Symptom Response Dynamics for Personalised Therapy with Subcutaneous Infliximab in Crohn's Disease: Insights from the Randomised, Placebo-Controlled, Phase 3 LIBERTY-CD Trial.

Symptom Response Dynamics for Personalised Therapy with Subcutaneous Infliximab in Crohn’s Disease: Insights from the Randomised, Placebo-Controlled, Phase 3 LIBERTY-CD Trial - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Adv Ther . 2026 Mar 30;43(6):2510–2526. doi: 10.1007/s12325-026-03533-3 Symptom Response Dynamics for Personalised Therapy with Subcutaneous Infliximab in Crohn’s Disease: Insights from the Randomised, Placebo-Controlled, Phase 3 LIBERTY-CD Trial Stefan Schreiber 1, ✉ , Bruce E Sands 2 , Silvio Danese 3 , Edward V Loftus Jr 4 , Ae Lee Jeong 5 , Dong-Hyeon Kim 5 , Young Nam Lee 5 , Jean-Frédéric Colombel 2, ✉ Author information Article notes Copyright and License information 1 Department of Medicine I, University Hospital Schleswig-Holstein, Kiel University, Rosalind-Franklin-Strasse 12, 24105 Kiel, Germany 2 Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Gastroenterology, IRCCS San Raffaele Hospital and Vita-Salute University, Milan, Italy 4 Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN USA 5 Global Medical Division, Celltrion Inc., Incheon, Republic of Korea ✉ Corresponding author. Received 2025 Nov 7; Accepted 2026 Feb 9; Issue date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ . PMC Copyright notice PMCID: PMC13222256  PMID: 41910935 Abstract Introduction The LIBERTY-CD study demonstrated superior efficacy of subcutaneous infliximab-dyyb over placebo for maintenance therapy in patients with Crohn’s disease. This post hoc analysis characterised subgroups of patients with different response levels to subcutaneous infliximab. Methods Group-based trajectory modelling was conducted to deconvolute cohort-level data into individual response trajectories based on longitudinal patient-reported outcomes. Potential predictors of subcutaneous infliximab response were explored using multivariable analyses. Subgroups were compared for clinical, endoscopic, biochemical, and health-related quality of life outcomes; comprehensive disease control (achieving composite endpoints) at week 54; pre-dose serum infliximab levels; and safety. Results Four distinct subgroups of patients were identified: super-responders (rapid and high sustained improvement); fast responders; slow responders; and limited responders (partial improvement). In multivariable analyses, lower baseline body mass index ( p = 0.022) and pre-dose serum infliximab levels ≥ 14 μg/ml at week 10 ( p = 0.003) were associated with a super-response. At week 54, super-responders showed the highest rates of clinical remission (80.3%; p = 0.002), endoscopic response (63.9%; p = 0.009), health-related quality of life remission (72.1%; p = 0.0002), corticosteroid-free remission (59.1%; p = 0.007), and comprehensive disease control achievement (27.9%; p = 0.014) versus other trajectories. Among groups, super-responders maintained the highest pre-dose serum infliximab levels from week 10. Comparable overall safety profiles were observed across groups. Conclusion Distinct subpopulations with varying responses to infliximab were identified by group-based trajectory modelling using longitudinal symptom data, which may support the development of personalised therapy. Super-responders with rapid and sustained improvements during infliximab therapy were more likely to achieve desirable long-term outcomes. Trial Registration ClinicalTrials. gov identifier, NCT03945019 (08 May 2019). Supplementary Information The online version contains supplementary material available at 10.1007/s12325-026-03533-3. Keywords: Crohn’s disease, Subcutaneous infliximab, Trajectory modelling, CT-P13 SC, Inflammatory bowel disease Key Summary Points Why carry out this study? Given the chronic inflammatory nature and wide spectrum of severity of Crohn's disease, which leads to an unpredictable individual disease course, a personalised treatment approach is essential. An unsupervised clustering method was used to identify natural clusters of individuals exhibiting similar response trajectories to infliximab therapy with data from the phase 3 LIBERTY-CD study. What was learned from the study? Four distinct subgroups with varying responses to subcutaneous infliximab were identified. Among groups, super-responders showed rapid and high sustained improvements during infliximab treatment and had a higher likelihood of achieving desirable long-term outcomes. Baseline body mass index and pre-dose infliximab serum levels at week 10 were identified as factors associated with a super-response to subcutaneous infliximab. Open in a new tab Introduction Crohn’s disease (CD), a chronic inflammatory disorder that can affect any part of the gastrointestinal tract, is characterised by persistent or recurrent inflammation, progression of complications, and a wide spectrum of severity, leading to an unpredictable individual disease course and resultant disability [ 1 ]. Given the chronic nature of CD, considerable effort has been directed towards understanding the factors that influence long-term treatment outcomes. Factors associated with long-term outcomes in patients receiving infliximab have been evaluated by subtyping patients according to their baseline characteristics [ 2 , 3 ], early response [ 1 ], postinduction serum drug level [ 4 ], or postinduction patient-reported outcomes [ 5 ]. Despite such efforts, as a result of the individual heterogeneity in both disease course and treatment response, challenges remain to guide clinical decision-making [ 6 ]. Personalised approaches are essential for optimising patient management for chronic, lifelong diseases such as CD, particularly in the era of precision medicine and with multiple targeted therapy options. Landmark-based cohort-level assessments of