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 withmethotrexate.[13][8]
In May 2018, the USFood 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 anemergency 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]
Beingmetabolized only to a small extent, the substance has a low potential for interactions. In studies, inhibitors of the liver enzymesCYP3A4,CYP2C19, andCYP2C9, as well as the CYP3A4inducerrifampicin, had no relevant influence on baricitinib concentrations in the bloodstream. While baricitinib blocks a number oftransporter proteinsin vitro, clinically relevant interactions via this mechanism are considered very unlikely, except perhaps for the cation transporterSLC22A1 (OCT1).[13]
The substance is quickly absorbed from the gut with an absolutebioavailability of 79%. It reaches highestblood 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 bloodplasma 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 thefaeces.[13]
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]
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]
As of August 2016[update], 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[update], a phase III clinical trial showed hair regrowth for those withalopecia areata.[30]
In April 2020, Lilly announced they were investigating the use of baricitinib for treating people withCOVID-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 thecytokine 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 USFood 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 USNational 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 toEli 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 WHOSolidarity trial.[39][40]
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]
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, theRECOVERY trial reported that the use of baricitinib cut the risk of death by about a fifth in about 12,000 participants.[49][50][51]
^abcde"Olumiant EPAR".European Medicines Agency (EMA). 3 December 2019.Archived from the original on 25 August 2021. Retrieved17 March 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^Mesa RA (June 2010). "Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis".IDrugs.13 (6):394–403.PMID20506062.
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