ICA-105665 / Pfizer - LARVOL DELTA

Exploring potential key genes and disease mechanisms in Εarly-onset genetic epilepsy via integrated bioinformatics analysis. (PubMed, Neurobiol Dis) - "Enrichment analysis showed that among significant pathways were nicotine addiction, GABAergic synapse, synaptic vesicle cycle, regulation of membrane potential, cholinergic synapse, dopaminergic synapse, and morphine addiction. Clustering analysis of the PPI network via MCODE showed significant functional modules, indicating also other pathways such as N-Glycan biosynthesis and protein N-linked glycosylation, retrograde endocannabinoid signaling, mTOR signaling and aminoacyl-tRNA biosynthesis. Drug-gene interaction analysis identified a number of drugs as potential medications for EOE, among which the non-FDA approved drugs azetukalner (under clinical development), indiplon and ICA-105665 and the FDA approved drugs retigabine, ganaxolone and methohexital."

Journal • CNS Disorders • Epilepsy • Nicotine Addiction • Psychiatry • SCN8A • XBP1

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study to Evaluate the Safety and Efficacy of XEN1101 as an Adjunctive Therapy in the Treatment of Primary Generalized Tonic-Clonic Seizures (AAN 2023) - "In epilepsy patients with photosensitivity, ICA-105665, a Kv7 potassium channel opener no longer in development, suppressed paroxysmal EEG activity (Kasteleijn-Nolst Trenité et al, Epilepsia. Safety will be evaluated by severity and frequency of treatment emergent adverse events (AEs) and serious AEs; clinically significant changes in clinical laboratory findings, physical, neurologic and ophthalmologic exams, ECGs, vital signs, and urinary symptoms will also be evaluated. Conclusions X-ACKT will provide insight into the safety, tolerability, and efficacy of XEN1101 as adjunctive therapy in the treatment of PGTCS and is designed to support registration of XEN1101 for the treatment of PGTCS."

Clinical • P3 data • CNS Disorders • Epilepsy • Ophthalmology

Quantitative systems toxicology (QST) reproduces species differences in PF-04895162 liver safety due to combined mitochondrial and bile acid toxicity. (PubMed, Pharmacol Res Perspect) - P1 | "This study illustrates how DILIsym, a computational representation of liver injury, was able to reproduce species differences in liver toxicity due to PF-04895162 (ICA-105665)...Modeling even higher PF-04895162 liver exposures than were measured in the rat safety studies aggravated mitochondrial toxicity but did not result in rat hepatotoxicity due to insufficient accumulation of cytotoxic bile acid species. This investigative study highlights the potential for combined in vitro and computational screening methods to identify latent hepatotoxic risks and paves the way for similar and prospective studies."

Clinical • Journal • CNS Disorders • Epilepsy

Phase I study of PF-04895162, a Kv7 channel inhibitor, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis. (PubMed, Pharmacol Res Perspect) - P1; "During a randomized Phase 1 clinical trial the drug candidate, PF-04895162 (ICA-105665), caused transaminase elevations (≥grade 1) in six of eight healthy subjects treated at 300 mg twice daily for 2-weeks (NCT01691274)...These data collectively suggest that the human liver injury by PF-04895162 was due to alterations in bile acid handling driven by dual BSEP/mitochondrial inhibition, two important risk factors associated with drug-induced liver injury in humans. Alterations in systemic bile acid composition were more important than total bile acids in the manifestation of clinical liver injury and may be a very early biomarker of BSEP inhibition."

Biomarker • Journal • P1 data