High hopes for arthritis drugs

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High hopes for arthritis drugs

Race is on to develop treatments that inhibit signalling proteins.

Published online 11 November 2010 | Nature | doi:10.1038/news.2010.596

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, Georgia, researchers announced

the results of a double-blind, randomized trial in more than 600 patients:

tasocitinib eased pain and inflammation in 65.7% of those who received the

highest dose of the drug, whereas only 26.7% 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 US 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 US$6.5 billion a year.

Meanwhile, Incyte, a pharmaceutical company in Wilmington, Delaware,

presented promising results from a smaller trial of its own kinase

inhibitor. And a paper published in September by the New England Journal of

Medicine1 reported that a kinase inhibitor made by Rigel Pharmaceuticals of

South San Francisco, California, lessened symptoms in up to 67% of the

patients who received the drug in a 457-patient study, compared to a 35%

response in the placebo arm.

Taken together, the results suggest that people with rheumatoid arthritis

may soon have new options for treatment, says 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 US$1.3 billion in 1998 to US$13 billion in 2009.

Therapies introduced in that time have revolutionized treatment, says

, 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 .

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, Pennylvania, which

earned about US$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 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 favourable 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 signalling 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, Indiana, for US$750 million.

Tasocitinib is expected to make it to market, says Stoll, an analyst

at IMS Health, a pharmaceutical market research company headquartered in

Norwalk, Connecticut. 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 US$100 million upfront, to be followed by up to US$1.2 billion

if the drug meets developmental milestones.

Overall, the results from oral kinase inhibitors are very exciting, says

. 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 . " 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. "

References

Weinblatt, M.E. et al. New Engl. J. Med. 363, 1303-1312 (2010). | Article |

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