Tag Archives: IL-23

What Caught My Eye in a Recent Anti-IL23 Commentary

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This recent commentary on the all-subcutaneous induction and maintenance treatment with guselkumab, an anti-IL23 agent, reviewed the GRAVITI study. Related post: Guselkumab for Crohn’s Disease: Pivotal GRAVITI Study

However, what captured my attention was the last sentence: “The convenience of subcutaneous induction enhances patient friendliness, positioning guselkumab as a strong market contender. Could an oral anti–IL-23 formulation be the next game changer?14“

“Johnson & Johnson (NYSE: JNJ) today announced positive topline results from ANTHEM-UC, a Phase 2b study of icotrokinra (JNJ-2113), the first investigational targeted oral peptide that selectively blocks the IL-23 receptor, in adults with moderately to severely active ulcerative colitis (UC)…

In the ANTHEM-UC study (n=252), three doses of once daily icotrokinra were tested with all meeting the primary endpoint of clinical response at Week 12. A response rate of 63.5% for patients treated with the highest dose of icotrokinra was achieved at Week 12 versus 27% for placebo (p<0.001). Further, 30.2% of patients treated with the highest dose of icotrokinra demonstrated clinical remission at Week 12 versus 11.1% of patients who received placebo (p<0.01). Remission and response rates continued to improve through Week 28.

  • Clinical response is defined as decrease from baseline in the modified Mayo score by greater than or equal to (>=) 30 percent (%) and >=2 points, with either a >=1-point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.
  • Clinical remission is defined as a Mayo stool frequency subscore of 0 or 1 and not increased from induction baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1 with no friability present on the endoscopy.”

My take: It would be terrific for patients with inflammatory bowel disease (and other immune-mediated diseases) to have another excellent oral therapy. A prior study of plaque psoriasis indicated that an oral IL-23 medication is feasible (Related post: In Trials: An Oral IL-23 Antagonist Peptide).

Related joke (regarding “caught my eye” in the title of this post):

A man who lived in a block of apartments thought it was raining and put his head out the window to check.  As he did so a glass eye fell into his hand. He looked up to see where it came from in time to see a young woman looking down. “Is this yours?” he asked.

She said, “Yes, could you bring it up?” and the man agreed. On arrival she was profuse in her thanks and offered the man a drink. Shortly afterwards she said, “I’m about to have dinner.  There’s plenty; would you like to join me?” He readily accepted her offer and both enjoyed a lovely meal. As the evening was drawing to a close the lady said, “I’ve had a marvelous evening.  Would you like to stay the night?”  The man hesitated then said, “Do you act like this with every man you meet?”

“No,” she replied, “only those who catch my eye.”

The Manneporte by Claude Monet (at the Metropolitan Museum of Art)

Guselkumab for Crohn’s Disease: Pivotal GRAVITI Study

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A Hart et al. Gastroenterol 2025 (ePUB Ahead of Print) Open Access! Efficacy and Safety of Guselkumab Subcutaneous Induction and Maintenance in Participants With Moderately to Severely Active Crohn’s Disease: Results From the Phase 3 GRAVITI Study

Background: “Guselkumab is a selective dual-acting IL-23p19 subunit inhibitor that potently neutralizes IL-23 by binding to the p19 subunit and to CD64, a receptor on cells that produce IL-23…In the double-blind Phase 2 GALAXI 1 study and the 2 identically designed double-blind Phase 3 GALAXI 2 and GALAXI 3 studies, guselkumab intravenous (IV) induction (200 mg at weeks 0, 4, and 8) followed by subcutaneous (SC) maintenance (200 mg every 4 weeks or 100 mg every 8 weeks) demonstrated efficacy compared with placebo… In addition, guselkumab demonstrated superiority to ustekinumab for multiple endoscopic-based endpoints at week 48 in pooled data from GALAXI 2 and GALAXI 3… The GRAVITI study…evaluated the efficacy and safety of guselkumab SC induction followed by SC maintenance in participants with moderately to severely active Crohn’s disease.

Methods: This was a Phase 3 double-blind, placebo-controlled, treat-through GRAVITI study randomized 347 participants 1:1:1 to guselkumab 400 mg SC every 4 weeks→100 mg SC every 8 weeks (n = 115), guselkumab 400 mg SC every 4 weeks→200 mg SC every 4 weeks (n = 115), or placebo (n = 117).  Placebo participants meeting rescue criteria received guselkumab from week 16 onward. 