efficacy in clinical trials often fail to account for patient heterogeneity, despite the clear variation in individual responses to treatment. Clinical experience indicates that some patients exhibit markedly better outcomes than others, underscoring the need for individualised assessments of efficacy in clinical studies. One promising strategy for defining therapeutic success at an individualised level is the use of a patient-level combination of endpoints, rather than relying solely on sequential cohort-based assessments. For instance, the CALM study combined clinical symptoms with biochemical markers (faecal calprotectin [FC] and C-reactive protein [CRP]) to define treatment failure and adjust therapy accordingly [ 7 ]. The CALM study also assessed deep remission in early-stage disease, as a combination of clinical remission and endoscopic remission and no steroids, which was related to a decreased risk of disease progression over a median time of 3 years [ 8 ]. Moreover, identifying distinct patient subgroups based on their response trajectories represents another critical step toward predicting individual responses to targeted therapies. This approach enables the early identification of patients most likely to benefit from specific treatments, thereby refining the use of first-line therapies and enhancing long-term treatment retention. Unsupervised clustering methods, such as group-based trajectory modelling (GBTM), have been developed and applied to estimate natural clusters of individuals following similar response trajectories with regards to particular outcomes over time, and can provide insight into the distribution of individual courses of disease and/or response to therapy throughout a given clinical study. GBTM has previously been used to characterise groups of patients with different longitudinal patterns of adherence to pharmacologic interventions [ 9 ], including adherence to biologics in patients with psoriasis [ 10 ]. More recently, GBTM was employed to characterise patterns of response to biologic therapies in patients with ulcerative colitis (UC) and resulted in the identification of different responder types [ 11 – 13 ]. A subcutaneous (SC) formulation of infliximab (CT-P13) was approved by the European Medicines Agency (EMA) in 2020 for the treatment of moderately to severely active CD and UC following the European registration phase 1 non-inferiority study ( NCT02883452 ) comparing the SC and intravenous (IV) formulations of infliximab [ 14 ]. The phase 3 LIBERTY-CD study ( NCT03945019 ) demonstrated a broad level of benefit for SC infliximab maintenance therapy compared with placebo in patients with moderately to severely active CD who responded to IV infliximab induction, leading to its approval by the US Food and Drug Administration (FDA) in 2023 as SC infliximab-dyyb [ 15 ]. This post hoc analysis of the LIBERTY-CD study used GBTM to examine whether subgroups of patients with different trajectories of response to infliximab therapy exist. The analysis also examined whether differences in early response patterns relate to maintenance outcomes, including a hard composite endpoint of comprehensive disease control (CDC), and aimed to identify predictors for each response trajectory. Key observations from the LIBERTY-CD study were replicated with an independent dataset from the European registration study. Methods Study Design and Participants We conducted a post hoc analysis using data from the pivotal, randomised, parallel-group, placebo-controlled LIBERTY-CD study ( NCT03945019 ). Full details of the study eligibility criteria, design, and results were reported previously [ 15 ]. Briefly, the study enrolled adults (aged 18–75 years) with moderately to severely active CD (defined as a Crohn’s Disease Activity Index [CDAI] score of 220–450 and a Simple Endoscopic Score for Crohn’s Disease [SES-CD] of ≥ 6 points for ileal-colonic CD or ≥ 4 points including an ulcer score for ≥ 1 segment for ileal CD or colonic CD). Enrolled patients received open-label IV infliximab 5 mg/kg at weeks 0, 2, and 6 as induction therapy. At week 10, patients with a clinical response (≥ 100-point decrease in CDAI score) were randomised at a 2:1 ratio to receive either SC infliximab 120 mg or placebo every 2 weeks (Q2W) up to week 54. From week 22 onwards, dose adjustment to SC infliximab 240 mg Q2W was permitted for patients in either treatment group who initially responded but subsequently lost response. The present post hoc analysis utilised data from patients randomised to the SC infliximab arm. Ethical Approval The study was performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki. Prior to study initiation, the study protocol was approved by an independent ethics committee or institutional review board at each participating site. The full list of study sites is reported in the primary manuscript supplementary materials [ 15 ]. All participants provided written informed consent prior to enrolment in the study. Replication Test Study A replication test was performed using data from the European registration study, an open-label, randomised, multicentre, parallel-group, phase 1 study ( NCT02883452 ) conducted in 131 patients with CD and UC, that compared SC infliximab versus IV infliximab [ 14 ]. All patients received IV infliximab 5 mg/kg at weeks 0 and 2 during the induction phase (weeks 0–6); at week 6 patients were randomised to SC infliximab or IV infliximab (1:1). Patients in the IV arm received IV infliximab 5 mg/kg Q8W from week 6 to week 22, when the primary endpoint was evaluated. From week 30, patients in the IV arm switched to receive SC infliximab Q2W to week 54, while patients in the SC arm received SC infliximab from week 6 to week 54. Group-Based Trajectory Modelling Unsupervised GBTM was conducted to deconvolute cohort-level data into patient subgroups characterised by similar individual