Ryplazim: The First Definitive Treatment for Congenital Plasminogen Deficiency

IT’S AN ultrarare autosomal recessive disorder that occurs in fewer than two of every million individuals,¹ but congenital plasminogen deficiency (PLGD) is known by several names, including type I plasminogen deficiency,* plasminogen deficiency and hypoplasminogenemia. PLGD results from inheritance of defective copies of both alleles of the PLG gene, which yields dysfunctional or too little plasminogen, the key mediator of fibrinolysis following its conversion to enzymatically active plasmin (Figure 1). The end result is impaired extracellular fibrin clearance during wound healing, presenting on affected mucous membranes throughout the body as accumulations of nondegraded fibrin as pseudomembranous ligneous — “woody” — growths. In most cases, the disease is diagnosed within the first year of life.

Ligneous conjunctivitis is by far the most common clinical manifestation of PLGD, occurring in more than 80 percent of diagnosed cases. It is usually triggered by an eye infection or other event that causes ocular inflammation. In the one-third of cases with corneal involvement, ligneous conjunctivitis can result in vision impairment or blindness (See image below).¹ These thick, fibrous pseudomembranous lesions can be surgically excised, but invariably they quickly return; in fact, the surgical procedure itself acts to accelerate or trigger lesion regrowth.

Ligneous growths can occur as well in the mouth, nasopharynx, duodenum, middle ear, brain, respiratory tract and female genital tract, resulting in a host of serious complications. The roughly 30 percent of patients who present with ligneous gingivitis experience both periodontal destruction and tooth loss.¹ Lesions involving the respiratory tract, reported in 20 percent of patients in one large case series,² can cause acute, life-threatening airway obstruction and death. Lesions in the middle ear may result in hearing loss. In roughly one in eight children, fibrin deposition in the cerebral ventricular system results in occlusive hydrocephalus.³ In general, a lower residual plasminogen activity level corresponds with a more severe disease burden.

For ligneous conjunctival lesions in particular, various treatments have been tried in an attempt to prevent them from recurring following surgical excision. Trials of nonspecific topical drugs, including corticosteroids, heparin and cyclosporine, have been disappointing.^4,5 A number of case reports have shown that topically administered donor fresh frozen plasma (FFP) eye drops has prevented recurrence over a period of many months or even years.^6,7,8,9 But the FFP must be readministered multiple times each day, and of course it offers no benefit for any other problematic ligneous lesions present elsewhere in the body.

In the late 1990s, several case reports described effective treatment of ligneous conjunctivitis with an investigational Lys-plasminogen product^10,11,12 that was developed by European plasma derivatives manufacturers for potential use as an adjunctive fibrinolytic therapy for vascular thromboses in combination with plasminogen activators.¹³ Accounting for less than 10 percent of circulating plasminogen, Lys-plasminogen is a modified form of the zymogen that binds more avidly to fibrin;** most circulating plasminogen is present as Glu-plasminogen. Unfortunately, with a very brief half-life of just 20 hours,¹⁴ Lys-plasminogen did not prove to be practical as a chronic treatment for this lifelong disease.

Clinicians would have to wait more than 20 years for a small Canadian company to develop, test and finally secure U.S. regulatory approval last year for RYPLAZIM, the first definitive treatment for ligneous lesions and their complications in patients afflicted with PLGD.¹⁵ RYPLAZIM is now produced and commercialized by Kedrion Biopharma.¹⁶

Plasminogen Replacement Therapy with RYPLAZIM

RYPLAZIM is a concentrate of native circulating Glu-plasminogen, purified to greater than a 95 percent purity level using a series of chromatographic adsorbents from large pools of donor human plasma. Any potentially contaminating enveloped and nonenveloped viruses that might have evaded screening tests are removed both by affinity chromatography and 20 nanometer nanofiltration; enveloped viruses, including HIV and hepatitis viruses, are additionally inactivated by solvent/detergent treatment. The mean in vivo half-life of this pooled Glu-plasminogen concentrate is 38 hours to 40 hours, roughly twice that of the Lys form.

Dosing frequency with RYPLAZIM plasminogen replacement therapy is individualized over the initial 12 weeks of therapy as dictated by post-infusion plasminogen activity level testing, and subsequently in accordance with its efficacy in resolving or stabilizing ligneous lesions. The first standard 6.6 mg/kg intravenous dose is administered after a blood draw to measure the patient’s baseline plasminogen activity level. If the 72-hour post-infusion trough plasminogen activity level is between 10 percent and 20 percent above baseline, the patient is maintained on an every-three-days (Q3D) dosing frequency over the next 12 weeks. Dosing is increased to Q2D if the 72-hour post-infusion plasminogen level is less than 10 percent above baseline or reduced to Q4D if it is more than 20 percent above baseline.

