Introduction
Dose escalation of IV infliximab is an option for inflammatory bowel disease (IBD) patients who lose response after induction therapy1,2. However, as yet, there is limited data for CT-P13 subcutaneous (SC) infliximab (CT-P13 SC) dose escalation in IBD patients.
Aims & Methods
The aim of the post hoc analysis was to evaluate the efficacy, safety, and immunogenicity of treatment with CT-P13 SC dose escalation in patients who initially responded but then lost response according to the loss of response (LOR) criteria in LIBERTY-UC3 and LIBERTY-CD4 studies, which were conducted in parallel over 54 weeks. Patients with moderately to severely active UC and CD were treated with 3 doses of infliximab IV 5mg/kg as induction therapy. Clinical responders at Week 10 were randomized (2:1) to receive either CT-P13 SC 120 mg or placebo every 2 weeks as maintenance therapy. From Week 22, the patients who received CT-P13 SC 120 mg every 2 weeks and who met LOR criteria were permitted to escalate the dose to CT-P13 SC 240 mg (double injection [2 shots] of CT-P13 SC 120 mg) every 2 weeks.
Results
A total of 294 and 231 patients were randomized to CT-P13 SC 120mg in UC and CD study, each. Among them, dose escalation from CT-P13 SC 120 mg to CT-P13 SC 240 mg prior to Week 54 was more common in UC than CD [27.6% (81/294) vs 16.9% (39/231)]. Of dose-escalated patients, 74.1% (60/81) and 51.3% (20/39) received their first dose of CT-P13 SC 240 mg at Week 22 in the UC and CD studies, respectively.
In both UC and CD studies, patients showed improvement in terms of clinical remission [In UC, 24.7% (20/81), In CD, 53.8% (21/39)] or endoscopic response [In CD, 28.2% (11/39)] after dose escalation. Compared to the first dose escalation visits, patients who escalated the dose had almost a half, statistically significant, reduction in modified Mayo score in UC and CDAI score in CD at Week 54. (Table 1).
The incidence rate of treatment-emergent adverse events (TEAEs) in the maintenance period of both studies was comparable between patients with and without dose escalation [In UC, 72.8% (67/92) vs 65.2% (133/204), In CD, 71.1% (32/45) vs 72.5% (140/193)]. Among these, TEAEs of infection were as follows [In UC, 27.2% (25/92) vs 28.4% (58/204), In CD, 35.6% (16/45) vs 30.1% (58/193)].
In both studies, rates of anti-drug antibody (ADA) and neutralizing antibody (NAb) positive conversion up to Week 54 showed no difference in patients with and without dose escalation as follows [In UC, ADA 55.7% (49/88) and 67.3% (134/199), NAb 87.8% (43/49) and 88.1% (118/134), respectively. In CD, ADA 68.2% (30/44) and 64.4% (121/188), NAb 96.7% (29/30) and 97.5% (118/121), respectively].
Table 1. Summary of efficacy outcome in CT-P13 SC treated patients at Week 54
| | CT-P13 SC in UC (N=294) | CT-P13 SC in CD (N=231) |
| Clinical remission1 | Clinical remission2 | Endoscopic response3 |
| Proportion of patients achieving efficacy outcomes at W54 regardless of dose escalation, n/N (%) | 147/294 (50.0 %) | 165/231 (71.4%) | 129/231 (55.8 %) |
| Proportion of patients with dose escalation achieving efficacy outcomes at W54, n’/N’ (%) | 20/81 (24.7%) | 21/39 (53.8%) | 11/39 (28.2%) |
| Mean change from dose escalation |
| Modified Mayo score | CDAI | SES-CD |
| At first visit of dose escalation | 5.8
(n’’=38) | 256.37
(n’’=28) | 7.8
(n’’=16) |
| At Week 54 | 3.4
(n’’=38) | 105.43
(n’’=28) | 6.5
(n’’=16) |
Change from first visit of dose escalation at Week 54,
p-value4 | -2.3,
<0.0001 | -150.94,
<0.0001 | -1.3,
0.1237 |
Abbreviation: CD, Crohn’s disease; CDAI, Crohn’s disease activity index; SES-CD, simplified endoscopic activity score for Crohn’s disease; UC, ulcerative colitis
N = Number of patients who were randomly assigned to CT-P13 SC 120 mg group; n = Number of patients achieving clinical remission or endoscopic response at Week 54 regardless of dose escalation; N’= Number of patients with dose escalation to CT-P13 SC 240 mg prior to Week 54 in CT-P13 SC 120 mg group; n’ = Number of patients achieving clinical remission or endoscopic response at Week 54 among dose-escalated patients; n’’= The patients with dose escalation before Week 54 who had efficacy outcomes at both dose escalation visit and Week 54.