response trajectories [ 16 ]. The model employed a maximum likelihood estimation with the expectation–maximisation algorithm based on the daily collection of patient-reported outcomes (PRO-2) of abdominal pain and stool frequency. Abdominal pain was calculated as the severity of worst daily abdominal pain (grade 0 [none] to 3 [severe]; sum of 7 days) multiplied by five. Stool frequency was calculated as the number (sum of 7 days) of liquid (watery) or very soft (loose) stools multiplied by two. Missing data were imputed using the last observation carried forward (LOCF) method to complete the longitudinal dataset. The best-fitting GBTM model was selected according to two factors: statistical criteria and clinical interpretation (to ensure findings were plausible from a clinical perspective). Quantitative criteria for selecting the best model were based on the following statistical indicators: (1) information criteria (log-likelihood, Bayesian information criterion [BIC], and Akaike information criterion [AIC]) [ 17 ]; and (2) optimally, a minimum number of patients ( n = 50) should be allocated to each group. Finally, mean posterior probability of group membership must be > 0.70. Clinical Outcomes The proportions of patients achieving the following clinical outcomes at week 54 were analysed and compared between the different response trajectories: clinical remission (CDAI score < 150), endoscopic remission (SES-CD of ≤ 4 and ≥ 2-point reduction from the baseline value with no segment sub-score of > 1), endoscopic response (≥ 50% decrease in SES-CD from baseline), FC normalisation (FC ≤ 250 μg/g), health-related quality of life (HRQoL) remission (Short Inflammatory Bowel Disease Questionnaire [SIBDQ] score ≥ 50), CDC [ 17 , 18 ] (defined as achieving a combination of clinical remission, endoscopic remission, FC normalisation, and HRQoL remission), and corticosteroid-free remission (CDAI score < 150 and having not received corticosteroids for ≥ 8 weeks prior to week 54, among patients who used oral corticosteroids at baseline). Pre-dose serum levels of infliximab were evaluated by response trajectory throughout the treatment period. Patient-reported daily abdominal pain plus stool frequency scores and daily general well-being scores (scale of 0 [generally well] to 3 [very poor]) were also used to evaluate the onset of symptomatic response. Safety endpoints, including rates of total and study drug-related treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), localised injection site reactions (ISRs), and infections through weeks 10–54, were also analysed and compared across response trajectories. To compare the different trajectories in terms of level of response and rate of response, super-responders versus limited responders and fast responders versus slow responders were analysed separately. The SIBDQ, authored by Dr. Jan Irvine et al., was used in this clinical study under license from McMaster University, Hamilton, Canada. Immunogenicity Assessments Immunogenicity assessments for LIBERTY-CD have been described in detail in the primary manuscript [ 15 ]. Briefly, anti-drug antibodies (ADAs) were evaluated using a highly sensitive and drug-tolerant electrochemiluminescent (ECL) affinity capture elution assay. For the present analysis, patients were categorised based on ADA status. Patients were defined as ADA-positive if at least one confirmed positive sample was detected at any time following treatment initiation, and ADA-negative if no positive samples were observed after treatment initiation. ADA-positive patients were further stratified according to the maximum serum dilution factor (ADA titer) used for ADA testing during the study: low (< 100), moderate (≥ 100 to < 1000), and high (≥ 1000). Statistical Analyses Sample size calculations for LIBERTY-CD have been published previously [ 15 ]. Baseline characteristics were analysed descriptively and statistical comparisons across response trajectories were performed using a chi-square test or one-way analysis of variance (ANOVA). Baseline factors associated with the super-response group of SC infliximab: demographics, prior treatment use, duration of the disease, disease phenotypes, disease severity, oral corticosteroid use at baseline, biomarkers, and serum level of infliximab at week 10 were examined in the different trajectories by univariable logistic regression. Thereafter, multivariable logistic regression analyses were performed to further evaluate the relationship between these baseline characteristics and the likelihood of being a member of the super-response group; the baseline characteristics with a p value < 0.20 after the univariable analyses were included in the model. Rates of clinical remission, endoscopic remission, FC normalisation, HRQoL remission, and CDC at week 54 included data for patients who received a dose adjustment; statistical comparisons across trajectories were evaluated by chi-square test. Corticosteroid-free remission and endoscopic response rates at week 54 were calculated, and patients who received a dose adjustment to SC infliximab 240 mg were considered as non-remitters/non-responders. Pre-dose serum infliximab levels by trajectory were analysed as observed using a Mann–Whitney U test and patients with missing data were excluded. Onset of symptomatic response was analysed descriptively. Statistical analyses were conducted using RStudio (version 2023.12.1 + 402 “Ocean Storm” release; R Core Team, 2023). Results Patient Disposition This post hoc analysis included the 231 patients randomised to the SC infliximab arm. Overall, 134 (58.0%) patients were male, and the majority were white (91.3%). At screening, median weight was 66.0 (interquartile range, 57.1–79.5) kg and body mass index (BMI) was 22.7 (19.7–26.0) kg/m 2 . Mean (SD) time since diagnosis of active CD was 4.34 (5.18) years [ 15 ]. Treatment Response Trajectories The