Understanding PLGD

Learn About Plasminogen Deficiency (PLGD)

In all patients with plasminogen deficiency, plasma plasminogen levels are markedly reduced.1 Plasminogen is a naturally occurring protein that is synthesized by the liver and circulates in the blood.

Activated plasminogen, known as plasmin, is an enzymatic component of the fibrinolytic system and the main enzyme involved in the lysis of clots and clearance of extravasated fibrin.2 Activated plasminogen is also involved in wound healing, cell migration, tissue remodeling, angiogenesis, and embryogenesis.3

Plasminogen deficiency has been classified as hypoplasminogenemia, or true type I plasminogen deficiency, and as dysplasminogenemia, or type II plasminogen deficiency. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries.4

Type I plasminogen deficiency is a rare autosomal recessive disorder that leads to severe clinical manifestations primarily related to the formation of fibrous depositions on mucous membranes throughout the body.5 The prevalence of type I plasminogen deficiency has been theoretically estimated at 1.6 cases per million population.1 There is no effective therapy currently available for this disease.

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Plasminogen Background

Native PLG is produced in two main forms, Glu-PLG and Lys-PLG, named for the N-terminal amino acid of either glutamic acid or lysine. Glu-PLG is composed of the entire amino acid sequence designated by the gene sequence (excluding the activation peptide), while Lys-PLG is the result of a cleavage of the Glu-PLG between Lys-77 and Lys-78. The circulating half-life of Lys-PLG is considerably shorter than Glu-PLG (2-2.5 days for Glu-PLG, 0.8 days for Lys-PLG). Glu-PLG is the dominant form of PLG present in plasma with very little Lys- PLG detected in circulation (Violand, 1978; Collen, 1975).2, 6

PLG is a zymogen of plasmin (Figure 1). It contains 791 amino acids with a molecular weight of about 90 kD and a pI (isoelectric point) of approximately 7.0, although differential glycosylation and/or removal of the N-terminal activation peptide can result in a pI range of 6.2 to 8.0. It is a single-chain protein with 24 intra-chain disulfide bridges, 5 kringle domains (involved in the binding to fibrin and to the inhibitor α2-antiplasmin), a serine protease domain (P), and an activation peptide (AP) consisting of the first 77 amino acids.

There is one N-linked glycosylation site and one O-linked site, although a second O-linked site has been identified (Goldberg, 2006).7 Approximately 70% of the PLG in circulation contains only O-linked glycosylation while the rest contains both N- and O-linked sugars.

PLG is synthesized in the liver and secreted into plasma. PLG is distributed throughout the body, and when conditions are present for activation, the PLG pro-enzyme is converted to the active enzyme, plasmin, by tissue-type plasminogen activator (t-PA) or by urokinase plasminogen activator (u-PA). Plasmin then degrades fibrin and converts latent matrix metalloproteinases (pro-MMPs) into active MMPs, which in turn further degrade extracellular matrix (ECM) as part of the tissue healing/remodeling process. PLG activation mediated by t-PA is primarily involved in fibrin homeostasis, while plasmin generation via u-PA, forming a complex with its receptor u-PAR, plays a role in tissue remodeling.

Figure 1: Schematic of the kringle domains of plasminogen
Schematic of the kringle domains of plasminogen

References:

1. Tefs K, Gueorguieva M, Klammt J, et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood. 2006;108(9):3021-3026.

2. Collen D, Ong EB, Johnson AJ. Human plasminogen in vitro and in vivo evidence for the biological integrity of NH2-terminal glutamic acid plasminogen. hromb Res. 1975;7(4):515-529.

3. Castellino FJ, Ploplis VA. Structure and function of the plasminogen/plasmin system. Thromb Haemost. 2005;93(4):647-654.

4. Shoseyov D. Congenital plasminogen deificiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.

5. Schott D, Dempfle C-E, Beck P, et al. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. N Engl J Med. 1998;339(23):1679-1686.

6. Violand BN, Byrne R, Castellino FJ. The effect of a-w-amino acids on human plasminogen structure and activation. J Biol Chem. 1978;253(15):5395-5401.

7. Goldberg HJ, Whiteside CI, Hart GW, Fantus IG. Posttranslational, reversible O-glycosylation is stimulated by high glucose and mediates plasminogen activator inhibitor-1 gene expression and Sp1 transcriptional activity in glomerular mesangial cells. Endocrinology. 2006;147(1):222-231.

