breakfast. The primary outcome of the 2-week randomised trial was the change from baseline (ie, last week of the 2-week run-in) in the frequency of spontaneous bowel movements during week 1 of treatment. The primary outcome of the 52-week open-label trial was safety (type, severity, and incidence of adverse drug reactions) at all times from treatment initiation. All efficacy analyses were based on the modified intention-to-treat (ITT) population without imputation for any missing data. Safety analyses included all patients who received at least one dose of study drug. These trials are registered with the Japan Pharmaceutical Information Center (numbers JapicCTI-153061 and JapicCTI-153062) and have been completed.
Between Nov 4, 2015, and June 11, 2016, we assigned 133 patients to treatment in the 2-week randomised trial: 70 to elobixibat (69 included in the modified ITT and safety populations) and 63 to placebo. The frequency of spontaneous bowel movements per week during week 1 of treatment was greater with elobixibat (least-squares mean 6·4, 95% CI 5·3-7·6) than with placebo (1·7, 1·2-2·2), p<0·0001). Between Oct 31, 2015, and March 15, 2017, we allocated 341 patients to 52 weeks of elobixibat (340 included in the modified ITT and safety populations). 163 (48%) patients in the 52-week trial had an adverse drug reaction, the most common of which were mild gastrointestinal disorders (in 135 40% patients). Inguinal hernia was reported in one patient with elobixibat in the 52-week study as a moderate adverse drug reaction. The most common adverse drug reactions in both trials were mild abdominal pain (13 19% patients with elobixibat and one 2% with placebo in the 2-week randomised trial, and 82 24% patients in the 52-week trial) and diarrhoea (nine 13% patients with elobixibat and none with placebo in the 2-week randomised trial and 50 15% in the 52-week trial).
Elobixibat resolved constipation in the short-term, and was well tolerated with both short-term and long-term treatment. The evidence supports the use of this novel approach to increase intracolonic concentrations of endogenous bile acid for the treatment of chronic constipation.
EA Pharma and Mochida Pharmaceutical.
Hyperphosphorylated tau protein deposits and, inflammatory processes are characteristic components of Alzheimer disease (AD) pathology. We here aimed to visualize in vitro the distribution of tau ...deposits and activated astrocytes across the cortical layers in autopsy AD brain tissue using the radiotracers
H-THK5117 and
H-deprenyl.
H-THK5117 and
H-deprenyl autoradiographies were carried out on frozen brain sections from three AD patients and one healthy control.
H-THK5117 showed a distinct laminar cortical binding similar to
H-deprenyl autoradiography, with an extensive binding in the superficial and deep layers of the temporal neocortices, whereas the middle frontal gyrus showed an even binding throughout the layers. Globally, eventhough some differences could be observed, AT8 (tau) and GFAP (astrocyte) immunostaining showed a laminar pattern comparable to their corresponding radiotracers within each AD case. Some variability was observed between the AD cases reflecting differences in disease phenotype. The similar laminar cortical brain distribution of tau deposits and activated astrocytes supports the hypothesis of a close pathological interconnection. The difference in regional binding patterns of
H-THK5117 and AT8 antibody staining suggest additional tau binding sites detectable by
H-THK5117.
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