Pharmacokinetics of Intravenous Infusion of Glu-Plasminogen Concentrate in Patients with Hypoplasminogenemia
Authors: Hardesty Brandon M. , Plum Stacy , Thibaudeau Karen , Lee Martin , Shapiro Amy D. 
Published: October 2019

Abstract

Background: Hypoplasminogenemia is a rare multisystem disease associated with fibrous deposition on mucous membranes throughout the body, primarily affecting the eyes, ears, sinuses, tracheobronchial tree, genitourinary tract, and gingiva. The best defined clinical manifestation of hypoplasminogenemia is ligneous conjunctivitis, which is characterized by thick, woody (ligneous) growths on the conjunctiva of the eye. Several genetic defects leading to plasminogen deficiency have been identified. Replacement therapy with exogenous plasminogen can achieve resolution of the lesions, but no approved replacement product is available. ProMetic BioTherapeutics, Inc. (ProMetic) is developing a lyophilized human Glu-plasminogen for systemic treatment of hypoplasminogenemia. No pharmacokinetic (PK) data for Glu-plasminogen in plasminogen-deficient patients are available in the literature. However, PK parameters may vary among patients, depending on mutation type or presence of active lesions. The current Phase I dose escalation study is being conducted to provide data on the pharmacokinetic profile and safety of this plasminogen product in patients with hypoplasminogenemia.
Methods: Patients with hypoplasminogenemia (plasminogen activity level ≤40% of normal values) received a single IV infusion of 2 mg/kg of plasminogen as the first dosing cohort of a clinical study titled "A Phase 1, Dose Escalation, and Pharmacokinetic Study of ProMetic Plasminogen Administered as Intravenous Infusion in Adults and Children with Hypoplasminogenemia." The initial dose was chosen based on data generated in the GLP toxicology studies performed with the molecule. The product was supplied in 50 mL vials at a concentration of 6.3 mg/mL, which was reconstituted in 12.5 mL of sterile water for injection. The final concentration of reconstituted plasminogen was 5 mg/mL. Blood samples for PK analysis were taken 30 min prior to dosing, and then at 15 minutes, 1, 6, 24, 48, 72, 96, 120, 168, and 216 hours after infusion. This data is part of a planned analysis after completion of cohort 1 including 5 individuals.
Results: Five patients (1 male, 4 females), median age 24 (range 14-38) years received a mean (±SD) volume of 26.6 ± 5.2 ml of plasminogen solution, infused over 10 minutes. Plasminogen activity levels increased from a mean of 34.6 ± 3% to 70.4 ± 7.7% at 15 minutes and slowly decreased to a mean of 45 ± 5.9% at 48 hours (reference range, 70-130%). Plasminogen activity levels for individual patients are shown in Figure 1 below. PK parameters for plasminogen activity through 48 h are shown in Table 1 below. No adverse events considered possibly related to the product were reported following intravenous administration of 2 mg/kg plasminogen. At day 30 no patient exhibited antibodies to plasminogen.
Conclusions: ProMetic's lyophilized Glu-plasminogen administered at 2 mg/kg can be given safely to patients with plasminogen deficiency. PK parameters after infusion of 2 mg/kg of plasminogen support moving forward with the next dosing cohort in the clinical trial (6 mg/kg). These data represent the first PK profiles for Glu-plasminogen in plasminogen-deficient patients. The half-life was 27.2 hours, compared with the half-life of 3-4 hours previously reported for Lys-plasminogen in plasminogen-deficient patients.
Table 1. PK parameters for plasminogen activity after infusion of 2 mg/kg plasminogen solution in 5 patients with hypoplasminogenemia Geometric mean (95% CI) Half-life (h) 27.2 (16.2-45.7) Cmax (%) 35 (27-46) AUClast (h*%) 935 (683-1280) AUCINF (h*%) 1359 (797-2317) Vz (µg/%/kg)a 57.7 (47.7-69.8) Cl (µg/(h*%)/kg)a 1.47 (0.86-2.51) MRTlast (h) 17.5 (15.0-20.5) MRTINF (h) 38.1 (22.0-65.9) HL, half-life; AUClast, area under the curve up to last measurable concentration; AUCINF, AUC extrapolated to infinity; Vz, volume of distribution; Cl, clearance; MRTlast, mean residence time to the last sampling time; MRTINF, MRT extrapolated to infinity. aPK analysis was performed with plasminogen activity in %; therefore, units cannot be reduced.
Figure 1. Plasminogen activity after infusion of 2 mg/kg plasminogen solution in 5 patients with hypoplasminogenemia Figure 1. Plasminogen activity after infusion of 2 mg/kg plasminogen solution in 5 patients with hypoplasminogenemia

Disclosures
Hardesty: Biogen: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Prometic Biotherapeutics: Research Funding. Plum:ProMetic Biotherapeutics: Employment. Thibaudeau:ProMetic BioTherapeutics: Employment. Lee:ProMetic: Consultancy. Shapiro:ProMetic Life Science, Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octopharma, OPKO, PTC Therapeutics, Selexys: Research Funding; Baxalta, Novo Nordisk, Biogen: Membership on an entity's Board of Directors or advisory committees; Baxalta, Novo Nordisk, Biogen: Consultancy; Biogen: Speakers Bureau.