Baricitinib

Last updated

Baricitinib
Baricitinib structure.svg Baricitinib-portrait-ligand-3JW-from-PDB-xtal-4W9X-Mercury-3D-balls.png
Clinical data
Trade names Olumiant, others
Other namesINCB28050, LY3009104
AHFS/Drugs.com Monograph
MedlinePlus a618033
License data
Pregnancy
category
  • AU:D [1] [2]
  • Use is contraindicated
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 79%
Protein binding 50%
Metabolism CYP3A4 (<10%)
Elimination half-life 12.5 hours
Excretion 75% urine, 20% faeces
Identifiers
  • 2-[1-Ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.219.080 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H17N7O2S
Molar mass 371.42 g·mol−1
3D model (JSmol)
  • CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
  • InChI=1S/C16H17N7O2S/c1-2-26(24,25)22-9-16(10-22,4-5-17)23-8-12(7-21-23)14-13-3-6-18-15(13)20-11-19-14/h3,6-8,11H,2,4,9-10H2,1H3,(H,18,19,20)
  • Key:XUZMWHLSFXCVMG-UHFFFAOYSA-N

Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. [7] [8] [9] [10] It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2. [11]

Contents

Baricitinib is approved for medical use in the European Union [8] and in the United States. [9] [12] [10]

Medical uses

In February 2017, baricitinib was approved for use in the European Union as a second-line therapy for moderate to severe active rheumatoid arthritis in adults, either alone or in combination with methotrexate. [13] [8]

In May 2018, the US Food and Drug Administration (FDA) approved baricitinib for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. [12] [9] [7]

In May 2022, the FDA approved baricitinib for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [7] [14] [15] Baricitinib is the first immunomodulatory treatment for COVID-19 to receive FDA approval. [15]

In the United States, baricitinib is authorized under an emergency use authorization (EUA) for the treatment of COVID-19 in hospitalized people aged 2 to less than 18 years of age who require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. [14]

In June 2022, the FDA authorized baricitinib for the treatment of severe alopecia areata. [10] [16]

Contraindications

During pregnancy, the use of baricitinib is contraindicated. [2] [13]

Side effects

In studies, upper respiratory tract infections and high blood cholesterol levels (hypercholesterolemia) occurred in more than 10% of participants. Less common side effects included other infections such as herpes zoster, herpes simplex, urinary tract infections, and gastroenteritis. [13]

Interactions

Being metabolized only to a small extent, the substance has a low potential for interactions. In studies, inhibitors of the liver enzymes CYP3A4, CYP2C19, and CYP2C9, as well as the CYP3A4 inducer rifampicin, had no relevant influence on baricitinib concentrations in the bloodstream. While baricitinib blocks a number of transporter proteins in vitro , clinically relevant interactions via this mechanism are considered very unlikely, except perhaps for the cation transporter SLC22A1 (OCT1). [13]

An additive effect with other immunosuppressants cannot be excluded. [13]

Pharmacology

Mechanism of action

Baricitinib is a Janus kinase (JAK) inhibitor that reversibly inhibits Janus kinase 1 with a half maximal inhibitory concentration (IC50) of 5.9  nM and Janus kinase 2 with an IC50 of 5.7 nM. Tyrosine kinase 2, which belongs to the same enzyme family, is affected less (IC50 = 53 nM), and Janus kinase 3 far less (IC50 > 400 nM). Via a signal transduction pathway involving STAT proteins, this ultimately modulates gene expression in immunological cells. [13]

Other JAK inhibitors include tofacitinib, which is indicated for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis; [17] [18] fedratinib, [19] and ruxolitinib. [20] [21]

Pharmacokinetics

The substance is quickly absorbed from the gut with an absolute bioavailability of 79%. It reaches highest blood plasma levels after about an hour; in different individuals the time to reach this level ranges from 0.5 to 3 hours. Food intake has no relevant influence on the drug's pharmacokinetics. 50% of the circulating baricitinib are bound to blood plasma proteins. [13]

Less than 10% of the substance is metabolized to four different oxidation products by CYP3A4; the rest is left unchanged. Elimination half-life is 12.5 hours on average. About 75% is eliminated via the urine, and 20% via the faeces. [13]

History

Baricitinib was discovered by Incyte and licensed to Eli Lilly. [22]

Society and culture

In January 2016, Eli Lilly submitted a new drug application to the US Food and Drug Administration (FDA) for the approval of baricitinib to treat moderately-to-severely active rheumatoid arthritis. [23]

In December 2016, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of baricitinib as a therapy for rheumatoid arthritis. [11] European Union approval was granted in February 2017. [8]

Despite widespread expectations that the FDA would approve baricitinib for rheumatoid arthritis, [24] in April 2017, the FDA issued a rejection, citing concerns about dosing and safety. [25] [26]

In May 2018, baricitinib was approved in the United States for the treatment of rheumatoid arthritis. [9] [12] [10]

