Presentation Details
| Safety and Efficacy of Long-Term Treatment of Type 1 Plasminogen Deficiency Patients with Intravenous Plasminogen Replacement Therapy Amy D Shapiro1, Heather McDaniel2, Robert W Decker3, Jeremy Lorber3, Karen Thibaudeau4, Joseph M Parker5. 1Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA.2Vanderbilt University, Nashville, TN, USA.3Cedars Sinai Medical Center, Los Angeles, CA, USA.4Kedrion, Laval, Canada.5Kedrion, Fort Lee, NJ, USA |
Abstract
Background: Type 1 Plasminogen Deficiency (PLGD-1) is an ultrarare autosomal-recessive disorder of the fibrinolytic system, with an estimated prevalence of 1.6 individuals per million people. The primary manifestation of PLGD-1 is the development of abnormal extra-vascular fibrin-rich, ligneous lesions on mucosa throughout the body. The most commonly observed lesions are in the eye (ligneous conjunctivitis) with lesions also noted in other systems including the ears, mouth, central nervous system, skin, and respiratory, gastrointestinal, and genitourinary tracts. Lesions may have life-altering and life-threatening consequences including vision and/or hearing loss, airway obstruction, hydrocephalus, and infertility. Plasminogen, human-tvmh is a plasma derived human Glu-plasminogen concentrate indicated for the treatment of subjects with PLGD-1. It is a lyophilized formulation administered IV at a dose of 6.6mg/kg every 2 to 4 days at home or in the clinic. Plasminogen, human-tvmh was FDA-approved in 2021 in the US based on a phase 2/3 pivotal trial (Shapiro et al, 2023). IV plasminogen replacement therapy is the only approved therapy specific for this disorder. Here are reported the safety and continued efficacy of plasminogen, human-tvmh evaluated in a long-term extended treatment trial for PLGD-1 patients who previously participated in the phase 2/3 or expanded access clinical trials. Objectives: Determine the safety and the efficacy of plasminogen replacement therapy on the recurrence or development of new ligneous lesions during long-term maintenance treatment. Methods: US patients with PLGD-1 who participated in the phase 2/3 pivotal trial (NCT02690714) or in individual expanded access trials were eligible for participation in this study. Patients continued receiving plasminogen, human-tvmh starting at the same dose and frequency as the qualifying trial. Frequency of dosing was adjusted by the investigator based upon clinical evaluation and drug availability. Safety and efficacy assessments were performed every 26 weeks until trial conclusion including physical examinations and laboratory testing as deemed necessary by the investigator. Blood samples for plasminogen activity trough levels and anti-plasminogen antibodies were collected at study site at the discretion of the investigator. Treatment continued until plasminogen, human-tvmh was commercially available. Results: This long-term treatment protocol (NCT03642691) enrolled 12 patients, 7 pediatric and 5 adults. Eight (8) patients continued from the phase 2/3 pivotal trial and 4 patients were included from individual expanded access trials. Patients were treated for a mean duration of 159 (range 107 - 183) weeks. There were no new or recurrent ligneous lesions which developed during the observation time period under recommended treatment. However, there were recurrences in 4 subjects which ensued during reduced or missed dosing due to supply issues. The majority of adverse events were mild to moderate and did not require patients to interrupt or discontinue dosing. There were 5 reported severe adverse events however none were deemed drug related. Plasminogen activity levels when measured remained appropriate for the dosing interval and there was no development of anti-plasminogen antibodies. Conclusions: Intravenous plasminogen replacement therapy was observed to be well tolerated and effective in this long-term extended treatment trial.
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