Efficacy and Safety of Intravenous Induction and Subcutaneous Maintenance Therapy with Guselkumab for Patients with Crohn’s Disease: Written Recap

In this Managed Healthcare Executive "Between the Lines" video series, Remo Panaccione, M.D., and Anita Afzali, M.D., M.P.H., discussed the treatment of Crohn’s disease and the GALAXI-2 and GLAXI-3 trials that assessed guselkumab, sold under the brand name Tremfya, as a new treatment for the condition. Panaccione, the lead investigator of the trials and first author of the study reporting the results in The Lancet in July 2025, is a professor of medicine at the University of Calgary and the director of the Inflammatory Bowel Disease Unit there. Afzal, who was also among the investigators of the GALAXI trials, is a professor of medicine at the University of Cincinnati.

Treatment strategy

Panaccione and Afzali started by discussing the advantages of keeping patients with Crohn’s disease on one therapy. Patients are switched from one treatment to another if they stop responding to a treatment or if there are safety concerns, Afzali noted. However, routine rotation of medication is not a good idea, she said, because it can affect the efficacy and duration of the response. Panaccione said that routine switching can limit treatment options if a change is necessary. They also discussed barriers to access. Afzali pointed to step therapy as a problem. “It’s quite challenging because we continue to deal with payers and insurance companies where they are mandating fail-first or step therapy,” she said. Panaccione said that these requirements impinge on shared decision-making between clinicians and patients and on healthcare provider autonomy.

Mechanisms of action

Afzali gave a brief overview of many of the current therapies for Crohn’s disease. She mentioned infliximb [sold under the brand name Remicade and as biosimilars to Remicade] and adalimumab [sold under the brand name Humira and as biosimilars to Humira], which interrupt inflammatory processes by inhibiting tumor necrosis factor (TNF)-alpha. Vedolizumab [sold under the brand name Entyvio] is an anti-integrin agent that is “gut-selective therapy” that blocks leukocyte trafficking to the intestinal tract, she explained. Ustekinumab [sold under the brand name Stelara, among others] targets the shared p40 subunit of both interleukin (IL)-12 and IL-23. Afzali also mentioned upadacitinib, a Janus kinase (JAK) inhibitor that inhibits cytokine signaling via the JAK-signal transducer and activator of transcription pathway. Guselkumab stands out, Afzali said, as having a dual-action mechanism that targets the p19 subunit of IL-23, blocking IL-23 and modulating the Th17 inflammatory cascade, while also reducing CD64 expression on intestinal macrophages. Panaccione noted that ustekinumab was developed when IL-12 was thought to be the dominant cytokine in the inflammatory process that causes Crohn’s disease. Only later, he said, was the importance of blocking the p40 subunit, which is shared between IL-12 and IL-23, recognized. With the anti-p19 therapies, including guselkumab, “I think we just have a more targeted anti-IL23 agent," Panaccione said.

GALAXI trial design

GALAXI-2 and GALAXI-3 were identical in design, phase 3 clinical trials that enrolled adult patients with moderately to severely active Crohn’s disease. Afzali said that an important feature of the trials was the treat-through design, which meant that patients remained on the treatment they were initially allocated to. (Patients in the placebo group who did not respond to treatment by week 12 were treated with ustekinummab on a blinded basis.) Afzali also noted the both trials had an active comparator, ustekinumab, to guselkumab; enrolled patients who had been previously treated with a biologic; and included endoscopic assessments at week 12 and week 48.

Paccione said the fact that there were two separate trials “gives us additional confidence in the results” and also allowed for a pooled analysis that lent more statistical power to the comparison with ustekinumab. He also said the coprimary composite end points at week 12 and week 48, which involved clinical and endoscopic assessments, were key features. “Success wasn’t measured really at a population level, the way we usually do for many of our clinical trials, but at the individual patient level, and I think that really adds to the robustness of the program.”

The patients enrolled in the GALAXI studies were adults with moderate to severe Crohn’s disease, defined by Crohn’s Disease Activity Index scores ranging from 220 to 450. Participants were required to have objective evidence of active inflammation based on endoscopic assessment, with a Simple Endoscopic Score for Crohn’s Disease of at least 6, or 4 if inflammation was limited to the ileum. This endoscopic requirement added robustness to patient selection by confirming disease location and severity, Afzali noted. Panaccione said the inclusion and exclusion criteria led to a “broad population” being recruited into the two trials. Panaccione noted, though, that the necessary exclusion of patients who had been treated with ustekinumab or related agents would limit interpretation of the data.

