WEEK 48 EFFICACY OF GUSELKUMAB AND USTEKINUMAB IN CROHN’S DISEASE BASED ON PRIOR RESPONSE/EXPOSURE TO BIOLOGIC THERAPY: RESULTS FROM THE GALAXI 2 &AMP; 3 PHASE 3 STUDIES

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Introduction

The Phase 3 QUASAR Maintenance Study is a randomized-withdrawal, double-blind, placebo (PBO)-controlled, study that evaluated the efficacy and safety of maintenance treatment with subcutaneous (SC) guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor that binds to CD64, in patients (pts) with moderately to severely active ulcerative colitis (UC) who had prior inadequate response or intolerance to conventional or advanced therapy (ADT) and demonstrated a clinical response to GUS IV induction.

Aims & Methods

At maintenance baseline, clinical responders to 12 weeks of GUS IV induction from QUASAR Phase 2b and Phase 3 induction studies (NCT04033445) were randomized 1:1:1 to SC GUS 200mg q4w, GUS 100mg q8w, or PBO (GUS withdrawal). The primary endpoint was clinical remission at Week (Wk) 44. Major secondary endpoints included corticosteroid-free clinical remission, maintenance of clinical remission, maintenance of clinical response, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization (remission) at Wk44.

Results

The primary analysis population included 568 pts (mean age, 40.7yr; mean UC duration, 7.8yr; mean modified Mayo score, 6.9 [63.9% with severe disease]; Mayo endoscopy subscore of 3, 66.4%; baseline oral corticosteroid use, 40.0%). Approximately 42% had prior inadequate response or intolerance to ADT (TNF antagonists, vedolizumab, or tofacitinib), and 48.3% of these pts failed ≥2 ADT. Disease characteristics were similar across treatment groups at induction and maintenance baseline.
With both GUS SC maintenance regimens, a significantly higher proportion of pts achieved the primary endpoint and all the major secondary endpoints at Wk44 compared with GUS withdrawal (Table 1).
The proportion of pts with ≥1 adverse events (AEs) was similar across treatment groups: GUS 200mg q4w, 70.0%; GUS 100mg q8w, 64.5%, and GUS withdrawal, 68.2%. The most common AEs in the combined GUS group vs withdrawal group were COVID-19 (11.2% vs 14.1%), UC (11.2% vs 29.7%), and arthralgia (6.1% vs 6.8%), respectively.
No cases of death, active tuberculosis, opportunistic infection, anaphylaxis, serum sickness, Hy’s Law, or serious hepatic AEs were reported. Two cases of malignancy (clear cell renal carcinoma, rectal adenocarcinoma) and 1 major adverse cardiovascular event (hemorrhagic stroke) were reported among GUS-treated pts (primary safety population).

Table 1. Primary and major secondary endpoints at Week 44: Primary analysis population

