Conference: 2014 International PHA Conference and Scientific Sessions
Release Date: 06.21.2014
Presentation Type: Abstracts
CTX-4430 is a new oral drug being studied as a potential once-daily, anti-inflammatory treatment for Pulmonary Arterial Hypertension (PAH). Mechanistically, CTX-4430 is a small molecule inhibitor of Leukotriene A4 Hydrolase (LTA4H), the rate limiting enzyme in the production of the potent bioactive lipid Leukotriene B4 (LTB4) which is a key driver of neutrophil and macrophage-mediated inflammation.
Background: CTX-4430 is a new oral drug being studied as a potential once-daily, anti-inflammatory treatment for Pulmonary Arterial Hypertension (PAH). Mechanistically, CTX-4430 is a small molecule inhibitor of Leukotriene A4 Hydrolase (LTA4H), the rate limiting enzyme in the production of the potent bioactive lipid Leukotriene B4 (LTB4) which is a key driver of neutrophil and macrophage-mediated inflammation. There is increasing evidence that macrophage-mediated inflammation plays a critical role in promoting vascular damage and remodeling in PAH, especially in patients with co-existing connective tissue disease (CTD). In tissue from patients with PAH, and in a rodent model, there are increased perivascular macrophages that express high levels of LTA4H and LTB4 which are thought to mediate damage to the vascular endothelium. LTA4H inhibitors have been shown to reduce elevated pulmonary artery pressure and vascular remodeling with minimal effects on systemic blood pressure in animal models of PAH.
Methods: This was a first-in-human study of CTX-4430 in healthy volunteers conducted in an ascending dose, placebo controlled, double-blind design. First, a single-dose arm examined safety and pharmacokinetics of CTX-4430 given once under fasting conditions to cohorts consisting of 6 treated and 2 placebo subjects (8 total subjects per cohort). In the single dose arm, doses escalated from 5 mg to 200 mg over 6 cohorts (48 total subjects). Additionally, the two cohorts receiving doses of 50 and 100 mg CTX-4430, crossed over to a food effect sub-study wherein the dose was taken 2 hours after a standard high fat meal. Finally, a multiple dose arm consisted of 4 cohorts receiving once daily doses of placebo or CTX-4430 ranging from 50 mg to 200 mg for 14 days. In the multiple dose arms, cohorts consisted of 9 treated and 3 placebo subjects (48 total subjects).
Results: Once daily oral CTX-4430 was well-tolerated in all treatment groups, with no clinically significant changes in vital signs, physical exams, ECGs, spirometry, or clinical labs. No dose limiting toxicities or SAEs were observed in the study. Observed Adverse Events were mostly mild in nature and not dose dependent. CTX-4430 was well absorbed by oral administration, with pharmacokinetics consistent with once-daily dosing. CTX-4430 pharmacokinetics were largely dose-proportional and exhibited an accumulation to steady state over the first 7 days of treatment. In the food effect cohorts, eating a high fat meal prior to CTX-4430 administration resulted in a 4 hour delay in Tmax with a reduction in Cmax but no significant change in AUC at either the 50 mg or 100 mg dose. Pharmacodynamic profiles of CTX-4430 action in blood demonstrated maximal inhibition of LTB4 production 3 hr after the first 100 mg dose, which persisted through the entire 14 day course of treatment. The same maximal effect on LTB4 production in blood was also observed at the 150 mg and 200 mg doses.
Conclusion: CTX-4430, a LTA4H inhibitor, is a well-tolerated potential new oral, anti-inflammatory treatment for Pulmonary Arterial Hypertension. A Phase 2 study with CTX-4430 is planned with PAH patients to assess safety and dosing.
Type: Clinical Science