Introduction
The phase 3 QUASAR maintenance study (NCT04033445) evaluated the efficacy and safety of guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64 (a receptor on cells that produce IL-23), in patients (pts) who achieved clinical response to 12 weeks of IV GUS. Here we present results for effects of GUS maintenance on histologic and combined histologic and endoscopic outcomes at Week 44.
Aims & Methods
At maintenance baseline, clinical responders following 12 weeks of GUS IV induction from the QUASAR Phase 2b and 3 induction studies were randomized 1:1:1 to GUS 200 mg SC q4w, GUS 100 mg SC q8w, or GUS withdrawal (PBO SC). Colonic biopsies were collected during endoscopy at maintenance baseline and Week 44 to evaluate treatment effect on histology measured using Geboes, Robarts, and Nancy Histological Index. Histologic improvement, histologic remission, the combination of histologic improvement and endoscopic improvement (histo-endoscopic mucosal improvement; HEMI), the combination of histologic remission and endoscopic improvement, and the combination of histologic remission and endoscopic normalization (remission) were evaluated at Week 44 (see Table for definitions).
Results
Of the 568 pts randomized (at induction baseline: mean age, 40.7yrs; mean UC disease duration, 7.8yrs; mean modified Mayo score, 6.9 [63.9% with severe disease]; Mayo endoscopy subscore of 3, 66.4%), 190 were receiving GUS 200 mg q4w, 188 receiving GUS 100 mg q8w, and 190 receiving PBO. Baseline characteristics were similar across treatment groups. Histologic activity at maintenance baseline was similar for the GUS 200 mg q4w, GUS 100 mg q8w, and PBO treatment groups (mean continuous Geboes total score: 6.7, 6.8, and 6.9, respectively).
Improvements in histologic activity at Week 44 were observed in pts treated with GUS 200 mg q4w and GUS 100 mg q8w, while pts assigned to PBO worsened (mean change from maintenance baseline in continuous Geboes total score at Week 44: -1.0, -1.2, and 2.2, respectively [both nominal P<0.001]). At Week 44, a significantly greater proportion of pts treated with GUS 200 mg q4w and GUS 100 mg q8w achieved HEMI compared to PBO (47.9% and 43.6% vs 16.8%, respectively; both P<0.001). Greater proportions of pts in both GUS treatment groups achieved other relevant endpoints at Week 44 compared to PBO-treated pts as presented in Table. Across biologic/JAK inhibitor therapy history subpopulations, greater proportions of GUS-treated pts achieved the assessed endpoints compared to PBO.
| Table. Summary of Histologic and Combined Histologic and Endoscopic Outcomes at Week 44 |
| GUS Withdrawal
(Placebo)
| GUS 100 mg SC q8w
| GUS 200 mg SC q4w
|
Primary analysis population, N
| 190
| 188
| 190
|
Histologic improvement, n (%)
(Neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system [ie, Geboes histologic score ≤3.1])
Adjusted treatment difference (95% CI)
Nominal p-value
| 58 (30.5)
-
| 122 (64.9)
33.6 (24.3, 42.9)
P<0.001
| 122 (64.2)
32.6 (23.3, 41.9)
P<0.001
|
Histologic remission, n (%)
(Absence of neutrophils from the mucosa [both lamina propria and epithelium], no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system [ie, Geboes histologic score ≤2 B.0])a
Adjusted treatment difference (95% CI)
Nominal p-value
| 51 (26.8)
-
| 111 (59.0)
31.2 (21.9, 40.5)
P<0.001
| 115 (60.5)
32.6 (23.5, 41.8)
P<0.001
|
Histo-endoscopic mucosal improvement (HEMI), n (%)
(Achieving a combination of histologic improvement and endoscopic improvement [Mayo endoscopy subscore of 0 or 1 with no friability])
Adjusted treatment difference (95% CI)
Multiplicity-controlled p-value
| 32 (16.8)
-
| 82 (43.6)
25.7 (17.1, 34.3)
P<0.001
| 91 (47.9)
29.6 (21.1, 38.0)
P<0.001
|
Histologic remission and endoscopic improvement, n (%)
(Geboes histologic score ≤2 B.0 and endoscopic improvement)
Adjusted treatment difference (95% CI)
Nominal p-value
| 30 (15.8)
-
| 78 (41.5)
24.7 (16.2, 33.2)
P<0.001
| 89 (46.8)
29.6 (21.3, 38.0)
P<0.001
|
Histologic remission and endoscopic normalization (remission), n (%)
(Geboes histologic score ≤2 B.0 and Mayo endoscopy subscore of 0)
Adjusted treatment difference (95% CI)
Nominal p-value
| 27 (14.2)
-
| 59 (31.4)
16.2 (8.2, 24.3)
P<0.001
| 62 (32.6)
16.9 (9.2, 24.7)
P<0.001
|
a Results for histologic remission by alternative definitions using Robarts Histopathology Index (RHI ≤ 3, with subscores of 0 for lamina propria neutrophils and neutrophils in the epithelium and without ulcers or erosion) and Nancy Histological Index (NHI ≤ 1) were identical.