Prevalence of Type 1 Plasminogen Deficiency

Prevalence of Plasminogen Deficiency

Type I plasminogen deficiency is a very rare condition, with 1 to 2 cases per million, where patients present with no or very little plasminogen. The number of patients with some plasminogen, although still lower than normal, is presumed to be somewhat higher.1

The incidence rate of (heterozygous) hypoplasminogenemia has roughly been estimated in different geographic regions:

  • Minnesota (only white subjects), 0.35%
  • Southern Germany, 0.13%
  • Scotland, 0.26%
  • Japan, 0.42%.2

The median age of first clinical manifestation of ligneous conjunctivitis and/or other complications is typically in the pediatric population, but a range of 3 days to 61 years has been reported.1

References:

1. Tefs K, Gueorguieva M, Klammt J, et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood. 2006;108(9):3021-3026.

2. Shoseyov D. Congenital plasminogen deificiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.

Recognize the Signs and Symptoms
brain eye female gums respiratory skin ear gastro tract kidney
ear gastro tract kidney
Signs and Symptoms kidney overlay
~2% Kidneys lesions Kidneys ligneous lesions may lead to renal impairment.
kidney icon
Signs and Symptoms gastro-tract overlay
~2% Gastrointestinal tract lesions Ligneous lesions on the gastrointestinal tract may result in ulcers.
gastro-tract icon
Signs and Symptoms ear overlay
~14% Auditory ligneous lesions Lesions in the ear put PLGD patients at risk of chronic ear infection (otitis media), inner ear damage, and loss hearing.
ear icon
Signs and Symptoms brain overlay
~12% Occlusive hydrocephalus Occlusive hydrocephalus puts PLGD patients at high risk of cognitive impairment and Dandy-Walker malformation.
brain icon
Signs and Symptoms eye overlay
~80%
Ligneous Conjunctivitis Ligneous conjunctivitis is a sentinel manifestation of PLGD. It can lead to cornea damage, vision loss, and blindness.
eye icon
Signs and Symptoms female overlay
~8%
Ligneous lesions in the genital tract Lesions and inflammation of the female genital tract put patients at risk of impaired ovulation, spontaneous abortion, and infertility.
female icon
Signs and Symptoms gums overlay
~34%
Ligneous gingivitis Some PLGD patients experience ligneous gingivitis which can lead to periodontal disease, destruction of alveolar bone, and tooth loss.
gums icon
Signs and Symptoms respitory overlay
~16%
Ligneous lesions in the respiratory tract Some PLGD patients experience lesions in the respiratory tract (larynx, vocal cords, tracheobronchial tree).
respiratory icon
Signs and Symptoms skin overlay
~2% Severely impaired wound healing Reduced plasminogen activity leads to severely impaired wound healing.
Skin icon

Recognize the Signs and Symptoms

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The most common clinical manifestations include

ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations, such as involvement of the respiratory tract (16%), the ears (14%), ligneous vaginitis (8%), or the gastrointestinal tract (2%).1

More than 12% of patients with severe hypoplasminogenemia exhibit congenital occlusive hydrocephalus.2

There is extensive heterogeneity in type I plasminogen deficiency; patients may experience different types of fibrous lesions (location, size, and various organ system involvement).1 These fibrous lesions are often quite painful and can compromise organ function, creating emergencies, such as a collapsed lung, kidney failure, or impaired vision. As a result of this condition, patients may suffer substantial morbidity, and in some cases complications can be fatal.

Lesions tend to occur throughout life and, in the absence of replacement therapy, tend to recur after surgical excision, hence may lead to permanent disability, such as loss of eyesight or bronchial or ureteric obstruction.

Patients may be subjected to dozens or even more surgical procedures.1 The frequency of recurrence of fibrous growths in the eye following surgery is unknown, although anecdotally, some patients have required more than 20 operations.

