Ganaxolone for use in treating tuberous sclerosis complex and seizure disorders
Inventors
HULIHAN, Joseph • Aimetti, Alex • BRAUNSTEIN, Scott
Assignees
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Publication Number
US-12115169-B2
Publication Date
2024-10-15
Expiration Date
Abstract
The disclosure to methods for treating tuberous sclerosis complex and epilepsy disorders comprising administering to a subject in need thereof a therapeutically effective amount of ganaxolone or a pharmaceutically acceptable salt thereof.
Core Innovation
The disclosure relates to treating a seizure or epilepsy disorder with ganaxolone and addresses a two-phase ganaxolone titration intended to mitigate an unexpected interaction with concomitant cannabidiol (CBD). It links higher CBD exposure, including CBD dose levels greater than about 10 mg/kg/day, with reduced seizure efficacy and increased somnolence-related adverse events.
The disclosure further states that the association between higher CBD exposure and reduced seizure efficacy corresponds with elevated ganaxolone plasma concentrations. It therefore states that minimizing somnolence via titration improves efficacy while targeting therapeutically effective plasma concentrations, and characterizes somnolence as associated with higher ganaxolone concentrations and improved efficacy as associated with lower concentrations within a therapeutically effective range.
The disclosure describes dosing and titration regimens including staged daily dose escalation over about 4–5 weeks to reach steady therapeutically effective plasma levels, with an option to further increase dosing up to about 1,800 mg/day. It also outlines patient stratification based on CBD exposure level, reports clinical evidence from a phase 2 open-label TSC study, and describes a phase 3 randomized placebo-controlled study using the two-phase titration concept.
The disclosure further states that the approach is applied to seizure disorders and specific TSC-related seizure types, including focal motor, focal impaired awareness, focal evolving to bilateral tonic-clonic, generalized tonic-clonic, atonic/drop, and related categories. It identifies ganaxolone as a CNS GABA-A receptor positive allosteric modulator and mentions oral or intravenous formulations, concomitant therapy with CBD including EPIDIOLEX, and dose-related plasma concentration ranges.
Claims Coverage
The provided independent claims are clm-00001 and clm-00011. Each independent claim covers an orally administered staged ganaxolone dose-escalation regimen for treating a seizure or epilepsy disorder, with independent constraints defined by a specific escalation schedule across successive about one-week periods. Across both independent claims, the main inventive features include quantified dosing regimens, optional dosing frequency refinements, response criteria requiring seizure-frequency reduction, and tolerability characterization including somnolence constraints.
Staged oral dose escalation using once-daily amounts
Orally administering ganaxolone to a subject using staged daily dose escalation of about 150 mg per day for about one week, followed by about 300 mg per day for about one week, followed by about 600 mg per day for about one week, followed by about 1,200 mg per day for about one week, followed by about up to 1,800 mg per day for the remaining treatment period.
Staged oral dose escalation using weight-based amounts
Orally administering ganaxolone to a subject using staged daily dose escalation of about 6 mg/kg/day for about one week, followed by about 12 mg/kg/day for about one week, followed by about 24 mg/kg/day for about one week, followed by about 42 mg/kg/day for about one week, followed by about up to 63 mg/kg/day for the remaining treatment period.
Treatment achieves seizure-frequency reduction
Administering ganaxolone such that the administration results in a reduction in seizure frequency of about 20% or more compared with baseline seizure frequency.
Avoiding somnolence as an outcome constraint
Administering ganaxolone to a subject such that the administering does not cause somnolence.
Oral suspension or oral solution administration
Administering ganaxolone as an oral suspension or an oral solution.
Across the independent claims, the claim coverage centers on staged oral ganaxolone titration over successive about one-week periods using defined escalation amounts or weight-based escalation amounts, with dependent claim features emphasizing seizure-frequency reduction, absence of somnolence, and administration via oral suspension or oral solution.
Stated Advantages
Improved seizure efficacy when somnolence is minimized via titration in the presence of concomitant cannabidiol (CBD).
Reduced somnolence-related adverse events by minimizing somnolence via titration.
Improved treatment outcomes associated with minimizing somnolence and targeting therapeutically effective plasma concentrations.
Documented Applications
Treatment of Tuberous Sclerosis Complex (TSC)-related epilepsy, including specified TSC-associated seizure types.
Treatment of a seizure or epilepsy disorder more broadly, including focal and generalized seizures and multiple named epilepsy syndromes and conditions with increased seizure activity or breakthrough seizures.
Clinical evaluation in a phase 2 open-label TSC study and a phase 3 randomized placebo-controlled study employing the two-phase titration.
Concomitant cannabidiol (CBD) setting, where the ganaxolone titration is used to mitigate an unexpected interaction with CBD.
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