As reported in the previous section, a few papers have suggested efficacy with topical and systemic plasminogen concentrates.2,64,65,66 Two recent clinical trials evaluating the use of topical (ophthalmologic drops) and systemic (IV preparation) plasminogen concentrates are reported below, along with interim results.
Kedrion initiated the first study (NCT01554956) in September 2012. This phase 2/3 study was designed to evaluate the safety and efficacy of plasminogen ophthalmologic drops for treatment of ligneous conjunctivitis in subjects with type I plasminogen deficiency.
The study design comprised 3 segments: a 4-week treatment for clinical safety/efficacy followed by surgical excision of residual lesions; an 8-week post-operative treatment/monitoring phase for those requiring removal of residual lesions; and a continuation phase with long-term safety monitoring until licensure. Segments 1 & 2 completed enrollment; segment 3 is ongoing. Treatment regimens are 2 drops per eye 4-12 times a day, based on symptoms, study group and segment.
At the interim analysis, 11 subjects were enrolled;57 seven had unilateral and 4 had bilateral lesions at enrollment. Three subjects did not require surgical intervention at end of segment 1; the remaining 8 subjects required excision of residual lesions after 4 weeks of therapy. In all subjects available for primary efficacy analysis (9 subjects, 12 eyes), full regression and/or absence of recurrence post-excision was reported. Two subjects developed anti-plasminogen antibodies without change in clinical response; both patients were subsequently antibody negative despite continued therapy. The significance and specificity of transient anti-plasminogen antibodies requires further investigation.
Prometic initiated the second study (NCT02690714) in May 2016. This phase 2/3 study was designed to determine safety and efficacy of intravenous Glu-plasminogen. Fifteen subjects received repeated IV doses of 6.6 mg/kg Glu-plasminogen for 48 weeks. An interim analysis was performed after 10 subjects had completed 12 weeks of treatment;58,67 and a paper by Shapiro, et al summarized data on 14 subjects who completed at least 12 weeks of treatment.39
Subjects were treated every 2, 3, or 4 days to maintain trough plasminogen activity levels at least 10% above individual baseline values. Target plasminogen trough activity levels were achieved in all 14 subjects. PK parameters were comparable to baseline at 12 weeks. No anti-plasminogen antibodies developed. Nine of 14 subjects had 23 visible ligneous lesions in the conjunctiva and gingiva before receiving plasminogen concentrate. All 23 conjunctiva and gingiva lesions resolved or improved by week 12. Seven subjects had 10 nonvisible lesions at baseline including nasopharynx, bronchus, kidney, colon, cervix, and vagina. Seven lesions in 4 assessed subjects resolved or improved by week 24. One subject with chronic obstructive lung disease from tracheobronchial lesions was able to stop therapy with multiple inhaled medications during treatment with plasminogen concentrate: improvement of 75% in FEV1 was documented between baseline (FEV1 46.7%) and week 4 (FEV1 91.4%) of therapy.
The availability of both plasminogen concentrates, topical ophthalmologic and intravenous systemic, will significantly impact the ability to treat this rare disease. Both therapeutics could potentially benefit patients as topical ophthalmologic drops could be a useful addition especially for very young patients with only ligneous conjunctivitis.
Improved understanding of the phenotypic disease presentation and course (HISTORY)
Registries play an important role in rare disorders by collecting data and informing clinical care in numbers that no single clinic or physician could achieve; they further describe the natural history of the disease and responses to intervention. Rare coagulation disorders are typically orphan diseases and plasminogen deficiency as an ultra-rare genetic disorder fits that definition.
A new international retrospective and prospective study (HISTORY, NCT03797495) was launched in 2019 to collect information on 100 affected individuals as well as their immediate family members with the aim of improving our understanding of this disease including those factors which impact clinical phenotype.22 This study is a disease specific extension of the prospective Rare Bleeding Disorder Database. The international study is a result of a collaboration between the Indiana Hemophilia and Thrombosis Center (IHTC) in the US and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center (ABBHTC) in Italy under the RBDD-PLG project. The main goals of this study are to recruit and characterize clinically and phenotypically affected families worldwide, collect prospective data, assess the diagnostic assays, evaluate the genetic basis and heterogeneity and the relationship between phenotype and genotype. This registry became available for participation in 2019 and can be accessed at https://www.plgdeficiency.com
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
