In polycythemia vera (PV), point mutation in JAK2 kinase (V617F) confers constitutive intracellular activity to JAK2 leading to a condition with excessive erythropoiesis that is independent of erythropoietin. Elevated hematocrit (HCT) and hyper-viscosity in the blood are risk factors for thrombosis and other symptoms. There is an increased iron demand required to support excessive erythropoiesis in the bone marrow. Hence, regulation of systemic iron in PV provides a mechanism for erythropoiesis control with potential disease modifying effects (Ginzburg YZ, Leukemia 2018).
PTG-300 is an injectable hepcidin peptidomimetic drug currently in Phase 2 clinical studies for polycythemia vera and hereditary hemochromatosis. Pharmacodynamic (PD) effects of PTG-300 are reductions in serum iron and transferrin-saturation due to reduced expression on cells of ferroportin which exports iron into the peripheral circulation. Splenic red pulp macrophages that recycle iron from senescent RBCs are the primary source of serum iron for erythropoiesis.
PTG-300 administration in cynomolgus monkey resulted in dose dependent reduction in serum iron (Fig. 1). Single subcutaneous (SC) dose of 0.3 mg/kg achieved a maximum of ~54.9% reduction in serum iron at 24 hr post-dose, serum iron returned to baseline in < 60 hr. Maximum PTG-300 concentration of 171.6±31.2 nM was observed at 8 hr, and concentration had reduced to 25.5±3.9 nM by 72 hr. SC dose of 1 mg/kg achieved ~75.8% reduction in serum iron at 24 hr post-dose (from baseline 31.3±2.3 µM to 7.6±0.9 µM). This dose exhibited a more sustained PD, with serum iron returning to baseline at ~108 hr. For 1 mg/kg, maximum PTG-300 concentration was 472.5±47.2 nM at 6 hr, and concentration reduced to 70.9±13.7 nM by 72 hr. At both doses a delay of 16-18 hr was observed between the maximum PTG-300 concentration and the maximum PD response.
In a dose limiting GLP toxicity study in monkeys (over 13 weeks), weekly SC dosing of PTG-300 resulted in dose-dependent reductions in HCT (Fig. 2). In 2 mg/kg dose group, HCT reduction from baseline was 2.5% on Day 27 and 5.3% on Day 90 in males, and 3.5% on Day 27 and 6.8% on Day 90 in females. There were no decreases in mean corpuscular volume as is otherwise observed in phlebotomy dependent PV patients who are iron-deficient, indicating that PTG-300 may not create an iron deficient state but rather restricts iron availability to the bone marrow thereby reducing RBC levels. At higher dose of 6 mg/kg, HCT reduction was 14.2% at Day 27 and 19% at Day 90 in males, and 12.4% at Day 27 and 14.5% at Day 90 in females. In concurrence with HCT, dose dependent reductions were observed in hemoglobin (HGB). 0.6 mg/kg dose did not show significant reductions in HCT or HGB, albeit only marginal reductions at Day 90 (data not shown). HCT and HGB returned to baseline after a recovery period of 30 days post-last dose for all groups.
In a mouse model for acquired secondary erythrocytosis, wild type mice were administered with daily injections of exogenous erythropoietin (EPO; 50 units/dose) for 7 days(Wang J, Haematologica 2018), resulting in elevated HCT. Concurrent treatment with peptide A (hepcidin mimetic with in vitro and in vivo potencies similar to PTG-300) on alternate days showed dose dependent reductions in HCT, RBCs and reticulocytes (Fig. 3). 5 mg/kg dose was able to normalize all three parameters to levels similar to control group that did not receive any EPO. Dose dependent reductions in spleen weight indicate that peptide A was effective in lowering extra medullary stress erythropoiesis in the spleen.
The desired end points for PTG-300 as a therapy for PV are sustained reduction of HCT to circumvent the need for chronic phlebotomy and prevent the exacerbation of systemic iron deficiency. Our pre-clinical data support the efficacy of our hepcidin mimetics in limiting erythrocytosis with sustained control of hematocrit through iron redistribution. In addition to lowering hematocrit and reducing the need for phlebotomy treatment, we believe that PTG-300 has the potential to reduce debilitating symptoms associated with chronic iron deficiency by restoring tissue iron to meet the needs of critical/normal cellular functions (Krayenbuehl PA, Blood 2011). PTG-300 would potentially provide a novel mechanism for selective hematocrit control while maintaining adequate body iron levels in polycythemia vera and other congenital and acquired erythropoietic disorders.
Disclosures
Mattheakis: Protagonist Therapeutics: Current Employment, Current equity holder in private company. Zhao:Protagonist Therapeutics: Current Employment, Other: shareholder. Lee:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Tovera:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Zhao:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Cheng:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Liu:Protagonist Therapeutics: Current Employment, Current equity holder in private company.
Correction of Iron Deficient Yellowing of Huangguogan by Different Application of Chelated Iron under Different Mulching Material