GBTM analysis was conducted as outlined in the Methods section. The optimal trajectory model was selected using specific criteria; based on information criteria, a polynomial degree of 2 was selected. The GBTM analysis revealed that three models exhibited very similar BIC values: the three-, four-, and five-trajectory models (Supplementary Table 1 ). Despite the five-trajectory model having a marginally lower BIC, the four-trajectory model was selected to account for factors such as the distribution of patients across groups and the clinical relevance of the model. Four distinct trajectory groups were identified that were clearly separated and stabilised around weeks 10–14. Figure 1 shows CDAI scores and the sum of abdominal pain and stool frequency scores stratified according to trajectory group from baseline to week 54. Super-responders ( n = 61) depicted a rapid and high sustained improvement; fast responders ( n = 56) exhibited a rapid response, followed by a less sustained improvement than super-responders; slow responders ( n = 63) displayed a gradual response, followed by a less sustained improvement than super-responders; and limited responders ( n = 51) showed partial improvement following induction that was sustained during the maintenance phase. Fig. 1. Open in a new tab CDAI score ( a ) or AP and SF ( b ) according to response trajectory in patients treated with SC infliximab. The values accompanying each trajectory represent the number of patients who continued treatment at each timepoint. The horizontal dashed line indicates the threshold for clinical remission (CDAI score < 150 points). Disease activity is visualised by AP and SF pooled, whilst GBTM was used to identify trajectories based on PRO-2 of AP and SF separately. AP abdominal pain, CDAI Crohn’s Disease Activity Index, CI confidence interval, GBTM group‑based trajectory modelling, PRO-2 Patient-Reported Outcome 2, SC subcutaneous, SF stool frequency, W week Further analysis of patient-reported measures for abdominal pain and stool frequency and general well-being scores showed that the onset of symptomatic response was observed earlier than week 2 for all trajectories (Supplementary Fig. 1 ). In addition, super-responders achieved a symptomatic response by week 10, which was sustained until the end of the study at week 54. Replication of Response Trajectories Similar to the result of LIBERTY-CD, four distinct trajectories were identified when performing a replication test using data from the SC infliximab arm of the European registration study in patients with CD: super-responders ( n = 5) showed the most rapid response with sustained improvement, fast responders ( n = 5) displayed rapid response but less than super-responders, slow responders ( n = 15) exhibited a gradual response, and limited responders ( n = 3) appeared to have partial response and the CDAI score rebounded at the end of the study (Supplementary Fig. 2 ). Baseline Characteristics by Response Trajectories Super-responders had lower baseline body weight (mean 65.9 kg; p = 0.028), lower BMI (mean 22.1 kg/m 2 ; p = 0.046), and higher baseline CDAI score (mean 331.5; p = 0.002) compared with other trajectories; the proportion of female patients was 41.0% ( n = 25) (Table 1 ). Table 1. Baseline characteristics by response trajectories Characteristic Super-responders ( n = 61) Fast responders ( n = 56) Slow responders ( n = 63) Limited responders ( n = 51) P value a Sex, n (%) Male 36 (59.0) 38 (67.9) 38 (60.3) 22 (43.1) 0.071 b Female 25 (41.0) 18 (32.1) 25 (39.7) 29 (56.9) Biologic or JAK inhibitor prior use, n (%) 10 (16.4) 8 (14.3) 7 (11.1) 1 (2.0) 0.088 b Oral corticosteroid use, n (%) 22 (36.1) 27 (48.2) 23 (36.5) 27 (52.9) 0.175 b CD duration, years, mean (SD) 4.2 (5.5) 4.9 (4.6) 4.7 (6.2) 3.4 (5.3) 0.436 History of surgery, n (%) c 2 (3.3) 4 (6.3) 4 (7.1) 4 (7.8) 0.744 History of anal disease, n (%) d 6 (9.8) 9 (16.1) 6 (9.5) 6 (11.8) 0.675 Age, years, median (IQR) 35.0 (23.0–42.0) 34.0 (27.0–39.3) 34.0 (24.0–42.0) 39.0 (28.5–49.5) 0.171 Weight, kg, mean (SD) 65.9 (14.3) 72.8 (16.3) 70.9 (14.5) 65.6 (16.6) 0.028 BMI, kg/m 2 , mean (SD) 22.1 (5.0) 24.2 (4.5) 23.8 (4.1) 23.0 (4.7) 0.046 SES-CD, mean (SD) 13.1 (4.0) 11.2 (6.2) 10.4 (7.4) 11.0 (6.3) 0.152 CDAI score, mean (SD) 331.5 (54.7) 310.8 (57.7) 312.9 (56.3) 289.1 (52.9) 0.002 FC, mg/kg, median (IQR) 1114.0 (525.5–2423.0) 1004.5 (653.8–2760.3) 760.0 (234.5–1948.0) 508.0 (188.0–1316.0) 0.622 CRP, nmol/L, median (IQR) 73.4 (28.8–263.6) 44.8 (14.7–249.3) 44.8 (13.3–92.4) 42.9 (15.7–96.4) 0.781 Lymphocytes, cells × 10 9 /L, mean (SD) 1.8 (0.4) 1.7 (0.8) 1.6 (0.7) 1.7 (0.6) 0.469 Neutrophils, cells × 10 9 /L, mean (SD) 6.0 (3.2) 5.6 (2.2) 5.6 (2.9) 5.2 (2.2) 0.386 Albumin, g/L, mean (SD) 44.0 (3.3) 43.8 (5.4) 44.6 (4.6) 43.6 (4.2) 0.716 W10 serum infliximab level ≥ 14 μg/mL, n / N (%) 32/60 (53.3) 21/56 (37.5) 22/62 (35.5) 18/49 (36.7) 0.157 Open in a new tab ANOVA analysis of variance, BMI body mass index, CD Crohn’s disease, CDAI Crohn’s Disease Activity Index, CRP C-reactive protein, FC faecal calprotectin, IQR interquartile range, JAK Janus kinase, SD standard deviation, SES-CD Simple Endoscopic Score for Crohn’s Disease, W week a Statistical comparison analysed by one-way ANOVA unless otherwise indicated b Statistical comparison analysed by chi-square test c Patients who had colectomy or ileocolectomy d Patients who had or have anal fistula or fissure or abscess Identification of Variables Associated with Response Trajectories Using Logistic Regression In unadjusted logistic regression analyses, lower BMI ( p = 0.016), higher SES-CD score ( p = 0.027), and higher CDAI score ( p = 0.002) at baseline, and week 10 pre-dose serum infliximab levels ≥ 14 μg/mL ( p = 0.025), were identified as factors associated with a super-response (Table 2 ). After adjustment, lower BMI ( p = 0.022) and week 10 pre-dose serum infliximab