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(PK) parameters, using area under the concentration-time curve over the dosing
interval (AUCtau) and maximum serum concentration (Cmax) at steady state.
Based on their extrapolation criteria, Health Canada extended approval of CT-P13
for plaque psoriasis and psoriatic arthritis. However, Health Canada, at time of
approval, denied extrapolation to adult and pediatric Crohn’s disease and UC. This
denial was based on the observed differences in degree of afucosylation and
FcγRIIIa receptor binding in addition to differences in some in vitro antibody-
dependent cell-mediated cytotoxicity (ADCC) assays [ 42 ]. In addition, Health
Canada observed that the safety profile in rheumatic diseases is different, specifi-
cally citing the risk of hepatosplenic T-cell lymphoma in IBD. In the absence of
clinical studies in IBD, it was felt that extrapolation was not warranted for CD or
UC in adults or pediatric patients [ 42 ].
On the other hand, the European Medicines Agency (EMA) and the FDA Arthritis
Advisory Committee (AAC) concluded that extrapolation was warranted to all the
diseases for which reference infliximab had previously received EMAand FDA
approval [ 10 , 43 ]. The agencies reviewed the data supplied by Celltrion and con-
cluded that the issue of diminished afucosylation and ADCC activity occurred only
in the most sensitive experimental in vitromodel using NK cells of patients with
high-affinity genotypes. In further examination of efficacy and safety of efficacy in
IBD, Celltrion had committed to increase enrollment in a post-marketing surveil-
lance study and plans to conduct an additional comparative trial of CT-P13 versus
reference infliximab in active CD.
In summary, the totality of evidence analyzed and considered by the FDA AAC
(Table 15.3) resulted in a vote of 21 to 3 in favor of extrapolation,based on the
results of the RA and AS trials, to all the indications for which reference infliximab
had been approved, including adult and pediatric UC and CD resulting in the FDA
approval of CT-P13 for all previously approved indications for infliximab [ 44 ].
Similarly,for ABP 501, theFDA granted extrapolation to all indicated diseases for
which adalimumab had been previously approved.
Table 15.3 The totality of the evidence leading the FDA to approve extrapolation of the biosimilar
to infliximab
- Structural similarity in primary, secondary, and tertiary structure
- Similar posttranslational profiles and in vitro and in vivo functional characteristics
- Similar potency to bind and neutralize TNF, reverse signaling, and Fc region-mediated
potential mechanisms of action - Similar mechanism of action of TNF inhibitors, noting that ADCC is only one of several
plausible mechanisms of action, and only found to be altered in the most sensitive of a number
of assays - No clinically meaningful differences between CT-P13 and US-licensed Remicade in bridging
studies - Similarities in PK parameters for US-licensed Remicade in Crohn’s disease patients as
compared to RA and AS pts - Similar immunogenicity between CT-P13 in patients with CD
C.Y. Ha and A. Kornbluth