The recent approval of Pfizer Inc.'s Janus kinase (JAK) inhibitor tofacitinib, branded Xeljanz, for moderate to severe rheumatoid arthritis (RA) has investors salivating over the prospects for baricitinib, the drug in the same class for the same indication from Incyte Corp. and partner Eli Lilly and Co., entering Phase III trials.

"We were quite pleased to see tofacitinib get approved," said William Macias, medical director for Indianapolis-based Lilly. "We think that's actually very good for patients, very good for physicians, but potentially as important, very good for clinical research. That was very nice to see this week."

Pfizer, of New York, will launch tofacitinib soon. Already, the two JAK inhibitors are being compared by their nicknames "tofa" and "bari."

Macias spoke during an investor event at the American College of Rheumatology (ACR) meeting in Washington, where his company and Wilmington, Del.-based Incyte lifted the lid this week on 24-week Phase IIb data with baricitinib.

The results showed that efficacy held at levels comparable to the 12-week data in ACR scores and other measures, and even improved in some cases. Data from the 12-week to 24-week portion of the study, which did not include a placebo control, showed that patients who continued to receive 2-mg, 4-mg or 8-mg baricitinib once-daily doses maintained or improved ACR20, ACR50 and ACR70 responses. Patients reported satisfaction in quality of life, and improvements showed up in magnetic resonance imaging.

Previously undisclosed plans for added Phase III trials rolled out at the meeting, too. Along with the studies already disclosed, experiments will test baricitinib in patients who respond inadequately to disease-modifying antirheumatic drugs (including those not on methotrexate and showing joint erosions), and another in those who respond inadequately to tumor necrosis factor (TNF) inhibitors. Other Phase III trials are using the compound in methotrexate-naïve RA patients, and pitting baricitimib against Humira (adalimumab, Abbott).

The Phase III program overall will include about 3,000 patients. In order to keep the royalty rate promised by Lilly, Incyte has to pay 30 percent of the Phase III costs, which could total more than $500 million, estimated Wells Fargo analyst Brian Abrahams in a research report.

But that could be more than worthwhile, if baricitinib can carve its place in the lucrative RA market, where – until Pfizer came along with its JAK inhibitor – patients had to make do with injectable TNF inhibitors such as Humira, Enbrel (etanercept, Amgen Inc.) and Remicade (infliximab, Johnson & Johnson).

Work by Pfizer, Incyte/Lilly and others have led the industry to suspect that JAKs are better. Cambridge, Mass.-based Vertex Pharmaceuticals Inc. has VX509 in an ongoing Phase IIb study in the U.S. and Europe. And Galapagos NV, of Mechelen, Belgium, landed a $1.35 billion deal with Abbott Park, Ill.-based Abbott earlier this year, focused on the JAK inhibitor GLPG0634. (See BioWorld Today, March 1, 2012.)

Whatever the mechanism, competition is fierce in oral drugs for RA. Late-stage candidates include South San Francisco-based Rigel Pharmaceuticals Inc.'s fostamatinib, a Phase III syk inhibitor in a potential $1.2 billion partnership with AstraZeneca plc, of London. (See BioWorld Today, Feb. 17, 2010.)

For now, though, the comparisons persist between Pfizer's drug and baricitinib, to the extent such match-ups are possible. Incyte/Lilly noted at the investor event that the Disease Activity Score 28 (DAS28), which examines the level of RA in 28 joints, could be helpful in predicting early response, and said Phase III trials were set up to show structural benefit better than Pfizer's radiographic peeks.

Abrahams was skeptical, calling it "unclear whether DAS28 prediction is unique to baricitinib, and tofacitinib would likely have structural benefits ultimately added to its label by the time baricitinib is approved. One area of potential differentiation could be a lower rate of infections and/or malignancies, in part given the different JAK selectivity, though it is too early to tell at this time. In the end, baricitinib's once-daily dosing could prove to be its most definitive commercial differentiator."

Lilly's Macias would not speculate. "We're pretty confident that we're taking the most effective dose of baricitinib forward into Phase III testing," he said. "We don't think we've left any efficacy on the table. How we position that relative to tofacitinib depends on what the data [show] in our Phase III program."