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Exl01
Crohn's Disease
Faecalibacterium Prausnitzii
in Inflammatory Bowel Diseases
Faecalibacterium Prausnitzii
immuno-oncology
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Exl01
Next-generation immunotherapy inhibiting Th1 immunity and activating IL-10 specific secretion by a Treg subpopulation
Work in progress
Learn more about
F. praustnizii
in Inflammatory Bowel Diseases
Learn more abouT Exl01
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There is no cure for Crohn's disease. The main aim of treatment is to reduce inflammation to relieve symptoms, by treating flare-ups, putting the disease in remission and maintaining remission. There is an urgent need to develop new, well-tolerated treatments that maintain remission in patients with CD without the serious side effects associated with some of the current therapies in use, as well as improving the quality of life and delaying the need for surgery. Conventional treatments focus on suppressing the immune response, and have not actually addressed the microbial component.
Based on the body of in vitro and in vivo data, it is anticipated that the delivery of a well-characterised, nonmodified strain of
F. prausnitzii
to the site of inflammation in patients with CD, may provide a safe treatment to prolong the maintenance of remission. The abundance of
F. prausnitzii
in healthy individuals suggests this approach is safe and may reduce the need for prolonged conventional immunosuppressive therapy.
Exeliom Biosciences is conducting a phase 1 study to provide safety and preliminary efficacy data for EXL01, in regard to the maintenance of steroid-induced clinical response or remission in participants with mild-to-moderate CD.
Learn more about
F. praustnizii
in Inflammatory Bowel Diseases
HOW DOES EXL01 WORK IN CROHN’S DISEASE?
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In vitro studies have shown that the EXL01-strain has strong anti-inflammatory properties, as indicated by the stimulation of the high ratio of IL-10/TNF-α secreted from human PBMCs. These effects have been confirmed in vivo in TNBS-induced colitis and DSS-induced colitis murine models.
IN VITRO ASSAYS
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We assessed the anti-inflammatory properties of the EXL01-strain produced in two different media: our proprietary media (GMP compliant medium) and a conventional laboratory culture media. The study also included a strain from another species (
F. Duncan
) which is similar to
F. prausnitzii
(produced in the conventional laboratory culture media) and LPS as a chemical positive control.
Fresh human PBMCs from healthy donors were incubated with resuspended EXL01-strain bacterial pellets, in triplicate, per PBMC donor. IL-10 (anti-inflammatory cytokine) and TNF-α (pro-inflammatory cytokine) concentrations in coculture supernatants were determined by an enzyme-linked immunosorbent assay.
The EXL01-strain, regardless of medium of production, stimulated a statistically significant increase in secretion of IL-10 (Figure 1A; p<0.05) but not TNF-α (Figure 1B), compared to RPMI media alone. The
F. duncan
strain stimulated numerically higher levels of TNF-α compared to the EXL01-strain, but this did not reach statistical significance (Figure 1B). The EXL01-strain demonstrated a higher IL10/TNF-α ratio (i.e. indicative of stronger anti-inflammatory properties), compared to the
F. duncan
strain, suggesting the EXL01-strain is a good therapeutic candidate (Figure 1C). The medium of EXL01-strain production (proprietary media vs. conventional media) had no impact on the anti-inflammatory properties of the EXL01-strain under the conditions tested.
A) IL-10
B) TNF-α
C) IL-10/TNF-α ration
Figure 1 :
Concentrations of IL-10, TNF-α and the ratio IL-10/TNF-α in PBMCs co-cultured with EXL01-strain pellets produced in a proprietary GMP-compliant and conventional non-GMP medium.
Abbreviations:
Other strain
=
F. Duncan
strain produced in conventional media; EXL01 non-GMPc = EXL01 strain produced in conventional laboratory media; EXL01 GMPc = EXL01 strain produced in GMP compliant proprietary media; IL10 = interleukin-10; LPS = Lipopolysaccharides; RPMI = Roswell Park Memorial Institute culture media supplemented with 5% foetal calf serum; SEM = standard error of the mean; TNF-α = tumour necrosis factor-alpha. The results are expressed in mean ± SEM. *=p <0.05; **=p <0.01; ***=p<0.001.
PRECLINICAL DNBS RAT MODEL
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A) Macroscopic Scores
B) Histological Scores
Dose 1 > Dose 2 > Dose 3 > Dose 4 > Dose 5Abbreviations: PBS = phosphate buffered saline; SEM = standard error of the mean; TNBS = 2,4,6-trinitrobenzene sulfonic acid. Vehicle = PBS/glycerolP-values are calculated in relation to the TNBS + Vehicle: *p<0.05; **p<0.01; ***p<0.001.Data are expressed as mean ± SEM of 3 pooled independent experiments.Vehicle n = 14; TNBS + Vehicle n = 29; TNBS + EXL01 Dose 1 n = 28; TNBS + EXL01 Dose 2 n = 27; TNBS + EXL01 Dose 3 n = 30; TNBS + EXL01 Dose 4 n = 19; TNBS + EXL01 Dose 5 n = 9; TNBS + Pentasa® n = 26.
