PORT-77, a Novel and Potent Inhibitor of ABCG2, Protects Against Skin Photo Toxicity and Liver Damage in a Mouse Model of Erythropoietic Protoporphyria (EPP)

• Published in: Blood 2024-11, Vol.144, p.11-11
• Main Authors: Shah, Bhavik, Huang, Edmond, Pak, Yvonne, Henry, Chris, Babbar, Sunita, Hutchaleelaha, Athiwat, Zamboni, Robert, Ma, Xiaochao, Schmidt, Pete, Paull, Morgan, Sinha, Uma
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-205391

Introduction PORT-77 is an orally bioavailable inhibitor of the ABCG2 (also known as BCRP) transport protein and is under development for the treatment of EPP. EPP is a rare, genetic form of photodermatosis resulting from autosomal recessive mutations in ferrochelatase (FECH), the enzyme in the heme biosynthesis pathway that inserts Fe2+ into protoporphyrin IX (PPIX) to form heme. The defect in FECH activity results in accumulation of PPIX in marrow reticulocytes and circulating RBCs, which is eventually released into the plasma, leading to its deposition in liver and skin. The accumulated PPIX in skin, when activated by sunlight exposure, generates singlet oxygen mediated free radicals which, in combination with other inflammatory processes, leads to cutaneous damage and excruciating pain. Notably, the transport of PPIX from RBCs to plasma is mediated by the transporter ABCG2. The role of ABCG2 in mediating PPIX efflux from RBCs has been established using FECH mutant mice (Fech m1Pas), a mouse model of EPP. Genetic ablation of ABCG2 in FECH mutant mice results in a substantial decrease in serum PPIX concentrations by compartmentalizing the PPIX inside RBCs, and a subsequent decrease in PPIX in skin and liver. Importantly, ABCG2 deficiency protects against EPP-associated phototoxicity and hepatotoxicity, suggesting that ABCG2 plays a critical role in the pathophysiology of EPP by mediating PPIX efflux from RBCs. Taken together, we hypothesized that pharmacological inhibition of ABCG2 would reduce plasma PPIX concentrations by decreasing efflux from RBCs and marrow reticulocytes. This is predicted to decrease PPIX levels in disease compartments including skin and liver and result in clinical improvement by reducing EPP-associated skin phototoxicity and liver damage. Methods In vitro testing of PORT-77 was performed using both biochemical and cell-based assays. In vivo efficacy of PORT-77 was investigated in the FECH mutant mice by evaluating EPP associated skin phototoxicity and liver damage. PPIX concentrations were measured by LC-MS/MS method. Results1In vitro testing of PORT-77 showed dose dependent inhibition of human and mouse ABCG2 activity with IC50 values in the low nanomolar range.2Oral dosing of PORT-77 in FECH mutant mice resulted in protection against light induced skin damage which was associated with ~50% reduction in serum PPIX concentration.3Chronic dosing (8-weeks) of PORT-77 in FECH mutant mice resulted in a marked reduction in liver PPIX