levels ≥ 14 μg/mL ( p = 0.003) were associated with a super-response (Table 2 ). Table 2. Univariable and multivariable logistic regression analyses for predictors of super-response Characteristic Univariable Multivariable OR (95% CI) P value OR (95% CI) P value Sex Female 1.00 (Reference) – Male 1.06 (0.59–1.93) 0.853 Prior biologic or JAK inhibitor use 1.89 (0.78–4.37) 0.144 2.50 (0.94–6.54) 0.062 Oral corticosteroid use 0.68 (0.37–1.24) 0.213 0.58 (0.29–1.16) 0.128 History of surgery 0.24 (0.01–1.28) 0.177 0.30 (0.02–1.74) 0.270 History of anal disease 0.77 (0.27–1.91) 0.600 Age, years 1.00 (0.99–1.00) 0.380 Weight, kg 1.00 (0.99–1.00) 0.087 BMI, kg/m 2 0.98 (0.97–1.00) 0.016* 0.91 (0.84–0.98) 0.022* SES-CD 1.01 (1.00–1.02) 0.027* 1.04 (0.99–1.09) 0.157 CDAI score 1.00 (1.00–1.00) 0.002* 1.01 (1.00–1.01) 0.064 FC, mg/kg 1.00 (1.00–1.00) 0.828 CRP, nmol/L 1.00 (1.00–1.00) 0.412 Lymphocytes, cells × 10 9 /L 1.05 (0.98–1.13) 0.185 1.38 (0.90–2.12) 0.141 Neutrophils, cells × 10 9 /L 1.02 (0.99–1.01) 0.162 1.05 (0.92–1.20) 0.471 Albumin, g/L 1.00 (0.99–1.01) 0.959 W10 serum infliximab level ≥ 14 μg/mL 1.97 (1.09–3.58) 0.025* 2.75 (1.41–5.48) 0.003* Open in a new tab BMI body mass index, CDAI Crohn’s Disease Activity Index, CI confidence interval, CRP C-reactive protein, FC faecal calprotectin, JAK Janus kinase, OR odds ratio, SES-CD Simple Endoscopic Score for Crohn’s Disease, W week *Statistically significant In adjusted logistic regression analyses of super-responders versus limited responders, lower baseline oral corticosteroid use ( p = 0.031) and higher CDAI score ( p = 0.005) were associated with a super-response. Achieving serum infliximab levels ≥ 12 μg/mL at week 14 was also associated with a super-response during treatment with SC infliximab (Supplementary Table 2 ). No significant factors were identified in the analysis contrasting fast responder and slow responder groups (Supplementary Table 3 ). Clinical Outcomes by Response Trajectories At week 54, super-responders had high rates of clinical remission (80.3%; p = 0.002), endoscopic remission (42.6%; p = 0.080), FC normalisation (50.8%; p = 0.045), and HRQoL remission (72.1%; p = 0.0002) compared with other trajectories (Fig. 2 ). When these four endpoints were analysed as a composite endpoint, CDC, in terms of deep remission, a significantly higher proportion of super-responders (27.9%; p = 0.014) achieved CDC at week 54 relative to fast responders (16.1%), slow responders (25.4%), and limited responders (5.9%). The proportions of patients achieving three or more components of the CDC endpoint were similar among super-responders (54.1%) and slow responders (54.0%), both of which were higher compared with fast responders and limited responders (44.7% and 33.4%, respectively) (Supplementary Table 4 ). Super-responders had the highest rates of corticosteroid-free remission (59.1%) and endoscopic response (63.9%) at week 54, compared with other trajectories (Supplementary Fig. 3 ). Fig. 2. Open in a new tab Clinical outcomes including clinical remission* ( a ), endoscopic remission** ( b ), FC normalisation † ( c ), HRQoL remission ‡ ( d ), and CDC ¤ ( e ) at week 54 by response trajectories. *Clinical remission, an absolute CDAI score < 150; **Endoscopic remission, SES-CD of ≤ 4 and ≥ 2-point reduction from the baseline value with no segment sub-score of > 1; † FC normalisation, FC level ≤ 250 μg/g; ‡ Remission by HRQoL, SIBDQ score ≥ 50; ¤ CDC was defined as achieving clinical remission, endoscopic remission, FC normalisation, and remission by HRQoL, simultaneously; § Statistical comparisons were analysed by chi-square test. Rates of clinical remission, endoscopic remission, FC normalisation, HRQoL remission, and CDC included data for patients who received a dose adjustment. CDAI Crohn’s Disease Activity Index, CDC comprehensive disease control, FC faecal calprotectin, FR fast responders, HRQoL health-related quality of life, LR limited responders, SES-CD Simple Endoscopic Score for Crohn’s Disease, SIBDQ Short Inflammatory Bowel Disease Questionnaire, Sl-R slow responders, SR super-responders Clinical response and clinical remission rates in the trajectory groups throughout the study period are shown in Supplementary Fig. 4 . At week 54, rates of clinical response were 98%, 89%, 92%, and 65% in the super-responder, fast responder, slow responder, and limited responder groups, respectively. Serum Infliximab Levels and Immunogenicity by Response Trajectories Among response trajectories, super-responders maintained the highest pre-dose serum infliximab levels throughout the maintenance period from week 10. The median (95% confidence interval [CI]) of pre-dose serum infliximab at week 10 in super-responders was the highest, 14.5 (1.7) μg/ml, compared with other trajectories: fast responders, 12.5 (2.0) μg/ml; slow responders, 12.0 (1.9) μg/ml; and limited responders, 10.5 (1.9) μg/ml (Fig. 3 ). In contrast, the proportion of ADA-positive patients at week 10 was lowest in the super-responders compared with the other response trajectories: super-responders, 3.3% (2/61); fast responders, 7.1% (4/56); slow responders, 9.5% (6/63); and limited responders, 9.8% (5/51) (Supplementary Table 5 ). No significant differences were observed in the distribution of ADA titer levels (low, moderate, and high) across the response trajectories (Supplementary Table 6 ). Fig. 3. Open in a new tab Pre-dose serum infliximab level during treatment by response trajectories. Data in the table below the figure represent infliximab serum levels (μg/mL), median (95% CI). † Statistical comparisons were analysed using the Mann–Whitney U test. CI confidence interval, FR fast responders, LR limited responders, n number, NA not applicable, Sl-R slow responders, SR super-responders, W week A significant difference was observed between super-responders and other trajectories in serum infliximab