Baricitinib (OLUMIANT): The Wrong Choice for Rheumatoid Arthritis

Baricitinib (OLUMIANT) is the newest member of the diseasemodifying antirheumatic drug (DMARD) family. DMARDs are drugs that reduce signs and symptoms of rheumatoid arthritis and decrease progression of joint damage.

Baricitinib was approved by the Food and Drug Administration (FDA) on May 31, 2018, for the treatment of adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to one or more of the injectable biologic DMARDs that block tumor necrosis factor (for example, adalimumab [AMJEVITA, CYLTEZO, HUMIRA], etanercept [ENBREL, ERELZI] and infliximab [INFLECTRA, IXIFI, REMICADE, RENFLEXIS]).[1]

Baricitinib is a potent suppressor of the immune system that is taken orally.[2] It works by inhibiting certain enzymes found in white blood cells that play a key role in the joint inflammation and damage that occurs in rheumatoid arthritis patients.

The FDA’s approval of baricitinib came despite serious concerns about the drug’s safety and represents another example of the agency’s reckless approach to the oversight of prescription drugs. Public Citizen’s Health Research Group has designated this drug as Do Not Use because it has unique risks of serious harm — in particular, an increased risk of life-threatening blood clots — but has not been shown to offer any unique advantages at the FDA-approved dose over many other available DMARDs.

Initial FDA rejection

Baricitinib’s manufacturer, Eli Lilly, originally applied for FDA approval of the drug in January 2016.[3] The company sought approval for two dosages — 2 milligrams (mg) and 4 mg once daily — for treatment of adults with moderate-to-severe active rheumatoid arthritis.

Among the data provided by Eli Lilly in its initial application to the FDA were results from four randomized clinical trials.[4] Two six-month trials that enrolled more than 1,200 subjects compared baricitinib at a dosage of 2 mg or 4 mg with a placebo once daily. Two one-year trials that enrolled nearly 1,900 subjects compared only the 4-mg dose of baricitinib with the first-line oral DMARD methotrexate (OTREXUP, RASUVO, TREXALL, XATMEP), adalimumab or a placebo. Data from these trials demonstrated that baricitinib at both the 2-mg and 4-mg doses was effective in improving the signs and symptoms of rheumatoid arthritis and physical function and in slowing the progression of joint damage.[5] Of note, only one of the four trials enrolled patients who had had an inadequate response to a biologic DMARD that blocks tumor necrosis factor.

These same clinical trials and others also demonstrated that baricitinib causes an increase in numerous serious adverse effects that are typical of other rheumatoid arthritis drugs that are potent suppressors of the immune system, including a wide range of infections and cancer (see text box, below, for the black-box safety warnings in baricitinib’s product labeling).[6]

However, data from the major clinical trials showed that baricitinib, at both the 2-mg and 4-mg doses, increased the risk of dangerous blood clots, including deep venous thrombosis (blood clots forming in large veins, usually in the leg) and pulmonary embolism (blood clots in veins that dislodge, move through the blood and lodge in the lungs).[7] There also were several cases of arterial blood clots in subjects who received baricitinib. No such blood clot events occurred in subjects who received a placebo. Moreover, FDA reviewers noted that such adverse events had not been seen with any other DMARDs.[8]

Importantly, baricitinib also was found to cause dose-dependent increases in the levels of blood platelets, which play a key role in clot formation.[9] Increased platelet counts are another unique adverse effect of baricitinib and may be related to the drug’s increased risk of dangerous blood clots.

Baricitinib treatment also causes low white blood cell counts and anemia.

The director of the FDA division that reviewed the initial application for approval of baricitinib noted the following in his highly critical assessment of the drug:

“The thrombosis [blood clot] findings are of particular concern because these events are not predictable, and some were associated with death… There will need to be further safety data generated to understand the thrombosis risk for baricitinib, and it would be reasonable to obtain the data and address this safety risk pre-approval… Given that baricitinib is another member of the DMARD class that has many choices, and baricitinib is not serving an unmet medical need that is above and beyond [biologic] DMARDs and tofacitinib [XELJANZ], it would be reasonable to not approve any of the doses of baricitinib at this time and have Lilly assess efficacy of a dose or doses lower than 2 mg and assess safety of these doses.”[10]

Having concluded that “the overall benefit/risk profile for baricitinib was not favorable” because of the risk of dangerous blood clot events, the FDA in April 2017 rejected Eli Lilly’s application for approval of the drug.[11] Notably, the safety concerns raised by the FDA in its rejection letter could only have been adequately addressed by new clinical trials testing lower dosages of the drug.

FDA’s shocking reversal

In December 2017, Eli Lilly resubmitted an updated application to the FDA for approval of baricitinib. The company again sought approval of the 2-mg and 4-mg once-daily dosages but narrowed the intended patient population to adults with moderateto- severe active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.[12]

The updated application did not include any data from new clinical trials testing the safety and effectiveness of lower dosages of baricitinib. Instead, Eli Lilly provided a series of flawed analyses of data from the previously conducted clinical trials, including additional long-term follow-up data from subjects enrolled in these trials.[13] The company also analyzed data from commercial health insurance records of a large group of rheumatoid arthritis patients and compared the rate of blood clot events in these patients with the rate of these adverse events in subjects enrolled in the clinical trials for baricitinib.

