Introduction
CT-P13 subcutaneous (SC) infliximab formulation demonstrated superiority over placebo in maintenance therapy in Crohn's disease (CD)1 and Ulcerative Colitis (UC)2 patients in two parallel 54 weeks studies (LIBERTY-CD and LIBERTY-UC). We performed a post-hoc subgroup analysis comparing patients treated with CT-P13 SC with and without combination immunosuppressants (IS) at baseline in CD and UC.
Aims & Methods
Patients with moderately to severely active CD and UC who responded at W10 to CT-P13 intravenous infliximab 5mg/kg (Weeks 0, 2 and 6) were randomized (2:1) to receive CT-P13 SC 120 mg (CT-P13 SC) or placebo every 2 weeks until W54 as maintenance therapy. IS (azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) were allowed if patients maintained stable doses at least 8 weeks prior to W0, and stable doses were maintained up to W54.
Results
231 CD and 294 UC patients were randomized to receive CT-P13 SC maintenance therapy. Among them, 71 (30.7%) and 65 (22.1%) patients received CT-P13 SC with IS in CD and UC, respectively (In CD; 63, 4 and 4 patients of AZA, 6-MP, MTX, respectively, In UC; 63, 2 and 0 patients of AZA, 6-MP, MTX, respectively). There were no statistically significant differences in all of the efficacy outcomes between monotherapy and combination therapy groups at W54 in both studies (Table 1). A trend is seen for higher rates of corticosteroid-free remission with combination therapy in both CD and UC patients.
No statistically significant differences were seen between monotherapy and combination therapy groups in the maintenance period in incidences of treatment-emergent adverse event (TEAE), systemic injection reactions (SIR) in combined analysis of CD and UC patients (TEAE 68.0% vs 74.3% [p=0.1989], SIR 3.3% vs 1.4% [p=0.3743], respectively).
A significantly lower incidence of infection was seen with monotherapy during the maintenance period in combined analysis of both studies (26.9 % monotherapy vs 36.4% combination therapy [p=0.0400]). In the combined analysis of both studies, the serious infections were reported for 10 (2.5%) patients in the monotherapy and 3 (2.1%) patients in the combination therapy.
In combined analysis of CD and UC patients, rate of anti-drug antibody [ADA] positive conversion up to W54 was statistically lower in combination therapy group (70.2% monotherapy vs 47.8% combination therapy [p<0.0001]).
Table 1. Proportion of patients achieving efficacy outcomes at W54
CT-P13 SC 120mg in LIBERTY-CD
| CT-P13 SC 120mg in LIBERTY-UC
|
n (%)
| Monotherapy
(N=160)
| Combination therapy
(N=71)
| P-valuea
| n (%)
| Monotherapy
(N=229)
| Combination therapy
(N=65)
| P-valuea
|
Clinical remissionb
| 97 (60.6)
| 47 (66.2)
| 0.7194
| Clinical remissionh
| 95 (41.5)
| 32 (49.2)
| 0.4119
|
Endoscopic responsec
| 81 (50.6)
| 37 (52.1)
| 0.9492
| Endoscopic-histologic mucosal improvementi
| 78 (34.1)
| 27 (41.5)
| 0.4763
|
Clinical responsed
| 103 (64.4)
| 49 (69.0)
| 0.7686
| Clinical responsej
| 124 (54.1)
| 34 (52.3)
| 0.5760
|
Corticosteroid-free remissione
| 27/76 (35.5)
| 13/23 (56.5)
| 0.4875
| Corticosteroid-free remissionk
| 32/94 (34.0)
| 12/26 (46.2)
| 0.1966
|
Clinical remission (alternative definition)f
| 89 (55.6)
| 42 (59.2)
| 0.5647
| -
| -
| -
| -
|
Endoscopic remissiong
| 55 (34.4)
| 25 (35.2)
| 0.8439
| -
| -
| -
| -
|
a The nominal p-value was obtained from Cochran-Mantel-Haenszel test
b Clinical remission at Week 54, defined as an absolute Crohn’s disease activity index (CDAI) score of <150 points
c 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
d Clinical response at Week 54, defined as a decrease in CDAI score of 100 points or more from the baseline value
e Corticosteroid-free remission at Week 54, defined as being in clinical remission (by an absolute CDAI score of <150) in addition to not receiving any corticosteroids for at least 8 weeks prior to Week 54, among the patients who used oral corticosteroids at baseline
f Clinical remission at Week 54, defined as Stool frequency subscore of 0 or 1 point, rectal bleeding subscore 0 point, and endoscopic subscore 0 or 1 point
g Endoscopic remission at Week 54, defined as an absolute SES-CD score of ≤4 and at least 2-point reduction from the baseline value with no sub-score of >1
h Clinical remission at Week 54, defined as modified Mayo score with stool frequency subscore of 0 or 1 point, rectal bleeding subscore 0 point, and endoscopic subscore 0 or 1 point
i Endoscopic-histologic mucosal improvement at Week 54, defined as absolute endoscopic subscore of 0 or 1 point from modified Mayo score and an absolute Robarts Histopathology Index (RHI) score of 3 points or less with an accompanying lamina propria neutrophils and neutrophils in epithelium subscore of 0 point
j Clinical response at Week 54, defined as decrease in modified Mayo score from baseline of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point
k Corticosteroid-free remission at Week 54, defined as being in clinical remission (by modified Mayo score) in addition to not requiring any treatment with corticosteroid for at least 8 weeks at Week 54, among the patients who used oral corticosteroids at baseline
|
Conclusion
No statistical differences in efficacy outcomes at W54 were observed between monotherapy and combination therapy in CD and UC patients. Concomitant IS use was associated with less ADA formation, whereas more infections are seen for combination therapy during maintenance period in CD and UC patients. The overall safety profile during maintenance period was otherwise comparable between monotherapy and combination therapy in CD and UC patients. This post-hoc analysis suggests limited benefit of concomitant IS with CT-P13 SC but a higher infection risk. Notably, patients were not randomized according to IS use nor were the studies ‘powered’ to demonstrate differences.
References
1 Colombel JF et al. DOP86 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
2 Sands BE et al. P492 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.
Disclosure
- 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.
- 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,Takeda, TiGenix, Vifor. Hold stock options in Intestinal Biotech Development.
- 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. 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.
- 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.
