Treatment of type 1 plasminogen deficiency in women and girls with reproductive tract lesions: Pharmacokinetics and clinical outcomes with plasminogen therapy
Notice bibliographique
Résumé
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.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».