Baricitinib Offers Promise of Remission in Refractory RA

Janis C. Kelly

March 31, 2016

Baricitinib provides meaningful clinical improvement for patients with rheumatoid arthritis (RA) who did not respond to other treatments, including biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) inhibitors, data from a pivotal phase 3 trial suggest.

Lead author Mark Genovese, MD, told Medscape Medical News that in this group of extensively pretreated patients with refractory RA, 24 days of baricitinib at 4 mg/day by mouth added to background therapies was significantly more effective than placebo at inducing American College of Rheumatology 20% (ACR20) response, reducing disability (Health Assessment Questionnaire–Disability Index [HAQ-DI]), and reducing disease activity and levels of inflammatory modulators (28-joint Disease Activity Score based on C-reactive protein level [DAS28-CRP]).

Dr Genovese, the James W. Raitt Professor of Medicine and co-chief, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, California, and colleagues report the trial results in an article published in the March 31 issue of the New England Journal of Medicine.

Study data also suggest that baricitinib might make remission possible, even for patients with otherwise refractory RA. Although the number of patients achieving remission at the prespecified endpoint of 12 weeks was not significantly higher in the baricitinib 4-mg group, there were more remissions associated with baricitinib 4 mg than with placebo at 24 weeks.

Dr Genovese said, "A 12-week time frame is probably too early to expect significant number of patients with long-standing refractory disease to achieve remission. However, with longer durations of exposure, we start to see an increase in this outcome, even in this population."

Baricitinib is a small-molecule Janus kinase (JAK) inhibitor that preferentially inhibits JAK1 and JAK2. The JAK family of kinases has been implicated in the autoimmune inflammatory response.

The researchers conducted a 24-week randomized, double-blind, placebo-controlled trial with 527 patients at 178 centers in 24 countries. Patients had moderate to severe RA (six or more tender joints of 68 joints examined, six or more swollen joints of 66 joints examined, and a serum CRP level of 3 mg/L or higher). All patients had previously taken one or more TNF inhibitors or other biologic DMARDs, but discontinued because of adverse effects or lack of efficacy.

Patients were randomly assigned to baricitinib, at a dose of 2 or 4 mg daily, or to placebo for 24 weeks. Patients were allowed to continue concomitant treatment with stable doses of conventional synthetic DMARDs, nonsteroidal antiinflammatory drugs, analgesic agents, and/or glucocorticoids (≤10 mg prednisone or the equivalent per day).

The researchers report that at week 12, ACR20 responses, which were the primary endpoint, had occurred in significantly more patients receiving baricitinib 4 mg than in those receiving placebo (55% vs 27%; P < .001). Patients in the baricitinib 4-mg group also had significantly greater improvements in HAQ-DI scores and in DAS28-CRP (P < .001).

The proportion of patients reaching remission, defined as a Simplified Disease Activity Index (SDAI) score of 3.3 or less (SDAI ≤ 3.3), was not significantly different between the baricitinib 4-mg group and the placebo group at week 12 (5% vs 2%). However, significantly more baricitinib 4-mg patients were in remission by week 24 (9% vs 2%; P ≤ .01).

Petros Efthimiou, MD, associate chief of rheumatology at New York Methodist Hospital and an associate professor of medicine and rheumatology at Weill Cornell Medical College, New York City, told Medscape Medical News, "I believe the Genovese paper convincingly shows efficacy, at least short term, of baricitinib at the dose of 4 mg daily for refractory patients that failed treatment with biologic DMARDs, both TNF- and non-TNF inhibitors." Dr Efthimiou was not involved in the study.

Response to baricitinib 4 mg was not affected by number of prior biologic DMARDs, number of prior TNF inhibitors, or number of biologic DMARDs other than TNF inhibitors. The authors note this is likely to be important moving forward because of the growing number of patients with RA with inadequate disease control despite previous treatment with multiple biologic agents.

To control for type 1 error and multiple comparisons, the researchers used a stepwise hierarchical hypothesis-testing strategy. They first analyzed the 12-week ACR20 response and then the HAQ-DI change from baseline, the DAS28-CRP, and then the SDAI. The analysis sequence proceeded to the next test in the hierarchy only if the previous result was statistically significant. Data for baricitinib 4 mg vs placebo were analyzed first, and analysis proceeded to baricitinib 2 mg only if all of the baricitinib 4 mg tests were statistically significant. Because the proportion of patients reaching SDAI scores of 3.3 or less was not significantly higher for baricitinib 4 mg than for placebo, the analysis did not proceed to the 2 mg vs placebo comparisons.

Rates of serious adverse events through week 24 were similar for the baricitinib 4 mg (10%), baricitinib 2 mg (4%), and placebo (7%) groups. However, baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels.

"Serum creatine kinase levels increased in both baricitinib groups; all the patients who had grade 3 or 4 abnormalities reported having engaged in exercise or other physical activity before being tested or had elevated baseline levels," the authors write.

Dr. Genovese said, "Changes in serum creatinine kinase are not surprising, given that they have also be reported in studies with other JAK inhibitors in patients with RA. The underlying trigger for this remains unclear. It is something clinicians should be aware of, but implications for monitoring remain unclear."

Dr Efthimiou said, "While baricitinib is not the first JAK inhibitor to be approved (tofacitinib was approved for use in RA in November 2012), it is the first selective (JAK 1 and JAK 2) inhibitor. This study confirms that efficacy is maintained, even in the most refractory RA patients, with a narrower-spectrum JAK inhibitor."

Dr Genovese said he would like to see long-term studies on the safety and durability of response, and ultimately an integrated safety summary across phase 3 clinical trials. "I was not surprised at the results of this trial. Given this agent's performance in phase 2 studies, we expected that we could demonstrate meaningful responses even in this difficult-to-treat population. Regarding new questions, the natural extension of this study is to want to see the safety and sustainability of response with longer-term study."

Similarly, Dr Efthimiou said, "A major unanswered question that cannot be answered by this study alone, is whether baricitinib, having a narrower spectrum of JAK inhibition, can offer safety advantages. A comprehensive safety analysis of all baricitinib studies may be able to answer that." He noted that additional unanswered questions include the long-term outcomes of baricitinib treatment and whether baricitinib inhibits radiographic progression in patients with refractory RA.

The study was supported by Eli Lilly and Incyte. Lilly has filed for approval of the drug with the US Food and Drug Administration. Dr Genovese reports grant support and personal fees from Eli Lilly during the conduct of the study; grant support and personal fees from Pfizer, Vertex, AbbVie, and Astellas; and personal fees from Galapagos outside the submitted work. Dr Genovese also has been serving as a consultant with Lilly and was involved in its successful phase 2 trials of baricitinib for rheumatoid arthritis. One coauthor reports receiving grant support and personal fees from Eli Lilly during the conduct of the study, grant support from Pfizer and Novartis, grant support and personal fees from Eli Lilly, and other support from Corrona outside the submitted work. Another coauthor reports receiving grant support from Eli Lilly during the conduct of the study and grant support from Eli Lilly, Bristol-Myers Squibb, Pfizer, AbbVie, and UCB outside the submitted work. Another coauthor reports receiving grant support and personal fees from Eli Lilly during the conduct of the study and grant support and personal fees from AbbVie, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Samsung, and UCB outside the submitted work. All but one of the other coauthors report receiving personal fees and other support from Eli Lilly outside the submitted work. Dr Efthimiou has disclosed no relevant financial relationships.

N Engl J Med. 2016;374:1243-1252. Abstract

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