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Ameliorating Active Ulcerative Colitis via an Orally Available Toll-Like Receptor-9 Modifier: A Prospective
Iris Dotan1, Etgar Levy-Nissenbaum2, Yehuda Chowers3
1Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv, Israel. irisd@tlvmc.gov.il.
Background:
Treatment of active ulcerative colitis is associated with incomplete efficacy, adverse events, and loss of response. Toll-like receptor-9 mediates innate and adaptive immune response toward intestinal microorganisms. The oral synthetic oligonucleotide toll-like receptor-9 modulator has demonstrated anti-inflammatory properties in colitis murine models and a satisfactory safety profile in humans.
Aim:
To evaluate the efficacy and safety of BL-7040 (a Toll-like receptor-9 modulator) in patients with moderately active ulcerative colitis.
Methods:
Moderately active ulcerative colitis patients were included in this multicenter, open-label phase IIa trial. Concomitant mesalamine and steroids at a stable dose were allowed. Clinical outcome was evaluated using the Mayo score, histology, and mucosal cytokine levels. Side effects were registered.
Results:
Sixteen out of 22 patients completed a 5-week treatment course and 2-week follow-up. Six patients discontinued the study, three of them due to adverse events. Clinical remission was observed in two patients (12.5 %), and clinical response as well as mucosal healing were achieved in half (50 %) of the patients, while all others remained stable. Furthermore, mucosal neutrophil (p = 0.002) and mucosal interleukin-6 levels (p = 0.046) were significantly reduced in responders compared to non-responders. Toll-like receptor-9 was well tolerated with only one unrelated to study drug serious adverse event (hemoglobin decrease) and 29 mild-to-moderate adverse events.
Conclusions:
Oral administration of the Toll-like receptor-9 agonist BL-7040 appeared efficacious, safe and well tolerated in patients with moderately active ulcerative colitis.
Insights
A novel Toll-like receptor-9 (TLR9) modulator, BL-7040, showed promise in treating ulcerative colitis. This oral treatment demonstrated efficacy and a good safety profile in patients with moderately active disease.
Area of Science:
- Immunology
- Gastroenterology
- Pharmacology
Background:
- Ulcerative colitis treatment faces challenges with efficacy, safety, and sustained response.
- Toll-like receptor-9 (TLR9) plays a role in immune responses to gut microbes.
- An oral synthetic oligonucleotide TLR9 modulator demonstrated anti-inflammatory effects in preclinical models and a favorable safety profile in humans.
Purpose of the Study:
- To assess the efficacy and safety of BL-7040, an oral TLR9 modulator, in patients with moderately active ulcerative colitis.
Main Methods:
- A multicenter, open-label phase IIa clinical trial was conducted.
- Patients with moderately active ulcerative colitis were enrolled, with allowed concomitant mesalamine and stable-dose steroids.
- Efficacy was measured by Mayo score, histology, and mucosal cytokine levels; safety was monitored through adverse event reporting.
Main Results:
- Of 22 patients, 16 completed the study. Clinical remission was achieved in 12.5%, with 50% experiencing clinical response and mucosal healing.
- Responders showed significant reductions in mucosal neutrophils and interleukin-6 levels compared to non-responders.
- BL-7040 was well-tolerated, with mostly mild-to-moderate adverse events and one serious adverse event unrelated to the study drug.
Conclusions:
- Oral BL-7040 demonstrated efficacy and a good safety profile in patients with moderately active ulcerative colitis.
- The drug appears to modulate inflammatory pathways relevant to ulcerative colitis.
- Further investigation into TLR9 modulation for ulcerative colitis is warranted.
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