Pfizer Inc. is wasting no time with the rollout of its Janus kinase (JAK) inhibitor tofacitinib, branded Xeljanz, which gained FDA approval late Tuesday for adults with moderate to severely active rheumatoid arthritis (RA).

The company will be ready to launch the drug within approximately three weeks, giving RA patients the first new disease-modifying antirheumatic drug (DMARD) in more than a decade and opening the door to an entirely new treatment paradigm for those accustomed to injectable TNF inhibitors, including Humira (adalimumab, Abbott), Enbrel (etanercept, Amgen Inc.) and Remicade (infliximab, Johnson & Johnson).

Approval of Xeljanz came two weeks ahead of the drug's Nov. 21 PDUFA date, which had been extended by the FDA in August so the agency could review additional data analyses submitted by New York-based Pfizer. Although the drug was studied in both a 5-mg and 10-mg twice-daily dosing regimen, only the 5-mg twice-daily dose was approved for patients who failed to respond adequately or were intolerant of methotrexate.

"Pfizer has studied Xeljanz in a multitude of situations: as monotherapy; in combination with methotrexate and other non-biologic DMARDs after inadequate response with DMARDs, including TNF-inhibiting therapies; and with an active control (adalimumab)," said Pfizer spokeswoman Victoria Davis. "The clinical trial results showed consistent efficacy for Xeljanz across all of these different trial designs."

In May, the Arthritis Advisory Committee voted 8-2 to recommend the drug's approval as a second-line treatment in RA. (See BioWorld Today, May 8, 2012, and May 10, 2012.)

Pfizer agreed to conduct postmarketing clinical trials to evaluate the long-term safety of Xeljanz and to assess the drug in the pediatric population with polyarticular juvenile idiopathic arthritis.

The FDA indicated additional data also are needed to assess the risk/benefit profile of the 10-mg twice-daily dose.

"We are interested in working with the FDA to include radiographic and additional efficacy/safety data in the label based on our clinical data," Davis told BioWorld Today. "Pfizer plans to continue to accumulate data on both the 5-mg and 10-mg doses as part of our ongoing studies for Xeljanz, and we are committed to working with the FDA to understand the additional data needed for further assessment of the 10 mg twice-daily dose."

Broad Label Places Xeljanz Ahead of Anti-TNFs

The FDA approved Xeljanz with a broad label that includes a reasonable risk evaluation and mitigation strategy consisting of a medication guide for patients and a communication plan for prescribers outlining potential risks associated with the drug, including infections, tuberculosis, cancers and lymphoma.

"We think the Street will view this favorably, though initially we believe most rheumatologists will use tofacitinib in anti-TNF failures," said ISI Group analyst Mark Schoenebaum.

Davis declined to specify Pfizer's marketing approach for the drug but said the company "will deploy a specialty team that has extensive rheumatology experience to appropriately educate health care professionals."

One potential downside is the absence of language indicating Xeljanz inhibits structural damage associated with slowing the progression of RA. In contrast, Enbrel, Humira and Remicade include that language, which could hurt potential uptake of Pfizer's drug, according to Schoenebaum.

Davis said Pfizer plans to meet with the FDA as soon as possible to review the submission of results from its ORAL Start (A3921069) study, which showed both the 5-mg and 10-mg twice-daily doses demonstrated superiority to methotrexate and statistically significant changes consistent with inhibiting structural damage, as measured by change from baseline in modified Total Share Score, and in reducing signs and symptoms of RA, as measured by ACR70 responses.

Both primary endpoints assessed tofacitinib vs. methotrexate at six months. The data came from a planned analysis at one year. (See BioWorld Insight, Aug. 13, 2012.)

The ORAL Start study was ongoing at the time of the new drug application (NDA) filing for tofacitinib and was not included in the original submission.

The drug's wholesale acquisition cost is $2,055.13 for a 30-day supply. That amounts to approximately $25,000 per year – a discount of 7 percent to Enbrel and Humira, according to Schoenebaum, compared to the 30 percent discount his model anticipated.

"If we simply plug in the higher sales price in our model (assuming a 15 percent gross to net discount), our 2016 U.S. sales increase from [about] $900 million to $1.2 billion," Schoenebaum wrote.

Although the more comparable price to anti-TNFs doesn't support an advantage when negotiating with insurers about the inclusion of Xeljanz in formularies, "it's easier to make price reductions (vs. substantial increases in prices following approval) if [Pfizer] believes such action would support a formulary advantage and uptake during the launch,' Schoenebaum added.

