Treatment-Resistant Crohn's Disease May Respond to Ustekinumab

Caroline Helwick

June 03, 2011

June 3, 2011 (Chicago, Illinois) — The monoclonal antibody ustekinumab (Stelara, Centocor, Inc), directed against interleukin (IL) 12 and IL-23, induced and maintained clinical responses in patients with moderate-to-severe Crohn's disease (CD) who had previously failed treatment with tumor necrosis factor (TNF) α antagonists, according to a multicenter phase 2b study presented here at Digestive Disease Week (DDW) 2011 by William J. Sandborn, MD, from the University of California–San Diego in La Jolla.

Clinical responses were observed in nearly 40% of these highly treatment-refractory patients receiving ustekinumab. "Furthermore, during the maintenance phase, a statistically significant greater proportion of patients who responded at week 6 achieved clinical remission in the ustekinumab-treated group compared with placebo-treated patients," Dr. Sandborn announced at a plenary session.

IL-12 and IL-23 are implicated in the pathophysiology of CD, Dr. Sandborn noted. Ustekinumab normalizes IL-12- and IL-23-mediated signaling, cellular activation, and cytokine production. It is currently approved for the treatment of moderate-to-severe plaque psoriasis.

Patients in the study had moderate-to-severe CD and had previously failed, or proved intolerant to, TNF antagonists. Scores on the Crohn's Disease Activity Index (CDAI) were 220 or higher and 450 or lower.

Patients were randomly assigned to receive intravenous (IV) placebo or ustekinumab in 1 of 3 doses: 1 mg/kg, 3 mg/kg, or 6 mg/kg. At week 8, patients who received IV ustekinumab induction and who were either responders or nonresponders at week 6 were then rerandomized separately to maintenance therapy with 90 mg ustekinumab given subcutaneously (SC) or placebo SC at weeks 8 and 16, and were then followed through week 22.

Responders to IV placebo received placebo SC at weeks 8 and 16, whereas nonresponders received ustekinumab 270 mg SC at week 8 and ustekinumab 90 mg SC at week 16.

The primary endpoint was clinical response (≥100 point reduction from baseline CDAI) at week 6.

The investigators randomly assigned a total of 526 patients whose median disease duration was 10.3 years and whose mean baseline CDAI was 324. "Almost half the patients had failed 2 or more TNF antagonists. [Of these], one third lost response, and two thirds...were intolerant," Dr. Sandborn said. "This was a very sick population of patients." Half of the patients were receiving concomitant corticosteroids or budesonide, 22% were receiving an immunodulatory drug, and 17% were receiving aminosalicylates.

Clinical Response Achieved By 40% at Week 6

"The study met its primary endpoint," Dr. Sandborn reported. "A clear effect was seen in all treatment [dose] groups." The 6-mg dose tended to produce the best responses, he noted.

At week 6, clinical response was observed in 39.7% of patients in the 6 mg/kg ustekinumab group vs 23.5% in the placebo group (P = .005). By week 8, the clinical response rate rose to 43.6% in the ustekinumab group but dropped to 17.4% with placebo (P < .001).

"We saw a dose response at week 8. There was clear evidence of efficacy," he said.

There were no significant differences in clinical remission at week 6, with 15% of the ustekinumab and 10.8% of the placebo group in remission.

"At week 6, clinical remission rates were numerically, but not statistically, different at this early time point," he said.

However, both remission rates improved by week 8, to 18.3% with 6 mg ustekinumab vs 10.6% with placebo (P = .074), Dr. Sandborn noted.

There were also statistically significant changes at week 6 for all doses vs placebo in CDAI scores, levels of C-reactive protein, fecal lactoferrin and calprotectin levels, and scores on the inflammatory bowel disease questionnaire.

Drug Effective, Safe for Maintenance

"In the maintenance phase, there were significant differences favoring ustekinumab at 22 weeks," Dr. Sandborn said.

Patients who had a clinical response to ustekinumab by 6 weeks were continued on drug or placebo and were assessed at 22 weeks for rates of remissions and response. At this point, clinical remissions were observed in 41.7% (30/72) of the patients receiving SC ustekinumab vs 27.4% (20/73) of the patients receiving SC placebo (P = .029), and responses were observed in 69.4% of the patients receiving SC ustekinumab vs 42.5% of the patients receiving SC placebo (P < .001).

"Through week 22, there were no deaths, serious opportunistic infections, major cardiovascular events, malignancies, or cases of tuberculosis. Infusion- and injection-site reactions were uncommon in both arms, and none were serious," he noted.

Both the IV and SC forms of the drug were well tolerated. Seventy-one percent of the placebo group and 65% of the combined-dose ustekinumab group experienced an adverse event, typical of the CD population, with 7.6% and 5.8% being reported as serious, Dr. Sandborn reported. Only 0.7% of the patients developed antibodies to ustekinumab at any time.

Maria T. Abreu, MD, chief of gastroenterology at the University of Miami Miller School of Medicine, Florida, moderated the Distinguished Abstracts Plenary session at which the results were presented. She commented to Medscape Medical News that, "Ustekinumab seems very effective. I think what is exciting about the drug is that it seems to work in patients who have already failed anti-TNF therapy, and we don't have anything else to offer them. It's already approved for psoriasis, so my hope would be, because we have a lot of safety data, it will be easy to get ustekinumab into the clinic for our [CD] patients who are really desperate."

Dr. Sandborn consuls for ActoGeniX, AGI Therapeutics, Alberio AB, AM-Pharma BV, Amgen, Astellas Pharma Inc, Athersys, Atlantic Healthcare Limited, Axcan Pharma, BioBalance, Celgene Corporation, Celek Pharmaceuticals LLC, Cellerix SL, Chemocentryx, CoMentis, Cosmo Technologies, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai, Enteromedics, and Ferring Pharmaceuticals and receives grant or research support from Abbott, Bristol-Myers Squibb, Centocor, and Elan Pharmaceuticals. Dr. Abreu has disclosed no relevant financial relationships.

Digestive Disease Week (DDW) 2011: Abstract 593. Presented May 8, 2011.

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