Nonclinical Safety and Toxicokinetics of MnTE-2-PyP (BMX-010), a Topical Agent in Phase 2 Trials for Psoriasis and Atopic Dermatitis.

Abstract

Since our earlier publication (Gad et al, 2013), BioMimetix has advanced BMX-010 (Manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin or MnTE020PyP; CASRN 219818-60-7) into clinical development as a topical agent for the treatment of psoriasis, atopic dermatitis, and pruritus (idiopathic nonspecific itch). A multiple dose phase I study has been completed in 64 patients without any serious adverse effects. During the course of development, the formulation was initially a gel but has been modified to a cream formulation. The nonclinical safety program has been carried onward to assess preclinical risk to patients. Additional studies completed and reported here include dermal sensitization in a Guinea Pig maximization test study, 2 rabbit phototoxicity studies, a 28-day oral toxicity study in juvenile mice, a 28-day topical systemic toxicity study in Gottingen minipigs, range-finding studies, and complete embryo-fetal developmental toxicity (Segment II) studies in mice and rabbits, an ICH M7 compliant qualification of impurities using 2 (Q)SAR in silico methods, and a 14-day subcutaneous toxicity study of mice to qualify an impurity. All studies (except the (Q)SAR evaluations) were performed in accordance with Good Laboratory Practices (GLP) using Good Manufacturing Practices (GMP) drug substance. The systemic toxicity studies, with the exception of the juvenile toxicity study, included toxicokinetic evaluations, which are reported here. The phase I clinical study had 67 patient participants who received topically applied BMX-010, and there were no notable safety findings and included pharmacokinetic determinations on these patients which are also reported here. Chronic GLP toxicity studies have been initiated in the mouse (6-month oral) and minipig (9-month dermal). To date, the only observed nonclinical toxicity remains a reversible hypertension seen in mice in response to Cmax levels with a no effect threshold, and there have been no drug-related adverse effects.