BLOO7 schreef op 23 april 2018 11:33:
April 23, 2018: Arthritis Advisory Committee Meeting
Safety
One of the challenges of the baricitinib clinical program is assessment of safety. As with other
RA programs, there was a limited placebo control period and patients could escape and/or cross
over to baricitinib 4 mg. When most of the safety data are from baricitinib treatment groups and
there are limited control group data, interpretation of imbalance in adverse reactions between
treatment groups is problematic. In addition, the fact that the baricitinib 2 mg dose was only
included in 2 clinical trials complicated assessment of the safety of baricitinib 2 mg. To address
some of these limitations, several strategies to combine the safety data were used (e.g. integrated
phase 3 trials, integrated phase 2 and 3 trials, and integrated data from trials that included both
baricitinib 2 and 4 mg doses). This is important to note when reviewing the safety analyses as
there may be slightly different numbers of events, exposures, rates, and statistics, depending on
the strategy for integrating safety data. The FDA reviews provide annotation and further
contextual information where appropriate. These strategies, however, cannot overcome the
limited placebo control data and limited safety database with the baricitinib 2 mg dose.
The FDA reviews identified a safety profile of baricitinib consistent with that of a potent
immunosuppressant with major safety risks of serious and some fatal infections, including
opportunistic infections and tuberculosis, malignancy, laboratory abnormalities of increase in
platelet counts, decrease in neutrophil counts, and increases in lipid parameters, and serum
creatine phosphokinase (CPK). Many of these adverse reactions appeared to be dose-dependent.
Additionally, arterial and venous thromboses were observed in association with baricitinib
treatment. While many of the adverse reactions listed are typical for immunosuppressive therapy
used for RA patients, the dose dependent platelet elevations and reports of thrombotic events are
noteworthy. FDA considered a plausible mechanism related to JAK inhibition and platelet
elevation as discussed in further detail in the Summary of Re-submission.
Benefit/Risk
Because the majority of the safety data are with the higher dose of baricitinib, the identified
safety issues raised concern regarding the 4 mg dose of baricitinib. The limited safety database
with the lower dose complicated the benefit/risk assessment of the 2 mg dose of bariticitinib.
Whether the benefit/risk assessment is favorable for the 4 mg or the 2 mg dose of baricitinib for
the treatment of RA is the main issue for discussion at the upcoming AC meeting