A Nonclinical Safety Assessment of MnTE-2-PyP, a Manganese Porphyrin

Abstract

Manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP or BMX-010; CASRN 219818-60-7) is a manganese porphyrin compound developed as a potential drug substance for use as a radioprotective and for the ex vivo treatment of cells, tissues, and organs intended for transplantation. In preparation for an investigational new drug filing, a full good laboratory practice nonclinical safety assessment was conducted in order to evaluate the safety of MnTE-2-PyP and included the performance of in vitro genotoxicity studies, local tissue tolerance evaluation, safety pharmacology core battery studies, and single- and repeat-dose intravenous (iv) toxicity studies in mice and monkeys. The MnTE-2-PyP was determined not to be genotoxic or hemolytic, did not demonstrate flocculation or elicit adverse pharmacologic effects on respiration, the central nervous system (CNS), and had limited transitory effects on the cardiovascular system only at levels well above the therapeutic target dose. The intended iv clinical solution did not cause venous irritation in rabbits. The no observed adverse effect level (NOAEL) in mice was determined to be 10 mg/kg/day after 18 consecutive days of bolus iv dosing once daily in the morning. The NOAEL in monkeys after 14 days of bolus iv dosing in the morning was determined to be 5 mg/kg/day. At doses relevant to clinical use in humans, neither study revealed any indication of any specific target organ toxicity, including the classic heme porphyrin kidney, liver, CNS, or cardiac toxicities, or manganese toxicity. Mortality seen shortly after dosing in individual animals at higher doses was not accompanied by any organ or clinical pathology indications, suggesting a functional pharmacological-mediated effect. Based on the results of these studies, a conservative safe initial starting clinical dose of 5.0 mg (0.083 mg/kg in a 60 kg adult) was proposed for the initiation of human trials. Because of patent life issues, use of MnTE-2-PyP as a transplantation aid or radioprotective agent is not currently being pursued past the preclinical stages. It serves as a model for the clinical development of this class of drugs.

MnTE-2-PyP Treatment, or NOX4 Inhibition, Protects against Radiation-Induced Damage in Mouse Primary Prostate Fibroblasts by Inhibiting the TGF-Beta 1 Signaling Pathway

“…TGF-β-targeted therapy is proposed in fibrotic and postirradiation therapy for malignancies (59, 60), but there has been concern that inhibition of TGF-β may be advantageous to the tumor. On the contrary, manganese porphyrins treatment is currently in clinical trials and have demonstrated no significant clinical side effects, and several published in vivo tumor studies have indicated that manganese porphyrins do not protect tumor cells from radiation-induced damage (61, 62). Therefore, we can suggest that MnTE-2-PyP can prevent the profibrotic response in irradiated fibroblasts to the same extent as pharmacological TGF-β1 signaling inhibitors without the adverse clinical effect of direct TGF-β1 receptor inhibitors.…”

Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death

“…MnTE-2-PyP 5+ (E2) is available as GMP grade and a Phase I clinical trial in mice and monkeys has shown excellent safety/toxicity profile [75]. Such data provide the feasibility of the development of this compound in IBC therapy and pave the way to many other compounds that operate via similar mechanisms [23].…”

Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer

“…We have demonstrated that MnPs synergistically enhance AscH − -induced cytotoxicity in pancreatic cancer both in vitro and in vivo (30). Furthermore, at doses relevant to clinical use in humans, these compounds have not revealed any indication of manganese toxicity or specific target organ toxicity, including those classically associated with heme porphyrins in the kidneys, liver, CNS, and heart (31). …”