New Oral Biologic Improves Symptoms in Refractory RA

Pam Harrison

June 18, 2015

ROME — Daily baricitinib, an oral Janus kinase (JAK)1/2 inhibitor, produces rapid clinical improvement in the signs and symptoms of rheumatoid arthritis in patients with active disease who have failed at least one tumor necrosis factor (TNF) inhibitor, the RA-BEACON trial indicates.

"The average disease duration in this cohort was 14 years, and roughly 30% of the patients had been on more than three previous biologic disease-modifying antirheumatic drugs [DMARDs], so this cohort was highly refractory," said Mark Genovese, MD, from Stanford Health Care in Palo Alto, California.

However, at weeks 12 and 24, an improvement of 20% was achieved in about 55% of patients who received baricitinib. In fact, the difference between the baricitinib and placebo groups was "statistically significant by week 1," he reported.

Dr Genovese presented results from the study here at the European League Against Rheumatism Congress 2015.

RA-BEACON involved 527 patients who had previously failed at least one TNF inhibitor. A high percentage of these patients had been previously treated with one or several biologic agents that were not TNF inhibitors.

At enrollment, patients were on a stable background of conventional DMARD therapy but still had active disease, defined as more than six tender and six swollen joints, out of a 68 joint count, and an elevated level of acute-phase protein.

The primary study end point was an improvement of 20% in American College of Rheumatology criteria at 12 and 24 weeks.

All biologic DMARDs were discontinued at least 28 days before the study regimen was started.

Patients were randomized to baricitinib — 4 mg/day or 2 mg/day — in addition to background conventional DMARD therapy or to placebo.

"Patients had to have had an inadequate response to at least one TNF inhibitor," Dr Genovese pointed out. "Notably, they were allowed to be exposed to previous non-TNF biologic DMARD therapy without number and without limit."

In patients previously exposed to one biologic DMARD, a 20% improvement was achieved at week 12 by more patients in the baricitinib 4 mg group than in the placebo group (64% vs 32%). The same pattern held for patients previously exposed to at least three biologic DMARDs (53% vs 13%; P < .001).

A 50% improvement was achieved by more patients in either of the baricitinib groups than in the placebo group at week 12 (34% vs 13%) and at week 24 (40% vs 22%; P < .001).

Disease activity score (DAS)-CRP, which assesses C-reactive protein instead of the erythrocyte sedimentation rate, declined in a linear fashion over time in the two baricitinib groups, although to a greater extent with the 4 mg dose, than in the placebo group (P < .001).

Reductions in Clinical Disease Activity Index scores mirrored the DAS-CRP. Again, scores were significantly greater in the two baricitinib groups, although more so with the 4 mg dose, than in the placebo group (P < .001).

Adverse Events

There were more serious adverse events in the 4 mg group than in the 2 mg group at 12 and 24 weeks, Dr Genovese reported.

The rate of serious infections remained fairly constant in all three groups — at 2% to 3% — and there was no significant difference in rates between any of the groups.

In contrast, there were more cases of herpes zoster in the 4 mg group than in the 2 mg group or the placebo group (7 vs 2 vs 2).

"However, these cases tended to occur in patients who had had multiple previous biologic exposures. This could be a proxy for older age, more refractory illness, or simply more exposure to immunomodulatory agents," Dr Genovese explained.

There was also a mild decrease in hemoglobin and neutrophil counts, but no grade 3/4 elevations in liver enzymes, and discontinuations because of laboratory abnormalities were infrequent.

Other studies of baricitinib in DMARD-naive patients and in patients who do not achieve an adequate response to methotrexate are ongoing.

Rapid Onset of Action

Baricitinib is an attractive treatment option for patients with rheumatoid arthritis because it acts quickly and it can be taken orally, said session cochair Rene Westhovens, MD, from Catholic University of Leuven in Belgium.

"What a patient really wants is a drug that has a rapid onset of action, so that's probably more important than the fact that baricitinib is available orally," he told Medscape Medical News.

However, in RA-BEACON, the risk for herpes zoster increased and hemoglobin levels declined, Dr Westhovens pointed out, "so I think we have to look very carefully at the side effects of this drug before we can say for certain that baricitinib will become an established therapy."

The study was funded by Eli-Lily and Incyte Corporation. Dr Genovese reported receiving grant or research support from AbbVie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, and Vertex; and serving as a consultant for AbbVie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, and Vertex. Dr Westhovens reports being a consultant for Bristol-Myers Squibb and Schering-Plough Belgium.

European League Against Rheumatism (EULAR) Congress 2015: Abstract OP0029. Presented June 11, 2015.

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