Introduction
Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that was efficacious in double-blind, placebo-controlled, treat-through trials in participants (pts) with moderately to severely active Crohn’s disease (CD) using IV induction and SC maintenance (GALAXI 2 & 3) or SC induction and maintenance (GRAVITI). Assessment of histologic disease activity is becoming increasingly important as a measure of treatment efficacy. Here we report histologic outcomes at Weeks (W) 12 & 48 from GRAVITI.
Aims & Methods
Pts were randomized 1:1:1 to GUS 400 mg SC every 4 weeks (q4w)→200 mg SC q4w, GUS 400 mg SC q4w→100 mg SC every 8 weeks (q8w), or placebo (PBO). Biopsies were obtained from the most affected area (or if no disease activity present, from normal-appearing mucosa) in 5 segments: terminal ileum, ascending colon, transverse colon, descending colon, and rectum. Histologic response, histologic remission, and the composite endpoints of histo-endoscopic response and histo-endoscopic remission were evaluated using Robarts Histopathology Index (RHI), Global Histologic Activity Score (GHAS), and Geboes scoring. Histologic response was assessed in pts with baseline histologic disease; histologic remission, histo-endoscopic response, and histo-endoscopic remission were assessed in the full analysis set (see definitions in table legend). Pts who met rescue criteria at W16 were considered non-responders at W48. Histologic endpoints in GRAVITI were exploratory and not controlled for multiple comparisons; p-values are nominal.
Results
Of the 347 pts in the full analysis set, 273 (78.7%) had baseline histologic disease per RHI score. SC induction with GUS (400 mg SC at W0, W4, & W8) resulted in greater rates of histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission compared to placebo at W12 (Table). At W48, greater proportions of pts receiving GUS 100 mg SC q8w or GUS 200 mg SC q4w maintenance also achieved histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission compared to PBO. Comparable outcomes were observed using GHAS or Geboes scoring criteria.
| Placebo | GUS 400 mg SC
Combined
| GUS 400 mg SC→
100 mg SC q8w
| GUS 400 mg SC→
200 mg SC q4w
|
Full analysis set,a N
| 117 | 230 | 115 | 115 |
Histologic responseb at W12
| 34.0%
| 52.0%
Δ 17.7%
(6.2, 29.2)
p=0.003
| --- | --- |
Histo-endoscopic responsec at W12
| 12.0% | 30.9%
Δ 18.9%
(10.7, 27.2)
p<0.001
| --- | --- |
Histologic responseb at W48
| 10.6% | --- | 49.5%
Δ 39.1%
(27.1, 51.1)
p<0.001
| 63.6%
Δ 52.9%
(41.1, 64.7)
p<0.001
|
Histologic remissiond at W48
| 10.3% | --- | 44.3%
Δ 34.1%
(23.4, 44.7)
p<0.001
| 44.3%
Δ 33.9%
(23.4, 44.5)
p<0.001
|
Histo-endoscopic responsec at W48
| 6.0% | --- | 35.7%
Δ 29.6%
(19.9, 39.4)
p<0.001
| 38.3%
Δ 32.4%
(22.4, 42.3)
p<0.001
|
Histo-endoscopic remissione at W48
| 5.1% | --- | 25.2%
Δ 20.2%
(11.3, 29.0)
p<0.001
| 23.5%
Δ 18.2%
(9.5, 26.9)
p<0.001
|
Data presented as percentage of participants attaining the endpoint, with adjusted treatment difference (Δ), (95% confidence interval), and nominal p-value versus placebo. Adjusted treatment differences, 95% CIs, and p-values were based on the common risk difference by use of Mantel-Haenszel stratum weights and the Sato variance estimator, using stratification factors of baseline CDAI score (≤300 or >300), baseline SES-CD (≤12 or >12), and prior history of inadequate response or intolerance to biologics (Yes or No).
