Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency

Abstract

Congenital plasminogen deficiency is caused by mutations in PLG, the gene coding for production of the zymogen plasminogen, and is an ultrarare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes. Left untreated, these lesions may impair organ function and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered IV at 6.6 mg/kg every 2 to 4 days in 15 patients with congenital plasminogen deficiency is ongoing. Reported here are data on 14 patients who completed at least 12 weeks of treatment. The primary end point was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary end point was clinical success, defined as ≥50% improvement in lesion number/size or functionality impact from baseline. All patients achieved at least an absolute 10% increase in trough plasminogen activity above baseline. Clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), nonvisible (nasopharynx, bronchus, colon, kidney, cervix, and vagina), and wound-healing manifestations of the disease. Therapeutic effects were rapid, as all but 2 lesions resolved or improved after 4 weeks of treatment. Human Glu-plasminogen was well tolerated in both children and adults. This study provides critical first evidence of the clinical utility of ongoing replacement therapy with human Glu-plasminogen for the treatment of children and adults with congenital plasminogen deficiency. This trial was registered at www.clinicaltrials.gov as #NCT02690714.

Conflict of interest statement

Conflict-of-interest disclosure: A.D.S. and C.N. received nonfinancial (clinical research) and other support (speaker fee, consulting, and travel) from Prometic, whose drug is studied in this work, and Kedrion. N.T. received nonfinancial support (clinical research) from Prometic and Kedrion. B.M.H. received personal fees and nonfinancial support from Shire, Novo Nordisk, and Octapharma AG. P.L., J.E.M., J.M.P., K.T., and G.R.A. received personal fees from Prometic Life Sciences, Inc. or its affiliates, outside the submitted work. In addition, Prometic has a patent number pending. P.M.S. declares no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Study schematic of the open-label, phase 2/3 trial of human Glu-plasminogen in children and adults with congenital plasminogen deficiency. This is an ongoing open-label study with a 21-day screening period (for eligibility) and 3 treatment segments. Patients were given human Glu-plasminogen at 6.6 mg/kg administered as a 10- to 30-minute IV infusion every second, third, or fourth day based upon individual PK in segments 1 and 2. In segment 3, patients started with the same dose and frequency as in segment 2, with the investigator having the option to modify the dosing schedule based on clinical response and plasminogen activity trough levels. Patients will be treated for 48 weeks in Norway or until product licensing or study termination by the sponsor (whichever is later) in the United States.

Figure 2.

Mean plasminogen activity levels after the first and week 12 doses of plasminogen (human). (A) Mean plasminogen activity levels after the first dose of plasminogen (human) in 14 patients with hypoplasminogenemia; this includes 6 patients (1 child and 5 adults) who received a single 6-mg/kg dose in the phase 1 study (2002C005G) and 8 patients (4 children and 4 adults) who received a single 6.6-mg/kg dose in the phase 2/3 study. (B) Mean plasminogen activity levels after the week 12 dose of 6.6 mg/kg plasminogen (human) in the same 14 patients.

Figure 3.

LC before and after replacement therapy with plasminogen (human). (A) Left eye lesion for patient 2 at day 0, prior to administration of plasminogen (human). The subject received plasminogen (human) at an IV dose of 6.6 mg/kg every second day. (B) Complete resolution of the left eye lesion after 4 weeks of treatment with plasminogen (human).