Introduction
The QUASAR program (NCT04033445) evaluated guselkumab (GUS), a dual-acting interleukin (IL)-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64 (a receptor on cells that produce IL-23), in patients (pts) with moderately to severely active ulcerative colitis (UC). Induction Week 12 (Week I-12) nonresponders to intravenous (IV) GUS received subcutaneous (SC) GUS through Week I-24.1 Week I‑24 responders were eligible for maintenance therapy. Here, we present the efficacy and safety of maintenance SC GUS among GUS Week I-24 responders.
Aims & Methods
Pts who were not in clinical response (see Table for definition) at Week I-12 after IV GUS 200 mg or 400 mg received SC GUS 200 mg at Weeks I-12, I-16, and I-20. Those who were in clinical response at Week I-24 (GUS Week I-24 responders) received SC GUS 200 mg every 4 weeks during the maintenance study in a blinded fashion and were evaluated as part of the nonrandomized study population. Clinical, symptomatic, endoscopic, histologic, and patient-reported outcome measures at maintenance Week 44 (Week M-44) and safety throughout the maintenance study are reported for GUS Week I-24 responders.
Results
Overall, 123 of 203 (60.6%) Week I-12 nonresponders to IV GUS achieved clinical response at Week I-24 and entered the maintenance study phase. Induction baseline characteristics of GUS Week I-24 responders were: 74.8% had severe disease (modified Mayo score 7-9), 77.2% had a Mayo endoscopy subscore of 3, median C-reactive protein was 5.0 mg/L (upper limit of normal, 3 mg/L), and 59.3% had a history of inadequate response or intolerance to biologic or Janus kinase inhibitor therapy for UC. At Week M‑44, 67.5% of the pts maintained clinical response and 30.1% were in clinical remission. Additional efficacy outcomes are shown in the Table. The proportion of GUS Week I-24 responders in symptomatic remission (defined as a stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0) at maintenance baseline (58.5%) was sustained through Week M‑44 (56.9%). Adverse events (AEs) were reported for 78.0% of GUS Week I-24 responders, serious AEs for 5.7%, and serious infections for 1.6%. No opportunistic infections or deaths occurred. No new safety concerns were identified.
| Table. Efficacy Outcomes at Maintenance Week 44 for GUS Induction Week 12 Nonresponders Who Achieved Clinical Responsea at Induction Week 24 |
|---|
| GUS 200 mg SC q4w
N=123
n (%)
|
Clinical remissionb
| 37 (30.1)
|
Endoscopic improvementc / Endoscopic normalization (remission)d
| 44 (35.8) / 21 (17.1)
|
Corticosteroid-free clinical remissione
| 37 (30.1)
|
Maintenance of clinical responsef
| 83 (67.5)
|
Histologic-endoscopic muscosal improvementg
| 34 (27.6)
|
Fatigue responseh
| 49 (39.8)
|
Maintenance of clinical remissioni, N=20
| 10 (50.0)
|
GUS=guselkumab; PROMIS=Patient-Reported Outcomes Measurement Information System; pts=patients; q4w=every 4 weeks; SC=subcutaneous; Week M-44=maintenance Week 44.
Note: Includes only pts with modified Mayo score 5-9 at induction baseline.
a Clinical response was defined as a decrease from induction baseline in the modified Mayo score by ≥30% and ≥2 points, with either a ≥1-point decrease from induction baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.
b Clinical remission was 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.
c Endoscopic improvement was defined as an endoscopy subscore of 0 or 1 with no friability present on the endoscopy.
d Endoscopic normalization (remission) was defined as an endoscopy subscore of 0.
e Corticosteroid-free clinical remission was defined as clinical remission at Week M-44 without any use of corticosteroids for ≥8 weeks prior to Week M-44.
f Maintenance of clinical response was defined as clinical response at Week M-44 among pts in clinical response at maintenance baseline.
g Histologic-endoscopic muscosal improvement was defined as achieving a combination of histologic improvement (defined as neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system [i.e., Geboes score ≤3.1]) and endoscopic improvement.
h Fatigue response was defined as a ≥7-point improvement from induction baseline in the PROMIS Fatigue Short Form 7a.
i Maintenance of clinical remission was defined as clinical remission at Week M-44 among pts in clinical remission at maintenance baseline.
|
Conclusion
In this refractory population of GUS Week I-24 responders, maintenance treatment with GUS provided clinical benefit across a range of clinically relevant efficacy endpoints. Safety results were consistent with the overall population and safety profile of GUS in its approved indications.
