From the AGA Journals

Guselkumab found promising for Crohn’s in phase 2 study

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Bringing hope to clinicians

Over the last 20 years, multiple targeted therapies have been developed for Crohn’s disease (CD) and have changed the management landscape for this chronic disease. Despite many successes, a proportion of patients still experience treatment failure or intolerance to the currently available biologics, and the need for ongoing development of new therapies remains. This study by Sandborn and colleagues highlights the development of a novel therapy for Crohn’s disease patients. The novel therapy, guselkumab, targets a more specific interleukin pathway (IL-23p19 inhibition) than is currently available. In the study, guselkumab was found to be effective at improving multiple clinical parameters such as Crohn’s Disease Activity Index and Patient-Reported Outcome–2 as well as objective parameters including biomarker response and endoscopic response in patients with moderate to severe CD. There was no apparent exposure response observed over multiple dose regimens. Guselkumab also demonstrated a favorable safety profile.

Robin Dalal, MD, is an assistant professor of medicine, director of IBD education, and director of the advanced IBD fellowship at Vanderbilt University Medical Center in Nashville, Tenn.

Dr. Robin Dalal

As clinicians, the promising results from this phase 2 trial bring hope for additional treatment options for Crohn’s disease patients. As the management landscape for CD further changes, options for patients will grow and thoughtful decisions regarding sequencing of the available therapies will become more important. More selective interleukin inhibition with IL-23p19 has been shown to be superior to dual blockade of IL-12/IL-23 in psoriasis; however, it is unknown if the same will be true for Crohn’s disease. Further research will be needed in the future to address any potential efficacy and safety differences between the more specific target of IL-23 signaling.

Robin Dalal, MD, is an assistant professor of medicine, director of IBD education, and director of the advanced IBD fellowship at Vanderbilt University Medical Center in Nashville, Tenn. She reported being a consultant for AbbVie.



Treatment with the human monoclonal antibody guselkumab over 12 weeks was shown to be safe and more effective than placebo in patients with moderate to severe Crohn’s disease, according to phase 2 trial data

Conventional first-line therapies for Crohn’s disease (CD) often are not effective for maintaining clinical remission and are associated with significant toxicity concerns, wrote study investigator William J. Sandborn, MD, of the University of California, San Diego, and colleagues. Guselkumab is a human monoclonal antibody that selectively inhibits the p19 subunit of interleukin 23, a cytokine that plays an important role in gut inflammation, the researchers wrote. Their report was published online Feb. 5 in Gastroenterology.

In the phase 2 GALAXI-1 study, Dr. Sandborn and colleagues evaluated the safety and efficacy of guselkumab in 309 patients with moderate to severe CD for at least 3 months. All patients previously had experienced either an inadequate response or intolerance to convention treatment or biologic agents.

Patients were randomly assigned to either placebo (n = 61); intravenous guselkumab at doses of 200 mg (n = 61), 600 mg (n = 63), or 1,200 mg at weeks 0, 4, and 8 (n = 61); or a reference arm comprising ustekinumab approximately 6 mg/kg IV at week 0 and subcutaneous 90 mg at week 8 (n = 63).

The study’s primary endpoint included the change from baseline to 12 weeks in the CD Activity Index score. The mean age of the population was 38.8 years and the mean duration of CD was 8.8 years.

There were patients in the primary efficacy analysis set who discontinued the study through week 12. At one point the study was paused to assess a serious adverse event of toxic hepatitis in a guselkumab-treated patient. Fifty-one patients were discontinued from the study because their induction treatment was paused during the adverse event evaluation; however, these patients were included in the safety analyses.

At the 12-week follow-up assessment, patients assigned to all doses of guselkumab experienced significantly greater reductions in the CD Activity Index from baseline when compared with placebo (least squares mean: 200 mg: –160.4; 600 mg: –138.9; and 1,200 mg: –144.9 vs. placebo: –36.2; all P < .05). In addition, a significantly greater proportion of patients in each guselkumab arm achieved clinical remission compared with the placebo group (CD Activity Index < 150; 57.4%, 55.6%, and 45.9% vs. 16.4%; all P < .05).

Among the patients who had an inadequate response or intolerance to prior biologic therapy, 47.5% of those in the combined guselkumab arm and 10.0% in the placebo arm met the criteria for clinical remission at 12 weeks. In addition, 62.4% of patients in the combined guselkumab group and 20% in the placebo group within the prior biologic therapy subgroup achieved clinical response at week 12.

Of patients with inadequate response or intolerance to prior conventional therapy, approximately 60% treated with guselkumab at all doses vs. 22.6% of the placebo group had clinical remission by 12 weeks. Also within this subgroup, 70.2% of patients in the combined guselkumab arm and 29% in the placebo arm had clinical response.

Finally, among the 360 patients in the safety analysis set, the proportions of patients with at least one adverse event were similar across the treatment groups during the treatment period (60% for placebo; 45.7% for guselkumab combined; 50.7% for ustekinumab).

There was no observable relationship between the dose of guselkumab and the proportion of patients with adverse events. Infection rates were 21.4% in the placebo arm, 15.1% in the combined guselkumab group, and 12.7% in the ustekinumab arm. Approximately 3.7% of patients in the combined guselkumab arm, 5.7% of patients in the placebo arm, and 5.6% of patients in the ustekinumab arm experienced at least one serious adverse event.

Greater proportions of patients receiving guselkumab achieved clinical response, Patient Reported Outcomes–2 remission, clinical-biomarker response, and endoscopic response at week 12 vs. placebo. Efficacy of ustekinumab vs. placebo was demonstrated. Safety event rates were generally similar across treatment groups.

Limitations of the study included the small number of patients in the overall dataset and the relatively short treatment period of 12 weeks. The researchers noted that phase 3 studies of guselkumab for the treatment of Crohn’s disease are underway.

Several of the researchers reported conflicts of interest with the pharmaceutical industry. The study received funding from Janssen Research & Development, LLC.

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