Abstract:

Baricitinib
(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.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

    

1.      
Introduction

Baricitinib,
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).

 

1.1        
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,
2017).
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,
2017).
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.

 

1.2        
Patents

Patents
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.

 

2.      
Methods
for development of Baricitinib

According
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.

 

2.1        
Preclinical
trials

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

The
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.

In
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.

For
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 <15% pSTAT3 levels at four hours after the oral dose (3mg/kg). Furthermore, administering the maximum efficacious dose of 10mg/kg caused no detectable pSTAT3 inhibition. This shows that INCB028050 has significant efficacy in this model without complete and continuous pathway inhibition (Fridman, et al., 2017). Another mouse model of arthritis caused mainly by humoral mechanisms, collagen-induced arthritis (CIA), was used to explore the potential therapeutic efficacy of INCB028050 (Fridman, et al., 2017). Researchers have used the CIA model to assess novel therapeutics and summarize the clinical and histological features of human rheumatoid arthritis. Oral INCB028050 was found to be efficacious in this model. By comparing histologic changes in paws from the vehicle group and the 10mg/kg INCB028050 treatment group, it was found that the composite score for joint damage was increased by 47% in the INCB028050 group. Moreover, all other indicators showed significant increases, including inflammation (43%), pannus (53%), cartilage damage (41%), and bone damage (53%). Therefore, it was also efficacious that oral INCB028050 in the CIA model which depended on T and B cells. The third model used is the collagen Ab-induced arthritis (CAIA) model, which is dependent on Abs (Fridman, et al., 2017). This model can be used to avoid the humoral immune response. When comparing histologic damage markers between the vehicle control and INCB028050 treatment groups, the INCB028050 (10mg/kg) group showed decreased pannus and bone damage (74%; p<0.05 and 78%; p<0.05, respectively). Moreover, the treatment was found to improve cartilage damage (43%; p>0.05) and inflammation (33%; p>0.05), and the
total treatment score for diseases was 53%.

The
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.

 

 

2.2        
Phase III
Clinical trials

In
order to characterize the efficacy of baricitinib as a treatment for AR, the
following four major Phase III trials have been conducted (Markham,
2017):
 

·      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.

 

2.2.1
RA-BEGIN

The
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,
2017).
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).

 