levels ≥ 14 µg/mL at week 10 ( p = 0.032). Super-responders were also more likely to achieve week 14 serum infliximab levels ≥ 12 µg/mL compared with other trajectories ( p = 0.002) (Supplementary Table 7 ). Comparison of pre-dose serum infliximab levels between super-responders and limited responders, and between fast responders and slow responders, revealed no significant differences, except for serum infliximab levels ≥ 12 µg/mL at week 14 between super-responders and limited responders (Supplementary Table 7 ). Safety Profile by Response Trajectories SC infliximab was well tolerated, with comparable overall safety profiles observed across all response trajectory groups (Table 3 ). The proportions of patients experiencing TEAEs and TESAEs (total), respectively, were comparable across trajectories (super-responders, 70.5% and 3.3%; fast responders, 66.1% and 7.1%; slow responders, 74.6% and 7.9%; limited responders, 74.5% and 7.8%). Similar and low proportions of patients across trajectories experienced localised ISRs and infections. Table 3. Safety profiles during maintenance treatment, by response trajectories Characteristic, n (%) Super-responders ( n = 61) Fast responders ( n = 56) Slow responders ( n = 63) Limited responders ( n = 51) TEAE Total 43 (70.5) 37 (66.1) 47 (74.6) 38 (74.5) Related 16 (26.2) 12 (21.4) 16 (25.4) 17 (33.3) TESAE Total 2 (3.3) 4 (7.1) 5 (7.9) 4 (7.8) Related 0 0 0 1 (2.0) Localised ISR Total 4 (6.6) 2 (3.6) 4 (6.3) 4 (7.8) Related 4 (6.6) 2 (3.6) 4 (6.3) 4 (7.8) Infection Total 17 (27.9) 16 (28.6) 24 (38.1) 15 (29.4) Related 2 (3.3) 0 5 (7.9) 7 (13.7) Open in a new tab ISR injection site reaction, TEAE treatment-emergent adverse event, TESAE treatment-emergent serious adverse event Discussion This post hoc analysis employed GBTM to identify distinct subpopulations with individually different dynamics, rates, and levels of response to IV/SC infliximab in a large group of patients with moderately to severely active CD enrolled in the phase 3 LIBERTY-CD study. Significant heterogeneity in therapy response kinetics was found early in the course of therapy that was linked to endpoints at the end of the maintenance observation. Notably, four different subgroups were differentiated, among which a subgroup of super-responders exhibiting rapid and high sustained improvements in PRO-2 measures were identified and shown to have a higher likelihood of achieving desirable long-term outcomes, such as deep remission levels including CDC. Super-responders were also characterised by the highest pre-dose serum infliximab levels throughout maintenance treatment (from week 10) and showed a trend towards having lower baseline body weight and BMI, and higher baseline clinical and endoscopic disease activity, compared with other response trajectories. In multivariable analyses, pre-dose serum infliximab levels at week 10 and baseline BMI were also identified as being independently associated with super-response. When comparing trajectories by types of response, less oral corticosteroid use at baseline was identified as an independent predictor of super-responders compared with limited responders, along with achieving serum infliximab levels ≥ 12 µg/mL threshold at week 14. To our knowledge, this is the first study to fully report individual response trajectories in adult patients with CD using a GBTM approach. Similar findings were reported in the VIVID study in mirikizumab-treated patients with moderately to severely active CD using a growth mixture model that identified four distinct responder subpopulations, again with the highest rates of remission endpoints observed in super-responders [ 19 ]. Several other studies have previously employed GBTM to examine response trajectories in biologic-treated paediatric patients with CD [ 20 ] and adult patients with UC treated with advanced drugs [ 11 – 13 ]. A GBTM analysis using retrospective chart data from infliximab-treated paediatric patients with CD used serum CRP concentrations to distinguish three subgroups of patients with differential relapse-and-remission profiles. Individual patients with the best treatment response were reported to have the lowest risk of inflammatory bowel disease-related surgery and disease-related complications within 10 years of treatment [ 20 ]. In adult patients with moderately to severely active UC, a post hoc analysis of data from a phase 2b/3, placebo-controlled trial of filgotinib used daily recordings of partial Mayo scores to identify five response trajectories, including fast and sustained, slow and sustained, or gradual improvements, as well as slow and fast rebounds [ 12 ]. Sustained improvement was observed in higher proportions of biologic-naïve, female patients with a lower endoscopic inflammation burden and a strong FC response at week 10 [ 12 ]. Similarly, a post hoc GBTM analysis of data from the phase 3 True North study of ozanimod in patients with moderately to severely active UC identified five unique response trajectories based on partial Mayo score. In agreement with our findings, the latter study reported the highest rates of clinical and endoscopic endpoints in GBTM-identified groups with fast sustained, slow sustained, or gradual improvements [ 11 ]. In contrast to these earlier studies [ 11 , 12 ], no rebound groups were identified during SC infliximab maintenance in the present analysis, and rates of clinical remission (51.0%) and endoscopic response (45.1%) in the limited response group were much higher than those reported for the rebound groups with other agents [ 11 ]. A GBTM-based approach was also used to identify response clusters for vedolizumab and adalimumab using data from the phase 3 VARSITY study (treat-through design) [ 13 ]. Similar to our findings, the analysis identified four trajectories: super, fast, and partial responder groups and an incomplete/non-response group (but no rebound