Afzali and Panaccione said that the patients enrolled in the GALAXI trials were representative of those seen in clinical practice. The median duration of disease was 8 to 10 years, Afzali noted. Panaccione pointed out that there was an approximately 50-50 split among the study participants between those who had been exposed to treatment with a biologic and those who had not. Among those who had been exposed to a biologic, over 90% had been exposed to an anti-TNF agent.

‘Obviously’ positive

Afzali said the GALAXI-2 and GALAXI-3 results showed favorable results for gusekkumab on multiple fronts: efficacy, durability of response, rapidity of response — and “with a clean safety profile.” Panaccione agreed with the overall takeaway. “I mean, obviously this was a positive trial.”

Digging into the particulars, Panaccione mentioned the results that showed that guselkumab was superior to placebo with respect to both clinical and endoscopic end points at both a 100-milligram (mg) subcutaneous dose given every eight weeks during the maintenance phase of therapy and a 200-mg dose given every four weeks, also during the maintenance phase. He said “perhaps more important” was gusekumab’s superiority to ustekinumab across multiple end points, including endoscopic response, endoscopic remission and a composite of endoscopic and clinical remission. “That superiority over a drug that I think many of our colleagues are using in clinical practice is a very, very powerful message,” Panaccione said.

Afzali noted that the GALAXI end points were designed to align with STRIDE [Selecting Therapeutic Targets in Inflammatory Bowel Disease]-II guidelines that delineate short-, intermediate-, and long-term treatment goals for Crohn’s disease, and the results show that guselkumab achieved those treat-to-target results.

“For patients, those clinical end points are super important because the symptoms are the way patients live their daily lives,” Panaccione commented, adding that achieving endoscopic end points “pays forward.”

“We know that that's associated with decreased hospitalization, decreased surgeries, decreased steroid use [and] decreased flares in the future,” he said.

Safety

The adverse event data from the GALAXI trials did not signal any safety issues with guselkumab, Afzali and Panaccione said. In fact, Panaccione said, there were more serious infections and serious adverse events in the placebo group than in the study participants randomly assigned to guselkumab. “I think that the data are reassuring, and I think that this is a very safe medication,” said Panaccione. Afzali said that nothing in the GALAXI trial results would cause her to monitor patients receiving guselkumab any differently than patients taking other medications. A primary concern isthat patients are up to date with their immunizations and avoiding live vaccines.

“I completely agree there's nothing in the safety profile or adverse events that is going to make me evaluate or monitor patients differently,” said Panaccione. “If anything, you could probably say that you don't need to monitor as much because of the lack of adverse events here. But I agree. I have a standard monitoring protocol — what I say to patients and what I would do as far as blood work — and it's not going to change with this therapy.”

Limitations

Afzali and Panaccione agreed that the GALAXI trials' limitations were of the kind seen with any client trial: to provide clear answers certain patient populations need to be selected so others are left out and not every end point be assessed. Afzali noted that patients with penetrating or stricturing disease phenotypes were excluded, and Panaccione noted the absence of patients with perianal fistulizing disease. “We really need to start including patients who have a more aggressive phenotype into our trials,” said Afzali. Panaccione said, though, that experience with other Crohn’s disease therapies has shown them to be effective in these kinds of patients, and therefore there is reason to be confident that the same will be true for guselkumab. He mentioned that there is a study underway to assess guselkumab as a therapy among patients with perianal fistulizing disease, and that another trial is using transmural healing as an end point.

Takeaways

For patients, Afzali would emphasize the symptomatic relief, endoscopic healing, and safety profile of guselkumab, and for providers, the rigorous design of the GALAXI trials. For payers, she said the message from the GALAXI trialss should be that guselkumab could help patients avoid steroid therapy and also complications from Crohn’s disease that could be costly to treat.

Panaccione gave guselkumab a ringing endorsement. “Patients can expect true control of inflammation, whether you measure that by symptoms or endoscopy, which is really going to lead to a better quality of life for these patients, and with a biologic agent that works not only in [treatment-]naive patients but also for those patients [who] have experienced other biologic therapies,” he said. Panaccione acknowledged the many treatment options for Crohn’s disease but said that guselkinumab might represent the “best balance of efficacy without really sacrificing safety and really represents a simple, effective drug that also has flexible dosing.” He said the GALAXI results should show clinicians that they are gaining a “potent, evidence-based option that can be positioned confidently in the treatment algorithms" and perhaps as a first-line treatment.

Payers may throw up obstacles to the use of guselkinumab, Panaccione said. However, he believes the evidence for guselkumab could overcome the resistance. “I think if people within those organizations truly looked at the data, the robustness of the trial design, the robustness of the end points, [they would see that] guselkumab really represents a high-value therapy with evidence of superiority and durable outcomes. I think that because of that, there are potential long-term savings for the payers.”