Participants who had a CD-related surgery (with the exception of minor procedures such as drainage of a superficial abscess or seton placement, etc.), had a prohibited change in CD medication, discontinued study intervention for any reason (other than COVID-19 related reasons [excluding COVID-19 infection] or regional crisis), or met rescue criteria (only applicable after Week 16) were considered not to have met the endpoint at the designated timepoint. Participants who discontinued study intervention due to COVID-19 related reasons (excluding COVID-19 infection) or regional crisis had their observed data used, if available. After accounting for the aforementioned data handling rules, participants who were missing data pertaining to an endpoint at a designated timepoint were considered not to have achieved the endpoint.
a. Full analysis set: all randomized participants who received ≥1 dose of study medication
b. Histologic response: ≥50% reduction in RHI score from baseline or a score ≤ 3 with sub-scores of lamina propria neutrophils and neutrophils in epithelium must be equal to 0, with no ulcers or erosions. Assessed in participants in the full analysis set with baseline histologic disease, defined as RHI score > 0 for any of Items 2-4 of RHI (lamina propria neutrophils, neutrophils in epithelium, or erosions or ulcerations); N = placebo (94), GUS 400 mg SC Combined (179), GUS 400 mg SC→100 mg SC q8w (91), GUS 400 mg SC→200 mg SC q4w (88).
c. Histo-endoscopic response: ≥50% reduction in RHI score from baseline or a score ≤ 3 with sub-scores of lamina propria neutrophils and neutrophils in epithelium must be equal to 0, with no ulcers or erosions AND ≥50% improvement from baseline in SES-CD or SES-CD ≤ 2. Assessed in the full analysis set.
d. Histologic remission: RHI score ≤ 3 with sub-scores of lamina propria neutrophils, neutrophils in the epithelium and erosions or ulcerations equal to 0. Assessed in the full analysis set.
e. Histo-endoscopic remission: RHI score ≤ 3 with sub-scores of lamina propria neutrophils, neutrophils in the epithelium and erosions or ulcerations equal to 0 AND SES-CD ≤ 4 and at least a 2-point reduction from baseline and no subscore greater than 1 in any individual component. Assessed in the full analysis set.
|
Conclusion
Compared to PBO, pts with moderately to severely active CD receiving SC induction and maintenance treatment with GUS achieved greater rates of histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission through W48. These results support the use of histologic and composite histologic and endoscopic endpoints as a measure of CD activity, and the efficacy of SC guselkumab in CD.
Disclosure
GRD’H: consultancy activities for AbbVie, Agomab, Alimentiv, AstraZeneca, AMT, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom, Galapagos, GlaxoSmithKline, Gossamerbio, Immunic, Index, Johnson & Johnson, Kaleido, Origo, Pfizer, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist Therapeutics Inc.; speaker’s bureau for AbbVie, Bristol Myers Squibb, Galapagos, Pfizer, and Takeda; and data monitoring board activities for AbbVie, AstraZeneca, Galapagos, and Seres Health.
ALH: lecturer and/or advisory board member for Bristol Myers Squibb, Celltrion, Falk, AbbVie, Johnson & Johnson, Takeda, Pfizer, Galapagos, MSD, and GSK.
RP: consulting fees from Abbivax, Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, AnaptsyBio, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Spyre Therapeutics, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx, and UCB; speaker’s fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Johnson & Johnson, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and participation in Advisory Boards for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx.
FS: consultant, speaker, or researcher for AbbVie, Amgen, Celltrion, Ferring, Johnson & Johnson, Pfizer, Sandoz, and Takeda.
QC: steering committee adviser for Bristol Myers Squibb and Johnson & Johnson; research grants from Takeda and Johnson & Johnson.
SD: consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB and Vifor; and lecture fees from AbbVie, Amgen, Ferring, Gilead, Johnson & Johnson, Mylan, Pfizer and Takeda
TH: grant support from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, and Kissei Pharmaceutical Co. Ltd.; consulting fees from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Johnson & Johnson, Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and Abivax; lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Johnson & Johnson, Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., and Kissei Pharmaceutical Co. Ltd.
BES: consulting fees from AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Johnson & Johnson, Pfizer, and Takeda; and stock/stock options from Ventyx Biopharma.
MO, LS, PB, WvD, NT: employees and shareholders of Johnson & Johnson
