Tofacitinib is first oral medication approved for use in treating moderate to severe ulcerative colitis

Aug. 18, 2018

The Food and Drug Administration (FDA) recently expanded the approval of tofacitinib to include adults with moderately to severely active ulcerative colitis (UC). Also approved for the treatment of rheumatoid arthritis in the U.S., tofacitinib is a selective Janus kinase (JAK) inhibitor and the first oral medication approved for use in treating moderate to severe UC. Janus kinases transduce the signals of multiple cytokines involved in immune function. Other FDA-approved treatments for patients with moderately to severely active UC who have failed mesalamine are administered through an intravenous infusion or subcutaneous injection.

"Many patients and providers will find tofacitinib appealing, when compared with an injection or infusion," explains Edward V. Loftus Jr., M.D. Dr. Loftus is a gastroenterologist specializing in inflammatory bowel disease (IBD) at Mayo Clinic's campus in Minnesota and has been a co-investigator on studies examining this drug. "The efficacy of this JAK antagonist was pretty impressive in the pivotal trials — the maintenance data in particular — with very large differences between study drug and placebo for the most relevant clinical outcomes such as clinical remission, mucosal healing and steroid-free remission.

"It also appears to be efficacious in both the anti-TNF-exposed and anti-TNF-naive populations. So this will be a welcome addition to our armamentarium of treatments for ulcerative colitis. It's also the first IBD drug approved with this mechanism of action."

Clinical trials: Efficacy and safety profile

The FDA examined results from three controlled clinical trials to assess tofacitinib's efficacy and safety. In two placebo-controlled induction trials — OCTAVE Induction 1 and 2 — tofacitinib outperformed placebo in achieving remission in patients with UC. Published in the New England Journal of Medicine in 2017, the results for these two eight-week placebo-controlled trials demonstrated that 10 mg of tofacitinib given twice daily induces remission in 17 to 18 percent of patients by week eight.

Patients who completed and achieved clinical response by week eight in the induction studies were then enrolled in a third study, OCTAVE Sustain, a 52-week trial evaluating 5 mg and 10 mg twice-daily doses of tofacitinib as a maintenance treatment. In that trial, the number of patients in remission at week 52 — the primary efficacy endpoint — was greater in both the 5 mg and 10 mg groups when compared with placebo.

By week 52, 34 percent of patients receiving the 5 mg dose and 41 percent of patients receiving the 10 mg dose achieved remission. Remission was defined as a Mayo score of 2 or less and a bleeding subscore of 0. Among patients who achieved remission after eight weeks of treatment, 35 percent of patients receiving the 5 mg dose and 47 percent of patients receiving the 10 mg dose achieved sustained, corticosteroid-free remission.

The safety of chronic use of tofacitinib for ulcerative colitis was studied in the OCTAVE Sustain trial and in the OCTAVE Open trial, a multicenter phase III open-label long-term extension (OLE) study. According to Dr. Loftus, a co-author of the abstract published in Gut in 2018, "the OCTAVE Open results showed no new safety concerns when compared with those observed during trials in patients receiving tofacitinib for treatment of rheumatoid arthritis. Efficacy results from this OLE study support sustained efficacy with tofacitinib 5 mg and 10 mg b.i.d."

The most common adverse events associated with tofacitinib treatment for ulcerative colitis are diarrhea, elevated cholesterol levels, headache, shingles (herpes zoster), increased blood creatine phosphokinase, nasopharyngitis, rash and upper respiratory tract infection.

Less common serious adverse events include malignancy and serious infections such as opportunistic infections. Tofacitinib has a black box warning for serious infections and malignancy.

"In the ulcerative colitis trials, there was a signal for herpes zoster at the higher maintenance dose of 10 mg b.i.d.," explains Dr. Loftus. "About 5 to 6 percent of patients treated with this dose developed shingles during the maintenance study. Patients should be made aware of this, and ideally, they should be vaccinated with the new recombinant shingles vaccine before initiation of tofacitinib."

When asked what role he expects tofacitinib to play in the treatment of ulcerative colitis, Dr. Loftus notes that this may evolve. "I suspect that this drug will be initially utilized as 'salvage therapy' in patients who have had inadequate response to or did not tolerate a biologic (or multiple biologics). But depending on the cost and access by third-party payers, and as we become more familiar with the drug, it may be used earlier in the treatment pathway. It will also be interesting to see if tofacitinib will treat some of the extraintestinal manifestations of IBD such as spondyloarthropathy or skin manifestations or uveitis."

Other JAK inhibitors such as upadacitinib and filgotinib are being studied in phase II and III studies of UC and Crohn's disease. Both of these molecules are selective JAK1 inhibitors, and data from phase II trials published in 2017 in The Lancet and Gastroenterology demonstrated their effectiveness as treatments for moderate to severe Crohn's disease.