If lesions resolve by 12 weeks, the patient can remain on the same dosing frequency with monitoring for new or recurrent lesions every 12 weeks thereafter. If they do not resolve by 12 weeks, or there are new or recurrent lesions, the dosing frequency can be increased in one-day increments every four weeks to eight weeks up to Q2D while reassessing clinical improvement until the lesions improve or stabilize without further worsening. However, if the desired outcome does not occur by 12 weeks and the trough plasminogen activity level is more than or equal to 10 percent above the baseline trough level, clinicians are advised to consider other treatment options such as surgical removal of the lesion in addition to plasminogen treatment.

This regimen was put to the test in an open-label Phase II/III study in 14 pediatric and adult patients who completed at least 12 weeks of RYPLAZIM treatment and had a plasminogen activity level less than or equal to 45 percent and documented history of lesions and symptoms consistent with a diagnosis of congenital plasminogen deficiency.¹⁷ Clinical manifestations at presentation ranged in duration from one year to 42 years, with the most extensive disease histories observed in patients with plasminogen activity less than 5 percent of normal.

Clinically visible lesions involving the eyes and gingiva were imaged and their length and width analyzed at baseline, weeks four, eight and 12 and every 12 weeks thereafter. Nonvisible lesions of the nasopharynx, bronchus, colon, kidney, cervix and vagina were variously assessed using medical imaging studies (e.g., ultrasound, magnetic resonance imaging), functional assessments (e.g., spirometry, audiogram, oximetry) or reported clinical symptoms.

All 14 study patients achieved and generally maintained their target trough pre-infusion plasminogen activity levels of more than or equal to 10 percent above baseline across the initial 12-week treatment period. Nine patients had 23 clinically visible lesions in the conjunctiva and gingiva, 18 of which completely resolved and five of which improved by week 12. Six of seven nonvisible internal lesions resolved by week 12, and the seventh resolved by week 24. All three patients who presented with manifestations of abnormal wound healing at baseline (wounds, scars, acne and palmar/plantar warts) showed improvement by week 12. Finally, no new lesions were observed, nor did any existing lesions recur over the study period.¹⁷ “Both the rapidity and the magnitude of the improvement has been remarkable, knowing that in many cases the lesions have been present for years,” noted co-investigator John Moran, MD, who helped to design the study.

RYPLAZIM was well-tolerated in both children and adults; there were no serious adverse events and no patient permanently discontinued treatment due to an adverse event. Headache and nasopharyngitis were the most commonly reported adverse events. Several patients experienced nonserious adverse events, including epistaxis, hematuria, dysmenorrhea and/ or elevated D-dimer level, which were consistent with fibrinogen’s physiologic fibrinolytic and lesion dissolution activity. Reassuringly, no antiplasminogen antibodies were detected in any patient.

RYPLAZIM “represents a pivotal breakthrough in the treatment of this very rare coagulation deficiency and an important therapeutic advance for affected patients who have suffered under the burden of their disease due to lack of an available efficacious therapy,” the study authors concluded.¹⁷

The Newest Rare Disease Plasma Protein Therapy

While PLGD affects only an estimated 500 U.S. children and adults,1 its health toll can be profound. “Congenital plasminogen deficiency can impact self-image, quality of life and ability to achieve full potential in school and/or work,” said Amy Shapiro, MD, who served as principal investigator on the pivotal Phase II/III trial. For these individuals, for whom no specific treatment was available until now, RYPLAZIM therapy can be transformative.

But Dr. Shapiro points out one final potential obstacle for PLGD patients: Its extreme rarity “results in frequent mis- and delayed diagnoses by professionals lacking specialist knowledge.”¹ This, in turn, has limited our understanding of the disease’s natural history, and to date has thwarted development of clinical guidelines.

To address this, Dr. Shapiro and collaborators have established a registry called the Plasminogen Deficiency Study, which will capture data from an inter-national population of people with PLGD and their immediate family members over a four-year period. Those who know of or care for anyone with PLGD are encouraged to visit the Plasminogen Deficiency Study website (www.plg deficiency.com) or contact Dr. Shapiro directly ([email protected]) at the Indiana Hemophilia & Thrombosis Center.

* In type I plasminogen deficiency (hypoplasminogenemia), a variety of nonsense and missense mutations, or a specific deletion, result in parallel reductions in the level of the protein’s immunoreactivity and functional activity. In type II plasminogen deficiency (dysplasminogenemia), plasminogen immunoreactivity is normal or near-normal, whereas its specific functional activity is markedly reduced; however, dysfibrinogenemia in isolation is not associated with any disease and may be considered a polymorphic variation in the general population.

•• The theoretical advantage of Lys-plasminogen in clot thrombolysis is its higher affinity for fibrin and its more rapid conversion to the active fibrinolytic enzyme plasmin than native Glu-plasminogen.