Congenital occlusive hydrocephalus and Dandy-Walker (malformation of the cerebellum) have also been reported in type I plasminogen deficiency.1

In patients with plasminogen deficiency, wound-healing capability is markedly diminished and is most pronounced in mucous membranes. Lesions in these areas are typically rich in fibrin due to lack of proteolytic capacity. As fibrin degradation is limited, the process halts at the stage of granulation tissue formation.2

Severe hypoplasminogenemia is associated with compromised extracellular fibrin clearance during wound healing, leading to pseudomembraneous (ligneous) lesions on affected mucous membranes (eye, middle ear, mouth pharynx, duodenum, upper and lower respiratory tracts, and female genital tract).2

Impaired secretion of mutant plasminogen proteins is a common molecular pathomechanism in type I plasminogen deficiency.1

Patients are subject to lifelong medical problems, which currently have no effective treatment.

References:

1. Tefs K, Gueorguieva M, Klammt J, et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood. 2006;108(9):3021-3026.

2. Shoseyov D. Congenital plasminogen deificiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.

Genetics

Multiple distinct mutations in the plasminogen deficiency gene have been identified. The most common genetic alteration appears to be a K19E mutation found in 34% of patients.1

Besides this K19E mutation, a variety of other genetic abnormalities have been identified in the plasminogen gene in subjects with heterozygous, homozygous, and compound-heterozygous hypoplasminogenemia.2

Although type I plasminogen deficiency shows autosomal-recessive inheritance, a female-to-male ratio of 1.27:1 has been observed.1

There are many mutations found: missense mutations, nonsense mutations, frame shift mutations, splice site mutations, an amino acid deletion mutation and an amino acid insertion mutation.2

Plasminogen is converted to plasmin by cleavage of the Arg561–Val562 peptide bond by either tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator.2

References:

1. Tefs K, Gueorguieva M, Klammt J, et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood. 2006;108(9):3021-3026.

2. Shoseyov D. Congenital plasminogen deificiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.

Congenital Plasminogen Deficiency (PLGD) Clinical Trials & Regulatory Status

Prometic Life Sciences (Prometic) is developing a novel protein replacement therapy for congenital plasminogen deficiency (PLGD) – a rare disorder for which there is no approved therapy currently available.

Prometic’s plasminogen (human) intravenous (IV) formulation was granted Fast Track, Orphan Drug and Rare Pediatric Disease Designations by the United States (US) Food and Drug Administration (FDA). The Rare Pediatric Disease Designation is granted for serious or life-threatening diseases in which the clinical manifestations primarily affect individuals aged from birth to 18 years, or age groups often called neonates, infants, children, and adolescents. Additionally, the FDA has accepted the Biologics License Application (BLA) for plasminogen (human) IV and set a Prescription Drug User Fee Act (PDUFA) action date for April 14, 2018. Prometic anticipates filing a New Drug Submission (NDS) with Health Canada in December 2018. Health Canada has granted priority review status for the NDS for plasminogen (human) IV with a review performance target of 180 days. Prometic is also in discussions with the European Medicines Agency (EMA) with regards to the requirements to support submission and evaluation of a Marketing Authorisation Application (MAA) in the European Union (EU).

Prometic has completed a planned interim analysis of the pivotal Phase 2/3 clinical trial in 10 patients with congenital PLGD treated with plasminogen (human) IV for 12 weeks. Both the primary and secondary endpoints were met. In addition to being well tolerated and without any drug related serious adverse events, plasminogen replacement therapy achieved a 100% success rate of its primary end point, namely, >80% of patients achieving a targeted increase in the trough blood plasma concentration level of plasminogen as a surrogate target. Regarding the secondary endpoint, all patients with active, visible lesions when enrolled in the trial, experienced significant healing of their lesions within 12 weeks of treatment; an overall response rate of 93.3% was achieved. Prometic has also obtained similar positive data on 2 patients treated on an expanded access basis in the USA and 4 patients treated on a named patient basis in Germany and the United Kingdom (UK).

The pivotal Phase 2/3 protocol includes an extension segment of at least an additional 36 weeks. Patients are treated for a total duration and drug exposure period of at least 48 weeks. Clinical trial data reported to date, from 10 patients who completed 48 weeks of plasminogen (human) IV therapy, demonstrates that there was no recurrence of lesions and no safety or tolerability issues observed related to this longer-term dosing. The Phase 2/3 trial is ongoing and the complete dataset for all 15 enrolled patients, treated over a period of 48 weeks, is expected to demonstrate the long-term efficacy and safety of plasminogen (human) IV therapy in patients with congenital PLGD.

Healthcare providers may contact Prometic or visit clinicaltrials.gov for further information.