Pharmacokinetics of Plasminogen, Human-Tvmh in Subjects with Plasminogen Deficiency Type 1

Introduction: Plasminogen deficiency type 1 (PLGD-1) or hypoplasminogenemia is an ultra-rare disease characterized by a reduction of both plasminogen activity and antigen levels, resulting in accumulation of extra-vascular fibrin-rich lesions on mucosal surfaces.

Plasminogen, human-tvmh (PLG) is a plasma derived human plasminogen concentrate indicated for the treatment of subjects with PLGD-1 and FDA-approved in 2021 in the US (Shapiro et al, 2023). It is a lyophilized formulation containing the native circulating form of plasminogen, Glu-plasminogen, reported to have a longer t_1/2 (2.2 days) than Lys-plasminogen (0.8 days) in healthy subjects (Collen et al, 1975).

The (PK) characteristics of PLG administered IV to adults and children with PLGD-1 were assessed in phase 1 and phase 2/3 studies. Dosing intervals were determined based on individual PK profiles with the aim to increase and maintain plasminogen activity trough levels by at least an absolute 10% above baseline.

Here are reported the PK properties of single and repeated doses of PLG administered every 2 to 4 days for 12 weeks in subjects with PLGD-1.

Methods: A total of 15 subjects (9 adult and 6 pediatric subjects; 4 males and 11 females, 4 to 42 years of age) were administered 6.6 mg/kg PLG every 2 to 4 days for at least 48 weeks.

Plasma samples were collected up to 96 hours post-dose after the first dose on week 1 and repeated doses on week 12 to obtain full PK profiles. Six subjects had their first dose in phase 1 and 9 subjects in the phase 2/3 study (segment 1).

Samples were also collected every 2 weeks before PLG infusion to measure trough levels (phase 2/3 segment 2).

Both plasminogen activity and antigen levels were measured using validated methods and baseline-adjusted PK parameters were derived from concentration-time curves using non-compartmental analysis (NCA).

Serum samples for anti-drug antibodies (ADA) analyses were collected prior the first dose and on Week 4, Week 8, Week 12, and every 12 weeks until end of study.

Results: All subjects were included in the PK population and received an actual dose of 5.6-6.8 mg/kg PLG infused over 10 to 17 minutes.

Plasminogen activity: Similar plasminogen activity profiles were observed in the adult and pediatric PK populations. Mean (± standard deviation [SD]) absolute plasminogen activity was 22.1 ± 12.9% before the first dose and reached a trough level of 51.0 ± 12.0% after 12 weeks of treatment (corresponding to a mean absolute increase of 29.9 ± 14.1%).

Mean (± SD) PLG peak concentration (C_max) increased from 95 ± 23.5% after the first dose to 125 ± 23.3% after 12 weeks of treatment.

Mean (± SD) PLG terminal half-life (t_1/2) was 34.0 ± 11.7 hours after the first dose and increased slightly to 39.2 ± 6.2 hours after 12 weeks.

Individual plasminogen activity trough levels were successfully increased and maintained by at least an absolute 10% above baseline.

Transient ADA were confirmed in 2 subjects during the 12 weeks of treatment however their presence did not alter subjects' plasminogen activity levels and associated PK parameters.

Plasminogen antigen: Similar plasminogen antigen profiles were observed in the adult and pediatric PK populations. However, larger variability was observed in plasminogen antigen levels compared to plasminogen activity, which did not allow reliable interpretation of plasminogen antigen levels and associated PK parameters.

Conclusion: PLG administered IV at a dose of 6.6 mg/kg every 2 to 4 days increased plasminogen activity to physiological levels with no safety concerns.

Dosing interval based on each individual PK profile obtained after the first dose adequately maintained plasminogen activity trough levels by at least 10% above baseline during 12 weeks of treatment.

Robust plasminogen activity data obtained during phase 1 and phase 2/3 studies were used for the development of a population PK model supporting prophylactic replacement therapy for PLGD-1 patients that was successfully integrated into the WAPPS-Hemo platform (Chelle et al, 2024).

References:

Collen et al, Thromb Res. 1975; 7(4):515-29.

Shapiro et al, Haemophilia. 2023; 1-9

Chelle et al, Haemophilia. 2024; 1-10

Thibaudeau:Kedrion Biopharma: Current Employment. Parker:Kedrion: Consultancy. Shapiro:Hema Biologics: Membership on an entity's Board of Directors or advisory committees; Be Biopharma: Membership on an entity's Board of Directors or advisory committees; Cantessa Pharmaceuticals/ApcinteX Ltd.: Research Funding; Pharmacosmos A/S: Research Funding; Novo Nordisk Haemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Indiana Hemophilia & Thrombosis Center, Inc.: Current Employment; Takeda Pharmaceuticals: Research Funding; Regeneron: Research Funding; Sanofi-Genzyme/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech/Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kedrion Biopharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Plasminogen Deficiency Foundation: Membership on an entity's Board of Directors or advisory committees; BioMarin: Membership on an entity's Board of Directors or advisory committees; NHPCC: Other: Medical Director.