# Abstract

 

## Background Elobixibat is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor in development against chronic constipation (CC) and constipation-predominant Irritable Bowel Syndrome (IBS-C). CC is associated with an increased risk for cardiovascular disease and type2 diabetes mellitus. The objectives of this study were to evaluate metabolic effects of elobixibat. Effects on plasma lipids and BA synthesis were evaluated utilizing a 4-week, placebo-controlled study in patients with dyslipidemia while changes of glucagon-like peptide-1 (GLP-1) by elobixibat was assayed in samples from a 14 day high-dose elobixibat study in patients with CC. 

## Methods Thirty-six dyslipidemic patients, 21 females, mean age 63 years, were randomized to 2.5 mg or 5 mg elobixibat or placebo once daily for four weeks. The primary endpoint was the change in low density lipoprotein (LDL) cholesterol. Secondary endpoints included other lipid parameters and serum 7α-hydroxy-4-cholesten-3-one (C4), a marker of BA (bile acid) synthesis. Another study, in 36 patients with CC treated with high dose elobixibat; 15 mg or 20 mg/day or placebo for 14 days, was evaluated for changes in GLP-1. 

## Results In the dyslipidemia study LDL cholesterol was reduced by 7.4 % ( *p* = 0.044), and the LDL/HDL ratio was decreased by 18 % (*p* = 0.004). Serum C4 increased, indicating that BA synthesis was induced. No serious adverse events were recorded. In the CC study, GLP-1 increased significantly in both the 15 mg (20.7 ± 2.4 pmol/L; *p* = 0.03) and the 20 mg group (25.6 ± 4.9 pmol/L; *p* = 0.02). 

## Conclusions Elobixibat reduces LDL cholesterol and LDL/HDL ratio and increase circulating peak GLP-1 levels, the latter in line with increased intestinal BA mediated responses in humans. 

## Trial registrations ClinicalTrial.gov: [NCT01069783](#) and [NCT01038687](#) . # Results 

## Results of the dyslipidemia study 

### Patient flow and follow-up The study flow and patient demographics is shown in Fig. [1](#). Out of 81 screened subjects, 36 patients fulfilled eligibility criteria, entered the study and were randomized to treatment with elobixibat or placebo. All patients completed the study; the ITT and the Safety population include the same patients. At baseline, the demographic parameters were similar between the treatment groups (Table [1A](#)). Patients had a mean age of 63 years (range 34--80) and there was a slight preponderance for women (58 %). Baseline lipid profiles were similar across the groups (Table [ 1A](#)). No changes in safety laboratory values, including liver enzymes and plasma glucose, were identified during the study. <figure> <p><img src="" /></p> <figcaption>Patient flow chart in the Dyslipidemia study</figcaption> </figure> ::::table-wrap

::: caption
Demographics and baseline parameters
:::

