Treatment of type 1 plasminogen deficiency in women and girls with reproductive tract lesions: Pharmacokinetics and clinical outcomes with plasminogen therapy

Abstract Background: Type 1 plasminogen deficiency (PLGD-1) is an ultra-rare autosomal recessive disorder affecting approximately 1.6 individuals per million, characterized by fibrin-rich lesions on mucosal surfaces throughout the body. Involvement of the reproductive tract can lead to complications and diminished quality of life. Intravenous (IV) plasminogen concentrate (plasminogen, human-tvmh; Ryplazim®) is the first and only FDA-approved, targeted replacement therapy for PLGD-1. Methods: This subset analysis evaluated seven female participants (ages 5–42 years) from the pivotal phase 2/3 trial, with five continuing into the long-term study, while two received IV plasminogen concentrate therapy under compassionate use programs. At baseline, reproductive tract lesions were identified in the cervix (n=2), uterus (n=2), both cervix and uterus (n=1), and vagina (n=2). Historical reproductive tract symptoms included cervical pain and bleeding, dysmenorrhea, irregular menses, vaginal bleeding, and infertility. Six participants had lesions in other body systems. Plasma plasminogen activity and antigen pharmacokinetic (PK) profiles were assessed after the first and Week 12 doses and plasminogen trough levels were measured throughout the study. Results: Participants received 6.6 mg/kg IV plasminogen concentrate infusions. Median plasminogen activity was 20% (range: <5–31) before the first dose, increasing to a median trough level of 48% (range: 30–70) after 12 weeks of therapy. Plasminogen activity reached normal physiological levels (≥70%) immediately after the first dose and exceeded the upper limit of normal (>130%) in two participants. The plasminogen activity level remained above 70% for 24 hours in three participants. Similar plasminogen antigen profiles were observed between the women and girls, though higher variability compared to plasminogen activity precluded reliable interpretation of antigen-related PK parameters. Dosing frequencies were individualized from every 2–4 days during the initial 48 weeks, to daily to weekly after 48 weeks in the pivotal trial, and every 1–15 days during the long-term study. Site investigators adjusted the dosing frequency based on clinical response, plasminogen activity trough levels, and availability of drug supply. The participants received a median of 68 months of therapy (range: 42–71). Five participants achieved complete resolution of reproductive tract lesions, with a median time of 2.7 months (range: 1.8–24.5). Lesion improvement was observed at 10.9 months in the participant whose lesion completely resolved at 24.5 months. Two participants did not undergo lesion assessment, one with cervical lesions and one with uterine lesions. Repeated trough sampling demonstrated consistent attainment of target plasminogen activity (baseline + 10% absolute change in plasminogen activity) and no formation of new lesions or recurrence of existing lesions when dosing protocols were followed. Notably, a 33-year-old participant with well-documented infertility due to ligneous uterine adhesions achieved pregnancy and delivered a healthy baby during IV plasminogen concentrate therapy. All participants tolerated therapy well, with no neutralizing antibodies or serious adverse events related to IV plasminogen concentrate therapy. Conclusions: IV plasminogen concentrate therapy demonstrated excellent safety and efficacy in managing reproductive tract lesions in females with PLGD-1. Individualized dosing regimens, informed by PK monitoring, effectively resolved reproductive tract lesions in those assessed. This targeted therapy offers substantial therapeutic benefit to manage reproductive tract PLGD-1 associated lesions, with evidence to support improved quality of life; fertility was restored in one patient. The potential of Ryplazim® to restore PLGD-1 associated infertility in affected females requires further study.