Baricitinib: JAK Inhibitor for Rheumatoid Arthritis

Xeljanz Was First JAK Inhibitor Approved in US; Baricitinib Is Next

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Baricitinib is an oral JAK (Janus kinase) inhibitor which is to be taken for rheumatoid arthritis. In the first quarter of 2016, baricitinib was submitted for regulatory review and marketing approval in the US, the European Union, and Japan. The European Medicines Agency's Committee for Medicinal Products for Human Use recommended approval in December 2016. On February 13, 2017, the drug was approved to be marketed for rheumatoid arthritis in the European Union as Olumiant (baricitinib).

In the US, the FDA announced on January 13, 2017 that it had extended the review period for the new drug application for baricitinib. The extension allowed for review of additional data that was submitted after the initial drug application was made.

On April 14, 2017, the FDA surprisingly rejected baricitinib yet again. The FDA issued a complete response letter stating that the agency "is unable to approve the application in its current form". The FDA said that additional clinical data are needed to determine the most appropriate doses. Also, additional data are necessary to further characterize safety concerns across treatment arms. Timing of a resubmission will follow further talks with the FDA.

In addition, phase 2 trials are underway which are investigating baricitinib for systemic lupus erythematosus and atopic dermatitis. A phase 3 trial of baricitinib for psoriatic arthritis is expected to start in 2017.

Xeljanz Was First JAK Inhibitor for Rheumatoid Arthritis

Xeljanz (tofacitinib) was the first JAK inhibitor approved by the FDA in 2012 for adults with moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate. There are four JAK enzymes: JAK1, JAK2, JAK3, and Tyk2. Xeljanz primarily inhibits JAK1 and JAK3, and it is taken twice daily.

Comparatively, baricitinib inhibits JAK1 and JAK2 and is taken once daily.

The Four Phase 3 Trials for Baricitinib

Eli Lilly & Company and Incyte Corporation are partners in the development of baricitinib. Lilly and Incyte carried out four phase 3 clinical trials in study participants with moderate to severely active rheumatoid arthritis.

  • RA-BUILD study - 684 rheumatoid arthritis patients with active disease were randomly assigned 2 milligrams or 4 milligrams of baricitinib, or placebo for 24 weeks. Compared to placebo, both baricitinib groups exhibited significant improvement based on ACR20, ACR50, and ACR70 response rates. Also noteworthy in this study was evidence on x-ray of slowing disease progression with baricitinib, and the fact that response to baricitinib occurred quickly, sometimes after just one week.
  • RA-BEACON - 527 rheumatoid arthritis patients with an inadequate response to one or more TNF inhibitors were randomly assigned 2 milligrams baricitinib, 4 milligrams baricitinib, or placebo for 24 weeks. Higher ACR20 response rates were observed in both baricitinib groups compared to placebo. Sustained treatment benefit occurred only with 4 milligrams baricitinib.
  • RA-BEGIN - 584 patients with active rheumatoid arthritis who had limited or no treatment with traditional DMARDs were randomly assigned methotrexate monotherapy, 4 milligrams baricitinib, or 4 milligrams baricitinib with methotrexate for up to 52 weeks. Results were significantly better with baricitinib monotherapy compared to methotrexate monotherapy. The addition of methotrexate to baricitinib did not seem to positively impact the benefit, although the combination did seem to slow evidence of disease progression on x-ray.
  • RA-BEAM - 1307 patients with active rheumatoid arthritis, who were receiving background methotrexate but who did not adequately respond to it, were assigned 4 milligrams baricitinib once daily, or 40 milligrams Humira (adalimumab) every other week, or placebo. Significant clinical improvements were associated with baricitinib versus placebo or Humira.

Study participants who finished RA-BUILD, RA-BEGIN, or RA-BEAM were eligible to participate in an extension study, known as RA-BEYOND. The extension study concluded that the 4 milligram dose of baricitinib was most effective.

Safety Profile of Baricitinib

Information about the safety of baricitinib was gathered by analyzing all clinical trials from phase 1 through phase 3, plus the extension study.

The trials involved 3,464 patients altogether. Following exposure to baricitinib, there were no increases in deaths, malignancies, serious infections, opportunistic infections, or adverse events that caused discontinuation of the drug. Compared to placebo there was a statistically significant increase in the rate of herpes zoster infections in the patients treated with the 4 milligram dose of baricitinib. Treatment with baricitinib was also linked to changes in the the levels of hemoglobin, lymphocytes, transaminases, creatine kinase, and creatinine—but rarely significant enough to require discontinuation of the drug.

A Word From Verywell

JAK inhibitors are a third class of DMARDS, referred to as small molecule DMARDS. The availability of baricitinib will provide yet another treatment option for rheumatoid arthritis, once it is approved. That approval is expected in 2017. Patients who had an inadequate response to methotrexate, other DMARDs, or biologic drugs, will then have another oral drug as an option. For some patients, it may be a more convenient option and preferable to self-injectable biologic drugs or the biologics that are administered by infusion.

Sources:

Kuriya, Bindee et al. Baricitinib in Rheumatoid Arthritis: Evidence-to-date and Clinical Potential. Therapeutic Advances in Musculoskeletal Disease. 2017 Feb; 9(2):37-44.

Smolen, Josef S. et al. Patient-reported Outcomes From a Randomized Phase III Study of Baricitinib in Patients With Rheumatoid Arthritis and an Inadequate Response to Biological Agents (RA-BEACON). Annals of the Rheumatic Diseases. 2017;76:694-700.

Taylor, Peter C. MD, PhD et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. New England Journal of Medicine. 2017; 376:652-662. February 16, 2017.

US FDA Extends Review Period for Baricitinib, an Investigational Rheumatoid Arthritis Treatment. Lilly. January 13, 2017. 

US FDA Issues Complete Response Letter for Baricitinib. Lilly and Incyte via BusinessWire. April 14, 2017.

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