June 18, 2018
Baricitinib (Olumiant) Approved for Treatment of Rheumatoid Arthritis: In June 2018, the U.S. Food and Drug Administration approved baricitinib as the second janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis. Baricitinib is indicated for adults with moderately-to-severely active rheumatoid arthritis who have had an inadequate response to at least one tumor necrosis factor (TNF) inhibitor. It may be used alone or in combination with methotrexate or other nonbiologic DMARDs. It should not be used with the other approved JAK inhibitor (tofacitinib), biologic DMARDs, or other potent immunosuppressives (eg, azathioprine, cyclosporine).
Baricitinib (Olumiant) Approved for Treatment of Rheumatoid Arthritis
Author: Terry L. Schwinghammer, PharmD, BCPS, Professor Emeritus, School of Pharmacy, West Virginia University, Morgantown, WV
Topic: Baricitinib (Olumiant – Eli Lilly) was approved by the FDA in June 2018 as the second oral janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis (RA). Tofacitinib (Xeljanz, Xeljanz XR) was approved in November 2012.
Background: Baricitinib and tofacitinib are small-molecule, nonbiologic, disease-modifying antirheumatic drugs (DMARDs). They inhibit intracellular janus kinase (JAK) enzymes that modulate the cellular processes of hematopoiesis and immune cell function and are believed to activate inflammatory mediators in RA. Baricitinib is indicated for treatment of rheumatoid arthritis in adults with moderately-to-severely active rheumatoid arthritis who have had an inadequate response to at least one tumor necrosis factor (TNF) inhibitor.1
New Information: The efficacy and safety of the approved dose of baricitinib 2 mg orally once daily was assessed in two phase 3 clinical trials.1 The RA-BEACON study was a 24-week, randomized, double-blind, placebo-controlled study conducted at 178 centers in 24 countries.2 It randomized 527 patients with RA to baricitinib 2 mg, baricitinib 4 mg, or placebo in addition to DMARDs they were already receiving. Patients had shown an inadequate response or intolerance to at least one prior TNF inhibitor therapy and could have been treated with other biologic DMARDs in the past. From Weeks 16 through 24, nonresponding patients could be rescued with baricitinib 4 mg once daily. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at Week 12.
Patients receiving baricitinib 2 mg/day experienced significantly higher ACR20 response rates (49% vs. 27% for placebo-treated patients) at Week 12 (p<0.001). Response rates at 24 weeks for baricitinib 2 mg/day and placebo were 45% and 27%, respectively (p<0.001). In addition, higher ACR20 response rates were seen as early as Week 1 in patients receiving baricitinib 2 mg daily vs. placebo, indicating earlier relief of symptoms. Physical function as measured by the Health Assessment Questionnaire Disability Index was also significantly improved in baricitinib-treated patients at Week 24.
The approved baricitinib dose is 2 mg orally once daily with or without food. The FDA did not approve the 4-mg dose due to insufficient evidence of a favorable risk-benefit profile.3 Baricitinib may be used alone or in combination with methotrexate or other nonbiologic DMARDs. It should not be used in combination with the other approved JAK inhibitor (tofacitinib), biologic DMARDs, or other potent immunosuppressives (eg, azathioprine, cyclosporine) because of the risk of excessive immunosuppression resulting in serious infections.
Baricitinib is not recommended in patients with severe hepatic impairment or moderate to severe renal impairment. Baricitinib exposure is increased when given in combination with strong organic anion transporter 3 (OAT3) inhibitors (eg, probenecid), and combined therapy is not recommended.
The most common adverse events (occurring in at least 1% of baricitinib-treated patients in placebo-controlled trials) included upper respiratory tract infections, nausea, herpes simplex, and herpes zoster.1 The labeling contains a boxed warning about the risk of serious infections (including tuberculosis and bacterial, viral and fungal infections), malignancies, and thrombosis (including deep venous thrombosis, pulmonary embolism, and arterial thrombosis). Patients should be tested for latent or active tuberculosis before beginning the medication. If a serious infection occurs during treatment, therapy should be withheld until it is controlled. Gastrointestinal perforations have also been reported. Because JAK inhibitors may reduce myeloid and lymphoid cell lines and cause anemia, lymphopenia, and neutropenia, blood counts should be monitored routinely. Increased hepatic enzymes and lipid levels (total cholesterol, LDL-cholesterol, and HDL-cholesterol) have been reported; laboratory tests should be performed as described in the product labeling.1
Interpretation and Application: The oral JAK inhibitors baricitinib and tofacitinib offer an alternative for patients with moderately to severely active RA who have not responded to first-line therapies. There is no evidence indicating that one JAK inhibitor is superior to the other, and both drugs require periodic laboratory monitoring.
The FDA declined to approve baricitinib in April 2017 because safety concerns, including the risk of thrombosis, made the overall benefit-risk assessment of baricitinib 2 mg and 4 mg once daily unfavorable.4 Ultimately, the FDA approved only the 2-mg daily dose because of safety concerns with 4 mg once daily. Thrombosis is not included in the Warnings/Precautions or Adverse Reactions sections of the Xeljanz prescribing information.5
The safety and efficacy of baricitinib were established in controlled trials lasting only 24 weeks. Its long-term safety and efficacy are unknown, and the company agreed to conduct a randomized controlled clinical trial to assess long-term baricitinib safety in RA as part of the FDA approval.6 Xeljanz now has 6 years of accumulated safety data since its 2012 approval. The retail price of Olumiant is unknown at the time of this writing, but the company has reported that it will cost “60% less than the leading TNF inhibitor.”6 The retail cost of 30 days of therapy with the other JAK inhibitor products Xeljanz or Xeljanz XR is about $4,200 (www.GoodRx.com, June 21, 2018). Because of the added risk of thrombosis, Olumiant may need competitive pricing to gain market share from Xeljanz/XeljanzXR. Lilly will be offering a patient support program called “Olumiant Together” to help eligible patients with the medication cost. Given the lack of long-term safety data and potential cost considerations, the place of baricitinib in the treatment of RA must await further information. Other JAK inhibitors (upadacitinib and filgotinib) are also under investigation.
Product Information: Olumiant (baricitinib). Eli Lilly and Company: Indianapolis, IN, 2018. http://pi.lilly.com/us/olumiant-uspi.pdf. Accessed June 18, 2018.
Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374:1243–1252. doi: 10.1056/NEJMoa1507247.
Brown T. FDA Approves baricitinib for rheumatoid arthritis. Medscape June 1, 2018. https://www.medscape.com/viewarticle/897516. Accessed June 18, 2018.
U.S. Food and Drug Administration. FDA Briefing Document, Arthritis Advisory Committee Meeting, April 23, 2018: NDA 207924 Baricitinib, janus kinase (JAK) inhibitor for RA, Eli Lilly and Company (Lilly). https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm605061.pdf. Accessed June 18, 2018.
Product Information: Xeljanz (tofacitinib). Pfizer: New York, NY, 2018. http://labeling.pfizer.com/showlabeling.aspx?id=959. Accessed June 18, 2018.
FDA approves Olumiant (baricitinib) 2-mg tablets for the treatment of adults with moderately-to-severely active rheumatoid arthritis. PRNewswire June 1, 2018. https://www.prnewswire.com/news-releases/fda-approves-olumiant-baricitinib-2-mg-tablets-for-the-treatment-of-adults-with-moderately-to-severely-active-rheumatoid-arthritis-300658215.html. Accessed June 18, 2018.