	GUS Withdrawal (Placebo) (N=190)	GUS 100 mg q8w (N=188)	GUS 200 mg q4w (N=190)
Clinical remission (primary endpoint), n (%)^a Adjusted treatment difference (95% CI)	36 (18.9%)	85 (45.2%) 25.2 (16.4, 33.9), P<0.001	95 (50.0%) 29.5 (20.9, 38.1), P<0.001
Corticosteroid-free clinical remission, n (%)^b Adjusted treatment difference (95% CI)	35 (18.4%)	85 (45.2%) 25.7 (17.0, 34.5), P<0.001	93 (48.9%) 29.0 (20.5, 37.6), P<0.001
Maintenance of clinical remission, n/N (%)^c Adjusted treatment difference (95% CI)	20/59 (33.9%)	40/66 (60.6%) 25.9 (9.2, 42.5), P=0.004	50/69 (72.5%) 38.4 (22.7, 54.1), P<0.001
Maintenance of clinical response, n (%)^d Adjusted treatment difference (95% CI)	82 (43.2%)	146 (77.7%) 33.6 (24.5, 42.7), P<0.001	142 (74.7%) 30.7 (21.5, 40.0), P<0.001
Symptomatic remission, n (%)^e Adjusted treatment difference (95% CI)	71 (37.4%)	132 (70.2%) 31.9 (22.5, 41.2), P<0.001	131 (68.9%) 30.5 (21.2, 39.9), P<0.001
Endoscopic improvement, n (%)^f Adjusted treatment difference (95% CI)	36 (18.9%)	93 (49.5%) 29.5 (20.7, 38.3), P<0.001	98 (51.6%) 31.1 (22.5, 39.8), P<0.001
Histo-endoscopic mucosal improvement^g Adjusted treatment difference (95% CI)	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
Endoscopic normalization (remission), n (%)^h Adjusted treatment difference (95% CI)	29 (15.3%)	65 (34.6%) 18.5 (10.2, 26.8), P<0.001	64 (33.7%) 16.8 (9.0, 24.7), P<0.001
Primary Analysis Population included randomized patients with a modified Mayo score of 5-9 at induction baseline who received at least 1 maintenance study treatment dose. Adjusted treatment difference (Δ) was based on the Wald statistic with Cochran-Mantel-Haenszel (CMH) weight. P-values were based on the CMH test, stratified by clinical remission status at maintenance baseline and induction treatment, except for the maintenance of clinical remission, which was based on the CMH test stratified by induction treatment. ^aClinical remission: 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. ^bCorticosteroid-free clinical remission: Not requiring any treatment with corticosteroids for at least 8 weeks prior to Week 44 and also meeting the criteria for clinical remission (98.9% of guselkumab-treated patients who achieved clinical remission at Week 44 were not taking corticosteroids for at least 8 weeks prior to Week 44). ^cMaintenance of clinical remission: Clinical remission at Week 44 among patients in clinical remission at maintenance baseline. ^dClinical response: 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. ^e Symptomatic remission: A stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0. ^fEndoscopic improvement: An endoscopy subscore of 0 or 1 with no friability present on the endoscopy.^gHisto-endoscopic mucosal improvement: Achieving a combination of histologic improvement (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue per Geboes grading system) and endoscopic improvement. ^hEndoscopic normalization (remission): An endoscopy subscore of 0.

Conclusion

Among pts with moderately to severely active UC who responded to GUS IV induction, maintenance therapy with both GUS SC regimens was safe and efficacious. The primary endpoint of clinical remission and all secondary endpoints across clinical, symptomatic, endoscopic, and histologic measures were met with statistical significance by both GUS SC maintenance regimens. Safety results through maintenance Wk44 were consistent with the known and favorable safety profile of GUS in approved indications.

