ARTham Therapeutics, Inc.

Background: The natural history of venous malformation (VM) and Klippel-Trenaunay Syndrome (KTS) has not been quantitatively studied. To obtain benchmarks to guide designing clinical trials to assess safety and efficacy of novel drug candidates, the clinical course of the patients was followed for 6 months. Methods and Results: This is a multicenter prospective observational study evaluating the change rate in lesion volume from baseline with magnetic resonance images, as the primary endpoint. In addition, disease severities, performance status (PS), pain visual analog scale (VAS) score, quality of life (QoL), infections, and coagulation markers were also evaluated. Thirty-four patients (VM = 17, KTS = 17, 1-53 of age; median 15.9 years) with measurable lesion volume were analyzed. There was no statistically significant difference in the lesion volume between baseline and day 180, and the mean change rate (standard deviation) was 1.06 (0.28). There were no baseline characteristics that affected the change in lesion volume over 6 months. However, there were patients who showed more than 20% volume change and it was suggested that the lesion volume was largely impacted by local infection. There were no statistically significant changes in pain VAS score, severity, PS, QoL score, D-dimer, and platelet count over 6 months within all patients analyzed. Conclusion: The results showed the representative natural course of VM and KTS for a 6-month period with objective change of lesion volume and other factors, suggesting that it is scientifically reasonable to conduct a Phase 2 proof-of-concept study without a placebo arm, using the results of this study as the control. Clinical Trial Registration: NCT04285723, NCT04589650.

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.

Urinary liver-type fatty acid binding protein (L-FABP) has potential utility as an early prognostic biomarker ahead of traditional severity scores in coronavirus disease 2019 and sepsis, however, the mechanism of elevated urinary L-FABP in the disease has not been clearly elucidated. We investigated the background mechanisms of urinary L-FABP excretion through non-clinical animal model focusing on histone, which is one of the aggravating factors in these infectious diseases.

Male Sprague-Dawley rats were placed in central intravenous catheters, and these rats were given a continuous intravenous infusion of 0.25 or 0.5 mg/kg/min calf thymus histones for 240 min from caudal vena cava.

After the administration of histone, urinary L-FABP and gene expression of an oxidative stress marker in the kidney increased in a histone dose-dependent manner before increased serum creatinine. Upon further investigation, fibrin deposition in the glomerulus was observed and it tended to be remarkable in the high dose administrated groups. The levels of coagulation factor were significantly changed after the administration of histone, and these were significantly correlated with the levels of urinary L-FABP.

Firstly, it was suggested that histone is one of the causative agents for the urinary L-FABP increase at an early stage of the disease with a risk of acute kidney injury. Secondly, urinary L-FABP could be a marker reflecting the changes of coagulation system and microthrombus caused by histone in the early stage of acute kidney injury before becoming severely ill and maybe a guide to early treatment initiation.