Tag Archives: etanercept

New Anti-Inflammatory Drugs Will End Anti-TNF Dominance

Tumor necrosis factor inhibitor drugs began to dominate treatment of inflammatory diseases like rheumatoid arthritis, psoriasis, and the inflammatory bowel diseases ulcerative colitis and Crohn’s disease a little over a decade again. Now, the time when the importance of the anti-TNFs will wane and newer drugs will take their place is clearly visible on the horizon. It hasn’t happened yet, but the era of anti-TNF dominance for treating inflammatory diseases that persisted throughout the 2000s will end in the next 5 years.

The anti-TNF era began in 1998 with the approval of etanercept (Enbrel) for rheumatoid arthritis and infliximab (Remicade) to treat Crohn’s disease. In subsequent years, the list of approved anti-TNFs expanded to include adalimumab (Humira), golimumab (Simponi), and certolizumab (Cimzia), and the approved indications grew to include many inflammatory disease of joints, the GI tract, and skin. The anti-TNFs revolutionized inflammatory disease treatment and made treatment to remission possible for many patients.

tumor necrosis factor (green, purple, black) and TNF receptors (blue)/courtesy Bassil Dahiyat; Science

But reports from just the past month show that new agents are overtaking the anti-TNFs.

In May, I reported from Digestive Disease Week on phase III trial results with vedolizumab, which was compared against placebo for patients with ulcerative colitis. One of the study investigators noted that vedolizumab beat the placebo arm for steroid-free clinical remission by 30 percentage points. “Nothing else is that good,” Dr. William Sandborn, professor of medicine and chief of gastroenterology at the University of California, San Diego, told me, and the benchmark he had in mind was the performance of the anti-TNFs in similar patients.

More recently, at the European Congress of Rheumatology earlier this month I heard a report on a head-to-head comparison of the anti-IL-6 drug tocilizumab (Actemra) and the anti-TNF adalimumab in patients with rheumatoid arthritis. After 24 weeks of monotherapy, patients on tocilizumab had nearly a fourfold higher remission rate than patients on adalimumab. Though the monotherapy trial design did not mimic the way most rheumatoid arthritis patients get treated, the new drug tocilizumab absolutely blew adalimumab out of the water in a rare head-to-head comparison among different classes of anti-inflammatory drugs.

And at the same meeting several talks highlighted another new anti-inflammatory class of agents coming soon to the U.S. market, the Janus kinase (JAK) inhibitors, such as tofacitinib, which is expected to received FDA approval later this summer. Phase III results show that tofacitinib has safety and efficacy that seems at least comparable to anti-TNF drugs, with the advantage of oral dosing.

Vedolizumab, tocilizumab, and tofacitinib are just the tip of new waves of anti-inflammatory drugs that will soon substantially alter a landscape that the anti-TNFs have mostly had to themselves for the past 14 years. For the moment, the anti-TNFs have the advantage of a longer track record for safety, but changing that is only a matter of time.

—Mitchel Zoler (on Twitter “mitchelzoler)

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Filed under Allergy and Immunology, Dermatology, Drug And Device Safety, Family Medicine, Gastroenterology, Health Policy, IMNG, Internal Medicine, Practice Trends, Primary care, Rheumatology, The Mole

Beating the Rheumatoid Arthritis Clock

The sooner top-level rheumatoid arthritis treatment starts, the better a patient’s chances for remission, according to a new analysis reported last week at the annual European Congress of Rheumatology, EULAR, in Rome.

image courtesy Flickr user Jackie Kever

Two years ago, results from the COMET study showed that starting RA patients on a combined regimen of methotrexate and etanercept led to significantly more remissions after 1 year on treatment than methotrexate alone. The new, post-hoc analysis divided the 400+ patients in the study, who began treatment 3-24 months after their RA diagnosis, into two subgroups: patients who began treatment within 4 months after their RA diagnosis, and patients who started treatment beyond 4 months.

The striking results, reported last week by Paul Emery, a rheumatologist at the University of Leeds, U.K., showed that patients begun on the tumor necrosis factor (TNF) inhibitor etanercept plus methotrexate within the first 4 months following diagnosis achieved a 70% remission rate after 1 year compared with a 48% rate in patients started on the same regimen but after the first 4 months passed. This time-dependent effect on remission rates did not appear in patients begun on methotrexate alone. In the methotrexate arms about 1/3 of patients reached remission after a year regardless of when the methotrexate started.

The 70% remission rate in the very-early treatment group jumps out as remarkably good, a “dreamed of” response rate, Prof. Emery said. The findings also reveal a clear window of opportunity. Newly diagnosed RA patients hit early with top-level treatment stand the best chance for their disease to fully resolve, a finding that extends the growing trend in rheumatology to diagnose and treat patients asap.

But the finding also sets up a tension between the potential reward from giving a TNF inhibitor plus methotrexate upfront and early and the potential downside that this strategy will put many patients on an expensive TNF inhibitor who would never need it. After all, a third of the patients in the methotrexate-only arm went into remission without ever seeing a TNF inhibitor. Will rheumatologists now need to decide between taking advantage of a transient opportunity to get the most out of treatment and the risk of giving patients a drug they might never really need?

Not necessarily. COMET ran during 2004-2006, so patients had their RA diagnosed by now obsolete criteria. New RA diagnostic criteria introduced by EULAR and the American College of Rheumatology last October aim to diagnose RA patients much earlier, and in these patients the treatment window of opportunity may be longer.

Second, even if patients start on a TNF inhibitor and methotrexate, another recent report from the Leeds group suggests that once in remission some patients can withdraw from the TNF inhibitor and remain in remission.  And third, hopefully in the near future researchers will find factors that identify the patients who will not optimally respond to  methotrexate alone so that adding a TNF inhibitor will not need to be done universally and in some cases needlessly.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Filed under Family Medicine, IMNG, Internal Medicine, Rheumatology