Landos Biopharma has announced positive results from a first-in-patients 12-week Phase 2 proof-of-concept trial of BT-11, a novel, orally administered, gut-restricted Lanthionine Synthetase C-Like 2 (LANCL2) modulator in patients with mild to moderate ulcerative colitis (UC).
BT-11 is a novel, orally-active, gut-restricted small molecule investigational drug that targets the LANCL2 pathway impacting the gastrointestinal tract. LANCL2 plays an important role in the immunoregulatory process. By activating the LANCL2 pathway and modulating the interactions between immunological and metabolic signals in immune cells, BT-11 is designed to create a favourable regulatory microenvironment in the gut, decreasing the production of key inflammatory mediators and increasing anti-inflammatory markers in regulatory T cells (Treg) within the site of inflammation.
“The clinical remission rates observed in these initial BT-11 Phase 2 results compare favourably to standard of care treatments. However, as an oral, gut-restricted once a day tablet that targets LANCL2, Landos’ product candidate is designed to be well tolerated, avoid the serious side effects of systemic treatments and offer more convenience for patients,” said Dr Jean-Frederic Colombel, a Gastroenterologist at Mount Sinai School of Medicine. “BT-11’s encouraging results indicate its potential to transform the treatment paradigm for patients with ulcerative colitis. I look forward to seeing additional exciting clinical results in more patients in Phase 3 registrational clinical trials.”
The objective of the Phase 2 trial was to evaluate the safety and efficacy of BT-11 compared to placebo in subjects with mild to moderate UC. The Phase 2 study is a randomised, placebo-controlled, double-blind, parallel-group multicentre study which enrolled 198 UC patients in 53 sites throughout the US, Europe and Russia. Dosing was explored in two BT-11 cohorts (500 mg QD and 1,000 mg QD) or placebo (randomised 1:1:1) and clinical remission was analysed over a 12-week induction period, as defined by the 3-component modified Mayo Score, using a rectal bleeding subscore of 0, a stool frequency subscore of 0 or 1, and an endoscopic subscore of 0 or 1.
In the intent-to-treat (ITT) population, a positive trend in absolute clinical remission rates for the 1,000 and 500mg doses compared to placebo was observed (31.8% and 30.3% versus 22.7%; p=0.340 and 0.235). The resulting placebo-adjusted clinical remission rates of 9.1% and 7.6% for the 1,000 and 500 mg dose groups, respectively, are consistent with standard of care treatments in both mild to moderate and moderate to severe UC.
In a more moderate subset of patients (with Mayo score equal to or greater than 7 at baseline) the placebo-adjusted clinical remission rate was (11.5%; p=0.153 and 8.7%; p=0.273) for the 1,000 (n=47) and 500 mg (n=44) dose groups respectively versus placebo (n=50). Additionally, in a small subset of biologic experienced patients, positive placebo-adjusted remission trends were also observed (66% and 33% in the 1,000 (n=3) and 500mg (n=3) cohorts versus placebo n=3, 0%).
Normalization of faecal calprotectin levels, commonly cited to be one of the most predictive biomarkers of response to treatment in UC and Crohn’s disease, was detectable in a subset of patients (n=106) with abnormal baseline calprotectin levels (>250 ug/g), after two weeks of oral dosing in over 40% of patients treated with BT-11 (n=64), at either dose level, when compared to 21% of patients receiving placebo (n=42).
Additionally, the ability of BT-11 to normalise faecal calprotectin levels was maintained for the entire 12-week period. Notably, in patients with elevated baseline faecal calprotectin levels (>250ug/g), an indication of active disease, BT-11 dosing provided a placebo-adjusted clinical remission rate of up to 13.1%.
BT-11 was well tolerated with similar adverse events across placebo and BT-11 groups. Pharmacokinetic measurements confirmed dose proportional increases of BT-11 in stool samples across each dosing group. BT-11 was confirmed to be gut-restricted with no evidence of greater systemic absorption or increased exposure over time in UC patients relative to normal healthy volunteers. BT-11 stool concentrations were stable between two and 12 weeks of dosing.
Landos plans to advance development of this product candidate with a Phase 3 trial in 2021 that will evaluate induction of clinical remission at week 12 and maintenance of clinical remission at week 52 in patients with UC. Additionally, the company plans to initiate its Phase 2 trial of BT-11 for 150 patients with moderate to severe Crohn’s disease in the first half of 2021.
“We are excited by the very promising Phase 2 trial results evaluating BT-11, as it marks the first potential therapeutic to engage the novel target LANCL2. We believe this novel mechanism of action is responsible for modulating key immunological mechanisms associated with various autoimmune diseases such as ulcerative colitis and Crohn’s disease,” said Josep Bassaganya-Riera, Chairman, President and Chief Executive Officer of Landos. “These proof-of-concept results de-risk BT-11 and provide validation of the LANCL2 pathway and its potential as a new therapeutic approach for treating UC and a wide range of autoimmune diseases. This positive outcome also validates our advanced modeling and AI-based LANCE precision medicine platform, which efficiently identifies immunometabolic targets and develops novel product candidates designed to engage these conserved pathways, providing durable therapeutic activity. Building on the momentum from this Phase 2 trial, Landos will continue expanding its robust therapeutic inflammation and immunology pipeline, which currently contains seven product candidates based on novel immunometabolic mechanisms targeting a wide range of autoimmune diseases.”