(OlumiantTM) is a once-daily, oral, small-molecule, janus-associated
kinase (JAK) inhibitor that was developed by Eli Lilly and Co. and Incyte
Corporation. In February 2017, baricitinib was approved by the European Union
for the treatment of rheumatoid arthritis (AR). It can be used as a monotherapy
or in combination with methotrexate for the treatment of adult patients with
moderate to severe rheumatoid arthritis who do not tolerate or who respond
inadequately to one or more disease-modifying anti-rheumatic drugs (DMARDs). This
article describes how baricitinib was developed and the difficulties
encountered during that process.

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also known as INCB-028050, INCB-28050, LY-3009104, and Olumiant, was developed
by Eli Lilly and Co. and Incyte Corporation (Markham, 2017). It is
a once-daily, oral, small-molecule, reversible, selective janus-associated
kinase (JAK) inhibitor that can treat rheumatoid arthritis (RA), atopic
dermatitis and systemic lupus erythematosus. The JAKs include Tyk2, JAK1, JAK2
and JAK3 (O’Shea, et al., 2013). It has been shown that JAK-dependent
cytokines are involved in the pathogenesis of many inflammatory and autoimmune
diseases. Thus, JAK inhibitors can be used to treat a wide range of
inflammatory conditions, including rheumatoid arthritis. Baricitinib selectively
inhibits JAK1 (IC50=5.9 nM) and JAK2 (IC50=5.7nM), and
inhibits cytokines implicated in RA (Keystone, et al., 2014). In 2016, Baricitinib was submitted for
marketing approval in the US, the European Union and Japan for the treatment of
RA, and on February 13, 2017, it was first given global approval by the
European Union for the treatment of moderate to severe RA, as a monotherapy or
in combination with methotrexate, which is used in adult patients who show
inadequate response or intolerance to one or more disease modifying
anti-rheumatoid drugs (DMARDs) (Markham, 2017). In the United States and Japan, regulatory
approval for the use of baricitinib as a treatment for RA must also be secured.
Baricitinib is also being studied as a treatment for systemic lupus
erythematosus and moderate to severe atopic dermatitis. It is considered to
have the potential to treat psoriasis and diabetic kidney disease, yet such
studies have not been done so far (Markham, 2017).


Company cooperation

In February 2009, Eli Lilly and Incyte signed
an exclusive, worldwide cooperation agreement to develop and commercialize all of
the compounds related to baricitinib for patients with inflammation and/or autoimmune
diseases (company, 2017). According to the terms
of the agreement, Eli Lilly holds the international rights to the development
and commercialization of oral baricitinib for the treatment of inflammation (Markham,
In exchange for these rights, Eli Lilly paid firstly $90 million to Incyte and Eli
Lilly promised that if the product was successfully commercialized, Incyte
would receive as much as $665 million in additional development funding (company,
Incyte also retains the option to work with Eli Lilly to develop additional JAK1/JAK2
inhibitors on a compound-by-compound and indication-by-indication basis, from
the Phase IIb development stage. Moreover,
Incyte has the right to promote its products in the United States.



for baricitinib have been granted to Incyte and others are pending in the US,
EU and Japan (Markham, 2017). The patent will
expire in 2029, including granted and pending.


for development of Baricitinib

to clinicaltrials.gov, there are a total of 35 key clinical trials for
baricitinib. Of those, 26 of have been completed, 20 achieving satisfactory
results. Another 9 trials are ongoing. These clinical trials include
experiments on rheumatoid arthritis, psoriasis, atopic dermatitis and diabetic
kidney disease.



trials use four main methods: biochemical assays, cellular assays,
phospho-STAT3 analysis, and in vivo
experiments (Fridman, et al., 2017).

ability of INCB028050 to inhibit the enzymatic activity of four members of the JAK
family was assessed by measuring the biochemical potency and selectivity of the
compound for the JAK family of kinases (Fridman, et al., 2017). The IC50 value
of a compound is the concentration needed to inhibit 50% of the fluorescent
signal. It was found that INCB028050 potently inhibits JAK1 and JAK2, with IC50
values of 5.9 nM and 5.7 nM, respectively.

cellular assays, human peripheral blood mononuclear cells were isolated via leukapheresis
followed by Ficoll-Hypaque centrifugation. In PBMCs, INCB028050 was found to inhibit
IL-6-stimulated phosphorylation of the substrate STAT3 (pSTAT3), which is one
of the inflammatory cytokines, as well as the production of the chemokine MCP-1,
with IC50 values of 44 nM and 40 nM, respectively. Additionally, in
isolated native T-cells, INCB028050 inhibits pSTAT3, which is stimulated by
IL-23, with an IC50 value of 20 nM.