In March 2020, the US FDA granted breakthrough therapy designation to baricitinib for the treatment of alopecia areata [27] and granted approval in June 2022. [16]

The efficacy and safety of baricitinib in alopecia areata was studied in two randomized, double-blind, placebo-controlled trials (Trial AA-1 and Trial AA-2) with participants who had at least 50% scalp hair loss as measured by the Severity of Alopecia Tool for more than six months. [10] Participants in these trials received either a placebo, 2 milligrams of baricitinib, or 4 milligrams of baricitinib every day. [10] The primary measurement of efficacy for both trials was the proportion of participants who achieved at least 80% scalp hair coverage at week 36. [10]

Research

As of August 2016, 31 clinical trials had been registered for baricitinib of which 24 had completed, [28] and 4 of 6 phase 3 trials had completed. [29] [ needs update ]

As of March 2022, a phase III clinical trial showed hair regrowth for those with alopecia areata. [30]

COVID-19

In April 2020, Lilly announced they were investigating the use of baricitinib for treating people with COVID-19. The drug's anti-inflammatory activity was expected to act on the inflammatory cascade associated with COVID-19. [31] [32]

In April and June 2020, the first two studies of baricitinib prescribed for hospitalized people with COVID-19 were published online. [33] [34] Then in November 2020, published research showed baricitinib was beneficial in treating people with COVID-19. According to the paper "mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly people". [35]

In a clinical trial of hospitalized people with COVID-19, baricitinib, in combination with remdesivir, was shown to reduce time to recovery within 29 days after initiating treatment compared to participants who received a placebo with remdesivir. [36]

The data supporting the US Food and Drug Administration (FDA) emergency use authorization (EUA) for baricitinib combined with remdesivir was based on a randomized, double-blind, placebo-controlled clinical trial (ACTT-2), which was conducted by the US National Institute of Allergy and Infectious Diseases (NIAID). [37] [38] This clinical trial evaluated whether baricitinib impacted how long it took for subjects who were also taking remdesivir to recover from COVID-19. [37] The trial followed participants for 29 days and included 1,033 participants with moderate or severe COVID-19; 515 participants received baricitinib plus remdesivir, and 518 participants received placebo plus remdesivir. [37] Recovery was defined as either being discharged from the hospital or being hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. [37] The median time to recovery from COVID-19 was seven days for baricitinib plus remdesivir and eight days for placebo plus remdesivir. [37] The odds of a patient's condition progressing to death or being ventilated at day 29 was 31% lower in the baricitinib plus remdesivir group versus the placebo plus remdesivir group. [37] The odds of clinical improvement at day 15 was 30% higher in the baricitinib plus remdesivir group versus the placebo plus remdesivir group. [37] For all of these endpoints, the effects were statistically significant. [37] The EUA was issued to Eli Lilly and Company. [37]

In November 2020, the World Health Organization (WHO) updated its guideline on therapeutics for COVID-19 to include a conditional recommendation against the use of remdesivir, triggered by results from the WHO Solidarity trial. [39] [40]

In November 2020, the FDA issued an emergency use authorization (EUA) for the combination of baricitinib with remdesivir, for the treatment of suspected or laboratory confirmed COVID-19 in hospitalized people aged two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [41] [42] [37]

Then in September 2021, the largest randomized, placebo-controlled trial of hospitalized people with COVID-19 to date, COV-BARRIER, was published. [43] This trial randomized 1525 participants to either baricitinib or placebo. Nearly 80% of participants were receiving systemic corticosteroids at enrollment. There was an absolute risk reduction of 2.7 percent in the primary endpoint of progression to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. The 38.2% statistically significant reduction in all-cause 28-day mortality for participants receiving baricitinib compared to placebo was the largest mortality reduction to date and maintained at 60 days. This translates into one additional death prevented for every 20 participants treated with baricitinib. The frequencies of serious adverse events were lower for participants receiving baricitinib compared to those receiving placebo.[ citation needed ]

As of April 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) is evaluating the use of baricitinib to include treatment of COVID-19 in hospitalized people from ten years of age who require supplemental oxygen. [44]

In July 2021, the FDA revised the EUA for baricitinib authorizing it alone for the treatment of COVID-19 in hospitalized people aged two years of age or older requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [41] [42] [45] Under the revised EUA, baricitinib is not required to be administered with remdesivir. [45]

As of January 2022, the World Health Organization recommends baricitinib for people with severe or critical COVID-19. [46] Thereafter in February 2022, an exploratory randomized, placebo-controlled trial of participants receiving invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly to baricitinib or placebo. There was a 46% statistically significant relative reduction in all-cause mortality for participants receiving baricitinib compared to those receiving placebo at 28 days which was sustained at 60 days. [47]

Then in May 2022, the FDA approved use of baricitinib for the treatment of adults hospitalized with COVID-19 who require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation with a recommended dose of 4 mg once daily for 14 days or until hospital discharge, whichever happens first. [48]

In March 2022, the RECOVERY trial reported that the use of baricitinib cut the risk of death by about a fifth in about 12,000 participants. [49] [50] [51]

Related Research Articles

<span class="mw-page-title-main">Alopecia areata</span> Medical condition

Alopecia areata, also known as spot baldness, is a condition in which hair is lost from some or all areas of the body. It often results in a few bald spots on the scalp, each about the size of a coin. Psychological stress and illness are possible factors in bringing on alopecia areata in individuals at risk, but in most cases there is no obvious trigger. People are generally otherwise healthy. In a few cases, all the hair on the scalp is lost, or all body hair is lost. Hair loss can be permanent, or temporary.