2.2.2
RA-BUILD

In
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<0.01). After 24 weeks of treatment, the ACR20 response rates were 61% and 62% for the 2 and 4mg/day baricitinib groups, respectively, compared with 42% for the placebo group. During the 24-week treatment, the three groups showed similar adverse reaction rates: 71% for the placebo group, 67% for the 2mg baricitinib group and 71% for the 4mg baricitinib group. Two deaths occurred, both in the placebo group. In this study, RA patients who had an inadequate response or were intolerant to DMARs received significant efficacy when taking baricitinib compared with placebo. 2.2.3 RA-BEAM The RA-BEAM trial compared 52 weeks' treatment with placebo (switched to baricitinib after 24 weeks, n=488) and baricitinib 4mg once daily (n=487) to subcutaneous adalimumab 40mg given every other week (n=330), with the groups split up into a 3:3:2 ratio (Taylor, et al., 2017). The ACR response at week 12 was achieved by 70% of patients who received baricitinib compared with 40% of the placebo group (p<0.001). Results at week 24 were similar, 70% versus 37% (p<0.01). The ACR20 response rate for adalimumab was 61% and 66% (p<0.01) at week 12 and week 20, respectively. Therefore, the ACR20 response for baricitinib at week 12 was significantly higher than that of adalimumab (p=0.01). According to mTSS, radiographic progression of joint damage at week 24 was 0.41 in the baricitinib group compared with 0.9 for placebo (mean change from baseline, p<0.01) and 0.33 in the adalimumab group (p<0.001 compared with placebo). Similar outcomes were detected at week 52: radiographic progression was 0.71 in the baricitinib group and 0.60 in the adalimumab group, both significantly less than 1.80 for placebo (both p<0.001 compared with placebo). Data analysis showed that baricitinib has better efficacy than adalimumab. Consequently, this study established that RA patients with an inadequate response to MTX could achieve significant improvement on baricitinib compared with placebo and adalimumab.   2.2.4 RA-BEACON The RA-BEACON trial was a 24-week experiment. A total of 527 patients participated in the trial, all of whom showed inadequate response to or unacceptable side effects with tumor necrosis factor inhibitors, DMARDs, or both (Genovese, et al., 2016). The patients were randomly divided into three groups in a 1:1:1 ratio: baricitinib 2mg/day (n=174), baricitinib 4mg/day (n=177) and placebo (n=176). The high-dose baricitinib group showed a significantly increased ACR20 response compared with the low-dose group at week 12 (55% vs. 49%, p<0.001) and the ACR20 response was 27% in the placebo group (p<0.001). Similar results were found at 24 weeks of treatment. The ACR20 response rate in 4mg daily baricitinib group was higher than that of placebo (46 vs. 27%, p<0.001) and 2mg/day baricitinib achieved 45% (p<0.001 compared to placebo). Therefore, RA patients who take baricitinib daily can achieve improved clinical outcomes and a high dose may have a better effect than a low dose.   2.3         Phase II study In the first phase IIb study (NCT01185353), 301 patients were randomly separated into five groups in a 1:1:1:1:2 ratio: baricitinib 1mg/day (n=49), 2mg/day (n=52), 4mg/day (n=52), 8mg/day (n=50) and placebo (n=98) (Keystone, et al., 2014). Patients who received 2, 4 and 8mg/day baricitinib required another 12-week blinded treatment and patients in the other two groups received baricitinib 2mg twice daily or 4mg once daily during these additional 12 weeks. After 12 week's treatment, the ACR20 response was 76% in the baricitinib 2 and 8mg daily groups, compared with 41% for the placebo group (p<0.001). Up to week 24, the ACR20 response was maintained or improved in patients taking 2, 4 or 8mg baricitinib. Therefore, baricitinib can effectively improve the symptoms of RA in patients who show an insufficient response to MTX. Another double-blind and randomized phase IIb experiment was conducted in Japanese patients with RA and an inadequate response to MTX (NCT01469013) (Tanaka, et al., 2017). In this trial, 145 patients were randomized to the following groups: baricitinib 1mg (n=24), 2mg (n=24), 4mg (n=24), and 8mg (n=24) once daily, and placebo (n=49). After 12 weeks' healing, 2 and 4mg baricitinib produced a higher ACR20 response than placebo (77 vs. 31%, p<0.01). Moreover, in the extension study going up to 52 weeks, similar results found. During this period, only one patient taking baricitinib discontinued treatment because of an adverse event. The conclusion was that baricitinib can improve the symptoms of RA with good tolerance seen in Japanese patients with active RA.         2.4         FDA issues Eli Lilly and Company and Incyte Corporation submitted a New Drug Application (NDA) for baricitinib to the FDA in January 2016 (Anon., 2017). In January 2017, the FDA announced that the investigation of baricitinib for the NDA required a three-month extension to obtain more adequate data. On April 14, 2017, the FDA rejected the NDA for baricitinib as a once-daily oral JAK inhibitor for the treatment of moderate to severe RA (company, 2017). The FDA claimed that it was not possible to approve the application at this stage because of a lack of sufficient data and that additional clinical data was needed to support the most reasonable doses. Moreover, the FDA indicated that more trial data was essential to further ensure the safety of the treatment. The companies did not agree with this outcome and further discussion is needed regarded the future course of action.   