Eli Lilly and Company and Delaware based Incyte Corporation has presented the 12-week results from a phase IIb study of baricitinib, formerly LY3009104 (INCB28050), an orally available janus kinase (JAK) inhibitor, in patients with active rheumatoid arthritis (RA). The results were presented as a late-breaking oral presentation at the European League Against Rheumatism's (EULAR) Annual European Congress of Rheumatology (EULAR).

The phase IIb randomized double-blind, placebo-controlled, dose-ranging study, known as JADA, involved a total of 301 patients with active RA on stable doses of methotrexate. Patients were randomized to receive either placebo or one of four once-daily doses of baricitinib (one mg, two mg, four mg or eight mg) for 12 weeks.

The phase IIb trial achieved the primary endpoint by demonstrating a statistically significant difference in the American College of Rheumatology 20 (ACR20) response between the combined four mg and eight mg baricitinib groups (76 per cent) compared with placebo (41 per cent) after 12 weeks of treatment (p < 0.001). Statistically significant improvement was observed at the first assessment point after two weeks of treatment and was sustained through week 12.

A statistically significant difference in response for the ACR20, ACR50 and ACR70 secondary endpoints was observed with the one mg, four mg and eight mg dose groups compared with placebo.

The most common treatment-emergent adverse event class was infections, with a similar rate observed among patients in the placebo group (12 per cent) and patients receiving baricitinib (14 per cent). One patient in the placebo group was diagnosed with an opportunistic infection of toxocariasis. No deaths or opportunistic infections occurred in the active treatment groups.

There were seven serious adverse events reported in six patients (two events in the placebo group, four in the two mg group and one in the eight mg group). Dose-dependent changes in laboratory tests (haemoglobin, neutrophil, serum creatinine, LDL and HDL) were observed, with greater changes being observed in the eight mg baricitinib group.

This phase IIb trial consists of three parts: Part A, Part B and an open-label extension. Part A was randomized, double-blind and placebo-controlled. Patients randomized to baricitinib received one of four doses administered once daily for 12 weeks.

In Part B, patients initially randomized to placebo or the one mg baricitinib dose were re-randomized to receive either four mg once daily or two mg twice daily for 12 weeks. Patients initially randomized to the two mg, four mg and eight mg doses continued therapy for an additional 12 weeks.

Patients completing Part B were eligible to continue in an open-label extension arm on either the four mg or eight mg once daily doses of baricitinib for 52 additional weeks.

Part B of the study has completed and data analysis is underway. Patients are continuing to participate in the open-label long-term extension of the trial.

There are four known JAK enzymes: JAK1, JAK2, JAK3 and TYK2. These enzymes are critical components of signalling mechanisms utilized by a number of cytokines and growth factors, including those that are elevated in RA patients. Cytokines such as interleukin-6, 12, and 23 signal through the JAK pathway and have been clinically validated as therapeutic targets in inflammatory diseases. Additional JAK-dependent cytokines have also been implicated in a number of inflammatory and autoimmune diseases suggesting that JAK inhibitors may be useful for the treatment of a broad range of inflammatory conditions.

Baricitinib is an orally administered selective JAK1 and JAK2 inhibitor that is JAK3-sparing. Currently, baricitinib is in phase II development as a treatment for rheumatoid arthritis and psoriasis.

In December 2009, Lilly and Incyte announced an exclusive worldwide license and collaboration agreement for the development and commercialization of baricitinib and certain follow-on compounds for inflammatory and autoimmune diseases.

The disease is characterized by abnormal immune mechanisms that lead to joint inflammation and swelling with progressive destruction of joints. In addition to affecting the joints, RA can also affect connective tissue in the skin and organs of the body.

Current treatment of RA includes the use of non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs such as methotrexate, and the newer injectable biological response modifiers that target tumour necrosis factor, a pro-inflammatory cytokine implicated in the pathogenesis of RA.

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations.

Incyte Corporation is focused on the discovery, development and commercialization of proprietary small molecule drugs for oncology and inflammation.