Joseph M Parker, Pierre Laurin, Brandon M Hardesty, Karen Thibaudeau, Amy D Shapiro, Neelam Thukral, John E Moran, Gary R Albert, Per Morten Sandset, Charles Nakar
Congenital plasminogen deficiency is caused by mutation(s) in PLG, the gene coding for production of the zymogen plasminogen, and is an ultra-rare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes, such as the conjunctiva, gingiva, and linings of the airways and genitourinary tract. Left untreated, these lesions may impair normal tissue and organ function, and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the clinical manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered intravenously at 6.6 mg/kg every 2-4 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 endpoint was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary endpoint 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. Overall clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), non-visible (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.