Baricitinib Might Offer Oral Alternative to Adalimumab in RA

Janis C. Kelly

February 22, 2017

Baricitinib, a new oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 produced significant clinical improvements in rheumatoid arthritis (RA) symptoms when added to methotrexate (MTX) for patients with inadequate responses to MTX alone, according to a study reported in the February 16 issue of the New England Journal of Medicine. A head-to-head comparison with adalimumab suggests baricitinib may be an effective oral alternative to the older agent.

The phase 3 study, which was supported by Eli Lilly and Icyte, compared baricitinib plus MTX with adalimumab plus MTX and with placebo plus MTX.

"[T]he addition of once-daily oral baricitinib was associated with improvements in signs and symptoms, physical function, patient-reported outcomes, and progression of structural joint damage as compared with placebo and with improvements in [American College of Rheumatology (ACR20) response and Disease Activity Score for 28 joints with the use of high-sensitivity C-reactive protein (DAS28-CRP)] as compared with adalimumab," the authors conclude.

The multinational research team was led by Peter C. Taylor, MD, PhD, from the Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences and the Kennedy Institute of Rheumatology, University of Oxford, United Kingdom.

"The study by Taylor et al...did show superiority at 12 weeks of baricitinib plus MTX when compared to placebo plus MTX and adalimumab plus MTX, when using the ACR20 outcome as primary endpoint," Petros Efthimiou, MD, associate chief of rheumatology at New York Presbyterian/Brooklyn Methodist Hospital, and an associate professor of medicine and rheumatology at Weill Cornell Medical College, New York City, told Medscape Medical News.

"The combination of adalimumab plus MTX has been long thought to be current standard of care for efficacy, and this is the first study to show superiority of a new agent, used together with MTX, against this combination, using an outcome that measures clinical efficacy," continued Dr Efthimiou, who was not involved in the study.

The 52-week, phase 3, double-blind study (RA-BEAM) included both placebo and active-control (adalimumab) groups. The researchers enrolled 1307 patients who had active RA despite at least 12 weeks of MTX that included at least 8 weeks at stable doses of 15-25 mg/week. Inclusion criteria included three or more joint erosions of hands, wrists, and feet, or one or more joint erosions plus seropositivity for rheumatoid factor (RF) or anti–citrullinated peptide antibodies. Exclusion criteria included previous use of biologic disease-modifying antirheumatic drug (DMARD) therapy. Most subjects had received at least two prior DMARDs. The study was conducted at 281 centers in 26 countries.

Patients in the three-armed trial continued background therapy with MTX and were randomly assigned (3:2:2) to treatment with placebo, baricitinib 4 mg/day by mouth, or adalimumab 40 mg subcutaneous every other week. At week 24, patients in the placebo+MTX group were switched to baricitinib+MTX, but were unaware of the change. At week 16, patients with less than 20% reduction in tender and swollen joint count were switched to open-label rescue with 4 mg/day baricitinib.

The study was powered to test ACR20 response superiority at week 12 for baricitinib vs placebo (>95% power) and noninferiority of baricitinib vs adalimumab (93% power), with a 12% noninferiority margin.

At week 12, 70% of patients in the baricitinib group met the primary endpoint ACR20 compared with 40% in the placebo group and 61% in the adalimumab group.

The results demonstrated superiority of baricitinib vs placebo (P < .001) and noninferiority of baricitinib vs adalimumab. The authors write, "According to the statistical analysis plan, baricitinib was therefore considered to be significantly superior to adalimumab (P=0.01)."

In terms of secondary endpoints, at week 12, the change in mean DAS28-CRP also was significantly greater with baricitinib than with adalimumab (−2.24 for baricitinib vs −1.95 for adalimumab; P < .001).

In addition, using the van der Heijde modification of the total Sharp score (mTSS, range 0 - 448), the investigators saw greater reductions in radiographic progression of structural joint damage at week 24 for both baricitinib (0.41 of mTSS baseline score) and adalimumab (0.33 of mTSS baseline) vs placebo (0.90 of mTSS baseline).

Dr Efthimiou said, "Limitations of the study were the short duration of the true randomized controlled part of the study (12 weeks) and the fact that the study was not powered to make a meaningful comparison, regarding inhibition of radiographic progression between baricitinib+MTX vs adalimumab+MTX, although both combinations were found to be superior to placebo+MTX. Moreover, we do not have data regarding the combination of baricitinib with other synthetic DMARDs, beyond methotrexate."

However, the clinical implications of the study are difficult to evaluate, despite the authors' complex statistical analysis, Larry Moreland, MD, PhD, Margaret Jane Miller Endowed Professor of Arthritis Research and Chief, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pennsylvania, told Medscape Medical News.

"The comparison clinically to adalimumab was at 12 weeks. I am not sure that much definite can be concluded about this study except the radiographic data showed the two treatment arms to be equal," said Dr Moreland, who was not involved in the study.

Adverse events were more frequent with in the baricitinib and adalimumab groups than in the placebo group through week 24. Adverse event rates were similar with baricitinib and adalimumab through week 52. Rates of serious infection at 24 weeks were 1% for baricitinib and adalimumab and <1% for placebo. Herpes zoster rates were 2% for baricitinib and adalimumab. Serious adverse events were more frequent with baricitinib (5%) and placebo (5%) than with adalimumab (2%).

Dr Efthimiou added, "It will be a positive development having a second JAK inhibitor available on our armamentarium. The fact that this new agent is a pill and has a different mechanism of action (JAK1-2 inhibition) than the more commonly used injectable biologics, if approved, will provide the clinician with more options to customize antirheumatic drug treatment to different patient subpopulations."

The study was supported by Eli Lilly and Incyte. Dr Taylor reports personal fees, grant support, or other financial relationships with the following companies: Eli Lilly and Company, Celgene, Galapagos, UCB Pharma, AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Pfizer, and Takeda. Several coauthors are employees of Eli Lilly and Company and report personal fees and other support from Eli Lilly and Company outside the submitted work. One or more coauthors reports receiving personal fees, employment, grant support, or other financial relationships with one or more of the following companies: Eli Lilly and Company, AstraZeneca, Eli Lilly Japan, Novartis Pharmaceuticals, Sanofi-Aventis, Abbott Laboratories, Amgen Inc, Bristol-Myers Squibb, F. Hoffmann-La Roche Inc, Janssen Inc, Pfizer, UCB Pharma, Biotest, Crescendo Bioscience, Genentech, Merck Sharp & Dohme, Eisai, Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Astellas, AbbVie, Teijin, Asahi-kasei, YL Biologics, GlaxoSmithKline, Celgene, Daiichi-Sankyo, Gilead Sciences, and Regeneron. Dr Efthimiou and Dr Moreland have disclosed no relevant financial relationships.

N Engl J Med. 2017;376:652-662. Abstract

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