Abstract:Baricitinib(OlumiantTM) is a once-daily, oral, small-molecule, janus-associatedkinase (JAK) inhibitor that was developed by Eli Lilly and Co. and IncyteCorporation. In February 2017, baricitinib was approved by the European Unionfor the treatment of rheumatoid arthritis (AR). It can be used as a monotherapyor in combination with methotrexate for the treatment of adult patients withmoderate to severe rheumatoid arthritis who do not tolerate or who respondinadequately to one or more disease-modifying anti-rheumatic drugs (DMARDs). Thisarticle describes how baricitinib was developed and the difficultiesencountered during that process.    1.

      IntroductionBaricitinib,also known as INCB-028050, INCB-28050, LY-3009104, and Olumiant, was developedby Eli Lilly and Co. and Incyte Corporation (Markham, 2017). It isa once-daily, oral, small-molecule, reversible, selective janus-associatedkinase (JAK) inhibitor that can treat rheumatoid arthritis (RA), atopicdermatitis and systemic lupus erythematosus. The JAKs include Tyk2, JAK1, JAK2and JAK3 (O’Shea, et al., 2013). It has been shown that JAK-dependentcytokines are involved in the pathogenesis of many inflammatory and autoimmunediseases.

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Thus, JAK inhibitors can be used to treat a wide range ofinflammatory conditions, including rheumatoid arthritis. Baricitinib selectivelyinhibits JAK1 (IC50=5.9 nM) and JAK2 (IC50=5.7nM), andinhibits cytokines implicated in RA (Keystone, et al., 2014). In 2016, Baricitinib was submitted formarketing approval in the US, the European Union and Japan for the treatment ofRA, and on February 13, 2017, it was first given global approval by theEuropean Union for the treatment of moderate to severe RA, as a monotherapy orin combination with methotrexate, which is used in adult patients who showinadequate response or intolerance to one or more disease modifyinganti-rheumatoid drugs (DMARDs) (Markham, 2017). In the United States and Japan, regulatoryapproval for the use of baricitinib as a treatment for RA must also be secured.

Baricitinib is also being studied as a treatment for systemic lupuserythematosus and moderate to severe atopic dermatitis. It is considered tohave the potential to treat psoriasis and diabetic kidney disease, yet suchstudies have not been done so far (Markham, 2017). 1.1        Company cooperation In February 2009, Eli Lilly and Incyte signedan exclusive, worldwide cooperation agreement to develop and commercialize all ofthe compounds related to baricitinib for patients with inflammation and/or autoimmunediseases (company, 2017). According to the termsof the agreement, Eli Lilly holds the international rights to the developmentand 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 EliLilly promised that if the product was successfully commercialized, Incytewould 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/JAK2inhibitors on a compound-by-compound and indication-by-indication basis, fromthe Phase IIb development stage. Moreover,Incyte has the right to promote its products in the United States.

 1.2        PatentsPatentsfor baricitinib have been granted to Incyte and others are pending in the US,EU and Japan (Markham, 2017). The patent willexpire in 2029, including granted and pending.  2.      Methodsfor development of Baricitinib Accordingto clinicaltrials.gov, there are a total of 35 key clinical trials forbaricitinib.

Of those, 26 of have been completed, 20 achieving satisfactoryresults. Another 9 trials are ongoing. These clinical trials includeexperiments on rheumatoid arthritis, psoriasis, atopic dermatitis and diabetickidney disease. 2.1        Preclinicaltrials Preclinicaltrials use four main methods: biochemical assays, cellular assays,phospho-STAT3 analysis, and in vivoexperiments (Fridman, et al., 2017).Theability of INCB028050 to inhibit the enzymatic activity of four members of the JAKfamily was assessed by measuring the biochemical potency and selectivity of thecompound for the JAK family of kinases (Fridman, et al., 2017).

The IC50 valueof a compound is the concentration needed to inhibit 50% of the fluorescentsignal. It was found that INCB028050 potently inhibits JAK1 and JAK2, with IC50values of 5.9 nM and 5.7 nM, respectively. Incellular assays, human peripheral blood mononuclear cells were isolated via leukapheresisfollowed by Ficoll-Hypaque centrifugation. In PBMCs, INCB028050 was found to inhibitIL-6-stimulated phosphorylation of the substrate STAT3 (pSTAT3), which is oneof the inflammatory cytokines, as well as the production of the chemokine MCP-1,with IC50 values of 44 nM and 40 nM, respectively. Additionally, inisolated native T-cells, INCB028050 inhibits pSTAT3, which is stimulated byIL-23, with an IC50 value of 20 nM.Forthe in vivo experiments, all animalswere kept in facilities accredited by the Association and Accreditation ofLaboratory Animal Care International (Fridman, et al.

, 2017). Moreover, toevaluate the potential therapeutic efficacy of JAK1/2 inhibitors for thetreatment of RA, different arthritis rodent models have been used. In the adjuvant-induced arthritis ratmodel (rAIA), which can lead to T cell-dependent inflammatory arthritis,INCB028050 was shown to be efficacious, both after oral administration andthrough 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 fourhours after the oral dose (3mg/kg).

