By a vote of 8 to 2, an independent arthritis advisory committee recommended in May 2012 that the U.S. Food and Drug Administration (FDA) approve a new, oral medication called tofacitinib for patients with moderate to severe rheumatoid arthritis, or RA, whose disease does not respond to at least one other currently available treatment. Tofacitinib would be the first oral disease-modifying antirheumatic drug, or DMARD, approved in more than a decade. Its effectiveness is being compared to that of biologic drugs.

Many committee members also stressed the need for long-term studies to track the drug’s safety if it does receive FDA approval.

The drug’s maker, Pfizer Inc., says it appreciates the panel’s “robust discussion” that led to the recommendation. “The RA patient population needs additional treatment options, and Pfizer looks forward to working with the FDA on next steps as it completes its review of the tofacitinib application,” Yvonne Greenstreet, MD, senior vice president and the head of Medicines Development Group for Pfizer Specialty Care, said in a written statement.

The FDA is not expected to make a final decision on tofacitinib until August. The agency is not required to follow the recommendations of its advisory committees, but generally does. Pfizer says it plans to make tofacitinib available to patients as soon as possible upon FDA approval

Tofacitinib is part of a new class of drugs known as “JAK inhibitors” that block Janus-associated kinase, or JAK, pathways, which are involved in the body’s immune response. JAK inhibitors are expected to compete for sales with biologic agents such as adalimumab, or Humira, and etanercept, or Enbrel, which revolutionized the treatment of RA and other types of inflammatory arthritis when they hit the marketplace almost 15 years ago. Unlike biologics, which are made from large and complex engineered proteins and taken by injection or infusion, JAK inhibitors are small-molecule medications that would be taken orally, once or twice a day.

Because they are not as complicated to manufacture, JAK inhibitors are expected to be less expensive than biologics, which can cost tens of thousands of dollars per year. Pfizer is not commenting on pricing.

For patients, JAK inhibitors will serve as an alternative to biologics – although they act in different ways. Tofacitinib essentially fights inflammation from inside the cell, while biologics block pro-inflammatory cytokines from outside the cell. There are several other small-molecule drugs like tofacitinib in testing phases, but this is the first to come before the FDA for approval.

“I think what’s notable about tofacitinib is it’s a new strategy for treating autoimmune diseases by blocking intracellular signaling,” explains John O’Shea, MD, scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, or NIAMS, which is part of the National Institutes of Health, or NIH, in Bethesda, Md. Dr. O’Shea discovered one of the JAK pathways, for which he won the Arthritis Foundation's Howley Award in 2009. “What’s exciting to me about this is that we’ve gone from the discovery of a pathway about 20 years ago hopefully to new drugs that can help people with autoimmune diseases.”

Dr. O'Shea discloses he has had a collaborative research and development agreement with Pfizer since the 1990s and holds a patent with NIH for targeting JAKs.

If approved, the FDA will also have to decide on a dose – 5 mg and/or 10 mg – as well as the indication (the group of patients for which it will be approved).
 

Patience White, MD, vice president for public health at the Arthritis Foundation and professor of medicine and pediatrics at George Washington University School of Medicine in Washington, D.C., says she believes the panel’s recommendation is the start of a positive development for RA patients. “As a rheumatologist, I think it’s an exciting decision, because it gives a new option for patients who have not responded to the current therapies,” she says. “I am thrilled about the decision but also know I have to be judicious in who I would recommend this drug for because, like all drugs, it has a side effect profile we don’t know enough about.”

The advisory committee reviewed data from five phase 3 studies from Pfizer involving nearly 5,000 patients who hadn’t responded well to other RA drugs on the market, such as methotrexate or TNF-alpha blockers. The studies showed more patients experienced a 20 percent reduction in markers of disease activity when taking 5 mgs of the medication compared with those taking a placebo. Percentages of improvements were even higher among those on the 10 mg dose. Four studies showed patients taking the new medicine had improvements in their physical function, too.

In addition to reviewing scientific data, the panel members also heard comments and testimony from the public, including that of Jan Wyatt, RN, PhD, a member of the Arthritis Foundation's board of directors and an RA patient.

“I think it has a lot of exciting potential. If it would be as effective as the biologics and have the convenience of oral administration, it would obviously be a very attractive medication,” says Donald Miller, professor and chair of the pharmacy practice department at North Dakota State University in Fargo.

In its briefing documents, the FDA staff members did raise concerns about whether the benefits of tofacitinib outweigh the risks, which include increased rates of malignancies, particularly lymphoma. Study participants also experienced an increased risk of infections like pneumonia, saw their cholesterol levels and their liver enzymes rise and had increased rates of neutropenia, a condition in which the body’s white blood cell count gets low, making it hard to fight infection.

Because tofacitinib is part of a new class of drugs, its potential risks and benefits are different than those of traditional DMARDs, like methotrexate, and biologics. This point was highlighted by Sarah Yim, MD, associate director of the Division of Pulmonary, Allergy, and Rheumatology Products at the FDA. In those briefing documents, she wrote, “As a new molecular entity targeting a novel pathway in RA, tofacitinib may have a unique benefit-risk balance that cannot be inferred from previous experience with other products approved for RA.”

Pfizer says long-term studies are currently underway to better understand the pill’s long-term effects, but stresses that current research is promising and shows the drug is ready for the market. “We have seen benefits as early as two weeks and the efficacy was maintained up to three years in long term studies,” explains Tamas Koncz, MD, PhD, Pfizer’s Global Medical Leader for tofacitinib. “The efficacy profile and the safety profile is in line with the currently available treatment options.”

But, Miller says, it’s hard at this point in the process with any new medication to fully understand how a wide variety of patients will react to it in real-world conditions. “It’s been a couple thousand patients studied [so far], and when it comes on the market, it will be used by tens of thousands. That’s when a more rare side effect would be seen,” he says. “We need a few years of experience in wide use to see how its safety matches up to the biologics.”

For that reason, many rheumatologists say that for the vast majority of their patients, they’ll continue to rely on RA medications that have been available for years, even if tofacitinib becomes available. “It’s not a first-line drug for several reasons,” explains Daniel Furst, MD, director of rheumatology and therapeutic research at the Geffen School of Medicine at the University of California, Los Angeles. “We don’t have the long-term experience with it. We don’t know the long-term cardiovascular outcome, and we do have that experience with other drugs. I think it is very effective and I think it will be a significant advance, but you never get something for nothing, and there is definite baggage that goes along.”

Scott Zashin, MD, a clinical professor of medicine at the University of Texas, Southwestern Medical School and an attending physician at Presbyterian Hospital in Dallas, agrees that tofacitinib, while promising, likely won’t be something that he rushes to offer most of his patients.

“I tend to steer my patients to drugs that have been around for years and have a long-term track record,” Dr. Zashin explains, but notes that tofacitinib may be a good option for RA patients who don’t respond well to current treatments.