Top-line data from the first of four phase III trials with baricitinib, the Janus kinase (JAK) inhibitor for moderate to severe rheumatoid arthritis (RA) from Incyte Corp. and partner Eli Lilly and Co., set analysts buzzing about how once-daily "bari" might otherwise distinguish itself from the approved JAK inhibitor Xeljanz (tofacitinib) from Pfizer Inc., taken twice daily for RA.

Lilly, of Indianapolis, and Wilmington, Del.-based Incyte disclosed results from the RA-BEACON study with bari, which met its endpoint by improving ACR20 response as compared to placebo after 12 weeks, when tested in patients who previously failed one or more tumor necrosis factor (TNF) inhibitors and who were taking stable doses of conventional disease-modifying antirheumatic drug therapy.

Terence Rooney, rheumatologist and medical director of the phase III RA bari program, called the results "very encouraging" and said they would be detailed further at scientific meetings during the first half of 2015.

It's the severe adverse event (SAE) profile as compared to Xeljanz that will be "critical to determine whether the drug can help reduce some of the perceived 'baggage' associated with the JAK class in RA and make more meaningful commercial inroads vs. entrenched biologics," wrote Wells Fargo analyst Brian Abrahams in a research report, adding that "details in the press release were scant."

Rooney noted that researchers "haven't conducted any comparator studies, so we can't really provide you with any data" directly related to New York-based Pfizer's drug, but bari's "pharmacologic profile is unique," targeting JAK1 and JAK2, but without activity against JAK3. "We hope and, to date, have observed that has been associated with a quite satisfactory risk/benefit profile," he told BioWorld Today.

Other phase III trials are testing bari in earlier stages of RA, with active as well as placebo comparators. "Obviously, the results from those studies will determine the path forward with regulators," Rooney said. About 3,000 RA patients will be enrolled in the program. "We're quite pleased at the safety profile [so far]," he said. "Importantly, we didn't see any opportunistic infections, and we think that could be quite advantageous for patients struggling with this difficult disease."

Results also turned up no gastrointestinal perforations. Investigators did find more treatment-emergent adverse events with bari than placebo, including headache, upper respiratory tract infection and nasopharyngitis, but discontinuation rates due to adverse events were similar between treatment groups, and a "large majority" of patients opted to participate in a long-term extension study.

One positive noted by Abrahams is that the rate of serious infections for bari was no different from placebo, even at only three months, while "the totality of Xeljanz studies showed triple the incidence of serious infections for Xeljanz vs. placebo, suggesting an advantage for bari, though more data are needed to confirm this," he wrote. "The fact that no opportunistic infections were observed may be less meaningful, as differences between Xeljanz and placebo on this AE may not have emerged until longer follow-up." Xeljanz sells about $350 million per year. Abrahams projected sales of bari worldwide at $417 million in 2018, with $92 million paid in royalties to Incyte.

'UNDERAPPRECIATED ASSET'

Investors had cause to expect upbeat phase III news. In late 2012, at the American College of Rheumatology meeting in Washington, Lilly and Incyte unveiled 24-week phase IIb data from one of three phase II trials that showed 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 bari once-daily doses maintained or improved ACR20, ACR50 and ACR70 responses. Patients reported satisfaction in quality of life, too, along with improvements measurable by magnetic resonance imaging. (See BioWorld Today, Nov. 15, 2012.)

That's when the companies let their phase III plans be known, too. In order to keep the royalty rate promised by Lilly, Incyte must pay 30 percent of the phase III costs, which could total more than $500 million, by estimates of Wells Fargo's Abrahams. Bari could find a place in the giant RA market alongside Xeljanz – both oral improvements over injectable TNF inhibitors such as Humira (adalimumab, Abbvie Inc.), Enbrel (etanercept, Amgen Inc.) and Remicade (infliximab, Johnson & Johnson).

J.P. Morgan analyst Cory Kasimov said he was "not surprised by this positive [phase III] readout," but wants to see detailed data, due at a medical conference next year, before weighing bari against Xeljanz.

"Overall, we view bari as potentially the most underappreciated asset in Incyte's late-stage pipeline," Kasimov wrote in a research report, though he also wants to see results from the head-to-head study against Humira.

The phase III news comes on the heels of an Incyte win for the JAK1/JAK2 inhibitor Jakafi (ruxolitinib), cleared by the FDA a few days earlier for uncontrolled cases of the rare chronic bone marrow cancer polycythemia vera (PV), a condition that sometimes advances to myelofibrosis, the indication for which Jakafi was approved first. Expanding the label could double sales of the compound, according to some analysts. About 100,000 patients in the U.S. have PV, which occurs when too many red blood cells are made in the bone marrow. (See BioWorld Today, Dec. 8, 2014.)

Incyte's stock (NASDAQ:INCY) closed Tuesday at $78.89, up $1.67.