Oral baricitinib maintains lower radiographic progression than csDMARD, placebo in RA
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Oral baricitinib is linked to lower levels of 5-year radiographic progression than first-line conventional, synthetic disease-modifying antirheumatic drugs or placebo in rheumatoid arthritis, according to data published in The Journal of Rheumatology.
“DMARDs — including conventional synthetic DMARDs (csDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs) — can reduce joint pain and swelling and can provide protection against structural damage in a clinically meaningful way,” Désirée van der Heijde, MD, PhD, of Leiden University Medical Center, in the Netherlands, and colleagues wrote. “However, structural damage progression still occurs in some patients, even when they achieve adequate clinical control of their disease with DMARDs.
“Baricitinib, an oral, selective and reversible inhibitor of Janus kinase 1 and 2, has been studied in phase 3 randomized controlled trials showing clinical and functional benefits and is approved for the treatment of RA in at least 70 countries,” they added. “RA is a chronic disease; thus, it is imperative to show sustained inhibition of radiographic progression with treatment.”
To analyze the impact of baricitinib (Olumiant, Eli Lilly & Co.) in limiting the radiographic progression of structural joint damage in RA over 5 years, van der Heijde and colleagues conducted the multicenter, long-term extension trial RA-BEYOND. This study included patients with active, adult-onset RA who completed one of three prior phase-3 trials — RA-BEGIN, which included patients who were DMARD-naïve; RA-BEAM, with patients who had an inadequate response to methotrexate; and RA-BUILD, with patients with an inadequate response to conventional, synthetic DMARDs.
A total of 2,125 randomized patients entered RA-BEYOND. Participants received once-daily 4 mg or 2 mg baricitinib. Patients who initially received MTX or adalimumab (Humira, AbbVie) switched to baricitinib 4 mg at week 52, while those who originally received placebo switched to baricitinib 4 mg at week 24. The researchers scored radiographs at baseline and years 2, 3, 4 and 5. They then analyzed patients’ change from baseline in van der Heijde modified Total Sharp Score. In all, 1,837 participants completed the 5-year extension.
According to the researchers, from years 3 to 5, higher proportions of DMARD-naïve patients receiving initial baricitinib — either as monotherapy or with MTX — demonstrated no progression, compared with initial MTX. Percentages among these participants who demonstrated a change in modified Total Sharp Score of 0 or less at year 5 were 59.6% for baricitinib 4 mg, 66.2% for baricitinib 4 mg plus MTX, and 40.7% for MTX.
Higher proportions of patients who had an inadequate response to MTX on initial baricitinib or adalimumab, compared with placebo, demonstrated no progression, with 54.8% in the baricitinib 4 mg group, 55% in the adalimumab group and 50.3% of the placebo group having a change in modified Total Sharp Score of 0 or less at year 5.
Lastly, higher proportions of patients who had an inadequate response to conventional synthetic DMARDs on initial baricitinib 4 mg demonstrated less progression, compared with initial placebo or baricitinib 2 mg. Percentages of these patients who had a change in modified Total Sharp Score of 0 or less at year 5 were 66.7%, 58.2% and 60% in the baricitinib 4 mg, baricitinib 2 mg and placebo groups, respectively.
“Both 2 mg and 4 mg baricitinib maintained inhibition of radiographic progression in most patients while achieving clinically meaningful improvement in disease activity, sustained for 5 years,” van der Heijde and colleagues wrote. “Patients initially treated with baricitinib had less radiographic progression over the duration of the trial compared to those initially treated with a csDMARD plus placebo or MTX monotherapy (DMARD-naïve patients).
They added: “This observation suggests that one should start a medication such as baricitinib earlier in the disease course if patients have not reached remission, according to ACR/European League Against Rheumatism criteria or at least LDA with a metric such as the SDAI or CDAI, within 3 to 6 months as suggested by the treat-to-target strategy.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
In this study, both the 2 mg and 4 mg dose of baricitinib showed less radiographic progression in the long-term extension. In Europe, rheumatologists are allowed to decide if they want to use 4 mg or 2 mg. In fact, the EMA states: “The usual dose is 4 mg once a day, but this can be reduced to 2 mg once a day when the disease is under control. The dose may also need to be reduced in patients who have impaired kidney function, in patients who have an increased risk of infections and in those aged over 75 years or who are taking certain other medicines.”
In the U.S., the FDA has only approved the 2 mg and 1 mg doses of baricitinib. The EMA and FDA are the two major pharmaceutical regulatory agencies in the world. We know they may not see eye-to-eye on the same medication while reviewing the same data. As Gail A. Van Norman, MD, noted, the FDA “is sometimes seen as overplaying safety concerns at the cost of commercial enterprise, whereas the European systems are sometimes characterized as being primarily concerned with preserving commercial interests to the detriment of patient safety.”
Alternatively, the FDA has sometimes approved medications before the EMA; consider the approval of the antineoplastic tyrosine kinase inhibitors. On average, the review and approval times were 205.3 days for the FDA compared with 409.6 days for the EMA. As the world becomes smaller with multinational pharmaceutical companies and multinational pharmaceutical trials, clinicians could hope there would be some consistency in the approved dosages and indications for medications.
As Paul Howard and Yevgeniy Feyman put it in their Health Affairs blog – based on the emergency approval for Princeton University to administer the EMA-approved (but not FDA approved) Novartis meningitis group B vaccine to students after an outbreak – “If A Drug Is Good Enough For Europeans, It’s Good Enough For Us”. This article articulates the argument for reciprocity for approvals by the EMA and the FDA and the cost savings that would occur by such an arrangement. In the world of politics, though, this would be a very heavy lift.
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