Abstracts

While an estimated 1.2% of the US population has active epilepsy, up to 30% of patients with epilepsy fail to adequately respond to currently available treatments. Uncontrolled epilepsy is associated with increased mortality risk. In addition to seizures, patients with epilepsy are up to 20 times more likely to have psychiatric comorbidities such as depression and anxiety. There remains an unmet medical need for an agent with a novel mechanism of action (MOA) to treat refractory epilepsy and comorbidities.

Oral formulations comprising a novel GABA_AR PAM neuroactive steroid (NAS), eltanolone, and designated as LPCN 2101 is under development as an anti-seizure medication (ASM). Based on preclinical assessment, LPCN 2101 is expected to play a role in managing refractory epilepsy and associated psychiatric conditions. LPCN 2101 is a unique GABA_AR modulator expected to act on both synaptic and extrasynaptic receptors. Preclinical studies suggest potent and favorable binding to GABA_AR and safety at levels 10x that of the human levels targeted for efficacy in epilepsy.

The objective of this study was to assess oral clinical pharmacokinetics, impact of formulation design on PK, and determine single ascending dose (SAD) tolerability of LPCN 2101, a novel GABA_AR PAM candidate for epilepsy.

Oral formulations of LPCN 2101 were designed with solubilized and particulate eltanolone. SAD studies of low, medium, and high doses of capsule and tablet oral formulations were conducted under pre-meal and post-meal conditions in healthy postmenopausal women. Safety evaluations occurred during the washout period after each dosing period, prior to dose escalation.

Capsules were formulated with solubilized active and tablets with particulate active. LPCN 2101 levels as high as ~54 ng/mL were achieved with average concentration ranging from 0.9-9.8 ng/mL through oral administration. Relevant eltanolone levels with tablet formulation were achieved without regard to meal [mean (CV%) high dose tablet pre-meal C_avg 9.1 (59.7) ng/mL and post-meal C_avg 9.8 (59.7) ng/mL]. Capsule formulation resulted in fast absorption [median (min-max) high dose pre-meal T_max of capsule 1.0 (0.5-1.5) h and tablet 3.0 (1.0-4.0) h]. All adverse events were mild in severity and resolved without treatment.

Effective oral delivery of LPCN 2101 was confirmed in human with acceptable tolerability at all tested doses. Through formulation design, the PK of this novel NAS following oral administration can be tailored to meet specific therapeutic needs, supporting both acute and chronic treatment options. Results support clinical efficacy studies for this unique GABA_AR modulating oral ASM option with potential to address refractory epilepsy and comorbidities.