BMB-101 Heads for Registrational Trials Following Positive Phase 2 Data in Absence Seizures, Developmental Encephalopathies

In recent news, Bright Mind Biosciences announced positive topline results from its phase 2 BREAKTHROUGH trial (NCT06401538) assessing investigational BMB-101, a selective 5-HT2C biased agonist, in adults with drug-resistant absence seizures and developmental and epileptic encephalopathies (DEEs). Based on the positive data, which included BMB-101 meeting primary end point, the company is planning a global, registrational trial to further validate the agent’s efficacy and safety.

The trial data featured 24 patients, 15 of whom had absence seizures and 9 who had DEEs. In the absence cohort (n = 11), investigators recorded a 73.1% median reduction in the number of absence seizures for at least 3 seconds (P = .012), and a 74.4% median reduction in total time in seizures lasting at least 3 seconds during the 24 hours (P = .012). Above all the drug was considered well-tolerated, and patients achieved robust reduction of absence seizures regardless of seizure duration.

BREAKTHROUGH included a 4-week baseline, 4-week titration and maintenance period, with longer time allotted for patients with DEEs (4 weeks) vs the absence cohort (2 weeks). Among those within the DEE cohort who had efficacy data available (n = 6), treatment with BMB-101 led to a 63.3% median reduction in major motor seizures, the primary outcome for this cohort. More specifically, there was a 60.3% median reduction in patients with LGS (n = 4) and a 76.1% reduction in other DEEs, which included 1 patient with Dravet syndrome and 1 with Rett syndrome.

In terms of safety, the most common treatment-emergent adverse events (TEAEs) were respiratory infections (20.8%), fatigue (16.7%), constipation (16.7%), headache (12.5%), and drowsiness (12.5%), with most of these either mild (79.6%) or moderate (17.2%). Although there were no treatment-related serious AEs, investigators did record 3 serious AEs, including dry mouth, as well as 1 patient who had fractured shoulder and opiate-related drowsiness (not related).

Within the absence cohort, 3 patients discontinued treatment early due to: taste intolerance (related; drug product formulation subsequently updated), flu-like symptoms with muscle ache/fatigue (possibly related), dizziness (possibly related) and with insufficient baseline seizure counts. In the DEE cohort, 3 patients discontinued BMB-101, mainly because of taste intolerance, flu-like symptoms with muscle ache/fatigue, dizziness, and with insufficient baseline seizure counts.

Outside of seizure control, BMB-101 also demonstrated a positive impact on outcomes of sleep in treated patients. Treatment with BMB-101 increased REM sleep by approximately 90% (from 56.2 minutes at baseline to 106.7 minutes) without meaningfully changing total sleep duration (9.1 vs 8.9 hours), indicating that REM gains were independent of overall sleep time.

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When BREAKTHROUGH was initiated in late 2024, Ian McDonald, chief executive officer at Bright Mind, said in a statement, “With its unique pharmacological profile, we believe BMB-101 has the potential to be a best-in-class 5-HT2C agonist. In our Phase 1 study, we demonstrated central target engagement, which, in conjunction with the wealth of 5-HT2C data within refractory epilepsies, gives us great confidence in this study."

Prior to BREAKTHROUGH, BMB-101 was evaluated in a three-part phase 1 study conducted in Australia to assess its safety, tolerability, pharmacokinetics, and food effect in healthy volunteers. The trial included single-ascending dose (SAD) and multiple-ascending dose (MAD) components, each enrolling four cohorts with a 6:2 active-to-placebo ratio.

In the SAD portion, single doses reached the planned maximum of 180 mg/70 kg, approaching preclinical exposure limits, and demonstrated predictable pharmacokinetics with good overall tolerability; oral paresthesias related to the liquid formulation were the most common adverse event. In the MAD phase, twice-daily dosing for 7 days after meals achieved a top dose of 150 mg/70 kg twice daily and produced expected pharmacodynamic effects, including prolactin release and quantitative EEG changes. A separate food-effect analysis in 12 participants showed minimal impact of food on exposure at a 120 mg/70 kg dose, supporting administration without fasting requirements.

In late 2025, Bright Mind announced the initiation of a new phase 2a study, dubbed NOVA, that will test the efficacy, safety, and tolerability of BMB-101 in patients with Prader-Willi syndrome, a rare genetic disorder. At the time, McDonald wrote in a statement that, "This proof-of-pharmacology clinical study is designed to evaluate BMB-101's utility in addressing both hyperphagia and the behavioral/neuropsychiatric symptoms of PWS. We believe it will pave the way forward for a pivotal study with BMB-105, our dedicated compound, and expedite the development of the drug that aims at directly targeting the pathophysiology of PWS.”³

REFERENCES
1. Bright Minds Biosciences Announces Positive Topline Results from Phase 2 Clinical Trial of BMB-101 in Patients with Absence Seizures and Developmental and Encephalopathic Epilepsies (DEE). News release. Bright Mind Biosciences. January 6, 2025. https://www.globenewswire.com/news-release/2026/01/06/3213483/0/en/Bright-Minds-Biosciences-Announces-Positive-Topline-Results-from-Phase-2-Clinical-Trial-of-BMB-101-in-Patients-with-Absence-Seizures-and-Developmental-and-Encephalopathic-Epilepsie.html
2. Bright Minds Biosciences Announces Positive Topline Data for its First-in-Human Phase 1 Study of Lead Compound, BMB-101. News release. Bright Minds Biosciences. July 20, 2023. Accessed January 8, 2025. https://www.globenewswire.com/news-release/2023/07/20/2708030/0/en/Bright-Minds-Biosciences-Announces-Positive-Topline-Data-for-its-First-in-Human-Phase-1-Study-of-Lead-Compound-BMB-101.html
3. Bright Minds Biosciences Initiates New Prader-Willi Syndrome (PWS) Program; KOL Event Scheduled for November 6^TH. News release. November 6, 2025. Accessed January 8, 2025. https://www.globenewswire.com/news-release/2025/11/06/3182329/0/en/Bright-Minds-Biosciences-Initiates-New-Prader-Willi-Syndrome-PWS-Program-KOL-Event-Scheduled-for-November-6TH.html