Abstract

INTRODUCTION

Plasminogen deficiency is a rare autosomal recessive disorder with variable penetrance with multisystem manifestations that may result in significant morbidity. Most commonly, type-1 (quantitative defect) is associated with characteristic fibrin rich pseudomembranes in mucosal surfaces, the most common site being the eye, called Ligneous Conjunctivitis (LC). Two-thirds of patients have bilateral eye lesions and 1/3 have corneal involvement. Initially, patients present with non-specific conjunctivitis with epiphora, followed by white-red woody lesions replacing normal membranes and resulting in visual impairment/loss. LC may be triggered/exacerbated by infection, inflammation, or trauma. Although some non-specific modalities have been reported to result in lesion improvement/resolution, only FFP and topical/systemic plasminogen are consistently effective. Surgical intervention without effective replacement therapy results in lesion regrowth. Currently, local or systemic plasminogen replacement therapy is unavailable. Therefore, development of locally administered plasminogen concentrate represents an important advance in therapeutic options for LC.

OBJECTIVES

A phase 2/3 study is being conducted to evaluate the safety and efficacy of Kedrion plasma derived (pd) plasminogen ophthalmologic drops for treatment of LC associated with type I plasminogen deficiency.

METHODS

An ongoing open-label, multicenter, historically-controlled trial divided into 3 segments began on 5/22/2012. Three sites (1 US, 2 Italy) enrolled subjects. Segment 1 is 4 week treatment to evaluate clinical safety/efficacy followed by surgical excision of residual pseudomembranous, if required; segment 2 includes 8 weeks post-operative treatment/monitoring; segment 3 is a continuation phase with long-term safety monitoring until product licensure. Treatment regimens range from 2 drops/eye 4-12 times daily based on symptoms, study group and segment. The investigational medical product is a sterile human pd plasminogen, solvent/detergent treatment, nanofiltrated virally inactivated. During processing, the plasma pool is supplemented with bovine aprotinin to prevent plasminogen conversion to plasmin.

RESULTS

Segments 1 and 2 are complete; segment 3 is ongoing. The interim analysis is according to study protocol. Eleven subjects were enrolled (plasminogen activity range 5.1-34.26%; median 17.08%); age ranged between 1-44 yrs (median 4 yrs) including 4 males and 7 females; 7 had unilateral and 4 had bilateral lesions at enrolment. Three subjects did not require surgical intervention, and 8 required one excision of residual lesions after 4 weeks of therapy. In all compliant subjects, full regression and/or absence of recurrence post-excision were reported. One adult male subject, with bilateral involvement and severe visual impairment, was withdrawn due to noncompliance in study segment 2 after excision with subsequent lesion recurrence. Two subjects (1 during segment 1-2 and 1 during segment 3) developed plasma anti-plasminogen antibodies which are being further characterized as to specificity; these two subjects continue to respond to local therapy and remain symptom-free (Table 1). No viral seroconversion was detected.

CONCLUSION

LC in type 1 plasminogen deficiency can result in significant morbidity without an available effective local therapy. Kedrion human pd plasminogen ophthalmologic drops were found to be effective and well tolerated and represent an important advance in the treatment of this unusual manifestation of a rare disease, plasminogen deficiency.

Table 1.

Study Data Summary

Subject # Age (Yrs) Sex Eye Lesions Surgery Required Therapeutic Response Plasminogen Ab Withdrawal (Reason) 
Left Right 
 No Negative No 
44  Yes Negative No 
32 Yes Negative Yes (poor compliance) 
 No Negative No 
Yes Positive No 
 No Negative No 
 Yes Negative No 
Yes Negative No 
 Yes Negative No 
10 Yes Positive No 
11  Yes Negative No 
Total   8 procedures  
15 symptomatic 
Subject # Age (Yrs) Sex Eye Lesions Surgery Required Therapeutic Response Plasminogen Ab Withdrawal (Reason) 
Left Right 
 No Negative No 
44  Yes Negative No 
32 Yes Negative Yes (poor compliance) 
 No Negative No 
Yes Positive No 
 No Negative No 
 Yes Negative No 
Yes Negative No 
 Yes Negative No 
10 Yes Positive No 
11  Yes Negative No 
Total   8 procedures  
15 symptomatic 

F: Full regression of lesions by end segment 1; no surgery required, no recurrence in segment 3

P: Partial regression by the end of segment 1 with surgery required for residual lesion(s). No recurrence post-operatively or in segment 3.

R: Recurrence

Disclosures

Nakar:Kedrion: Research Funding. Caputo:Kedrion: Research Funding. Price:Kedrion: Research Funding; Alphaeon, Calhoun Vision Inc., Interactive Medical Publishing, Inc., ReVital Vision, TearLab,Valeant Pharmaceuticals/Bausch and Lomb: Equity Ownership; Cornea Research Foundation of America: Membership on an entity's Board of Directors or advisory committees; STAAR Surgical: Consultancy. Sartori:Kedrion: Research Funding. Suffredini:Kedrion SpA: Employment. Thukral:Kedrion: Research Funding. Secci:Kedrion: Research Funding. Jeng:Kedrion: Consultancy. Shapiro:Baxalta, Novo Nordisk, Biogen, ProMetic Life Sciences, and Kedrion Biopharma: Consultancy; Baxalta, Novo Nordisk, Biogen,: Membership on an entity's Board of Directors or advisory committees; Biogen: Speakers Bureau; Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, and Selexys: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.