Abstracts

Rationale: The gastrointestinal microbiota comprises a complex community of bacteria, fungi, and archaea that significantly influence health by modulating metabolic and neurological pathways. BL-001 is an oral, Live Biotherapeutic Product being developed for the treatment of multiple neurological diseases, including Dravet syndrome and other rare epilepsies. BL-001 was designed to mimic the antiepileptic effect of the ketogenic diet and has potency in cell-based assays and animal studies to eliminate neuronal hyperexcitability, increase GABA in the hippocampus, and reduce or eliminate seizure frequency and duration. The objective of this Phase 1 study was to evaluate the safety and tolerability of BL-001 in healthy adult participants.


Methods: The Phase 1 study of BL-001 was a randomized, double-blind, placebo-controlled, multiple dose of ascending doses study in healthy volunteers (NCT05818306). Participants were randomized to one of four sequential dose cohorts and underwent treatment for 28 days with a 14-day follow-up period. The study included 7 visits. Each cohort consisted of 6 treated and 2 placebo participants. Blood and fecal samples were collected to assess circulating and excreted metabolites via untargeted metabolomics. Fecal samples were also used to assess strain kinetics via microbiome analysis. Adverse events, vital signs, and clinical laboratory assessments were evaluated for safety and tolerability.


Results: 32 participants enrolled and completed the study (n=24 BL-001, n=8 placebo; age 20-51 years). All treatment-related Adverse Events (AEs) were mild except for one participant in the highest dose who experienced moderate fatigue over the course of 2 days. The most common AE in the highest dose was decreased appetite (3/6 participants). All treatment-related AEs were transient, except for decreased appetite (two participants), and all resolved without intervention. No clinically significant ECG abnormalities were reported. No AEs led to study drug withdrawal, and all participants completed the study. A positive strain kinetics profile was demonstrated with BL-001 strains identified in participant stool samples and overall minimal changes to the resident microbiota. Additionally, a metabolomics analysis provided additional support to the results observed in preclinical experiments including changes in plasma metabolites relevant to the ketogenic diet and seizure protection.


Conclusions: BL-001 demonstrated a favorable safety profile and was well tolerated with no Serious Adverse Events. There were 37.5% of participants (9/24) in the treated group with treatment-emergent adverse events compared to 25% in the placebo group (2/8). The tolerability of the treatment was largely acceptable, with 21% of participants (5/24) experiencing a treatment-related AE during the study. Favorable strain kinetics were observed with BL-001 component strains increasing in a dose-dependent manner, and this effect was consistent across patients. Metabolomics pathway results support the hypothesis that BL-001 may induce metabolic shifts with connections to the ketogenic diet, epilepsy, or both, with a dose-dependent impact.


Funding: This study was funded by Bloom Science.