Abstracts

The 5-HT2C receptor, a specific subtype of the serotonin receptor family, plays a pivotal role in numerous neurological and psychiatric disorders, rendering its agonists promising targets for therapeutic development. Significant efforts have been directed toward creating selective 5-HT2C agonists for treating developmental and epileptic encephalopathies (DEEs). Fenfluramine has been approved for treating Dravet Syndrome and Lennox-Gastaut Syndrome, showing efficacy in reducing seizure frequency. However, its therapeutic profile is not without concerns, in particularly cardiovascular risks, necessitating regular echocardiograms for patients during treatment. BMB-101 is a novel, highly selective 5-HT2C receptor Gq-protein biased (functionally selective) agonist that promises a favorable profile for chronic use.

Randomized, double-blind, placebo-controlled Phase I study of BMB-101 in healthy human subjects. This study was conducted at a single center in Australia (CMAX), consisting of 3 parts: a single ascending dose (SAD) (Part 1), a food effect (Part 2), and multiple ascending doses (MAD) (Part 3). The primary objective was to investigate the safety and tolerability of BMB-101 following single and multiple oral administration to healthy adult (18-65 yo) subjects.

BMB-101 was well tolerated at all doses, with no serious adverse events reported. The most common side effects were mild and included headaches, nausea, and oral paresthesia. At the highest doses, there were some CNS-related AEs, such as disequilibrium and mild visual disturbances, but no frank hallucinations occurred. The maximum tolerated dose of BMB-101 in this study was determined to be 180 mg/70 kg in the SAD study and 150 mg/70 kg BID in the MAD study. All reported adverse effects were transient and self-limited, thus considered tolerable. There were no clinically significant shifts in subject laboratory parameters, vital signs, or EKG parameters during this study.

The pharmacokinetics of BMB-101 were well behaved in all 3 parts of the Phase 1 study. The plasma half-life was approximately 5-7 hours, consistent with twice-a-day dosing. Evidence of target engagement at the 5-HT2C receptor in the CNS was established based on increased prolactin secretion (dose-dependent and transient) and quantitative EEG changes. There was a robust and significant increase in the power of the slow wave delta frequency (1-4Hz) seen after 150 mg/70 kg BMB-101. In contrast, there was a significant decrease in the alpha frequency (8-12Hz) power in subjects receiving BMB-101 compared to placebo. These changes are consistent with what would be expected from anticonvulsants. Interestingly, there was also an increase in gamma power in the frontal cortex.

The Phase 1 trial of BMB-101 has shown a favorable safety and pharmacokinetic profile, paving the way for its continued investigation in epilepsy patients. Due to its high selectivity and safety, BMB-101 holds promise as a 5-HT2C agonist for treating seizures in  DEEs and certain generalized epilepsies. Further clinical trials are planned to establish proof of concept in rare epilepsy conditions.