Disclosure

DTR: 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 is a co-founder of Cornerstones Health, Inc.
JRA: Finch Therapeutics, Artugen, Pfizer, Takeda, Janssen, and Iterative Scopes, Merck and BMS.
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.
NS, SY, KGH, MG, RW, and HZ: Employees of Johnson & Johnson.
BGF: AbbVie Inc., Amgen Inc., AdMIRx Inc., Akebia Therapeutics, Allergan, AstraZeneca/MedImmune Ltd., Applied Molecular Transport, Aptevo Therapeutics, Asta Pharma, Atlantic Pharmaceuticals Ltd., Avaxia Biologics Inc., Avir Pharma, Biogen Idec, BioMx Isreal, Boehringer -Ingelheim, Boston Pharmaceuticals, Bristol-Myers Sqibb, Calypso Biotech, Celgene Corporation, Celltech, Centocor Inc, Elan/Biogen, Ferring Pharma, Genentech Inc/Hoffmann-La Roche Ltd., Galapagos, Galen/Atlantica, GiCare Pharma, Gilead Sciences Inc., Gossamer Pharma, GlaxoSmithKline (GSK), Inception IBD Inc, Intact Therapeutics, Janssen Research & Development LLC., Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, merck, Mesoblast Pharma, Millennium, Nestles, Nextbiotix, Novonordisk, ParImmune, Parvus Therapeutics, Pfizer Inc., Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Qu Biologics, Rebiotix, Receptos Inc. / Celgene International, Salix Pharma, Sanofi, Santarus Inc., Shire, Sienna Biologics, Sihmoid Pharma, Sterna Biologics, Synergy Pharma Inc., Takeda Development Center Americas Inc., Teva Pharam, TiGenix, Tillotts Pharma AG, UCB, Vertex Pharma, Vivelix Pharma, VHsquared Ltd., Zyngenia and Senior Scientific Officer – Robarts Clinical Trials Inc.
TH: AbbVie, Daiichi-Sankyo, EA Pharma Co, Ltd. Janssen Research & Development LLC., JIMRO, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmacuetical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co., Ltd.,
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.
BB: Abbvie, Amgen, BI, BMS, Ferring, Janssen, Merck, Novartis, Organon, Pfizer, Sandoz, Takeda, Alimentiv, Allergan, AMT, Bausch Health, Celgene, Celltrion Healthcare, Eupraxia, Fresenius Kabi, Genentech, GSK, Gilead, Iterative Scopes, Jamp Pharma, Merck Amgen, Microbiome Insights, Mylan, Pendopharm, Protagonist, Qu Biologic, and Viatrisgen.
LPB: AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, CTMA, Enterome, Enthera, Ferring, Fresenius, Genentech, Gilead, Hikma, Index Pharmaceuticals, Janssen, Lilly, MSD, Mylan, Nestlé, Norgine, Oppilan Pharma, OSE Immunotherapeutics, Pfizer, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Sterna, Sublimity Therapeutics, Takeda, Tillots and Vifor; grants from AbbVie, MSD and Takeda.
BES: Abbvie, Abbivax, Alimentiv, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Morphic Therapeutics, MRM Health, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, Theravance Biopharma, TLL Pharmaceutical, and Ventyx Biosciences.
AD: Abivax, AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, CED Service GmbH, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Gilead, High5MD, Janssen, Lilly, Materia Prima, MedToday, MSD, Pfizer, Pharmacosmos, Roche/Genetech, Sandoz/Hexal, Takeda, Thieme, Tillotts, UniMed Verlag, and Vifor Pharma.

THE EFFICACY AND SAFETY OF GUSELKUMAB AS MAINTENANCE THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM THE PHASE 3 QUASAR MAINTENANCE STUDY

David T. Rubin 1, Jessica Allegretti 2, Julian Panés 3, Nicole Shipitofsky 4, Shadi Yarandi 4, Gary KH Huang 4, Matthew Germinaro 4, Rebbecca Wilson 4, Hongyan Zhang 4, Brian G. Feagan 5, Tadakazu Hisamatsu 6, Gary Lichtenstein 7, Brian Bressler 8, Laurent Peyrin-Biroulet 9, Bruce E. Sands 10, Axel Dignass 11

1 University of Chicago Medicine, Chicago, United States

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

3 Hospital Clínic Barcelona, Barcelona, Spain

4 Janssen Research & Development, LLC, Spring House, United States

5 Alimentiv Inc, London, Canada

6 Kyorin University School of Medicine, Tokyo, Japan

7 University of Pennsylvania School of Medicine, Merion Station, United States

8 University of British Columbia, Vancouver, Canada

9 Nancy University Hospital, Nancy, France

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

11 Agaplesion Markus Krankenhaus, Frankfurt/ Main, Germany

Conference

UEG Week Vienna 2024

Topics

IBD

Submission format

Abstract

Session

IL-23 inhibitor in UC and Crohn's disease: Part 2 (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Introduction

Ustekinumab is a recombinant human monoclonal IgG1 antibody targeting the interleukins IL-12 and IL-23. Ustekinumab is approved for treatment of moderately to severely active inflammatory bowel disorders, i.e. Crohn’s disease and ulcerative colitis, besides its approved use in moderate-to-severe plaque psoriasis and active psoriatic arthritis. The presented study provides the basis for the marketing authorisation of the proposed ustekinumab biosimilar FYB202, together with an extensive analytical characterisation and the results of an efficacy and safety trial in patients with moderate-to-severe plaque psoriasis.

