By Heidi Ledford

A wave of encouraging clinical-trial data is raising hopes for a new class of drugs to treat rheumatoid arthritis. The therapies, hotly pursued by pharmaceutical companies, inhibit proteins called kinases, and aim to halt the inflammation that causes debilitating pain and eventual destruction of bone and cartilage.

Leading the pack is a compound called tasocitinib, made by the New York-based pharmaceutical giant Pfizer. Yesterday, at the annual American College of Rheumatology meeting in Atlanta, Ga., researchers announced the results of a double-blind, randomized trial in more than 600 patients: tasocitinib eased pain and inflammation in 65.7 percent of those who received the highest dose of the drug, whereas only 26.7 percent of those who received a placebo reported relief.

The company intends to complete additional trials of the compound by mid-2011, and to submit an application for approval to the Food and Drug Administration about six months later. Analysts at Jeffries International, an investment banking firm headquartered in New York, say that sales of tasocitinib could reach $6.5 billion a year.

Meanwhile, Incyte, a pharmaceutical company in Wilmington, Del., presented promising results from a smaller trial of its own kinase inhibitor. And a paper published in September by the New England Journal of Medicine reported that a kinase inhibitor made by Rigel Pharmaceuticals of South San Francisco, California, lessened symptoms in up to 67 percent of the patients who received the drug in a 457-patient study, compared to a 35 percent response in the placebo arm.

Taken together, the results suggest that people with rheumatoid arthritis may soon have new options for treatment, says Gary Firestein, a rheumatologist at the University of California, San Diego School of Medicine. "We've crossed the Rubicon with respect to kinase inhibitors," he says. "It's a very exciting time."

Transformative treatments

Such drugs could have a wide reach. About one person out of every hundred has rheumatoid arthritis, and the global market for drugs to treat the condition swelled from $1.3 billion in 1998 to $13 billion in 2009.

Therapies introduced in that time have revolutionized treatment, says William Robinson, a rheumatologist at Stanford University School of Medicine in California. Back in 1998, "there were many patients in the waiting room with deformities from their rheumatoid arthritis," he says. "Their hands were deviated over and twisted."

Disfigured hands are now rare. Yet low-level disease persists in many patients, and some still face debilitating pain, says Robinson.

Many existing drugs for rheumatoid arthritis are expensive protein therapies, such as the blockbuster antibody drug Remicade (infliximab), marketed in the United States by Centocor of Horsham, Penn., which earned about $6 billion in global sales in 2009. But for around a third of rheumatoid arthritis patients, these drugs either fail or produce intolerable side effects, says Paul Friedman, chief executive of Incyte.

In addition, protein drugs must be injected, and often persist in the body for a long time. That can be a drawback for patients experiencing unwanted side effects. "One of the claims to fame is that you only have to be injected once a month," says Friedman. "But if something goes wrong, you also can't get it out of your system for at least that month."

As a result, companies have pushed to develop drugs that could be taken orally. Initial results were discouraging: attempts to simply replace the protein therapies with small-molecule drugs that hit the same targets largely failed, says Saeed Fatenejad, a rheumatologist at Pfizer who is responsible for clinical development of tasocitinib. "There's been a lot of effort to do that," he says. "We've tried them ourselves and obviously we haven't been successful."

And several attempts to carve a new target from a family of enzymes called p38 kinases have also failed, despite favorable results in animal models.

Kinases that work through different pathways, however, now seem to hold more potential.

A promising mechanism

Both tasocitinib and Incyte's drug, INCB028050, target Janus kinases, which mediate signaling by immune-system proteins called cytokines. Suppressing those signals could limit the autoimmunity that causes inflammation in rheumatoid arthritis patients. In December 2009, Incyte sold the commercialization rights to its compound to Eli Lilly, a drug-maker based in Indianapolis, Ind., for $750 million.

Tasocitinib is expected to make it to market, says Jeffrey Stoll, an analyst at IMS Health, a pharmaceutical market research company headquartered in Norwalk, Conn.. But the drug faces many hurdles. Early results show that it causes a drop in levels of certain white blood cells, increasing the possibility of infections, and raises cholesterol, a worrying side effect in a patient population that is already prone to cardiovascular disease. And none of these kinase inhibitors have yet been rigorously tested in a head-to-head comparison with the protein therapies already on the market.

Rigel's kinase inhibitor, called fostamatinib, targets spleen tyrosine kinase, which among other functions enables the formation of the large immune-cell complexes found in autoimmune diseases. In February, Rigel licensed its drug to AstraZeneca, a pharmaceutical company headquartered in London, for $100 million upfront, to be followed by up to $1.2 billion if the drug meets developmental milestones.

Overall, the results from oral kinase inhibitors are very exciting, says Robinson. But he adds that, as with any drug that suppresses autoimmunity, the risk that a diminished immune response could lead to infection remains a concern. Thus far, such side effects seen in clinical trials have been minor, but it sometimes takes years of exposure to a drug before deadly infections show up, he says.

Nevertheless, patients will ultimately benefit from a wide range of treatment options. Better understanding of the mechanisms driving rheumatoid arthritis in individual patients will ultimately fragment the disease into different subtypes, says Robinson. "There won't be a one-size-fits-all drug for rheumatoid arthritis," he says. "We'll need drugs targeting the mechanisms that drive arthritis in different subsets of patients."