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID‑19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

<span class="mw-page-title-main">Tofacitinib</span> Medication

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. It is a janus kinase (JAK) inhibitor, discovered and developed by the National Institutes of Health and Pfizer.

<span class="mw-page-title-main">Incyte</span> American pharmaceutical company

Incyte Corporation is an American multinational pharmaceutical company with headquarters in Wilmington, Delaware, and Morges, Switzerland. The company was created in 2002 through the merger of Incyte Pharmaceuticals, founded in Palo Alto, California in 1991 and Incyte Genomics, Inc. of Delaware. The company currently operates manufacturing and R&D locations in North America, Europe, and Asia.

<span class="mw-page-title-main">Filgotinib</span> Chemical compound

Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis (RA). It was developed by the Belgian-Dutch biotech company Galapagos NV.

<span class="mw-page-title-main">Remdesivir</span> Antiviral drug

Remdesivir, sold under the brand name Veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. It is administered via injection into a vein. During the COVID‑19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID‑19 in numerous countries.

<span class="mw-page-title-main">Upadacitinib</span> Biopharmaceutical drug

Upadacitinib, sold under the brand name Rinvoq, is a medication used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis. Upadacitinib is a Janus kinase (JAK) inhibitor that works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.

<span class="mw-page-title-main">COVID-19 drug repurposing research</span> Drug repurposing research related to COVID-19

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<span class="mw-page-title-main">COVID-19 drug development</span> Preventative and therapeutic medications for COVID-19 infection

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<span class="mw-page-title-main">Solidarity trial</span> Accelerated multinational clinical trial program to identify therapies against COVID-19

The Solidarity trial for treatments is a multinational Phase III-IV clinical trial organized by the World Health Organization (WHO) and partners to compare four untested treatments for hospitalized people with severe COVID-19 illness. The trial was announced 18 March 2020, and as of 6 August 2021, 12,000 patients in 30 countries had been recruited to participate in the trial.

<span class="mw-page-title-main">Molnupiravir</span> Antiviral medication

Molnupiravir, sold under the brand name Lagevrio, is an antiviral medication that inhibits the replication of certain RNA viruses. It is used to treat COVID‑19 in those infected by SARS-CoV-2. It is taken by mouth.

<span class="mw-page-title-main">Casirivimab/imdevimab</span> Antiviral combination medication

Casirivimab/imdevimab, sold under the brand name REGEN‑COV among others, is a combination medicine used for the treatment and prevention of COVID‑19. It consists of two human monoclonal antibodies, casirivimab and imdevimab that must be mixed together and administered as an infusion or subcutaneous injection. The combination of two antibodies is intended to prevent mutational escape. It is also available as a co-formulated product. It was developed by the American biotechnology company Regeneron Pharmaceuticals.

Bamlanivimab is a monoclonal antibody developed by AbCellera Biologics and Eli Lilly as a treatment for COVID-19. The medication was granted an emergency use authorization (EUA) by the US Food and Drug Administration (FDA) in November 2020, and the EUA was revoked in April 2021.

Bamlanivimab/etesevimab is a combination of two monoclonal antibodies, bamlanivimab and etesevimab, administered together via intravenous infusion as a treatment for COVID-19. Both types of antibody target the surface spike protein of SARS‑CoV‑2.

Chloroquine and hydroxychloroquine are anti-malarial medications also used against some auto-immune diseases. Chloroquine, along with hydroxychloroquine, was an early experimental treatment for COVID-19. Neither drug has been useful to prevent or treat SARS-CoV-2 infection. Administration of chloroquine or hydroxychloroquine to COVID-19 patients, either as monotherapies or in conjunction with azithromycin, has been associated with deleterious outcomes, such as QT prolongation. As of 2024, scientific evidence does not substantiate the efficacy of hydroxychloroquine, with or without the addition of azithromycin, in the therapeutic management of COVID-19.

<span class="mw-page-title-main">Sotrovimab</span> Monoclonal antibody

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Bebtelovimab is a monoclonal antibody developed by AbCellera and Eli Lilly as a treatment for COVID-19.

<span class="mw-page-title-main">Ritlecitinib</span> Medication to treat hair loss

Ritlecitinib, sold under the brand name Litfulo, is a medication used for the treatment of severe alopecia areata. Ritlecitinib is a kinase inhibitor which inhibits Janus kinase 3 and tyrosine kinase.

References

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