Xeljanz Leads a Boom in Oral RA Therapies

Analysts also were quick to speculate on the impact of Xeljanz's approval on other companies developing oral medicines to treat RA – potentially with once-daily dosing and/or a better safety profile than the Pfizer drug. Late-stage candidates include Rigel Pharmaceuticals Inc.'s fostamatinib, a Phase III syk inhibitor in a potential $1.2 billion partnership with AstraZeneca plc; Incyte Corp.'s baricitinib (INCB28050), licensed to Eli Lilly and Co. for up to $755 million; and Galapagos NV's GLPG0634, a JAK1 inhibitor that landed a $1.35 billion deal with Abbott in March. (See BioWorld Today, Feb. 17, 2010, Dec. 22, 2009, and March 1, 2012.)

Vertex Pharmaceuticals Inc. also has a JAK inhibitor, VX509, in an ongoing Phase IIb study in the U.S. and Europe.

The OSKIRA Phase III program for fostamatinib in RA is comprised of three pivotal studies of the compound's efficacy and tolerability. Two one-year studies will focus on patients who did not benefit from DMARDs, and a third will cover patients who failed on anti-TNF therapy.

The centerpiece of the program, OSKIRA-4, is evaluating improvements in the RA symptoms with fostamatinib monotherapy compared to placebo in patients who have not had a DMARD, are intolerant of DMARDs or who have not responded adequately to DMARDs. The trial will include three different dosing arms, a comparator arm dosing adalimumab and a placebo arm. AstraZeneca plans to file an NDA for the drug in the second half of 2013. (See BioWorld Today, Oct. 4, 2012.)

Leerink Swann LLC analyst Marko Kozul, writing in a research report on Rigel, noted, "We believe circumstances surrounding [Pfizer's] Xeljanz approval are close to a best case scenario for [Rigel's] Fos-D. Xeljanz's broad label suggests [the] FDA is favorably inclined toward this novel class of potent oral RA therapies."

In a flash comment, Wells Fargo Securities LLC analyst Brian Abrahams said the RA market is large enough to support multiple oral entrants. However, "we continue to believe [Rigel's and AstraZeneca's] fostamatinib could demonstrate more robust structural benefits, given its direct osteoclast inhibition mechanism, potentially a differentiating feature," he wrote. "We remain neutral on [Incyte], but believe this approval should improve enthusiasm around baricitinib."

The FDA is requiring physicians to monitor patients on Xeljanz quarterly for lymphocytes, neutrophils and hemoglobin and bimonthly for cholesterol levels – another differentiator with Enbrel and Remicade, which do not require such monitoring, and a potential disadvantage to the RA drugs still in development, according to Schoenebaum.

His conservative market analysis suggested Pfizer expects 4 percent penetration in the existing RA market next year, or $300 million in revenues, growing to a $1 billion to $1.5 billion opportunity by 2015. Those figures don't take into account that Xeljanz is currently under review in moderate to severely active RA by other regulatory agencies. The European Medicines Agency (EMA) filing was accepted in December 2011, "and we are continuing to work closely with regulatory agencies, including the EMA, on the tofacitinib application," Davis said.

But Schoenebaum dismissed notions that the approval of Xeljanz sounded the death knell for anti-TNFs, which account for the lion's share of a $20 billion market for all RA drugs. With only 400,000 of an estimated 1.7 million U.S. patients currently on approved treatments, the market offers ample room for competition.

"You don't have to sell all of your Amgen because [Xeljanz] is going to crush Enbrel," he said.

More from FDA: No Change to Aricept-23

Following the approval of Xeljanz, Pfizer received another piece of good news from the FDA, which rejected an effort by Public Citizen to ban Aricept (donepezil hydrochloride) 23 mg tablets from the market. The drug is manufactured by Eisai Co. Ltd. and marketed by Pfizer.

The public watchdog filed a petition in May 2011 that also asked the agency to add a warning to the labels for the 5- and 10-mg tablets of Aricept and generic donepezil about the increased toxicity associated with higher doses.

Public Citizen subsequently sued the FDA in September, after the agency failed to respond to its petition, claimed the delay violates the Administrative Procedures Act, claiming "the pace of the FDA's decisional process is lagging unreasonably in light of the nature and extent of the public health interests at stake." (See BioWorld Today, Sept. 7, 2012.)

In rendering its decision, the FDA said it did not err in approving the drug and rejected the petition.