Furthermore, administering the maximumefficacious dose of 10mg/kg caused no detectable pSTAT3 inhibition. This showsthat INCB028050 has significant efficacy in this model without complete andcontinuous pathway inhibition (Fridman, et al., 2017).Anothermouse model of arthritis caused mainly by humoral mechanisms, collagen-inducedarthritis (CIA), was used to explore the potential therapeutic efficacy ofINCB028050 (Fridman, et al., 2017). Researchers haveused the CIA model to assess novel therapeutics and summarize the clinical andhistological features of human rheumatoid arthritis. Oral INCB028050 was foundto be efficacious in this model.

By comparing histologic changes in paws fromthe vehicle group and the 10mg/kg INCB028050 treatment group, it was found thatthe composite score for joint damage was increased by 47% in the INCB028050group. 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 onT and B cells.

Thethird model used is the collagen Ab-induced arthritis (CAIA) model, which isdependent on Abs (Fridman, et al., 2017). This model can beused to avoid the humoral immune response. When comparing histologic damage markersbetween 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 improvecartilage damage (43%; p>0.05) and inflammation (33%; p>0.05), and thetotal treatment score for diseases was 53%.

Theabove data from CIA and CAIA models demonstrate that INCB028050, as a JAK1/2inhibitor, was efficacious in RA models in preclinical trials and that it affectscellular immune function rather than humoral immunity.  2.2        Phase IIIClinical trialsInorder to characterize the efficacy of baricitinib as a treatment for AR, thefollowing four major Phase III trials have been conducted (Markham, 2017): ·      RA-BEGIN(NCT01711359): baricitinib, methotrexate, or a combination treatment, inpatients with RA and no or limited prior DMARDs treatment·      RA-BUILD(NCT01721057): baricitinib in patients with inadequate response or intoleranceto conventional synthetic DMARDs·      RA-BEAM(NCT01710358): baricitinib versus placebo or adalimumab in RA patients·      RA-BEACON(NCT01721044): baricitinib in patients with refractory RA.

 2.2.1RA-BEGINTheRA-BEGIN trial aimed to compare baricitinib as a monotherapy or in combinationwith methotrexate (MTX) with MTX monotherapy in active RA patients who couldnot receive or could receive only a few traditional synthesis disease-modifyingantirheumatic drugs (DMARDs) and in those patients who were naive to biologicDMARDs (Fleischmann, et al., 2016). In early RApatients, the conventional treatment is the use of MTX alone or in combinationwith other DMARDs. However, about one-third of RA patients are intolerant toMTX and it is quite common to discontinue MTX treatment in the clinic.

Thus, itwas important to assess baricitinib’s potential as a new treatment option inplace of MTX. The RA-BEGIN trial was a double-blind, double-dummy, activecomparator-controlled study lasting 52 weeks. In the study, 588 patients wererandomized into three groups at a ratio of 4: 3: 4. Of the subjects, 210 receivedoral MTX 17.7 mg weekly as a monotherapy. 159 took 4 mg baricitinib daily as a monotherapyand 215 patients received combination therapy of 4 mg baricitinib one day andMTX. After 42 weeks of treatment, the American College of Rheumatology (ACR20) responserate for baricitinib monotherapy was 77%, which was significantly higher thanthat of MTX monotherapy, at 62% (p?0.01for noninferiority).

In addition, at 42 weeks, the efficacy of baricitinib monotherapy was superiorto that of MTX monotherapy (p?0.01) (Fleischmann, et al., 2016). Combination therapyshowed 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 andbaricitinib monotherapy, while it was 56% for MTX monotherapy. Over the courseof 52 weeks, the percentage of subjects who discontinued treatment due to anadverse event (AE) were 5%?6% and 11% for MTX monotherapy, baricitinibmonotherapy, and combination therapy, respectively (Fleischmann, et al., 2016).Moreover, three patients died; these deaths occurred in the MTX monotherapygroup. Finally, the study found that in early treatment, baricitinibmonotherapy and combination therapy were more efficacious and safe than MTXmonotherapy for patients with active rheumatoid arthritis (Fleischmann, et al., 2016). 2.

2.2RA-BUILDInthe RA-BUILD trial, 684 RA patients who had inadequate responses or weretolerant to conventional synthetic DMARDs were randomly divided into threegroups in a 1:1:1 ratio (Dougados, et al., 2016); 229 patients receivedbaricitinib 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 patientstaking 2 and 4mg baricitinib at 12 weeks were showed a higher ACR20 responserate than the placebo group (66% and 62% versus 39%, p<0.01).

