GUSELKUMAB PHARMACOKINETICS AND EXPOSURE-RESPONSE RELATIONSHIPS ARE CONSISTENT FOLLOWING INTRAVENOUS VERSUS SUBCUTANEOUS INDUCTION IN PARTICIPANTS WITH CROHN’S DISEASE

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Introduction

Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64, a receptor on cells that produce IL-23.¹ In the Phase 3 QUASAR maintenance study (NCT04033445), both the GUS 100mg every 8 weeks (q8w) and 200mg q4w subcutaneous (SC) maintenance dose regimens were efficacious.² Here, we evaluated efficacy of these dose regimens in clinically relevant subgroups of participants (pts) with and without extensive ulcerative colitis (UC) disease or high inflammatory burden.

Aims & Methods

Clinical responders after 12 weeks of GUS intravenous (IV) induction were randomized 1:1:1 to GUS 100mg SC q8w, GUS 200mg SC q4w or placebo (PBO) (GUS withdrawal) at start of the maintenance study (M-0). Efficacy endpoints were analyzed at Week (W)44 in the primary analysis population of pts randomized and treated in the maintenance study who had a modified Mayo score of 5-9 at induction baseline (I-0). Subgroup analyses were conducted by (1) extent of UC disease (limited to left side of colon vs extensive) based on screening endoscopy and/or medical history at I-0 and (2) inflammatory burden based on serum C-reactive protein (CRP) levels (≤3 vs >3mg/L) at M-0.

Results

Of 568 pts in the primary analysis population, 257 (45.2%) had extensive UC disease at I-0 and 182 (32.0%) had serum CRP >3mg/L at M-0.
Proportions of pts achieving W44 clinical and histologic-endoscopic efficacy endpoints were greater with both GUS dose regimens vs PBO across subgroups (Table). For pts with extensive UC disease, the proportion of pts achieving clinical remission at W44 was numerically greater with GUS 200mg q4w (62.7%) relative to GUS 100mg q8w (49.4%) (PBO, 11.6%). For those with elevated CRP (>3mg/L) at M-0, clinical remission at W44 was achieved by 48.2% of GUS 200mg q4w vs 30.2% of GUS 100mg q8w pts (PBO, 14.3%). Proportions of pts achieving endoscopic improvement, histo-endoscopic improvement, endoscopic remission, and maintenance of clinical remission were also greater with GUS 200mg q4w in these subgroups. Among pts with disease limited to the left side of the colon or CRP ≤3mg/L at M-0, proportions of pts achieving these efficacy endpoints were similar with GUS 100mg q8w and GUS 200mg q4w.