groups) in a cohort of patients with moderate to severe UC [ 13 ]. Evaluation of CDC (defined as achievement of a patient-level combination of clinical, endoscopic, and histological response with CRP/FC normalisation) across response trajectories showed that 15% and 18% of super-responders achieved disease control with adalimumab and vedolizumab, respectively. For comparison, 27.9% of super-responders in the present study achieved CDC (defined as achievement of a patient-level combination of clinical remission, endoscopic remission, FC normalisation, and HRQoL remission) with SC infliximab. The proportion of patients achieving three or more components of the CDC endpoint was 54.1% in the super-responders. This rate is slightly higher than real-world rates of deep remission (defined as at least a combination of clinical remission and mucosal healing/endoscopic remission) reported with infliximab in patients with CD (51.5%) [ 18 ], noting that our definition was more stringent, requiring the achievement of three or more endpoints. This study is the first to implement CDC as a patient-level combination of different stringent endpoints in CD, alongside the association between different responder profiles using GBTM. While numerous studies have explored the concept of ‘deep remission’ in CD [ 3 , 21 , 22 ], our investigation also marks the first endeavour to evaluate the combination of four distinct endpoints. While super-responders in this study were likely to achieve higher rates of stringent long-term outcomes, such as corticosteroid-free remission and CDC, our findings also suggest that the response of all patients who showed clinical response at week 10 with IV infliximab treatment was sustained with SC infliximab therapy at a clinically meaningful degree for 1 year in more than two-thirds of patients, irrespective of their response trajectory. Even though limited responders showed the lowest rate of achieving clinical outcomes compared with other trajectories, the mean (95% CI) CDAI score at week 54 was 148.7 ± 26.9; this is less than 150, the threshold of clinical remission. In clinical terms, patients experiencing a delayed response compared with super-responders would likely need to be monitored more tightly than others to optimise therapy. Baseline characteristics that are associated with a super-responder profile to SC infliximab may be important for directing therapy decisions. Patients who were identified as super-responders had relatively high disease activity, with low BMI. The factor most strongly associated with super-response was the infliximab serum level of ≥14 μg/mL at week 10. Moreover, the mean serum infliximab levels in super-responders were higher from week 10 throughout the entire course of maintenance treatment, suggesting that pharmacokinetic differences are linked to a super-responder trajectory for infliximab. When the different trajectories were compared in terms of level of response (super-responders versus limited responders), lower baseline oral corticosteroid use ( p = 0.031), higher CDAI score ( p = 0.005), and achieving serum infliximab levels ≥ 12 μg/mL at week 14 were associated with a super-response. However, no significant variables were identified in the comparison between the fast responder versus slow responder analysis. It appears that these could be important for clinical decision-making regarding patients suitable for SC infliximab during maintenance treatment. The present study has several strengths and limitations. The primary strength of this study is the application of innovative methodology to evaluate the individual SC infliximab response patterns longitudinally with no bias. This methodology has been used in other disciplines, but its application remains limited in UC and especially in adult CD. Moreover, we utilised a large sample of patients with moderately to severely active CD enrolled in a double-blinded, randomised, phase 3 study, which has allowed us to define distinctive trajectories of response from an early time for 1 year. A further strength of the present approach lies in the use of patient-reported measures (abdominal pain and stool frequency scores) rather than surrogate markers of disease activity, such as CRP or FC, as the basis for the GBTM. The fact that the response to infliximab can be identified using easily accessible patient-reported measurements may be advantageous in monitoring the treatment response. However, while these measures are clinically useful markers, the inclusion of objective surrogate markers, such as CRP or FC, in future analyses may help identify additional predictive factors and allow for a more refined and earlier differentiation between patient subgroups. The replication test using data from the European registration study, which also identified treatment response trajectories, further strengthens our observations from the LIBERTY-CD study. Lastly, this study represents the first instance of employing the concept of CDC in CD; it is a notable strength that the study contains the most stringent criteria by evaluating combinations of four distinct endpoints. Limitations of the study include that the phase 3 LIBERTY-CD study design included only randomised patients who achieved clinical response after receiving three full IV infliximab doses at week 10, leading to the exclusion of week 10 non-responder patients and presenting a limitation for direct application in real-world practice. However, it should be noted that the description of different early response groups and their association with long-term outcomes was described in several randomised controlled studies in UC including the treat-through design using GBTM in a comparable way [ 11 , 12 ]. Furthermore, our analysis does not allow prediction of response to infliximab prior to treatment selection but suggests that early observation of response patterns could be