Plasminogen Deficiency

What is Plasminogen Deficiency?

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

Patients may be born with the inability to produce sufficient plasminogen naturally, a condition referred to as congenital plasminogen deficiency (C-PLGD), or suffer an acute or acquired deficiency following a trauma or an illness.

The most common and visible lesion associated with plasminogen deficiency is ligneous conjunctivitis, which is characterized by thick, woody (ligneous) growths on the conjunctiva of the eye, and if left untreated, can lead to corneal damage and blindness. Ligneous growths tend to recur after surgical excision, thereby requiring multiple surgeries.

While ligneous conjunctivitis is the best characterized and visible lesion, congenital plasminogen deficiency is a multi-systemic disease that can also affect the ears, sinuses, tracheobronchial tree, genitourinary tract, and gingiva. Tracheobronchial lesions including hyper viscous secretions can result in respiratory failure. Hydrocephalus, a condition related to the deposition of fibrin in the cerebral ventricular system, has also been reported in children with severe plasminogen deficiency.

While our first R&D priority has been to study Ryplazim® (Plasminogen), or Ryplazim, in patients with C-PLGD, the Company intends to further explore the other potential clinical uses of plasminogen over the coming years.

Liminal has conducted preclinical research on pursuing new indications such as the treatment of wounds such as diabetic foot ulcers and tympanic membrane repair, acquired plasminogen deficiency in critical care such as severe burns and acute lung injury (“ALI”). The expansion of the plasminogen development program could enable the Company to target multiple clinical indications with unmet medical needs and leverage the same proprietary Active Biological Product (“ABP”) via different possible formulations and presentations.

In a pivotal phase 2/3 clinical trial for the treatment of C-PLGD, the Company enrolled 15 patients with C-PLGD, including six pediatric patients, for 48 weeks of therapy with Ryplazim®. All of the patients treated with Ryplazim® achieved the targeted increase from baseline in their individual trough plasminogen activity levels through 12 weeks of therapy. In addition, all patients who had active visible lesions when enrolled in the trial had complete healing of their measurable lesions within 48 weeks of initiating therapy. Adverse events reported in the clinical study were characterized as mild, with no patient deaths, serious adverse events or adverse events that caused study discontinuation reported.

Through its’ US subsidiary, Prometic Biotherapeutics Inc., the Company has resubmitted a BLA in September 2020 with the FDA seeking approval to treat patients with C-PLGD. The FDA confirmed that the resubmission is a complete, Class 2 response to the complete response letter issued in 2018 and has provided a Prescription Drug User Fee Act (“PDUFA”) target action date of June 5, 2021.

Ryplazim® has previously been granted Orphan Drug and Rare Pediatric Disease Designations by the FDA for the treatment of congenital plasminogen deficiency.

Selected Relevant Publications:

Shapiro, Amy D. et al. ‘Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency’ Blood. 2018 Mar 22;131(12) :1301-1310.

Shapiro, Amy D. et al. ‘An international registry of patients with plasminogen deficiency (HISTORY)’ Haematologica. 2020 Mar; 105(3):554-561.

For further information please visit Clinicaltrials.gov

*Ryplazim® is an investigational drug and is not approved by the FDA.

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.