Table. Key efficacy endpoints at maintenance W44 in subgroups of pts from QUASAR defined by extent of UC disease (limited to left side of colon vs extensive) at I-0 and inflammatory burden (serum CRP ≤3 vs >3mg/L) at M-0
Includes pts with modified Mayo score of 5-9 at induction baseline who achieved clinical response to GUS induction and were re-randomized at maintenance study entry. ^*P<0.05, ^†P<0.01, ^‡P<0.001 vs PBO (nominal P values), based on the Cochran-Mantel Haenszel test stratified by clinical remission status at maintenance baseline and induction treatment, except for maintenance of clinical remission where P values were based on Fisher’s exact test. ^aDenominator includes only pts with clinical remission at maintenance baseline. Clinical remission is defined as a stool frequency subscore of 0 or 1 and not increased from induction baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability. Maintenance of clinical remission is defined as clinical remission at W44 among pts in clinical remission at maintenance baseline. Endoscopic improvement is defined as an endoscopy subscore of 0 or 1 with no friability. HEMI is defined as achieving a combination of histologic improvement and endoscopic improvement. Endoscopic remission is defined as an endoscopy subscore of 0. Pts who had an ostomy or colectomy, dose adjustment, prohibited change in UC medication, or who discontinued study agent due to lack of efficacy or an AE of worsening of UC prior to W44 were considered not to have achieved the efficacy endpoints. For pts who discontinued study agent due to COVID-19 related reasons (excluding COVID-19 infection) or regional crisis in Russia and Ukraine prior to W44, the observed values were used if available. Pts who discontinued study agent for other reasons prior to W44 were considered not to have achieved the endpoint. Nonresponder imputation for missing data: pts who were missing 1 or more of the components pertaining to an endpoint at W44 were considered not to have achieved the endpoint. Pts who had an unevaluable biopsy were considered not to have achieved histologic endpoints. AE=Adverse event; CRP=C-reactive protein; GUS=Guselkumab; HEMI=Histologic-endoscopic mucosal improvement; I-0=Induction study baseline; M-0=Start of the maintenance study; PBO=Placebo; pts=Participants; Q4W=Every 4 weeks; Q8W=Every 8 weeks; SC=Subcutaneous; UC=Ulcerative colitis; W=Week.
	Extent of UC disease						Serum CRP
	Limited to left side of colon			Extensive			≤3mg/L			>3mg/L
	GUS withdrawal (PBO) (N=95)	GUS 100mg SC Q8W (N=109)	GUS 200mg SC Q4W (N=107)	GUS withdrawal (PBO) (N=95)	GUS 100mg SC Q8W (N=79)	GUS 200mg SC Q4W (N=83)	GUS withdrawal (PBO) (N=127)	GUS 100mg SC Q8W (N=125)	GUS 200mg SC Q4W (N=134)	GUS withdrawal (PBO) (N=63)	GUS 100mg SC Q8W (N=63)	GUS 200mg SC Q4W (N=56)
Clinical remission	26.3%	42.2%^*	40.2%^*	11.6%	49.4%^‡	62.7%^‡	21.3%	52.8%^‡	50.7%^‡	14.3%	30.2%^*	48.2%^‡
Maintenance of clinical remission^a	45.2% (14/31)	56.1% (23/41)	64.1% (25/39)	21.4% (6/28)	68.0%^‡ (17/25)	83.3%^‡ (25/30)	41.5% (17/41)	63.5%^* (33/52)	67.3%^* (35/52)	16.7% (3/18)	50.0% (7/14)	88.2%^‡ (15/17)
Endoscopic improvement	26.3%	47.7%^†	42.1%^*	11.6%	51.9%^‡	63.9%^‡	21.3%	56.8%^‡	51.5%^‡	14.3%	34.9%^*	51.8%^‡
HEMI	24.2%	43.1%^†	40.2%^*	9.5%	44.3%^‡	57.8%^‡	18.9%	51.2%^‡	48.5%^‡	12.7%	28.6%^*	46.4%^‡
Endoscopic remission	22.1%	31.2%	25.2%	8.4%	39.2%^‡	44.6%^‡	18.1%	40.0%^‡	34.3%^†	9.5%	23.8%^*	32.1%^†

Conclusion

For pts with moderately to severely active UC with extensive disease or high inflammatory burden, greater efficacy rates were observed with GUS 200mg SC q4w compared with GUS 100mg SC q8w.

References

1. Sachen KL et al. Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling. Front. Immunol. 2025;16:1532852.
2. Rubin DT et al. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. Lancet. 2025;405(10472):33-49.