2.5         Baricitinib for the treatment of other diseases 2.5.1 Psoriasis In a 12-week phase II clinical trial of baricitinib, it was found that baricitinib could effectively reduce the Psoriasis Area and Severity Index (PASI) 75% (PASI-75) scores in patients with moderate to severe chronic plaque psoriasis (NCT01490632) (Markham, 2017).   2.5.2 Diabetic kidney disease In a phase II study, patients with a high risk of diabetic kidney disease were treated with baricitinib or placebo. It was found that baricitinib decreased the 24 h urine albumin-to-creatinine ratio (UACR) compared with placebo (Markham, 2017). No further studies have been done for diabetic kidney disease.       3.       Conclusion Baricitinib, a once-daily, oral, small-molecule, JAK1/2 inhibitor developed by Eli Lilly and Co. and Incyte Corp., has passed clinical studies and has been approved by the EU. Studies have confirmed the efficacy and safety of baricitinib for the treatment of moderate to severe RA, but its long-term safety profile remains to be determined. The NDA for baricitinib was rejected by the FDA; additional clinical data and related experiments are needed to further verify its efficacy and safety for use in the US in the treatment of RA. The combination of baricitinib and MTX has also opened up as a new possibility for RA patients. The development of baricitinib may be an important milestone in the history of RA treatment. Furthermore, baricitinib has great potential for the treatment of atopic dermatitis and systemic lupus erythematosus; these applications are still in clinical trials.                                                     References Markham, A., 2017. Baricitinib: First Global Approval. Drugs, 77(6), pp.697-704. Fridman, J.S., Scherle, P.A., Collins, R., Burn, T.C., Li, Y., Li, J., Covington, M.B., Thomas, B., Collier, P., Favata, M.F. and Wen, X., 2010. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. The Journal of Immunology, 184(9), pp.5298-5307. Tanaka, Y., Emoto, K., Cai, Z., Aoki, T., Schlichting, D., Rooney, T. and Macias, W., 2016. Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis receiving background methotrexate therapy: a 12-week, double-blind, randomized placebo-controlled study. The Journal of rheumatology, 43(3), pp.504-511. Keystone, E.C., Taylor, P.C., Drescher, E., Schlichting, D.E., Beattie, S.D., Berclaz, P.Y., Lee, C.H., Fidelus-Gort, R.K., Luchi, M.E., Rooney, T.P. and Macias, W.L., 2014. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Annals of the rheumatic diseases, pp.annrheumdis-2014. Dougados, M., van der Heijde, D., Chen, Y.C., Greenwald, M., Drescher, E., Liu, J., Beattie, S., Witt, S., de la Torre, I., Gaich, C. and Rooney, T., 2016. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Annals of the rheumatic diseases, pp.annrheumdis-2016. Genovese, M.C., Kremer, J., Zamani, O., Ludivico, C., Krogulec, M., Xie, L., Beattie, S.D., Koch, A.E., Cardillo, T.E., Rooney, T.P. and Macias, W.L., 2016. Baricitinib in patients with refractory rheumatoid arthritis. New England Journal of Medicine, 374(13), pp.1243-1252. Taylor, P.C., Keystone, E.C., van der Heijde, D., Weinblatt, M.E., del Carmen Morales, L., Reyes Gonzaga, J., Yakushin, S., Ishii, T., Emoto, K., Beattie, S. and Arora, V., 2017. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. New England Journal of Medicine, 376(7), pp.652-662. Fleischmann, R., Schiff, M., van der Heijde, D., Ramos?Remus, C., Spindler, A., Stanislav, M., Zerbini, C.A., Gurbuz, S., Dickson, C., de Bono, S. and Schlichting, D., 2017. Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease?Modifying Antirheumatic Drug Treatment. Arthritis & Rheumatology, 69(3), pp.506-517. O'Shea, J.J., Kontzias, A., Yamaoka, K., Tanaka, Y. and Laurence, A., 2013. Janus kinase inhibitors in autoimmune diseases. Annals of the rheumatic diseases, 72(suppl 2), pp.ii111-ii115. Eli Lilly and Company, Incyte Corporation. US FDA extends review period for baricitinib, an investigational rheumatoid arthritis treatment media release. 13 Jan 2017.       Eli Lilly and Company, Incyte Corporation. Lilly and Incyte announce collaboration for development and commercialization of oral anti-inflammatory and autoimmune therapies media release. 21 Dec 2009.