Introduction
Guselkumab (GUS), a dual-acting interleukin-23p19 subunit inhibitor, demonstrated efficacy in participants (pts) with ulcerative colitis (UC) treated with intravenous (IV) or subcutaneous (SC) induction. Here, we report the efficacy and safety of SC induction followed by SC maintenance through Week (W) 48 in ASTRO, a phase 3, randomized, double-blind, placebo (PBO)-controlled, treat-through study in pts with moderately to severely active UC.
Aims & Methods
Eligible pts had modified Mayo scores of 5 to 9, rectal bleeding subscore of ≥1, and Mayo endoscopic subscore (MES) ≥2. Pts also had documented inadequate response/intolerance to biologics, Janus kinase (JAK) inhibitors, and/or sphingosine-1-phosphate (S1P) inhibitors (BIO/JAKi/S1Pi-IR) or to corticosteroids, 6-mercaptopurine, or azathioprine. Randomization was stratified by baseline BIO/JAKi/S1Pi-IR status and MES with 418 pts allocated 1:1:1 to GUS 400 mg SC every 4 weeks (q4w) (×3)→GUS 200 mg SC q4w (N=140), GUS 400 mg SC q4w (×3)→GUS 100 mg SC every 8 weeks (q8w) (N=139), or PBO SC (N=139). PBO pts who met rescue criteria were switched to GUS at W16; GUS pts who met rescue criteria stayed on their assigned GUS dose regimen (sham rescue).
Results
At W48, greater proportions of pts in the GUS groups achieved clinical remission compared with PBO (36.7% for GUS 100 mg q8w [Δ 29.5%], 42.9% for GUS 200 mg q4w [Δ 35.6%], 7.2% for PBO) (Table). Endoscopic remission proportions were 25.9% for GUS 100 mg q8w (Δ 20.9%), 26.4% for GUS 200 mg q4w (Δ 21.4%), and 5.0% for PBO. Clinical response, symptomatic remission, endoscopic improvement, histologic improvement, and histologic remission proportions were also greater for GUS vs PBO. Consistent with the results of the overall population, efficacy was also observed for subpopulations of BIO/JAKi/S1Pi-naïve and BIO/JAKi/S1Pi-IR pts. Safety events per 100 pts-years were not greater in the GUS groups compared with the PBO group: adverse events (AE) (GUS 100 mg q8w and 200 mg q4w vs PBO: 308.3 and 310.7 vs 357.1), serious AEs (6.5 and 8.2 vs 38.4), serious infections (0.8 and 2.5 vs 3.7), and AEs leading to treatment discontinuation (4.9 and 4.1 vs 19.8).
Table. Efficacy endpoints at Week 48 in the overall population and by biologic, JAK inhibitor, and/or S1P inhibitor history
| Overall | BIO/JAKi/S1Pi-naïve | BIO/JAKi/S1Pi-IR |
| Outcomes at Week 48 | Placebo SC
(N=139) | GUS 400 mg SC→
GUS 100 mg SC q8w
(N=139) | GUS 400 mg SC→
GUS 200 mg SC q4w
(N=140) | Placebo SC
(N=79) | GUS 400 mg SC→
GUS 100 mg SC q8w
(N=81) | GUS 400mg SC→
GUS 200mg SC q4w
(N=83) | Placebo SC
(N=56) | GUS 400 mg SC→
GUS 100 mg SC q8w
(N=57) | GUS 400 mg SC→
GUS 200 mg SC q4w
(N=55) |
| Clinical remission | 10 (7.2) | 51 (36.7)
Δ 29.5
P<0.001 | 60 (42.9)
Δ 35.6
P<0.001 | 6 (7.6) | 39 (48.1)
Δ 40.3
P<0.001 | 42 (50.6)
Δ 43.0
P<0.001 | 4 (7.1) | 12 (21.1)
Δ 13.7
P=0.034 | 18 (32.7)
Δ 25.2
P<0.001 |
| Clinical response | 26 (18.7) | 78 (56.1)
Δ 37.4
P<0.001 | 83 (59.3)
Δ 40.6
P<0.001 | 19 (24.1) | 52 (64.2)
Δ 39.5
P<0.001 | 54 (65.1)
Δ 40.8
P<0.001 | 7 (12.5)
| 25 (43.9)
Δ 30.9
P<0.001 | 29 (52.7)
Δ 39.3
P<0.001 |
| Endoscopic improvement | 16 (11.5) | 62 (44.6)
Δ 33.1
P<0.001 | 66 (47.1)
Δ 35.6
P<0.001 | 10 (12.7) | 46 (56.8)
Δ 44.0
P<0.001 | 45 (54.2)
Δ 41.7
P<0.001 | 6 (10.7) | 16 (28.1)
Δ 16.0
P=0.024 | 21 (38.2)
Δ 26.8
P<0.001 |
| Endoscopic remission | 7 (5.0) | 36 (25.9)
Δ 20.9
P<0.001 | 37 (26.4)
Δ 21.4
P<0.001 | 5 (6.3) | 27 (33.3)
Δ 26.9
P<0.001 | 28 (33.7)
Δ 27.5
P<0.001 | 2 (3.6) | 9 (15.8)
Δ 11.5
P=0.033 | 9 (16.4)
Δ 12.6
P=0.025 |
| Symptomatic remission | 20 (14.4) | 66 (47.5)
Δ 33.1
P<0.001 | 75 (53.6)
Δ 39.2
P<0.001 | 15 (19.0) | 47 (58.0)
Δ 38.6
P<0.001 | 51 (61.4)
Δ 42.3
P<0.001 | 5 (8.9) | 19 (33.3)
Δ 24.3
P=0.001 | 24 (43.6)
Δ 34.0
P<0.001 |
| Histologic improvement | 18 (12.9) | 65 (46.8)
Δ 33.8
P<0.001 | 73 (52.1)
Δ 39.2
P<0.001 | 13 (16.5) | 45 (55.6)
Δ 38.6
P<0.001 | 50 (60.2)
Δ 43.8
P<0.001 | 4 (7.1) | 20 (35.1)
Δ 26.8
P<0.001 | 23 (41.8)
Δ 34.1
P<0.001 |
| Histologic remission | 15 (10.8) | 52 (37.4)
Δ 26.6
P<0.001 | 63 (45.0)
Δ 34.2
P<0.001 | 11 (13.9) | 35 (43.2)
Δ 29.1
P<0.001 | 41 (49.4)
Δ 35.5
P<0.001 | 4 (7.1) | 17 (29.8)
Δ 21.5
P=0.002 | 22 (40.0)
Δ 32.4
P<0.001 |