A. Dyslipidemia study

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```
                             Placebo (*N* = 12)   Elobixibat 2.5 mg (*N*  = 12)   Elobixibat 5 mg (*N*  = 12)    
```

Female n (%) 8 (66.7) 7 (58.3) 6 (50.0)
Caucasian n (%) 12 (100.0) 12 (100.0) 12 (100.0)
Age (years) Mean (SD) 64.4 (10.1) 60.9 (13.2) 62.7 (11.4)
Weight (kg) Mean (SD) 76.2 (16.3) 78.1 (16.4) 76.6 (12.8)
BMI (kg/m^2^) Median 24.8 26.3 26.4
LDL-Cholesterol (mmol/L) Mean (SD) 4.29 (0.71) 4.61 (0.63) 4,78 (0.65)
Cholesterol (mmol/L) Mean (SD) 6.38 (0.75) 6.44 (0.57) 6.57 (0.72)
HDL-Cholesterol (mmol/L) Mean (SD) 1.53 (0.49) 1.34 (0.43) 1.23 (0.30)
LDL/HDL-Cholesterol (mmol/L) Mean (SD) 3.00 (0.92) 3.77 (1.60) 4.32 (1.73)
B. The CC study\
Placebo (*N* = 13) Elobixibat 15 mg (*N*  = 12) Elobixibat 20 mg (*N*  = 11)\
Female n (%) 13 (100.0) 12 (100.0) 11 (100.0)
Caucasian n (%) 11 (92.3) 12 (100.0) 12 (100.0)
Age (years) Mean (SD) 47.2 (9.30) 38.3 (8.18) 46.1 (6.36)
Weight (kg) Mean (SD) 70.2 (9.7) 72.9 (15.5) 75.0 (17.0)
BMI (kg/m^2^) Median 25.9 24.8 26.0
GLP-1 (pmol/L) Mean (SD) 18.45^a^ (8.63) 15.08 (5.38) 14.67^b^ (5.92)

^a^*n* = 11

^b^*n* = 9:::: 

### Effects of elobixibat on lipid profiles and on C4 There was a significant (*p* = 0.044) change from baseline to end of treatment in LDL cholesterol (7.4 %) for the 5 mg elobixibat treatment group -- the primary end point of the study (Fig. [2](#)). No significant change was achieved for the 2.5 mg elobixibat cohort. When analyzing the mean and median change values from baseline to Days 14 and 28, there was a more prominent reduction in the drug-treated groups as compared to placebo whereas on day 42 (14 days after cessation of treatment) there was no clear difference. <figure> <p><img src="" /></p> <figcaption>Median % changes (interquartile 25–75 % range) from baseline for plasma total cholesterol, LDL, HDL, LDL/HDL ratio and triglycerides (TG) in the Dyslipidemia study. \*: <em>p</em> = 0.044 \*\*: <em>p</em> = 0.004 (Wilcoxon)</figcaption> </figure> Elobixibat treatment did not significantly alter total cholesterol, HDL cholesterol or triglycerides (Fig. [2](#)). In contrast, the LDL/HDL ratio was significantly reduced on Day 28 in the 5 mg group (*p* = 0.004) (18 %) whereas no effect was seen in the 2.5 mg group (p = 0.06) (Fig. [2](#)). C4 was significantly increased in both the 2.5 mg and in the 5 mg elobixibat groups on Day 28 (*p* = 0.03 for both groups) (Fig. [3](#)). <figure> <p><img src="" /></p> <figcaption>Median % changes (interquartile 25–75 % range) from baseline for plasma C4 in the Dyslipidemia study. \*: <em>p</em> \<0.03 (Wilcoxon)</figcaption> </figure> 

### Safety assessments No serious adverse events (SAEs) were reported during the dyslipidemia study. AEs were most prevalent in the placebo group (92 % of the patients reported 27 AEs). In the 2.5 mg and 5 mg treatment groups, 50 % and 67 % of the patients reported a total of 11 and 14 AEs respectively. Most of the AEs were recorded as mild and transient and only four were moderate, two in the placebo group and two in the 5 mg group; none of them were judged to be related to the study drug. No patient discontinued the study. Table [2](#) outlines the incidence of AEs. The most common AEs were headache, diarrhea and constipation. Notably, diarrhea was reported in 3 patients on placebo, 2 patients on 2.5 mg and 3 patients on 5 mg. ::::table-wrap
::: caption
Adverse events occurring in more than one subject in the Dyslipidemia
study. No serious adverse events and no discontinuations were identified
:::

```
                                                     Placebo (*N* = 12)      A3309 - 2.5 mg (*N*  = 12)   A3309 - 5 mg (*N*  = 12)   
```

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MedDRA system organ class MedDRA preferred term n (%) n (%) n (%)
Gastrointestinal disorders Abdominal distension 1 (8.3) 1 (8.3) 1 (8.3)
Constipation 4 (33.3) 1 (8.3) -
Diarrhoea 3 (25.0) 2 (16.7) 3 (25.0)
General disorders and administration site conditions\
Pyrexia 1 (8.3) - 1 (8.3)
Infections and infestations\
Pharyngitis 1 (8.3) - 1 (8.3)
Rhinitis 2 (16.7) - -
Musculoskeletal and connective tissue disorders Myalgia 2 (16.7) - -
Nervous system disorders Dizziness 2 (16.7) - -
Headache 3 (25.0) 3 (25.0) 3 (25.0)
Renal and urinary disorders Polyuria 1 (8.3) 1 (8.3) -
Respiratory, thoracic and mediastinal disorders Cough 1 (8.3) - 1 (8.3):::: 

## Results of the CC study Demographic parameters are described in Table [1B](#). Efficacy on pharmacodynamics and clinical endpoints of CC and safety assessments have been reported previously \[[5](#)\]. No changes in safety laboratory values, including liver enzymes and plasma glucose, were identified during the study. 

### Effects of elobixibat on circulating GLP-1 levels in constipated patients Peak values for GLP-1 levels increased significantly during the day, when adjusted for baseline values, for both the 15 mg (20.7 ± 2.4 pmol/L) and the 20 mg (25.6 ± 4.9 pmol/L) groups ( *p* = 0.03 and *p* = 0.02 respectively) compared with placebo (12.8 ± 2.4 pmol/L) (Fig. [4](#)). Peak values were observed at lunch time. No significant differences were observed for the basal morning levels at Day 12 of treatment when compared to levels prior to treatment. Similarly, there were no significant differences in total AUC levels during the 480 min period (201 ± 12 pmol/L*hr (15 mg), 225 ± 27 pmol/L*hr (20 mg) and 180 ± 27 pmol/L\*hr (placebo). <figure> <p><img src="" /></p> <figcaption>GLP-1 (pmol/L) in the CC study. Data shown are the difference between peak values Day 12 and the basal pre-study value. Mean ± SEM. \*: <em>p</em> \< 0.05 (Wilcoxon)</figcaption> </figure>


Extracted trial result:
Outcome: LDL cholesterol (continuous)
Intervention: 2.5 mg
Comparator: placebo
Intervention group size: 12
Comparator group size: 12
Notes: no raw values given and can only be estimated from figure