ASH Clinical News Focus on Rare Diseases | Page 14

Immunogenicity
All clinical trial subjects were monitored for neutralizing
antibodies (inhibitors) to Factor VIII by the modified Bethesda
assay using blood samples obtained prior to the first infusion
of KOVALTRY, at defined intervals during the studies and at the
completion visit.
Clinical trials (Phases 1 through 3) with KOVALTRY evaluated a
total of 204 pediatric and adult patients diagnosed with severe
hemophilia A (Factor VIII <1%) with previous exposure to
Factor VIII concentrates ≥50 EDs, and no history of inhibitors.
In the completed studies, no PTP developed neutralizing
antibodies to Factor VIII. In an ongoing extension study, a
13 year old PTP had a titer of 0.6 BU after 550 EDs concurrent
with an acute infection and positive IgG anticardiolipin
antibodies. The Factor VIII recovery was 2.2 IU/dL per IU/kg,
annualized bleeding rate (ABR) was zero, and no change in
therapy was required.
In an actively enrolling clinical trial in PUPs, 6 of 14 treated
subjects (42.9% with a 95% Confidence Interval of 17.7-71.1%)
developed an inhibitor. Of these, 3 subjects (21.4%) had high
titer inhibitors, and 3 subjects (21.4%) had transient low titer
inhibitors for which no change in therapy was required.
The detection of antibody formation is dependent on the
sensitivity and specificity of the assay. Additionally, the observed
incidence of antibody (including neutralizing antibody) positivity
in an assay may be influenced by several factors including assay
methodology, sample handling, timing of sample collection,
concomitant medications, and underlying disease. For these
reasons, it may be misleading to compare the incidence of
antibodies to KOVALTRY with the incidence of antibodies to
other products.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no data with KOVALTRY use in pregnant women to
inform on drug-associated risk. Animal reproduction studies
have not been conducted using KOVALTRY. It is not known
whether KOVALTRY can cause fetal harm when administered to a
pregnant woman or can affect reproduction capacity. KOVALTRY
should be given to a pregnant woman only if clearly needed.
In the U.S. general population, the estimated background risk
of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
8.2 Lactation
Risk Summary
There is no information regarding the presence of KOVALTRY
in human milk, the effects on the breastfed infant, or the effects
on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother’s
clinical need for KOVALTRY and any potential adverse effects
on the breastfed infant from KOVALTRY or from the underlying
maternal condition.

8.4 Pediatric Use
Safety and efficacy studies with KOVALTRY have been
performed in pediatric PTPs. Body weight adjusted clearance of
Factor VIII in children ≤12 years of age is higher than in adults
and adolescents. Consider higher or more frequent dosing in
children to account for this difference in clearance [see Clinical
Pharmacology (12.3)].
8.5 Geriatric Use
Clinical studies with KOVALTRY did not include patients aged 65
and over to determine whether or not they respond differently
from younger patients. However, clinical experience with other
Factor VIII products has not identified differences between the
elderly and younger patients. As with any patient receiving
recombinant Factor VIII, dose select