Jan. 14, 2017
In September 2016, the Food and Drug Administration (FDA) approved the monoclonal antibody ustekinumab for treatment of active Crohn's disease (CD). Ustekinumab, which targets the cytokines interleukin (IL)-12 and IL-23, offers another option for the significant proportion of patients with CD who do not respond adequately or at all to anti-tumor necrosis factor (TNF) agents. It can be administered intravenously as a weight-based infusion or subcutaneously as a fixed-dose injection. Ustekinumab was approved for use in psoriasis in 2009 and for psoriatic arthritis in 2013.
Ustekinumab was first investigated for CD in a phase IIa induction trial and a subsequent multinational phase IIb trial. In the phase IIb trial, clinical response and glucocorticoid-free remission were significantly higher than placebo at 22 weeks. Those results were the basis for a phase III development program consisting of two 8-week induction trials — UNITI-1 and UNITI-2 — and one 44-week maintenance trial (IM-UNITI). Results of the three trials were published in The New England Journal of Medicine in 2016.
UNITI-1 investigated the safety and efficacy of a single intravenous dose of ustekinumab in 741 patients who had primary or secondary nonresponse to anti-TNF agents or experienced unacceptable side effects. UNITI-2 included 628 patients who had failed conventional therapy or had side effects. The primary end point in these trials was clinical response at six weeks, defined as a decrease in the Crohn's Disease Activity Index (CDAI) score of more than 100 points or a CDAI score less than 150.
In both UNITI-1 and UNITI-2, the response rates were significantly higher among patients receiving ustekinumab — 130 milligrams (mg) or 6 mg per kilo of body weight — than among those receiving placebo. Patients who completed the induction trials then participated in IM-UNITI, where they were randomized to receive subcutaneous maintenance injections of 90 mg of ustekinumab every eight weeks, every 12 weeks or placebo.
Approximately half of patients using ustekinumab were in remission at 44 weeks as opposed to 36 percent of those receiving placebo. Further, more than 50 percent of patients who didn't respond to the induction dose had a response after receiving an additional 90 mg subcutaneous dose at the start of maintenance therapy and about half of those were in remission at the end of the study.
At week 44 of IM-UNITI, approximately 80 percent of patients receiving ustekinumab experienced at least one adverse event compared with 83 percent receiving placebo. For those receiving a maintenance dose of 90 mg every eight weeks, every 12 weeks or placebo, the rates of serious adverse events were 9.9 percent, 12.1 percent and 15.0 percent, respectively. Serious infections occurred in 13 patients across all three groups.
The findings in patients with inflammatory bowel disease (IBD) don't contradict anything previously known about ustekinumab's safety profile although the doses in IBD are higher, according to Edward V. Loftus Jr., M.D., a gastroenterologist specializing in IBD at Mayo Clinic's campus in Rochester and an author of the UNITI studies.
"It's a relatively safe medication," he says. "Unlike anti-TNFs, it doesn't carry black box warnings for lymphoma and infections, and preliminary studies in psoriasis patients indicate the rate of serious infections with ustekinumab is lower."
One of those studies, published in the Journal of Drugs in Dermatology in 2015, found no increased risk of malignancy, serious infection or mortality with ustekinumab among a large registry of psoriasis patients.
Using the same registry data, Dr. Loftus and colleagues assessed serious infection rates among the subset of psoriasis patients who also had IBD. They found that the cumulative incidence of serious infections was higher for the IBD group than for the total psoriasis population, but rates were lower for those treated with ustekinumab compared with other therapies. The findings were presented at Digestive Disease Week (DDW) 2016 in San Diego.
Ustekinumab is more expensive than anti-TNF agents, and third-party payers are still deciding how to cover it. Dr. Loftus speculates patients will have to fail anti-TNF therapy before ustekinumab can be prescribed.
Ustekinumab is being investigated for ulcerative colitis (UC), but appropriate dosing remains a significant roadblock. Another drug, tofacitinib, a selective oral inhibitor of the Janus kinase (JAK) family of kinases, is further along in the investigative process. Janus kinases transduce the signals of multiple cytokines involved in immune function.
In 2012, tofacitinib was approved for use in rheumatoid arthritis in the U.S. In studies it has not shown effectiveness for Crohn's disease, but in two company-sponsored induction trials — OCTAVE Induction 1 and 2 — it outperformed placebo in achieving remission in patients with UC. Results of these studies were presented at the 11th Congress of the European Crohn's and Colitis Organization (ECCO) in Amsterdam.
Patients who completed and achieved clinical response in the induction studies were then enrolled in OCTAVE Sustain, a 52-week study evaluating 5 and 10 mg twice-daily doses of tofacitinib as a maintenance treatment. In that study, too, the number of patients in remission at week 52 — the primary efficacy endpoint — was greater in both the 5 and 10 mg groups compared with placebo. Remission was defined as a Mayo score of 2 or less and a bleeding subscore of 0.
Results of this trial are expected to be presented at both DDW and ECCO in 2017.
An earlier trial evaluated the efficacy of tofacitinib in 194 adults with active UC who were randomized to receive a twice-daily dose of 0.5, 3, 10 or 15 mg for eight weeks. Clinical response in those patients — defined as an absolute decrease in the Mayo score of 3 or more and an absolute bleeding subscore of 0 or 1 — was 32, 48, 61 and 78 percent, respectively, compared with 42 percent of patients receiving placebo. Clinical remission, defined as a Mayo score equal to or less than 2, occurred in 12, 33, 48 and 41 percent of patients receiving tofacitinib compared with 10 percent of those receiving placebo. Results of the trial were published in The New England Journal of Medicine in 2012.
Tofacitinib carries a black box warning for both infection and malignancy, although no signal for infection was seen in the UC trials. Still, Dr. Loftus cautions that since the results haven't been fully published, there is no real way to assess the rate of adverse events associated with the drug. Also unknown is where tofacitinib will be positioned in the treatment pathway after its expected approval sometime in 2017.
"We don't know if this small-molecule drug would be used before a biologic or after a patient has failed one or two biologics. That will be determined with clinical experience," he says.
For more information
Feagan BG, et al. Ustekinumab as induction and maintenance therapy for Crohn's disease. The New England Journal of Medicine. 2016;375:1946.
Papp K, et al. Safety surveillance for ustekinumab and other psoriasis treatments from the psoriasis longitudinal assessment and registry (PSOLAR). Journal of Drugs in Dermatology. 2015;14:706.
Panes J, et al. Improvement in patient-reported outcomes in 2 phase 3 studies of tofacitinib in patients with moderately to severely active ulcerative colitis. European Crohn's and Colitis Organization. Poster presentation P369.
Sandborn WJ, et al. Tofacitinib, an oral janus kinase inhibitor, in active ulcerative colitis. The New England Journal of Medicine. 2012;367:616.