Aims & Methods

The primary objective of the three-arm trial RUSTIC was A) to prove pharmacokinetic (PK) similarity in terms of AUC_0-inf and C_max of the proposed ustekinumab biosimilar FYB202 to both EU-approved (EU-Ref) and US-licensed ustekinumab (US-Ref) and B) to prove PK similarity of both reference drugs. PK similarity was concluded if the 90% confidence interval (CI) of the geometric mean ratios was contained within the acceptance interval of 80.00–125.00% (analysis of covariance [ANCOVA] with body weight as covariate). Treatments included a single 45-mg subcutaneous injection. The multi-centric clinical trial was conducted at four German trial sites. Safety analyses comprised immunogenicity (anti-drug antibodies [ADAs] and neutralising antibodies [NAbs]), adverse events (AEs), vital signs, body temperature, 12-lead electrocardiograms, and local tolerability (subject- and investigator-assessed). Healthy male and female subjects (18–55 years, body weight 60–90 kg, body-mass index 20.5–30.0 kg/m²) were included in the trial and observed for up to 112 days after dosing.

Results

Overall, 491 subjects were randomised (FYB202: n=164, EU-Ref: n=163, US-Ref: n=164); 486 subjects completed the trial, and 478 subjects were included in the PK analysis set. PK similarity was demonstrated for all three comparisons: all 90% CIs of the respective geometric mean ratios for AUC_0-inf and C_max were contained within the acceptance interval of 80.00–125.00% (Table 1). After administration of FYB202, fewer subjects had at least one positive ADA result at trial end compared to the reference groups (FYB202: 20%, EU-Ref: 42%, US-Ref: 51%). ADA titre levels were similar between all three groups. The percentage of subjects with at least one positive NAb-reactive result at trial end was slightly lower in the FYB202 group compared to the reference groups (FYB202: 11%, EU-Ref: 15%, US-Ref: 18%). More than half of the subjects had at least one treatment-related AE (FYB202: 53%, EU-Ref: 55%, US-Ref: 57%); no treatment-related serious AEs occurred. Local tolerability at the injection site was comparable in all treatment groups.

Table 1: Point estimates and 90% confidence intervals [%] for the primary pharmacokinetic parameters of ustekinumab (PK analysis set; N=478)

Parameter	FYB202 vs. EU-Ref	FYB202 vs. US-Ref	EU-Ref vs. US-Ref
AUC_0-inf	102.85 (96.84-109.23)	112.05 (105.24-119.30)	109.00 (102.84-115.53)
C_max	97.22 (92.05-102.67)	101.65 (96.19-107.42)	104.59 (99.06-110.44)

Observations: AUC_0-inf: n=318 each comparison; C_max: n=319 FYB202 vs. EU-Ref, EU-Ref vs. US-Ref; n=318 FYB202 vs. US-Ref

Conclusion

The RUSTIC trial demonstrated bioequivalent PK characteristics between FYB202 and both EU-approved and US-licensed ustekinumab and for the two reference drugs. No clinically meaningful differences with respect to the overall safety, immunogenicity and local tolerability were observed.

Disclosure

The trial is registered in the EU Clinical Trials Register (EudraCT no. 2022-000832-43).

The clinical trial was financed by Formycon AG, Martinsried, Germany and conducted by SocraTec R&D GmbH, Oberursel/Erfurt, Germany (data management: SocraMetrics GmbH, Erfurt, Germany). During conduct of the trial and preparation of the abstract, S.B. and K.N. were employees of Formycon AG. J.K. and M.A. were employees of SocraTec R&D GmbH. R-S.W. was an employee of SocraMetrics GmbH. B.S. was cofounder and managing director of SocraTec R&D GmbH and SocraMetrics GmbH.

PROPOSED USTEKINUMAB BIOSIMILAR FYB202: PHARMACOKINETIC EQUIVALENCE DEMONSTRATED IN A RANDOMISED, DOUBLE-BLIND, PARALLEL-GROUP, SINGLE-DOSE TRIAL IN HEALTHY SUBJECTS (RUSTIC)

Sigrid Balser 1, Katrin Nopora 1, Juliane Körner 2, Maria Anschütz 3, Ralph-Steven Wedemeyer 4, Barbara Schug 3

1 Formycon AG, Martinsried/Planegg, Germany

2 SocraTec R&D GmbH, Erfurt, Germany

3 SocraTec R&D GmbH, Oberursel, Germany

4 SocraMetrics GmbH, Erfurt, Germany