HHE Rheumatology and musculoskeletal supplement 2018 | Page 9
March 2017. The reasons behind this delay were
unresolved safety concerns (mainly infections)
and doubts about reduction of structural
progression. Pooled data from studies of
tofacitinib in patients with RA showed that the
overall risk of infection (including serious
infection) and mortality rates in RA patients
treated with tofacitinib were similar to those
observed in RA patients treated with biologic
agents. 11 Regarding joint damage, a subsequent
trial showed that tofacitinib monotherapy was
superior to MTX in preventing radiological
progression. 12 The overall rates and types of
malignancies observed in the tofacitinib clinical
programme remained stable over time with
increasing tofacitinib exposure and were in line
with what is expected in patients with moderate
to severe RA. 13
The EMA approved tofacitinib at a dose of 5mg
twice daily, being indicated in combination with
MTX for the treatment of moderate to severe
active RA in adult patients who have had an
inadequate response to MTX. It also can be used
as monotherapy in cases of intolerance to MTX or
when continued treatment with MTX is
inappropriate.
intolerant to, one or more disease-modifying
anti-rheumatic drugs. It may be used as
monotherapy or in combination with MTX.
Baricitinib approval was initially rejected by
the FDA, on the basis that additional clinical data
were needed to determine the most appropriate
doses and to further characterise safety concerns
across treatment arms. A major reason behind
this decision was the presence of thromboembolic
events in five patients receiving baricitinib in
clinical trials. It just has been approved by the
FDA at a dose of 2mg once daily in adult patients
with moderately-to-severely active RA who have
had an inadequate response to one or more tumor
necrosis factor (TNF) inhibitor therapies. It may be
used as monotherapy or in combination with
MTX or other csDMARDs. Baricitinib was
approved with a Boxed Warning for the risk of
serious infections, malignancies and thrombosis.
As part of the approval, the sponsor has agreed to
conduct a randomised controlled clinical trial to
evaluate the long-term safety of baricitinib in
patients with RA.
JAK1 inhibitors
Filgotinib is a selective inhibitor of JAK1 over
JAK2, JAK3 and TYK2. The rationale for the
development of more selective inhibitors such as
filgotinib is that less selective JAK inhibitors lead
to pan-JAK inhibition that might generate
dose-limiting side effects.
Published results of Phase II studies in patients
with insufficient response to MTX showed that
filgotinib was superior to placebo with an
acceptable safety profile. 17,18 It has also shown
efficacy as monotherapy. 19
Upadacitinib is another selective inhibitor of
JAK1. It has also demonstrated efficacy in Phase II
trials, with a favorable safety and tolerability
profile in patients with inadequate response to
MTX and to bDMARDs. 20,21 Phase III clinical trials
are currently ongoing.
JAK1/2 inhibitors
Baricitinib is a JAK1/2 inhibitor with moderate
activity on TYK2 and no influence on JAK3. Phase
III studies demonstrated that baricitinib alone or
in combination with MTX had superior efficacy to
MTX monotherapy as initial treatment for
patients with active RA. 7 In patients with
inadequate response to MTX, baricitinib was
superior when compared with placebo and
adalimumab. 14 It also demonstrated clinical
improvement and inhibition of progression of
radiographic joint damage in patients who failed
to respond to csDMARDs 15 and clinical
improvement in patients with inadequate
response to bDMARDs. 16
Baricitinib was approved by the EMA in March
2017 at a dose of 4 or 2mg once daily. It is
indicated for the treatment of moderate to severe
active rheumatoid arthritis in adult patients who
have responded inadequately to, or who are
JAK3 inhibitors
Decernotinib selectively inhibits JAK3 over the
other JAKs. Taking this into account it would be
expected that some of the side effects seen with
less specific JAK inhibitors might be avoided.
Decernotinib has shown superiority compared
with placebo in a Phase II study. 22 Development is
currently on hold.
Peficitinib inhibits all of the JAKs, having
a moderate selectivity for JAK3. Its milder effect
on JAK2 suggests that effects on red blood cells
and platelets caused by JAK2 inhibition might be
less intense. Results from Phase II trials have
demonstrated an acceptable response in patients
with inadequate response to csDMARDs. 23,24 Phase
III trials are underway.
Safety profile
Information from clinical trials is creating
a characteristic safety profile for this new class
of molecules. What is difficult to answer at this
moment is whether the different selectivities
of each JAK inhibitor will establish distinctions
between them. To date, it seems that there is
a large overlap between JAK inhibitors despite
their various specifities. Infections and changes
in laboratory parameters seem to be common
issues with JAK inhibitors. 25
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