Tag Archives: IL23

Pivotal Study: Guselkumab Efficacy in Ulcerative Colitis (QUASAR study)

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DT Rubin et al. Lancet 2024; 405: 33-49. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies

Background: “Guselkumab is a dual-acting, human IgG1, interleukin-23p19 subunit inhibitor that potently neutralises interleukin-23 and can bind to CD64.”

Methods:  “Two phase 3, randomised, double-blind, placebo-controlled studies (QUASAR phase 3 induction and maintenance) included randomised and treated adults with moderately to severely active ulcerative colitis (induction baseline modified Mayo score from 5 to 9) with inadequate response or intolerance to conventional or advanced ulcerative colitis therapy.”

“The induction study primary population included 701 patients (guselkumab 200 mg given intravenously 60% [421 patients]; placebo 40% [280 patients]). The maintenance study primary population included 568 guselkumab induction responders randomly assigned to receive guselkumab 200 mg given subcutaneously every 4 weeks (190 [33%] patients) or 100 mg every 8 weeks (188 [33%] patients) or placebo (guselkumab withdrawal 190 [33%] patients).”

Key findings:

  • INDUCTION DATA AT 12 WEEKS:
At induction week 12
At induction week 12
Induction symptomatic endpoints -response noted in majority of guselkumab-treated patients by 4 weeks

MAINTENANCE DATA AT 44 WEEKS

Results and Discussion points:

  • “Symptomatic improvement was observed as early as induction week 1 (first assessed timepoint)”
  • “Greater reductions in C-reactive protein and faecal calprotectin concentrations with guselkumab induction compared with placebo were observed as early as induction week 4 (first assessed timepoint)”
  • “Guselkumab efficacy was shown in both biologic naive and JAK inhibitor-naive patients, and in patients with a history of inadequate response or intolerance to biologics or JAK inhibitors”
  • “Overall, 34% (129 of 378) of patients in the guselkumab groups achieved endoscopic
    remission     at maintenance week 44. Among the 180 patients in the guselkumab groups in clinical remission at maintenance week 44, 124 (69%) of 180 were in endoscopic remission”
  • “Symptomatic remission and deep symptomatic remission achieved with guselkumab induction was generally maintained to maintenance week 44 with guselkumab relative to placebo”
  • “The incidences of anti-guselkumab antibodies and NAbs were low in both the induction and maintenance studies…titres were low and did not affect serum concentration, efficacy, or safety”
  • “Head-to-head comparison data with other IL-23 antagonists are currently not available”
  • “Safety results were consistent with the known and favourable safety profile of guselkumab in its approved indications. Rates of adverse events, serious adverse events, and adverse events leading to treatment discontinuation generally did not occur more frequently in patients treated with guselkumab versus placebo-treated patients”
  • Limitation: The primary analysis population for the maintenance study included only guselkumab induction responders following 12 weeks of intravenous treatment

My take: Overall, this is a pivotal study showing that guselkumab is an effective agent for moderately to severely active ulcerative colitis in those with and without prior treatments. More head-to-head studies are needed to determine the optimal positioning of therapies for UC. Currently, AGA guidelines (AGA Living Guideline for Moderate-to-Severe Ulcerative Colitis –The Good and The Bad) suggest that guselkumab should be considered in the top tier of medications used in patients naive to biologics/advanced therapies and in the second tier for those with prior biologic treatments.

Related blog posts:

Efficacy of Mirikizumab in Ulcerative Colitis: LUCENT-3 Study Results

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BESands, et al.  Inflammatory Bowel Diseases, 2024. 30: 2024 2245–2258. Open Access! Two-Year Efficacy and Safety of Mirikizumab Following 104 Weeks of Continuous Treatment for Ulcerative Colitis: Results From the LUCENT-3 Open-Label Extension Study

In this LUCENT-3 study, the authors examined response at 2 years among patients who had response to treatment at 1 year; patients received 200 mg mirikizumab every 4 weeks. The authors stratified patients by induction response and by previous biologic exposure.

Key findings (from Figure 4):

HEMR= histologic-endoscopic mucosal remission
  • No new safety signals were identified, and the discontinuation rate due to adverse events was 2.8%

My take: It is good to see extended data for mirkizumab. Head-to-head trials, though, are needed to better determine which therapies are most effective.

Related blog posts:

Pipeline Medications for Ulcerative Colitis (Part 2)

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To continue with topic of new medications for ulcerative colitis started yesterday -two more articles:

  • WJ Sandborn et al. Gastroenterol 2020; 158: 537-49
  • S Danese. Gastroenterol 2020; 158: 467-70 (commentary)

The first reference describes a randomized phase 2 study of mirikizumab with 249 patients.  Mirikizumab is a monoclonal antibody to the p19 subunit of IL23. A similar agent, ustekinumab is a monoclonal antibody directed at the p40 subunit of IL23 and IL12; thus mirikuzumab is more selective targeting of IL23. the authors examined response to the study drug at 3 doses: 50 mg, 200 mg, and 600 mg and compared to intravenous placebo.  All patients received dosing at weeks 0, 4, and 8. A subset of patients continued with subcutaneous treatment starting at week 12, with 47 receiving 200 mg every 4 weeks and 46 receiving 200 mg every 12 weeks. 63% of patients in this trial had previous exposure to biologics.

Key findings:

  • At week 12, 15.9% (50 mg), 22.6% (200 mg), and 11.5 % (600 mg) in the treatment groups achieved clinical remission compared to 4.8% of the placebo group
  • Clinical responses occurred in 41.3%, 59.7%, and 49.2% in the respective treatment groups compared to 20.6% in placebo group
  • At week 52, clinical remission was achieved in 46.8% of SC every 4 weeks and 37.0% every 12 weeks.

In the commentary, Danese reviews the pipeline of new drugs emerging for ulcerative colitis.  Full Text Link: New Drugs in the Ulcerative Colitis Pipeline: Prometheus Unbound

A couple of key points:

  • “Like Prometheus, who gave fire to humans and paid with the price of eternal torment, so the gift of new drugs in ulcerative colitis brings the consequence of patients with heterogeneous disease being cycled indiscriminately through similarly modestly effective agents.”
  • “Predictive biomarkers are needed” to optimize treatment and avoid ineffective and potentially harmful treatments

My take: The emergence of new treatments is welcome given the frequent loss of response or lack of response to current therapies.  Two questions: How will we decide which agent(s) is the best one to use? When will pediatric studies be available?