A randomized, placebo-controlled study to evaluate safety and pharmacokinetics of ART-001 with a novel oral pediatric formulation in healthy subjects.

ART-001 is an orally available selective PI3Kα inhibitor currently being developed for the treatment of slow-flow vascular malformations (SFVMs). ART-001 used to be developed for advanced solid tumors, but was suspended largely due to significant pharmacokinetic (PK) variability in its phase I studies. This phase I, randomized, double-blinded, placebo-controlled study evaluated safety, tolerability and PK of ART-001 with a newly developed dry syrup formulation, which was designed to optimize PK properties of ART-001 and to be compliant with the pediatric population. Single and multiple doses of ART-001 were administered to healthy male adults. ART-001 was rapidly absorbed after the single and repeated doses, and the exposure of ART-001 increased with increased dose. The dry syrup formulation substantially improved the intersubject PK variability. Food decreased area under the concentration-time curve (AUC) and maximum plasma concentration by 12% and 36%, respectively. The plasma concentration had reached a steady-state on day 5 of the repeated doses of 100 mg and AUC accumulation ratio was 1.9. There were no deaths or serious adverse events. The most frequent adverse event was hyperglycemia. All cases of hyperglycemia were mild to moderate and transient, and required no medical interventions. Serum creatinine increase was observed in 300 mg once daily dosing group leading to dose discontinuation on day 5. In conclusion, it was demonstrated that the single doses and repeated doses of the ART-001 dry syrup formulation, at up to 400 and 100 mg, respectively, were safe and tolerated with favorable PK profile, supporting further clinical development for the treatment of SFVMs.

Discovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H).

Cholesterol 24-hydroxylase (CH24H, CYP46A1), a brain-specific cytochrome P450 (CYP) family enzyme, plays a role in the homeostasis of brain cholesterol by converting cholesterol to 24S-hydroxycholesterol (24HC). Despite a wide range of potential of CH24H as a drug target, no potent and selective inhibitors have been identified. Here, we report on the structure-based drug design (SBDD) of novel 4-arylpyridine derivatives based on the X-ray co-crystal structure of hit derivative 1b. Optimization of 4-arylpyridine derivatives led us to identify 3v ((4-benzyl-4-hydroxypiperidin-1-yl)(2,4'-bipyridin-3-yl)methanone, IC50 = 7.4 nM) as a highly potent, selective, and brain-penetrant CH24H inhibitor. Following oral administration to mice, 3v resulted in a dose-dependent reduction of 24HC levels in the brain (1, 3, and 10 mg/kg). Compound 3v (soticlestat, also known as TAK-935) is currently under clinical investigation for the treatment of Dravet syndrome and Lennox-Gastaut syndrome as a novel drug class for epilepsies.

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice.

Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated human amyloid precursor protein and presenilin 1 (APP/PS1-Tg). These mice, with excitatory/inhibitory imbalance and short life-span, yielded a remarkable survival benefit when bred with CH24H-knockout animals. Soticlestat lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially reduced premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%. Furthermore, microdialysis experiments showed that soticlestat can suppress potassium-evoked extracellular glutamate elevations in the hippocampus. Taken together, these data suggest that soticlestat-mediated inhibition of CH24H may have therapeutic potential for diseases associated with neural hyperexcitation.