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BackgroundElobixibat is an oral treatment candidate for chronic constipation with a novel mechanism of action via inhibition of the ileal bile acid transporter. We performed this randomized, double-blind, placebo-controlled, dose-finding phase IIb study in Japanese patients with chronic constipation to determine the optimal clinical dose of elobixibat.MethodsJapanese patients with chronic constipation were randomized to receive elobixibat (5, 10, or 15 mg) or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements at Week 1 of treatment. Secondary endpoints and adverse events were also examined.ResultsAmong 226 patients who provided informed consent, 163 patients were randomized and included in the full analysis set. In the 10- and 15-mg groups, frequency of spontaneous bowel movements (±standard deviation) were significantly higher than baseline (5.7 ± 4.2 and 5.6 ± 3.5 times per week, respectively, compared with 2.6 ± 2.9 times per week in the placebo group [P = 0.0005, P = 0.0001, respectively]). Subgroup analysis indicated that elobixibat was equally effective in patients with or without constipation-predominant irritable bowel syndrome. Common adverse events included mild abdominal pain and diarrhea in the elobixibat groups; no serious or severe adverse events occurred. Elobixibat was well tolerated at once-daily oral doses up to 15 mg for 2 weeks.ConclusionsOur study results suggest that 10 mg of elobixibat is a clinically optimal dose for Japanese patients with chronic constipation.Clinical trial registration numberJapicCTI-142608.

Plasmodium falciparum, a human malaria parasite, invades an erythrocyte during one stage of its life cycle. In an infected erythrocyte, the P. falciparum organism develops a membrane structure called the parasitophorus vacuolar membrane. The parasitophorus vacuolar membrane extends into the host cell cytoplasm and forms a complex membrane structure, thus called the tubovesicular membrane network (reviewed in Refs. 1-3). These membrane systems outside the P. falciparum cell are important for the transport of various nutrients such as glucose, phospholipids, and amino acids and for extrusion of antimalarial agents so as to maintain suitable circumstances for them (3-6). In addition to the formation of such intraerythrocytic membrane systems, P. falciparum cells also transport some proteins such as erythrocyte membrane protein-1 of P. falciparum (PfEMP1) 1 and PfEMP3 to the erythrocyte plasma membrane, which results in the formation of a knob-like structure on the surfaces of the infected erythrocytes. These proteins are responsible for protection against immunological attack and attachment of infected erythrocyte to endothelial cells, one of the crucial steps for cerebral malaria (1-3, 7-11). Importantly, the extraparasite protein transport process can not rely upon the endogenous transport machinery in the host cells, because mature erythrocytes are completely devoid of machinery for protein trafficking. Thus, the malaria parasite must transport proteins through the plasma membrane and the membrane structure in the cytoplasm of the host cells by means of their own mechanism, although the molecular pathway for the transport of proteins through the parasite plasma membrane is less understood.It has been shown that the transport of some proteins from malaria parasites is sensitive to BFA (12-16), which is a well known macrolide antibiotic produced by fungi that blocks eukaryotic protein trafficking processes, especially transport from the endoplasmic reticulum to the Golgi apparatus by inhibiting the activities of ADP-ribosylation factors and guanine nucleotide exchange factors (17). These results suggest that the transport pathway from the endoplasmic reticulum to the Golgi apparatus is involved in the targeting of parasite

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.