Newly Initiated Phase 2 BREAKTHROUGH Trial to Test 5-HT2C Receptor Agonist BMB-101 in Drug-Resistant Epilepsies

Ian McDonald

According to an announcement from Bright Minds Biosciences, the company has initiated a new phase 2 study, dubbed BREAKTHROUGH, that will assess the safety and efficacy of its investigational agent BMB-101 in adults with classic absence epilepsy and development epileptic encephalopathy (DEE). The therapy, a 5-HT2C receptor agonist, has previously demonstrated efficacy in animal models of Dravet syndrome and numerous models of generalized seizures.¹

The study, designed as a basket clinical trial, features a 4-week baseline period, 8-to-12-week treatment period, and a 4-week follow-up phase for additional safety monitoring. BREAKTHROUGH is expected to include 20 adults aged 18-65 years old with absence epilepsy or a DEE. These comprise a range of rare epilepsy disorders, including epilepsy with eyelid myoclonia, also known as Jeavons Syndrome. Following the conclusion of the follow-up period, patients may be eligible to receive BMB-101 in an open-label extension that will last 12 months.

"We are excited to advance BMB-101 into this next phase of clinical development as we continue to build on the promising safety and pharmacodynamic data from our Phase 1 trial,” Ian McDonald, chief executive officer at Bright Mind Biosciences, said in a statement.¹ "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."

READ MORE: Radiprodil Significantly Reduces Seizure Frequency in Phase 1b Honeycomb Study of GRIN-Related Neurodevelopmental Disorder

BMB-101, a novel scaffold 5-HT2C Gq-protein biased agonist, was previously assessed in a 3-part, phase 1 study. The Australian-based study evaluated the safety, tolerability, pharmacokinetic (PK), and food effect of the agent in a single-ascending dose (SAD) and multiple ascending dose (MAD) fashion in healthy volunteers.

Both the MAD and SAD portions included 4 cohorts (6 drug and 2 placebo). In the SAD phase, a single dose of BMB-101 reached its planned top dose of 180 mg/70 kg, and approached preclinical exposure limits. The therapy was well tolerated, had a predictable PK, with oral paresthesias as the most common adverse event as a result of the liquid formulation. In the MAD, twice a day dosing for 7 days after meals resulted in a top dose of 150 mg/70 kg twice day, with noticeable effects on target biomarkers such as prolactin release and quantitative EEG.²

An analysis on food effect in 12 participants showed that BMB-101 had a relatively small effect, with investigators concluding that the therapy may be administered without the need for fasting. This group of patients crossovered with and without breakfast at a dose of 120 mg/70 kg.

McDonald added, "This compound is not only poised to make a significant impact in both the DEE and Absence Epilepsy communities but also has broad applicability across the 30% of all epilepsy patients who experience drug resistance. BMB-101 offers a differentiated treatment option for patients with refractory epilepsy, where current therapies often fall short, and could provide a new standard of care for a much wider population of epilepsy sufferers. We would like to thank the AECTN and the Epilepsy Study Consortium for their contributions to our upcoming study."

REFERENCES
1. Bright Minds Biosciences Initiates the BREAKTHROUGH Study: A Phase 2 Trial of BMB-101 in Absence Epilepsy and Developmental Epileptic Encephalopathy. Bright Minds Biosciences. News release. September 12, 2024. Accessed September 13, 2024. https://www.prnewswire.com/news-releases/bright-minds-biosciences-initiates-the-breakthrough-study-a-phase-2-trial-of-bmb-101-in-absence-epilepsy-and-developmental-epileptic-encephalopathy-302245921.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 September 13, 2024. 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