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
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 has also been reported in children with severe hypoplasminogenemia, apparently related to the deposition of fibrin in the cerebral ventricular system.
Patients may be born with the inability to produce sufficient plasminogen naturally, a condition referred to as congenital plasminogen deficiency or suffer an acute or acquired deficiency following a trauma or an illness. While our first priority is to provide the treatment of congenital plasminogen deficiency, the Company intends to further expand the clinical uses of plasminogen as a priority over the coming years.
Liminal has been working on pursuing new indications such as the treatment of wounds such as diabetic foot ulcers and tympanic repair, acquired plasminogen deficiency in critical care such as severe burns and acute lung injury (“ALI”). The expansion of the plasminogen development program enables the Company to target multiple clinical indications with unmet medical needs and leverage the same proprietary Active Pharmaceutical Ingredient (“API”) via different formulations and presentations.
Clinical trial information for treatment of Congenital Plasminogen Deficiency
In a pivotal phase 2/3 clinical trial for the treatment of congenital plasminogen deficiency (PLDG), Ryplazim® met its primary and secondary endpoints following the intravenous administration of Ryplazim® to 10 patients for 12 weeks. In addition to being well tolerated and without any drug related serious adverse events, the phase 2/3 clinical trial achieved a 100% success rate for its primary end point, namely, a targeted increase in the plasma level of plasminogen immediately prior to the next infusion (“trough level”). Moreover, clinical data observed indicate that all patients who had active visible lesions when enrolled in the trial had complete healing of all lesions within weeks of treatment, a 100% patient response rate for this critical secondary end point. Repeated IV doses of 6.6mg/kg of Ryplazim® demonstrated excellent efficacy in the resolution of lesions due to PLGD with no recurrences or new lesions while on replacement therapy for 48 weeks, with no safety concerns.
On March 28, 2018, Liminal BioSciences provided an update on the status of the FDA review of its BLA for Ryplazim®, and subsequently the FDA issued a Complete Response Letter (“CRL”). The FDA identified the need for Liminal BioSciences to make a number of changes in the Chemistry Manufacturing and Controls (“CMC”) section. These require the implementation and validation of additional analytical assays and “in-process controls” in the manufacturing process of Ryplazim®. Once completed and validated, Liminal BioSciences is required to manufacture additional Ryplazim® conformance batches to confirm the effectiveness of these process changes.
The FDA has indicated that the submission of the amended BLA for Ryplazim® will not impact the previously granted designations, including the Priority Review Status, the Orphan Drug Designation and the Rare Pediatric Disease Designation for Ryplazim® for the treatment of PLDG.
The Company expects to be filing an amendment to the BLA in H1 2020 .
- 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.
- 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.
- Castellino FJ, Ploplis VA. Structure and function of the plasminogen/plasmin system. Thromb Haemost. 2005;93(4):647-654.