1) Clinical remission at Week 54, defined as a stool frequency subscore of 0 or 1 point, and rectal bleeding subscore 0 point, and endoscopic subscore 0 or 1 point.
2) Clinical remission at Week 54, defined as an absolute Crohn’s disease activity index (CDAI) score of <150 points.
3) Endoscopic response at Week 54, defined as a 50% decrease in Simplified endoscopic activity score for Crohn’s disease (SES-CD) score from the baseline value.
4) P-value for difference in the mean of actual value between dose escalation visit and Week 54 visit within treatment group was obtained by paired t-test. |
Conclusion
Dose escalation of CT-P13 SC from 120 mg to 240 mg every 2 weeks may be effective in restoring efficacy. Safety profiles including immunogenicity results were generally comparable between patients with or without dose escalation. No new safety concerns were found after dose escalation.
References
1 Taxonera C et al. Infliximab dose escalation as an effective strategy for managing secondary loss of response in ulcerative colitis. Digestive Diseases and Sciences 2015; 60 (10): 3075-3084
2 Cesarini M et al. Dose optimization is effective in ulcerative colitis patients losing response to infliximab: A collaborative multicentre retrospective study. Dig Liver Dis.2014; 46(2): 135-139.
3 Bruce E. Sands et al. Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for ulcerative colitis: A phase 3, randomized, placebo-controlled study: Results of the Liberty-UC Study. Journal of Crohn's and Colitis. 2023;17(Supplement_1):i623–i624
4 J.F. Colombel et al. Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for Crohn’s disease: A phase 3, randomised, placebo-controlled study (LIBERTY-CD). Journal of Crohn's and Colitis. 2023;17(Supplement_1):i161-i162
Disclosure
- S. Danese: Consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor. Reports lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda.
- J.F. Colombel: Receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda. Receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda. Receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi,
- S.B. Hanauer: Consultancy from AbbVie, Allergan, Amgen, Arena, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cosmos, Catalys Pacific, Covance, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Progenity, Prometheus, Receptos, Salix, Samsung Bioepis, Seres Therapeutics, Sorriso, Takeda, TLL, UCB, Vhsquared. Clinical Research for AbbVie, Allergan, Amgen, Celgene, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer, Prometheus, Receptos, Takeda, UCB. Speaker for AbbVie, Bristol Myers Squibb, Janssen, Pfizer, Takeda. Independent Data Monitoring Conference for Arena, Boehringer Ingelheim, Bristol Myers Squibb, Gossamer, Prometheus, Protagonist.
- W.J. Sandborn: Consulting fees from Abbvie, Abivax, Alfasigma, Alimentiv, Beigene, Biora (Progenity), Celltrion, Forbion, Genentech, Gossamer Biosciences, Index Pharmaceuticals, Prometheus Biosciences, Protagonist Therapeutics, Shoreline Biosciences, Vedanta Biosciences, Ventyx Biosciences, Zealand Pharma. Stock or stock options from BeiGene, Gossamer Bio, Biora (Progenity), Prometheus Biosciences, Prometheus Laboratories, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Gastrosciences. Employee at Shoreline Biosciences and Ventyx Biosciences.
- B.E. Sands: Consultant/ Speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, Viela Bio. Stock options from Ventyx Biosciences.
- S. Schreiber: Consultancy and personal fees from AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Gilead, HIKMA, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz, Takeda, and Theravance.
- S.J. Lee, S.H. Kim, Y. Bae, S. Lee, S.G. Lee, J.H. Lee, J.M. Kim, S. Yang, J. Lee, G. Park, J. Lee: Employee of Celltrion, Inc.