FDA reviewers identified important deficiencies in each of the new analyses conducted by Eli Lilly.[14] They concluded that the additional data provided in the resubmitted application did not substantially alter the data on baricitinib’s safety and effectiveness in the original application.[15]

In April 2018, an FDA advisory committee was convened to consider whether baricitinib should be approved. Public Citizen testified before the committee and argued that FDA approval of the drug, with reliance on warnings in the product labeling and postmarket safety monitoring, would be a reckless approach and would not be in the interests of public health.[16] We therefore urged the committee to recommend that the FDA not approve the drug.

Ten of the 15 committee members concluded that there was not adequate safety data to support approval of the 4-mg dose of baricitinib, whereas six reached the same conclusion for the 2-mg dose.[17] By identical votes of 10 to 5, the committee opposed approval of the 4-mg dose of baricitinib but favored approval of the 2-mg dose. The FDA subsequently approved baricitinib at a dosage of 2 mg daily, but only for treatment of adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to one or more of the injectable biologic DMARDs that block tumor necrosis factor.

The FDA’s approval of another drug for treatment of rheumatoid arthritis that lacks any unique benefit over other DMARDs but causes unique life-threatening harms showed blatant disregard for the public health principles underlying the agency’s regulatory authority.

What You Can Do

You should avoid starting baricitinib if you are not currently taking it. If you are already taking baricitinib, consult with your doctor about switching to another DMARD. DMARDs that we have designated as Limited Use are adalimumab, etanercept, golimumab (SIMPONI), infliximab, anakinra (KINERET), abatacept (ORENCIA) and rituximab (RITUXAN). We have designated certolizumab pegol (CIMZIA) and tofacitinib as Do Not Use.

Do not stop taking any medication without consulting your doctor. Regardless of the treatment chosen by you and your doctor, you should consider engaging in an exercise program and physical therapy designed within the limits of pain. This will help to strengthen muscles and maintain or improve range of motion in the joints.

References

[1] Food and Drug Administration. Approval letter for NDA 207924/Original 1, baricitinib. May 31, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/207924Orig1s000ltr.pdf. Accessed October 1, 2018.

[2] Food and Drug Administration. Summary review, new drug application 207924Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000SumR.pdf. Accessed October 1, 2018. PDF page 6.

[3] Food and Drug Administration. Medical review(s), new drug application 207924Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000MedR.pdf. Accessed October 1, 2018. PDF pages 94 and 109.

[4] Food and Drug Administration. Medical review(s), new drug application 207924Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000MedR.pdf. Accessed October 1, 2018. PDF page 7.

[5] Ibid. PDF page 60.

[6] Food and Drug Administration. Briefing document for the April 23, 2018, meeting of the Arthritis Advisory Committee, NDA 207924 baricitinib, Janus kinase (JAK) inhibitor for RA. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605061.pdf. Accessed October 1, 2018. PDF pages 97-103.

[7] Ibid. PDF page 105.

[8] Food and Drug Administration. Medical review(s), new drug application 207924Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000MedR.pdf. Accessed October 1, 2018. PDF pages 7, 30 and 42.

[9] Food and Drug Administration. Briefing document for the April 23, 2018, meeting of the Arthritis Advisory Committee, NDA 207924 baricitinib, Janus kinase (JAK) inhibitor for RA. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605061.pdf. Accessed October 1, 2018. PDF pages 96 and 105.

[10] Food and Drug Administration. Medical review(s), new drug application 207924Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000MedR.pdf. Accessed October 1, 2018. PDF pages 30-32.

[11] Food and Drug Administration. Briefing document for the April 23, 2018, meeting of the Arthritis Advisory Committee, NDA 207924 baricitinib, Janus kinase (JAK) inhibitor for RA. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605061.pdf. Accessed October 1. PDF page 149.

[12] Food and Drug Administration. Summary review, new drug application 207924Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000SumR.pdf. Accessed October 1, 2018.

[13] Food and Drug Administration. Briefing document for the April 23, 2018, meeting of the Arthritis Advisory Committee, NDA 207924 baricitinib, Janus kinase (JAK) inhibitor for RA. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605061.pdf. Accessed October 1, 2018. PDF pages 149-150.

[14] Ibid. PDF pages 163-164 and 178.

[15] Ibid. PDF page 186.

[16] Public Citizen. Testimony before the FDA’s Arthritis Advisory Committee regarding New Drug Application 207924 for baricitinib for rheumatoid arthritis: No unique benefits, but unique serious safety concerns. April 23, 2018. https://www.citizen.org/sites/default/files/2418.pdf. Accessed October 1, 2018.

[17] Food and Drug Administration. Final summary minutes of the Arthritis Advisory Committee meeting, April 23, 2018. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM610770.pdf. Accessed October 1, 2018.