Tofacitinib Shows Efficacy for Ulcerative Colitis Treatment

Nancy A. Melville

August 15, 2012

August 15, 2012 — Tofacitinib (Pfizer), a selective oral inhibitor belonging to the new class of medications called Janus-associated kinase, or JAK, inhibitors shows efficacy over placebo in the treatment of moderate to severe ulcerative colitis, according to the results of a phase 2 clinical trial, published this week in the New England Journal of Medicine.

The double-blind study involved 194 patients with moderate to severe active ulcerative colitis, most of whom had failed to respond to conventional therapy, including mesalamine, glucocorticoids, immunosuppressants, or anti-TNF agents.

William Sandborn, MD, from the University of California, San Diego, La Jolla, and colleagues randomly assigned patients to receive either tofacitinib at a dose of 0.5, 3, 10, or 15 mg or placebo twice daily for 8 weeks.

The primary outcome was a clinical response, defined as a decrease from baseline in the Mayo scoring system score for ulcerative colitis activity, which ranks severity on a scale from 0 to 12, and a decrease of 1 point or more from baseline in the rectal bleeding subscore.

At 8 weeks 78% of the patients receiving the highest dose of tofacitinib showed a clinical response compared with 42% of those receiving the placebo (P < .001). None of the groups receiving lower doses showed rates of clinical response that reached statistical significance.

Ten percent of the patients in the placebo group experienced clinical remission, defined as a Mayo score of 2 or greater, with no subscore lower than 1. The rate of remission for the lowest dose (13%; P = .76) showed no significant difference from placebo, but the remaining groups did show statistically significant rates of clinical remission. In the 3-mg, group the remission rate was 33% (P = .01); it was 48% in the 10-mg group and 41% in the 15-mg group (P < .001 for both groups).

Through its mechanism of JAK inhibition, tofacitinib is designed to interfere with enzymes associated with inflammation. The drug has also shown efficacy in the prevention of organ allograft rejection and the treatment of psoriasis, rheumatoid arthritis, and other immunologic diseases.

Previous studies, largely with rheumatoid arthritis, have shown the most common adverse effects to include bronchitis, headache, and gastrointestinal symptoms, with more serious adverse effects including increased low-density lipoprotein (LDL) cholesterol and serum creatinine levels, as well as an increased risk for infection.

In the current study, investigators observed a dose-dependent increase in both LDL and HDL cholesterol concentrations, and 3 patients experienced absolute neutrophil count decreases to fewer than 1500/mm3.

There were no increases in aspartate aminotransferase, alanine aminotransferase, or serum creatinine concentrations, however, nor were there decreases in serum hemoglobin concentration.

The most serious adverse events related to infection and included influenza and nasopharyngitis, occurring in 6 patients each. Two patients in the twice-daily 10-mg dose group experienced serious adverse events from infection, including postoperative abscess in one and anal abscess in the other.

The authors noted that the causes for the adverse effects are still unclear. "The mechanism for the alterations in cholesterol profile is unknown," they write. "The clinical consequences of these laboratory abnormalities require further study."

According to Gil Y. Melmed, MD, director of clinical trials at the Cedars-Sinai Medical Center's Inflammatory Bowel Disease Center in Lon Angeles, California, the JAK inhibitors represent an intriguing new potential for ulcerative colitis.

"It's a new class of drugs that I think could potentially offer a new way to treat ulcerative colitis," said Dr. Melmed, who is also an assistant clinical professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles.

"Right now we don't have a lot of therapeutic options for patients with moderate to severe ulcerative colitis, especially for patients who fail mesalamine and require immunosuppressants," he told Medscape Medical News. Dr. Melmed was not involved in the phase 2 study.

"It's really that category of patients — with moderate to severe disease — that were studied in this particular trial, and for those patients who fail conventional and biologic therapy, who are at risk for worsening disease, and for whom hospitalization and surgery may be the appropriate next step," he continued.

Dr. Melmed added that the fact that tofacitinib is an oral drug is an additional benefit. "The current anti-TNF agent approved for ulcerative colitis (infliximab) is an intravenous drug, so I think it would be nice to have an oral option for patients who fail conventional immunosuppressive treatment."

Although agreeing that more needs to be understood about the potential adverse effects, Dr. Melmed noted that the older age of patients in rheumatoid arthritis trials may warrant different considerations for increases of cholesterol and neutropenia seen in patients treated with tofacitinib.

"Patients with rheumatoid arthritis are generally older than those with ulcerative colitis, so I'm not really sure how those side effects will or won't be relevant in the [ulcerative colitis] population," he said.

James A. Vecchio, MD, director of gastroenterology and hepatology and a professor of medicine at the University of Vermont in Burlington, agreed that the drug could represent a welcome addition to clinicians' armamentarium for ulcerative colitis.

"I believe this medication will be a valuable alternative medication for inflammatory bowel disease: an oral agent with a different mechanism of action," he told Medscape Medical News. He too was not involved in the study

"This was only an 8-week trial, so to extrapolate out to years of therapy is not supported by these data, still, this is exciting news and will definitely create a stir in the [inflammatory bowel disease] forums," he said. "The issues will be cost and … the adverse effects such as infections, liver-related injury, or cancers related to its use."

Another expert, Edward Loftus Jr, MD, director of the Inflammatory Bowel Disease Clinic at Mayo Clinic in Rochester, Minnesota, noted that with steep challenges in treating ulcerative colitis patients, effective new agents are high on physicians' wish-lists.

"These are tough patients because there is no one drug that works universally well, and there is a lot we don't understand about these chronic inflammatory conditions, so the more agents with different mechanisms of action the better," he told Medscape Medical News.

"The JAK inhibitors, rather than blocking a specific cytokine, have a novel way of trying to block inflammation by blocking downstream signaling intracellularly, so this is very promising," he concluded.

The study was sponsored by Pfizer. Dr. Sandborn has received grants, consulting fees, travel support, and other types of funding from Pfizer. Full conflict-of-interest information is available on the journal's Web site. Dr. Melmed is a local site investigator for the phase 3 clinical trial for tofacitinib in ulcerative colitis trial; however, he was not involved in the phase 2 trial. He has received an investigator-initiated grant from Pfizer for an unrelated product. He has also served as a consultant to Jannsen, Given Imaging, Amgen, and Celgene and has been a speaker for Abbott and Prometheus Labs. Dr. Vecchio has disclosed no relevant financial relationships. Dr. Loftus is a local site investigator for the phase 3 clinical trial for tofacitinib in ulcerative colitis trial; however, he was not involved in the phase 2 trial. He has been a consultant for Pfizer and has received research support from the company.

N Engl J Med. 2012;367:616-624.

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