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UNITI-1: Stelara induces response, remission in Crohn's refractory to anti-TNF
ORLANDO — Stelara was well tolerated and effective for inducing clinical response and remission in moderate-to-severe Crohn’s disease patients who failed one or more anti-tumor necrosis factor therapies, according to results from a phase 3 multicenter, double-blind, placebo-controlled trial presented at the Advances in Inflammatory Bowel Disease annual conference.
Stelara (ustekinumab, Janssen) “is a fully human IgG1 monoclonal antibody that targets the p40 subunit that is shared by interleukin-12 and interleukin-23,” William J. Sandborn, MD, from University of California San Diego, said during his presentation. “Ustekinumab is currently approved for psoriasis and psoriatic arthritis and has been in development for Crohn’s disease for some time. Induction therapy in the phase 3 program was presented in patients who were naive to anti-TNF therapy but failing conventional therapy in the UNITI-2 study.”
William J. Sandborn
To determine the safety and efficacy of IV ustekinumab induction among patients with moderate-to-severe active Crohn’s disease refractory to anti-TNFs, Sandborn and colleagues randomly assigned 245 patients to receive 130-mg ustekinumab, 249 to receive 6-mg/kg ustekinumab and 247 to receive placebo. Clinical response at week 6 served as the primary endpoint, and secondary endpoints included week 8 clinical remission, week 8 clinical response, and Crohn’s Disease Activity Index response at weeks 3 and 6.
Week 6 clinical response was achieved by 34.3% of the 130-mg dose group and 33.7% of the 6-mg/kg dose group vs. 21.5% of the placebo group (P = .002; P = .003, respectively). Week 8 clinical remission was achieved by 15.9% of the 130-mg dose group and 20.9% of the 6-mg/kg dose group vs. 7.3% of the placebo group (P = .003; P < .001, respectively). Adverse events occurred in 65.3% of the treatment groups vs. 64.9% of the placebo group, though no anaphylaxis or serious infusion reactions were reported.
“In patients with moderate-to-severely active Crohn’s disease who failed one or more anti-TNF agents, IV ustekinumab was significantly effective for inducing clinical response and clinical remission,” Sandborn said. “The magnitude of treatment effects was generally greater at the higher 6-mg/kg dose as compared to the 130-mg fixed dose, and that seemed to be particularly true for the week 8 induction endpoints. Clinical efficacy was confirmed by improvements in health-related quality of life and objective measures of inflammation, including CRP and fecal markers. Both IV ustekinumab induction regimens were well tolerated, and paired with the UNITI-2 data, … induction efficacy with ustekinumab has been demonstrated across the spectrum of moderate-to-severe active Crohn’s disease patient populations, including both anti-TNF naive and anti-TNF failure patients.” – by Adam Leitenberger
Reference: Sandborn W. Abstract O-001. Presented at Advances in Inflammatory Bowel Diseases; Dec. 10-12, 2015; Orlando, Fla.
Disclosures: Sandborn reports he is a consultant for AbbVie, Arena Pharmaceuticals, Celgene, Pfizer, Prometheus and Receptos.
Perspective
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Ustekinumab is an anti-IL-12/IL-23 agent that’s already marketed for psoriasis and psoriatic arthritis, and is a first-line drug for patients with moderate-to-severe psoriasis. It was tested in patients with Crohn’s disease who have had moderate-to-severe disease, not responding to corticosteroids or immunosuppressives. In one trial called UNITI-2, and in a second trial called UNITI-1, it was tested in patients who had failed conventional agents as well as anti-TNF agents.
In UNITI-2, where patients had failed conventional agents, the average duration of disease was 6 years, and in UNITI-1, which involved patients who had failed anti-TNF agents, the average duration of disease was approximately 10 years. It turns out that both trials showed ustekinumab was more effective, but there was actually a 20% difference between the response rates in UNITI-2 and UNITI-1. In other words, the longer duration of disease and the more refractory disease limits the absolute potential of this agent.
In a talk at AIBD 2015, I argued for earlier intervention with novel agents, and particularly one such as ustekinumab, which is safe enough to administer to a broad population of patients with psoriasis; but, based on the development in Crohn’s disease, it is more likely going to be reserved for late-stage disease. I think it is very ironic that patients with psoriasis are going to have availability of this drug early, but among patients with Crohn’s disease, it is the least likely patients to respond who are actually going to get this safe and — what looks to be — a very effective agent.