Data are presented as n (%); ∆% (adjusted treatment difference) versus placebo; nominal p-value versus placebo. The adjusted treatment difference was based on the common risk difference by use of the Mantel-Haenszel stratum weights and the Sato variance estimator. In the overall population, the p-values were based on the Mantel-Haenszel test, stratified by BIO/JAKi/S1Pi-IR status (Yes/No) and Mayo endoscopic subscore at baseline (Moderate [2]/Severe [3]). For the BIO/JAKi/S1Pi-naive/-IR subgroups, the p-values were stratified only by the Mayo endoscopic subscore at baseline. Participants who, prior to Week 48, had an ostomy or colectomy, a prohibited change in UC medications, discontinued study agent due to lack of efficacy or an AE of worsening of UC, or met rescue criteria per IWRS were considered not to have achieved any of the key efficacy endpoints shown at Week 48. For participants who discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis, their observed values were used, if available. Participants who discontinued study agent prior to Week 48 due to other reasons were considered not to have achieved any of the efficacy endpoints shown at Week 48. Participants who were missing one or more of the components pertaining to an endpoint at Week 48 were considered not to have achieved the endpoint.
Endpoint definitions: clinical remission, Mayo SFS 0/1 and not increased from BL, Mayo RBS=0, and MES 0/1 with no friability; clinical response, ≥30% and ≥2-point decrease from BL in Modified Mayo score with ≥1-point decrease from BL in RBS or RBS 0/1; endoscopic improvement, MES 0/1 with no friability; endoscopic remission, MES of 0; symptomatic remission, SFS 0/1 and not increased from BL and RBS=0; histologic improvement, neutrophil infiltration in <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue per Geboes grading system; histologic remission, absence of neutrophils from the mucosa (both lamina propria and epithelium); no crypt destruction; and no erosions, ulcerations, or granulation tissue per Geboes grading system.
AE=adverse event; BIO=biologic; BL=baseline; COVID-19=coronavirus disease 2019; GUS=guselkumab; IR=inadequate response; IWRS=Interactive Web Response System; JAK=Janus kinase; JAKi=JAK inhibitor; MES=Mayo endoscopic subscore; N=population size; n=sample size; [HZ1] q4w=every 4 weeks; q8w=every 8 weeks; RBS=rectal bleeding subscore; S1P=sphingosine-1-phosphate; S1Pi=S1P inhibitor; SC=subcutaneous; SFS=stool frequency subscore; UC=ulcerative colitis |
Conclusion
GUS SC induction followed by SC maintenance was efficacious through 1 year in pts with moderately to severely active UC, and the safety profile is consistent with GUS in its approved indications including UC.
Disclosure
ML reports research support from Lilly, Pfizer, and Takeda; consulting for AbbVie, Bristol Myers Squibb, Intercept, Janssen (Johnson & Johnson), Lilly, Pfizer, Prometheus, Roivant, Takeda, and Target RWE.
JRA reports grant support from Janssen, Merck, and Pfizer; consultancy fees from AbbVie, Adiso, Bristol Myers Squibb, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck, Pfizer, Roivant, Celltrion, TrexBio, Shattuck Labs and Seres Therapeutics; payments for speaking from AbbVie, Bristol Myers Squibb, and Janssen; and is a steering committee member and investigator for Janssen.
SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor; and reports lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
MG, TB, YA, KH, SJ, LJ, and HZ are employees of and may own stock in Johnson & Johnson.
TH reports research grants from AbbVie GK, Boston Scientific Corporation, EA Pharma Co. Ltd., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co. Ltd.; consulting fees from AbbVie GK, Abivax, Bristol Myers Squibb, EA Pharma Co. Ltd., Gilead Sciences, Janssen Pharmaceutical K.K., Lilly, Mitsubishi Tanabe Pharma Corporation, and Pfizer Inc.; and lecture fees from AbbVie GK, EA Pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co. Ltd.
DTR reports consulting and/or speaker fees and/or advisory board participation for AbbVie, Altrubio, Apex, Avalo, Bristol Myers Squibb, Buhlmann Diagnostics, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen (Johnson & Johnson), Lilly, Pfizer, Samsung Neurologica, and Takeda; Altrubio, Datos Health, and Iterative Health stock options; grants from Takeda; and membership on the Board of Directors of Cornerstones Health, Inc. and on the Crohn’s & Colitis Foundation’s Board of Trustees.
LPB reports grants or contracts from Celltrion, Fresenius Kabi, Medac, MSD, and Takeda; consulting and/or payment or honoraria and/or data safety monitoring board or advisory board participation for AbbVie, Abivax, Adacyte, Alfasigma, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Kern Pharma, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, and Ysopia; and meeting attendance/travel support from AbbVie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, and Tillots.