the in vivo experiments, all animals
were kept in facilities accredited by the Association and Accreditation of
Laboratory Animal Care International (Fridman, et al., 2017). Moreover, to
evaluate the potential therapeutic efficacy of JAK1/2 inhibitors for the
treatment of RA, different arthritis rodent models have been used. In the adjuvant-induced arthritis rat
model (rAIA), which can lead to T cell-dependent inflammatory arthritis,
INCB028050 was shown to be efficacious, both after oral administration and
through continuous infusion. It was found to inhibit the transduction of JAK1/2
(inhibition rate was not less than 50%) for up to 8 hours. In rAIA experiments,
efficacy was achieved at doses that inhibited 0.05) and inflammation (33%; p>0.05), and the
total treatment score for diseases was 53%.

above data from CIA and CAIA models demonstrate that INCB028050, as a JAK1/2
inhibitor, was efficacious in RA models in preclinical trials and that it affects
cellular immune function rather than humoral immunity.



Phase III
Clinical trials

order to characterize the efficacy of baricitinib as a treatment for AR, the
following four major Phase III trials have been conducted (Markham,

·      RA-BEGIN
(NCT01711359): baricitinib, methotrexate, or a combination treatment, in
patients with RA and no or limited prior DMARDs treatment

·      RA-BUILD
(NCT01721057): baricitinib in patients with inadequate response or intolerance
to conventional synthetic DMARDs

·      RA-BEAM
(NCT01710358): baricitinib versus placebo or adalimumab in RA patients

·      RA-BEACON
(NCT01721044): baricitinib in patients with refractory RA.



RA-BEGIN trial aimed to compare baricitinib as a monotherapy or in combination
with methotrexate (MTX) with MTX monotherapy in active RA patients who could
not receive or could receive only a few traditional synthesis disease-modifying
antirheumatic drugs (DMARDs) and in those patients who were naive to biologic
DMARDs (Fleischmann, et al., 2016). In early RA
patients, the conventional treatment is the use of MTX alone or in combination
with other DMARDs. However, about one-third of RA patients are intolerant to
MTX and it is quite common to discontinue MTX treatment in the clinic. Thus, it
was important to assess baricitinib’s potential as a new treatment option in
place of MTX. The RA-BEGIN trial was a double-blind, double-dummy, active
comparator-controlled study lasting 52 weeks. In the study, 588 patients were
randomized into three groups at a ratio of 4: 3: 4. Of the subjects, 210 received
oral MTX 17.7 mg weekly as a monotherapy. 159 took 4 mg baricitinib daily as a monotherapy
and 215 patients received combination therapy of 4 mg baricitinib one day and
MTX. After 42 weeks of treatment, the American College of Rheumatology (ACR20) response
rate for baricitinib monotherapy was 77%, which was significantly higher than
that of MTX monotherapy, at 62% (p?0.01for noninferiority).
In addition, at 42 weeks, the efficacy of baricitinib monotherapy was superior
to that of MTX monotherapy (p?0.01) (Fleischmann, et al., 2016). Combination therapy
showed a similar ACR20 response rate to that of baricitinib monotherapy (Markham,
The ACR20 response rate at week 52 was 73% for both combination therapy and
baricitinib monotherapy, while it was 56% for MTX monotherapy. Over the course
of 52 weeks, the percentage of subjects who discontinued treatment due to an
adverse event (AE) were 5%?6% and 11% for MTX monotherapy, baricitinib
monotherapy, and combination therapy, respectively (Fleischmann,
et al., 2016).
Moreover, three patients died; these deaths occurred in the MTX monotherapy
group. Finally, the study found that in early treatment, baricitinib
monotherapy and combination therapy were more efficacious and safe than MTX
monotherapy for patients with active rheumatoid arthritis (Fleischmann,
et al., 2016).



the RA-BUILD trial, 684 RA patients who had inadequate responses or were
tolerant to conventional synthetic DMARDs were randomly divided into three
groups in a 1:1:1 ratio (Dougados, et al., 2016); 229 patients received
baricitinib 2mg once daily, 227 patients were given baricitinib 4 mg once a day,
and 228 patients received placebo in a double-blind, 24-week study. AR patients
taking 2 and 4mg baricitinib at 12 weeks were showed a higher ACR20 response
rate than the placebo group (66% and 62% versus 39%, p