Disclosure

Study support: Johnson & Johnson.
JRA: Abbvie, Bristol Myer Squibb, Ferring, Finch, Iterative Scopes, Johnson & Johnson, Merck, Pfizer, Roivant, Seres Therapeutics and Roivant Adiso
TH: AbbVie, Bristol Myers Squibb, Daiichi-Sankyo, EA Pharma Co, Ltd., JIMRO, Eli Lilly, Gilead Sciences, Johnson & Johnson, Kissei Pharmaceutical Co, Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc and Takeda Pharmaceutical Co., Ltd
BB: AbbVie, Alimentiv, Allergan, Amgen, AMT, Bausch Health, Bristol Myers Squibb, Business Intelligence, Celgene, Celltrion, Eupraxia Fresenius Kabi, Ferring, Genentech/Roche, Gilead, Iterative Scopes, GlaxoSmithKline, Jamp, Johnson & Johnson, Merck, Microbiome Insights, Mylan, Novartis, Organon, Pendopharm, Pfizer, Protagonist, Qu Biologic, Sandoz, Takeda, and Viatris
LPB: AbbVie, Abivax, Adacyte, Alimentiv, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect, Cytoki, Eli Lilly, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech/Roche, Gilead, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG, InDex, Inotrem, Johnson & Johnson, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM, ONO, OSE, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Vectivbio, Ventyx, Viatris, Vifor, and Ysopia
MG, SY, NS, YM: Johnson & Johnson.
BES: AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Johnson & Johnson, Kaleido, Kallyope, Lilly, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics
DTR: Abbvie, Altrubio, Apex, Avalo Therapeutics, Bristol-Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Johnson & Johnson, Lilly, Pfizer, Samsung Neurologica, and Takeda.
AD: Abivax, AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, CED Service GmbH, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Gilead, High5MD, Johnson & Johnson, Lilly, Materia Prima, MedToday, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Thieme, Tillotts, UniMed Verlag and Vifor Pharma

EFFICACY OF GUSELKUMAB IN MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS BY EXTENT OF DISEASE AND INFLAMMATORY BURDEN: SUBGROUP ANALYSIS OF THE PHASE 3 QUASAR MAINTENANCE STUDY

Jessica Allegretti 1, Tadakazu Hisamatsu 2, Brian Bressler 3, Laurent Peyrin-Biroulet 4, Matthew Germinaro 5, Shadi Yarandi 5, Nicole Shipitofsky 5, Ye Miao 5, Bruce E. Sands 6, David T. Rubin 7, Axel Dignass 8

1 Brigham and Women´s Hospital Crohn's and Colitis Center, Boston, United States

2 Kyorin University, Tokyo, Japan

3 University of British Columbia, Vancouver, Canada

4 Nancy University Hospital, Université de Lorraine, Nancy, France

5 Johnson & Johnson, Spring House, United States

6 Icahn School of Medicine at Mount Sinai, New York, United States

7 University of Chicago Medicine, Chicago, United States

8 Agaplesion Markus Hospital, Frankfurt, Germany

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

	GUS 200 mg IV q4w (N=622)	GUS 400 mg SC q4w (N=229)
C_max(µg/mL) Mean (SD)	70.1 (25.1)	27.7 (9.06)
C_{ave, week 0-12}(µg/mL) Mean (SD)	21.4 (7.06)	18.9 (6.47)
C_{trough, week 12}(µg/mL) Mean (SD)	9.76 (5.38)	14.7 (6.65)
AUC_{week 0-12}(day*µg/mL) Mean (SD)	1,800 (593)	1,590 (543)
AUC_{week 0-12}=area under the concentration-time curve from week 0 to week 12 (induction); C_{ave, week 0-12}=average concentration from week 0 to week 12 (induction); C_max=maximum concentration; C_{trough, week 12}=trough concentration at week 12 (induction); IV=intravenous; PK=pharmacokinetic; q4w=every 4 weeks; SC=subcutaneous; SD=standard deviation; W=week.

Outcome	EBD (n=35)	ES (n=34)	p-value	Odds Ratio (95% CI)
Technical Success (%)	91.4% (32/35)	94.1% (32/34)	0.70	-
Clinical Recurrence (%)	48.6%	23.5%	0.026	0.343 (0.134–0.881)
Re-intervention Rate (%)	25.7%	8.8%	0.025	0.337 (0.131–0.870)
Surgery (%)	11.4%	5.9%	0.581	0.707 (0.207–2.422)
Stricture-related ED Visits (%)	20.0%	11.8%	0.062	0.404 (0.156–1.047)
Stricture-related Hospitalizations (%)	25.7%	8.8%	0.023	0.276 (0.091–0.840)
Any Adverse Event (%)	25.7% (9/35)	14.7% (5/34)	0.45	-

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