Figure 1Colonic Macroscopic Scores (A) and Histological Scores (B) in Rats With TNBS-induced Colitis Following Administration of Different Doses of EXL01-strain by Oral Gavage
The anti-inflammatory properties and efficacy of the EXL01-strain administered by daily oral gavage (comparing 5 different doses) were assessed in an acute TNBS-induced colitis model in rats.
TNBS colitis model in rats is a well-established model of chemically-induced inflammation in the gut. This model employs rectal instillation of the mucosal sensitizing TNBS diluted in ethanol. TNBS haptenizes the localized colonic and gut microbial proteins to become immunogenic, triggering the host’s innate and adaptive immune responses. This model is considered a gold standard method to study Inflammatory Bowel Diseases (IBD); it reproduces many features of the inflammation seen in human Crohn’s disease including a similar cytokine profile, transmural inflammation and positive effects of the drugs currently used in Crohn’s disease (1).
The administration of Pentasa® (Mesalazine; 5-aminosalicylic acid, 150 mg/kg/day), the standard care treatment for colitis, was used as a positive control.
A strong anti-inflammatory effect of the EXL01-strain at daily doses of Dose 1, Dose 2, Dose 3 and Dose 4/day was observed at the macroscopic level; the percentage of improvement versus TNBS + Vehicle ranged from 29% (Dose 4/day) to 34% (Dose 1/day and Dose 2/day) after 11 days of oral administration in a dose-related manner (Figure 1A). No significant anti-inflammatory effect, at the macroscopic level, was reported for the EXL01-strain at the lowest tested doses of Dose 5/day. The anti-inflammatory effects of the EXL01-strain were greater than those induced by the Pentasa®, showing a higher efficacy to decrease the intensity of inflammation at the dosage of ≥ Dose 3/day.
Results obtained at the macroscopic level correlated with those obtained at the histological level; a statistically significant dose-dependent anti-inflammatory effect was recorded at the histological level for the EXL01-strain administered during the dose of Dose 1, Dose 2 and Dose 3/day (Figure 1B). The percentage improvement versus TNBS + Vehicle ranged from 22% (Dose 3/day) to 34% (Dose 1/day). No anti-inflammatory effects at the histological level were recorded at the lowest dosages of Dose 4 and Dose 5/day, or Pentasa® indicating a potentially higher efficacy of the EXL01-strain to decrease inflammation compared to a benchmark treatment currently in use for patients with IBD.
The EXL01-strain had no observed effects on the mortality rate, body weight evolution or inflammation, suggesting that the administration of the EXL01-strain, by daily oral gavage at doses Dose 1 to Dose 5/day, for 11 consecutive days, was well-tolerated under inflammatory and noninflammatory conditions.
References:
1. Kiesler P, Fuss I J and Strober W. Experimental Models of Inflammatory Bowel Diseases. Cell. Mol. Gastroenterol. Hepatol. 2015;1(2);154-170.
EXL01’S ONGOING EVALUATION IN A PHASE 1 MAINTENANCE CLINICAL STUDY IN CROHN’S DISEASE PATIENTS
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MAINTAIN is a Phase 1, two-part study of the oral administration of EXL01 in the maintenance of corticosteroid induced clinical response and remission in participants with Crohn’s disease. The study will be conducted in two parts: Part A will be an open-label evaluation of safety in a small group of participants (n = 6), and if the results following at least six weeks of treatment and follow-ups indicate that EXL01 is safe, we will initiate the second part. Part B will be a randomised, double-blind, placebo-controlled evaluation conducted in a larger group of participants (n = 42) (Figure 1). To add further assurance of safety, a sentinel approach will be used in Part A for the start of the treatment using EXL01, with data reviewed by an IDMC (Independent Data Monitoring Committee).This study represents the first oral administration of EXL01 in humans.There are no hypotheses being tested. The primary objective is to evaluate the safety of orally administered EXL01 in participants with Crohn’s disease after achieving a corticosteroid induced clinical response or remission. Participants will have mild–to-moderate Crohn’s disease at the start of corticosteroid induction therapy. Secondary and exploratory endpoints are included to provide initial assessments of efficacy and target engagement (clinical, endoscopic, histological, microbiological and cytokine biomarkers).
Both parts of the study will enrol adult patients with Crohn’s disease and ileal or ileocolonic involvement diagnosed for at least three months, presenting with a clinically active disease at baseline.
Treatment in the Maintenance Period will consist of the progressive tapering of corticosteroids according to a standard regimen over six weeks, in combination with the study treatment (open-label EXL01 in Part A and blinded EXL01 or placebo in Part B) for up to 24 weeks.
Abbreviations: CDAI = Crohn’s disease activity index;
Figure 1 MAINTAIN: Two Part (A and B) Study Design
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