References
1. Bressler B, et al. Am J Gastroenterol. 2023;118(10S):806-807.
Disclosure
D. T. Rubin: research funding from Takeda; consultant to AbbVie, Altrubio, Allergan, Arena, Aslan, Athos, Bellatrix, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corp/Syneos, Connect, GalenPharma/Atlantica, Genentech/Roche, InDex, Ironwood, Iterative Scopes, Janssen, Lilly, Pfizer, Prometheus, Reistone, Takeda, and Techlab; and co-founder of Cornerstones Health.
A. Dignass: fees for participation in clinical trials, review activities (data monitoring boards, statistical analysis, endpoint committees) from Abivax, AbbVie, Bristol Myers Squibb, Dr Falk Foundation, Galapagos, Gilead, Janssen, and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Tillotts, and Vifor Pharma; payment for lectures/speaker’s bureaus from AbbVie, Biogen, CED Service GmbH, Celltrion, Falk Foundation, Ferring, Galapagos, Gilead, High5MD, Janssen, Materia Prima, MedToday, MSD, Pfizer, Sandoz, Takeda, Tillotts, and Vifor Pharma; payment for manuscript preparation from Abbvie, Falk Foundation, Janssen, Takeda, Thieme, and UniMed Verlag.
J. R. Allegretti: consultant for AbbVie, Adiso, Ferring, Finch, Iterative Scopes, Janssen, Merck, Pfizer, Roivant, and Seres Therapeutics; speaker for AbbVie, Bristol Myer Squibb, and Janssen; and research support from Janssen, Merck, and Pfizer.
Y. Rayyan: fees for participating in clinical trials for Janssen as principal investigator and payment from lectures including service on speaker’s bureaus from Janssen, AbbVie, and Amgen.
M. Saruta: grants or contracts from Mochida, Zeria Pharma, EA Pharma, Kissei, and EPS Corporation; and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AbbVie GK, Janssen, Mitsubishi Tanabe Pharma, Takeda, EA Pharma, Gilead Sciences, and Kissei.
D. Balderramo: advisor/speaker fees from AbbVie, Janssen, Pfizer, Takeda, and Amgen; and travel/congress support from AbbVie, Janssen, Takeda, and Ferring.
B. Bressler: advisor/speaker for AbbVie, Bristol Myers Squibb, Ferring, Janssen, Merck, Novartis, Organon, Pfizer, Sandoz, and Takeda; advisor for Alimentiv, Allergan, Amgen, AMT, Bausch Health, Bristol Myers Squibb, Celgene, Celltrion, Eupraxia Fresenius Kabi, Genentech/Roche, Gilead, Iterative Scopes, Jamp, Merck, Microbiome Insights, Mylan, Pendopharm, Protagonist, and Viatris; research support from AbbVie, Amgen, Business Intelligence, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Janssen, Merck, and Qu Biologic; and holds stock options in Qu Biologic.
L. Peyrin-Biroulet: consultant for AbbVie, Abivax, Alimentiv, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect, Cytoki, Lilly, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech/Roche, Gilead, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG, InDex, Inotrem, Janssen, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, and Ysopia; grants from Celltrion, Fresenius Kabi, and Takeda; honorarium for lectures from AbbVie, Amgen, Arena, Biogen, Celltrion, Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Janssen, Medac, MSD, Pfizer, Sandoz, Takeda, Tillots, Viatris, and Vifor; and fees from AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio.
T. Hisamatsu: grant support from AbbVie, Daiichi-Sankyo, EA Pharma, JIMRO, Mitsubishi Tanabe Pharma, Mochida, Nippon Kayaku, Pfizer, and Takeda; consulting fees from EA Pharma, Janssen Research & Development, Gilead Sciences, Lilly, and Bristol Myers Squibb; and lecture fees from AbbVie, EA Pharma, Mitsubishi Tanabe Pharma, Takeda, Mochida, and Kissei.
S. Yarandi, K.-H. G. Huang, M. Germinaro, J. Zhan, and H. Zhang: employees of Johnson & Johnson and own company stock/stock options.