After 24 weeksof treatment, the ACR20 response rates were 61% and 62% for the 2 and 4mg/daybaricitinib groups, respectively, compared with 42% for the placebo group. Duringthe 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 the4mg baricitinib group. Two deaths occurred, both in the placebo group. In thisstudy, RA patients who had an inadequate response or were intolerant to DMARsreceived significant efficacy when taking baricitinib compared with placebo.2.2.3RA-BEAMTheRA-BEAM trial compared 52 weeks’ treatment with placebo (switched tobaricitinib after 24 weeks, n=488) and baricitinib 4mg once daily (n=487) tosubcutaneous adalimumab 40mg given every other week (n=330), with the groupssplit up into a 3:3:2 ratio (Taylor, et al., 2017).

The ACR response atweek 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 forbaricitinib at week 12 was significantly higher than that of adalimumab(p=0.01).

According to mTSS, radiographic progression of joint damage at week24 was 0.41 in the baricitinib group compared with 0.9 for placebo (mean changefrom baseline, p<0.01) and 0.33 in the adalimumab group (p<0.

001 comparedwith placebo). Similar outcomes were detected at week 52: radiographicprogression 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 withplacebo). Data analysis showed that baricitinib has better efficacy thanadalimumab. Consequently, this study established that RA patients with aninadequate response to MTX could achieve significant improvement on baricitinibcompared with placebo and adalimumab. 2.

2.4RA-BEACONTheRA-BEACON trial was a 24-week experiment. A total of 527 patients participatedin the trial, all of whom showed inadequate response to or unacceptable sideeffects 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). Thehigh-dose baricitinib group showed a significantly increased ACR20 response comparedwith the low-dose group at week 12 (55% vs. 49%, p<0.001) and the ACR20response was 27% in the placebo group (p<0.001). Similar results were found at24 weeks of treatment. The ACR20 response rate in 4mg daily baricitinib groupwas higher than that of placebo (46 vs.

27%, p<0.001) and 2mg/daybaricitinib achieved 45% (p<0.001 compared to placebo). Therefore, RApatients who take baricitinib daily can achieve improved clinical outcomes and ahigh dose may have a better effect than a low dose.

 2.3        PhaseII studyInthe first phase IIb study (NCT01185353), 301 patients were randomly separatedinto 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 whoreceived 2, 4 and 8mg/day baricitinib required another 12-week blindedtreatment and patients in the other two groups received baricitinib 2mg twicedaily or 4mg once daily during these additional 12 weeks.

After 12 week’streatment, 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 ACR20response was maintained or improved in patients taking 2, 4 or 8mg baricitinib.

Therefore, baricitinib can effectively improve the symptoms of RA in patients whoshow an insufficient response to MTX.Anotherdouble-blind and randomized phase IIb experiment was conducted in Japanesepatients 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, andplacebo (n=49). After 12 weeks’ healing, 2 and 4mg baricitinib produced a higherACR20 response than placebo (77 vs. 31%, p<0.01). Moreover, in the extensionstudy going up to 52 weeks, similar results found.

During this period, only onepatient taking baricitinib discontinued treatment because of an adverse event. Theconclusion was that baricitinib can improve the symptoms of RA with goodtolerance seen in Japanese patients with active RA.       2.4        FDAissuesEli Lilly andCompany and Incyte Corporation submitted a New Drug Application (NDA) forbaricitinib to the FDA in January 2016 (Anon., 2017). In January 2017, theFDA announced that the investigation of baricitinib for the NDA required athree-month extension to obtain more adequate data. OnApril 14, 2017, the FDA rejected the NDA for baricitinib as a once-daily oralJAK inhibitor for the treatment of moderate to severe RA (company, 2017).

TheFDA claimed that it was not possible to approve the application at this stagebecause of a lack of sufficient data and that additional clinical data wasneeded to support the most reasonable doses. Moreover, the FDA indicated thatmore trial data was essential to further ensure the safety of the treatment. Thecompanies did not agree with this outcome and further discussion is neededregarded the future course of action. 2.

5        Baricitinibfor the treatment of other diseases2.5.1 Psoriasis Ina 12-week phase II clinical trial of baricitinib, it was found that baricitinibcould 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 Diabetickidney diseaseIna phase II study, patients with a high risk of diabetic kidney disease weretreated with baricitinib or placebo.

It was found that baricitinib decreased the24 h urine albumin-to-creatinine ratio (UACR) compared with placebo (Markham, 2017).No further studies have been done for diabetic kidney disease.     3.      ConclusionBaricitinib,a once-daily, oral, small-molecule, JAK1/2 inhibitor developed by Eli Lilly andCo. and Incyte Corp., has passed clinical studies and has been approved by theEU.

Studies have confirmed the efficacy and safety of baricitinib for thetreatment of moderate to severe RA, but its long-term safety profile remains tobe determined. The NDA for baricitinib was rejected by the FDA; additional clinicaldata and related experiments are needed to further verify its efficacy andsafety for use in the US in the treatment of RA. The combination of baricitiniband MTX has also opened up as a new possibility for RA patients. Thedevelopment of baricitinib may be an important milestone in the history of RAtreatment.

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