genic complications observed or reported.4
The manufacturing procedure for Mononine® includes multiple processing steps that have been designed to reduce the risk of virus transmission. Validation studies of the monoclonal antibody (MAb) immunoaffinity chromatography/chemical treatment step and two sequential ultrafiltration steps used in the production of Mononine® document the virus reduction capacity of the processes employed. These studies were conducted using the relevant viruses Human Immunodeficiency Virus (HIV) and Hepatitis A Virus (HAV), the specific model viruses Bovine Viral Diarrhea Virus (BVDV) for Hepatitis C Virus (HCV) and Canine Parvovirus (CPV) for Human Parvovirus B19, and the non-specific model virus Pseudorabies Virus (PRV). The results of these virus validation studies utilizing a wide range of viruses with different physicochemical properties are summarized in Table 1 below:
Table 1 in vitro Virus Reduction Studies Virus Cumulative Virus Reduction Capacity
(Log10 Reduction)
HIV ≥11.7
BVDV ≥12.2
PRV ≥15.5
HAV ≥5.1
CPV ≥12.0
CLINICAL STUDIES
The virus safety of Mononine®has been studied in clinical trials of two cohorts of hemophilia B subjects previously unexposed to blood or blood products.5 One cohort of subjects included those with moderate to severe factor IX deficiency requiring chronic replacement therapy (41 subjects were dosed); the second cohort included subjects with a mild deficiency requiring factor IX replacement for surgical procedures (10 subjects were dosed).
These subjects were followed for serum alanine aminotransferase (ALT) elevations, as well as for a range of viral serologies. Thirty-seven (37) subjects (30 with moderate to severe deficiency and seven with a mild deficiency) were eva luable for assessment of virus hepatitis safety by the International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee criteria. None of these subjects showed evidence of transmission of hepatitis A, B, C, or HIV.
Mononine® contains trace amounts of the murine monoclonal antibody (MAb) used in its purification (≤50 ng mouse protein/100 IU). While the levels of mouse protein are extremely low, infusion of such proteins might theoretically induce human anti-mouse antibody (HAMA) responses. To test this possibility, human IgG, IgM, and IgE antibodies to mouse IgG were assessed by immunoradiometric assay (IRMA) in 11 hemophilia B subjects who received Mononine® and were previously untreated with other blood products. HAMAs were eva luated prior to the first infusion and at 2 to 42 months after initial treatment. Human IgE antibodies to mouse IgG were below the level of detectability at all time points for all subjects, and there were no statistically significant increases in either human IgG antibodies or human IgM antibodies to mouse protein.6
In clinical studies of Mononine® subjects were monitored for evidence of disseminated intravascular coagulation. In six subjects eva luated after infusion, fibrinogen levels and platelet counts were unchanged, and fibrin degradation products did not appear.3
In further clinical eva luations of Mononine® in a crossover study with a Factor IX Complex concentrate, Mononine® was not associated with the formation of prothrombin activation fragment (F1+2) whereas the Factor IX Complex was associated with the formation of prothrombin activation fragment (F1+2).3,7 Prothrombin |