Note: Patients who had a prohibited change in UC medication, an ostomy or colectomy, a dose adjustment (including sham dose adjustment), discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC, or due to other reasons except for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis in Russia and Ukraine prior to Week 44 were considered not to have achieved the endpoint. Patients who had an unevaluable biopsy (ie, a biopsy that was collected, but could not be assessed due to sample preparation or technical errors) or were missing the endoscopy subscore (if applicable) or any of the histology components pertaining to an endpoint at Week 44 were considered not to have achieved the endpoint. The adjusted treatment difference and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel (CMH) weight. The p-values were based on the CMH chi-square test, stratified by clinical remission status at maintenance baseline (Yes/No), and induction treatment (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV crossover to guselkumab 200 mg IV). |
Conclusion
In this phase 3 maintenance study, pts with UC treated with GUS 200 mg SC q4w or GUS 100 mg SC q8w experienced clinically meaningful improvements in histologic and combined histologic and endoscopic outcomes at Week 44 compared to PBO-treated pts.
Disclosure
JP: AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman.
AD: Abivax, AbbVie, Bristol Myers Squibb, Dr Falk Foundation, Galapagos, Gilead, Janssen, Pfizer, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Celltrion, Ferring Pharmaceuticals, Fresenius Kabi, Lilly, MSD, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Tillotts, Vifor Pharma, CED Service GmbH, High5MD, Materia Prima, MedToday, Thieme, and UniMed Verlag.
TH: AbbVie, Daiichi-Sankyo, EA Pharma Co, Ltd. JIMRO, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmacuetical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Co., Ltd., and Janssen Research & Development, LLC.
SY, KGH, MG, SS, PB, RW, and HZ: Johnson & Johnson.
FM: AbbVie, Arena, Celltrion, Eli Lilly and Company, Ferring, Fresenius, Galapagos, GlaxoSmithKline, Janssen, Merck, Pfizer, Prometheus Biosciences, Roche, Sandoz, Tillots, Takeda, and Teva.
VJ: AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion, and Shire.
BGF: AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc, Arena Pharma, Avoro Capital Advisors, Atomwise, BioJamp, Biora Therapeutics, Boehringer-Ingelheim, Boxer, Celsius Therapeutics,Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Pharma, GSK, Hinge Bio, Hot Spot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, LifeSci Capital, Lument AB, Millennium, MiroBio, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Therapeutics and Diagnostics, Play to Know AG, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd., Viatris, Ysios, Ysopia, Zealand Pharma, Morgan Lewis and Lenczner Slaght, Ecor1Capital, and Axio Research.
GRL: Abbvie, Allergan, American College of Gastroenterology, American Gastroenterological Association, American Regent, Celgene, Chemed, Eli Lilly, Endo Pharmaceuticals, Ferring, Gastroenterology and Hepatology, Gilead, IMEDEX, Ironwood, Janssen/ Janssen Orthobiotech, MedEd Consultants, Merck, Morphic Therapeutics, Pfizer Pharmaceuticals, Professional Communications, Inc., Prometheus Laboratories, Inc, Romark, Sandoz, Salix Pharmaceuticals/Valeant, Shire Pharmaceuticals, SLACK, Inc, Springer Science and Business Media, Takeda, University of Kentucky, UCB, Up-To-Date, Vindico, and Virgo.
DTR: Takeda, AbbVie, Altrubio, Allergan, Inc., Arena Pharmaceuticals, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Ltd., Bristol Myers Squibb, Celgene Corp/Syneos, Connect BioPharma, GalenPharma/Atlantica, Genentech/Roche, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Eli Lilly, Materia Prima, Pfizer, Prometheus Biosciences, Reistone, Takeda, Techlab, Inc, and Cornerstones Health, Inc
BES: Abbvie, Adiso Therapeutics, Agomab, Alimentiv , Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Envied Biosciences, Evommune, Ferring, Fresenius Kabi, Fiat, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, 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, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, Abivax, Lilly, Bristol Myers Squibb, Janssen, Pfizer, Takeda, Theravance Biopharma, and Ventyx Biopharma.
