otential for immunogenicity. The detection ofantibody formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody (including neutralizing antibodies)positivity in an assay may be influenced by several factors including assay methodology,sample handling, timing of sample collection, concomitant medications and underlyingdisease. For these reasons, comparison of the incidence of antibodies in the studiesdescribed below with the incidence of antibodies in other studies or to other ravulizumabproducts may be misleading.
The immunogenicity of ravulizumab-cwvz has been eva luated using an enzyme linkedimmunosorbent assay (ELISA) for the detection of binding anti-ravulizumab-cwvz
antibodies. For patients whose sera tested positive in the screening immunoassay, an invitro biological assay was performed to detect neutralizing antibodies.
In clinical studies of patients with PNH, treatment-emergent antibodies to ravulizumabcwvzwere detected in 1 of 206 (0.5%) patients. No apparent correlation of antibodydevelopment to altered pharmacokinetic profile, clinical response, or adverse events wasobserved.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no available data on ULTOMIRIS use in pregnant women to inform a drugassociatedrisk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
There are risks to the mother and fetus associated with untreated paroxysmal nocturnalhemoglobinuria (PNH) in pregnancy (see Clinical Considerations). Animal studies usinga mouse analogue of the ravulizumab-cwvz molecule (murine anti-C5 antibody) showedincreased rates of developmental abnormalities and an increased rate of dead and
moribund offspring at doses 0.8-2.2 times the human dose (see Data).
The estimated background risk of major birth defects and miscarriage for the indicatedpopulation is unknown. All pregnancies have a background risk of birth defect, loss, orother adverse outcomes. In the U.S. general population, the estimated background risk ofmajor birth defects and miscarriage in clinically recognized pregnancies is 2-4% and15-20%, respectively.
Clinical Considerations
Disease-associated maternal and/or fetal/neonatal riskPNH in pregnancy is associated with adverse maternal outcomes, including worseningcytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternalmortality, and adverse fetal outcomes, including fetal death and premature delivery.
Data
Animal Data
Animal reproduction studies were conducted in mice using doses of a murine anti-C5antibody that approximated 1-2.2 times (loading dose) and 0.8-1.8 times (maintenance
dose) the recommended human ULTOMIRIS dose, based on a body weight comparison.
When animal exposure to the antibody occurred in the time period from before matinguntil early gestation, no decrease in fertility or reproductive performance was observed.
When maternal exposure to the antibody occurred during organogenesis, two cases ofretinal dysplasia and one case of umbilical hernia were observed among 230 offspring
born to mothers exposed to the higher antibody dose; however, the exposure did notincrease fetal loss or neonatal death. When maternal exposure to the antibody occurred inthe time period from implantation through weaning, a higher number of male offspringbecame moribund or died (1/25 |