Key Findings:

  •  At week 12, significantly greater proportions of participants receiving guselkumab 400 mg achieved clinical remission vs placebo (56.1% vs 21.4%; P < .001), and endoscopic response vs placebo (41.3% vs 21.4%; P < .001)
  • At week 48, significantly greater proportions of participants in both guselkumab groups (100 mg SC every 8 weeks: 60.0%; 200 mg SC every 4 weeks: 66.1%) achieved clinical remission vs placebo (17.1%; P < .001 each) and endoscopic response (44.3%; 51.3%; vs placebo 6.8%; P < .001 each)
  • Immunogenicity: “Antibodies to guselkumab were detected in 24 (8.8%) of the 274 guselkumab-treated participants through week 48. Only 3 of 274 participants (1.1% of the total population) were positive for neutralizing antibodies. Through week 48, no impact of antibodies to guselkumab on serum guselkumab concentrations, efficacy, or injection-site reactions was observed”
At week 12: Compared to placebo, patients receiving Guselkumab had improved clinical remission and endoscopic response. Being naive to previous biologics was associated with a higher endoscopic response but with a lower clinical remission rate.
At week 48: Being naive to previous biologics was associated with a higher clinical remission
At week 48: Being naive to previous biologics was associated with a higher endoscopic remission

Discussion: “The results presented here from GRAVITI were consistent with those reported in the double-blind, treat-through GALAXI trials in which guselkumab induction was administered IV in participants with moderately to severely active Crohn’s disease. For example, 41.3% of participants in the GRAVITI study achieved endoscopic response 12 weeks … whereas 36.9% of participants in the pooled GALAXI studies achieved endoscopic response 12 weeks after guselkumab… IV induction (placebo: 12.2%).”

My take: This study shows that Guselkumab with a SC induction is safe and effective in participants with moderately to severely active Crohn’s disease. IV induction does not appear to be needed. Though IL-23 agents have been important advances, there are still a large number of patients without a good response.

Related blog posts:

In Trials: An Oral IL-23 Antagonist Peptide

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R Bissonnette et al. NEJM 2024; 390: 510-521.An Oral Interleukin-23–Receptor Antagonist Peptide for Plaque Psoriasis

While this study shows that an oral IL-23 antagonist was effective for plaque psoriasis, this is exciting news for the GI physicians as biologic agents that target IL-23 have been shown to be very effective for inflammatory bowel disease (IBD) (eg. Ustekinumab, Risankizimab, Mirikizumab). This “FRONTIER” study shows how to achieve similar results as these biologic therapies.

Biologics are large monoclonal antibodies which cannot be orally absorbed and must be administered either intravenously or as an injection. However, “JNJ-77242113 is an oral interleukin-23–receptor antagonist peptide that selectively and potently blocks interleukin-23 proximal signaling and the production of downstream cytokines such as interleukin-17.” This medication needs to be taken on an empty stomach (this could effect real-world results).

My take: I am expecting that this medication will undergo trials for IBD and suggests that an oral effective therapy is in the therapeutic pipeline.

Guselkumab: Expanding the GALAXI of Treatments for Crohn’s Disease

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WJ Sandborn et al. Gastroenterol 2022; 162: 1650-1664. Open Access: Guselkumab for the Treatment of Crohn’s Disease: Induction Results From the Phase 2 GALAXI-1 Study

Background: Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis.

Methods: GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients with moderate to severe Crohn’s disease 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. n=309 with ~50% having disease refractory to prior biologics

Key findings:

  • At week 12, significantly greater reductions in Crohn’s Disease Activity Index from baseline (least squares means: 200 mg: –160.4, 600 mg: –138.9, and 1200 mg: –144.9 vs placebo: –36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo
  • Improvement compared to placebo was evident as early as week 4
  • Safety event rates were generally similar across treatment groups

My take: This is an exciting time for practitioners taking care of patients as there are an increasing number of pharmacologic and dietary treatments for inflammatory bowel disease. With guselkumab, there may be an overlapping mechanism with ustekinumab which targets IL-12/23.

Related blog post: Emerging Data on Risankizumab for Crohn’s Disease

Emerging Data on Risankizumab for Crohn’s Disease

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From Gastroenterology and Endoscopy News: New Anti–IL-23 Therapy Shows Benefit in Crohn’s Disease

An excerpt:

Two phase 3 placebo-controlled trials with the immune modulator risankizumab demonstrated control of Crohn’s disease whether or not patients had previously received a biologic agent.

Rates of clinical remission at 12 weeks with the interleukin (IL)-23 inhibitor risankizumab (Skyrizi, AbbVie), were about 48% in patients without prior exposure to biologic therapy and more than 40% in those with prior exposure…

The two trials, ADVANCE and MOTIVATE were presented together at the 2021 Digestive Disease Week (abstract 775a)…

Only 12% of patients in the placebo group achieved endoscopic remission versus 40.3% of those on the 600-mg dose of risankizumab (P<0.001). [Rates of endoscopic remission were higher in the biologic-naive (50.5%)]

My take: In addition to ustekinumab (already approved), a number of other therapeutic agents that target IL-23 are likely to be available soon to help manage Crohn’s disease. This includes risankizumab but others with phase 3 studies include brazikumab, mirikizumab, and guselkumab..

Slide from David Rubin Twitter Feed (March 2021). Ozanimod now approved.