meaningful. The most effective factor associated with different response trajectories appeared to be infliximab serum concentration level at week 10 following IV induction, although whether increasing infliximab exposure leads to higher percentages of super-responders was not tested. Our new taxonomy of response may aid prospective studies aiming to identify factors that predict a favourable response before the initiation of infliximab therapy and would help to elucidate which subgroups are most likely to benefit from infliximab treatment. An analysis designed in this approach would therefore include non-responder patients (who were not included in the present analysis), which may provide a greater ‘dynamic range’ to identify factors associated with different response trajectories. While symptom-based identification of response trajectories results in valuable clinical classifications, further extensions of this approach employing high resolution phenotyping during early exposure to therapy could add more sensitive markers and lead to even higher resolution for early identification of preferred responder populations. Further prospective studies are warranted to investigate long-term outcomes for different treatment response trajectories and to validate such trajectories in an independent sample of patients. Such prospective studies based on our observations would be necessary to evaluate whether this approach could be used to guide personalised therapy, including the validation of candidate cut-off values and their predictive performance, and to individually tailor monitoring and other aspects of patient care to different responder populations. Recognising these limitations, the present findings complement the primary findings of the LIBERTY-CD study, which demonstrated that maintenance therapy with SC infliximab provides both a robust clinical benefit and the convenience of SC administration in patients with moderately to severely active CD [ 15 ]. Conclusion Distinct subpopulations with different rates and levels of infliximab responses were detected by GBTM using data from a large group of patients with moderately to severely active CD who were undergoing IV infliximab and SC infliximab-dyyb maintenance therapy for 1 year. Super-responders with rapid and sustained improvements throughout infliximab treatment had a higher likelihood of achieving desirable long‑term outcomes, including deep remission. Baseline BMI and pre-dose infliximab serum levels at week 10 were identified as factors associated with a super-response to SC infliximab. The understanding of differential response trajectories increases the utility of an IV/SC sequence therapy with infliximab and supports its use as a first-line intervention in a world of increasing therapeutic complexity and choice in CD. Supplementary Information Below is the link to the electronic supplementary material. Supplementary file1 (PDF 966 kb) (1.2MB, pdf) Acknowledgements We thank all patients and investigators involved in the study. Medical Writing/Editorial Assistance Medical writing support (including development of a draft outline and subsequent drafts in consultation with the authors, assembling tables and figures, collating author comments, copyediting, fact checking and referencing) was provided by Iain Nicholson at Aspire Scientific (Manchester, UK), and funded by Celltrion Inc. (Incheon, Republic of Korea). Author Contributions Stefan Schreiber and Jean-Frédéric Colombel were involved in the study conceptualisation and supervision. Ae Lee Jeong, Dong-Hyeon Kim, and Young Nam Lee collected the data and were involved in its analysis and data interpretation. All authors (Stefan Schreiber, Bruce E. Sands, Silvio Danese, Edward V. Loftus Jr., Ae Lee Jeong, Dong-Hyeon Kim, Young Nam Lee, and Jean-Frédéric Colombel) contributed to the interpretation of the data, reviewed and critically revised the manuscript, approved the final draft, and are accountable for the accuracy and integrity of this work. Funding This work was supported by Celltrion Inc. (Incheon, Republic of Korea) and the Deutsche Forschungsgemeinschaft Excellence Cluster Precision Medicine in Inflammation (EXC2067). The rapid service fee and open access fees were funded by Celltrion Inc. Data Availability Redacted study protocols have been published as part of the supplementary materials for an earlier publication [ 15 ]. Individual participant data will not be shared. Declarations Conflict of Interest The authors disclose the following: Stefan Schreiber – advisory committee/board member, AbbVie, Amgen, Arena, Biogen, BMS, Celgene, Celltrion, Falk, Ferring, Fresenius, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz/Hexal, Takeda, Theravance, and UCB; lecturer, Hikma; stockholder of CONARIS AG. Bruce E. Sands – consulting fees from Abbvie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, 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 & Co., Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Palisade Bio, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Therapeutics, Spyre Therapeutics, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, and Ventyx Biosciences; 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, Eli Lilly & Company, Janssen, Pfizer, and Takeda; research grants and consulting fees from Janssen; and stock/stock options from Ventyx Biopharma. Silvio Danese – consultant 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, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB, Vial, and Vifor; lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer, and Takeda. Edward V. Jr. Loftus – consultant fees from AbbVie, Abivax, Astellas, Avalo Therapeutics, Biocon, Bristol Myers Squibb, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Janssen, Merck, Morphic, Ono Pharma, Spyre Therapeutics, Takeda, and TR1X Bio; research support from AbbVie, Gilead, Janssen, Merck, and TR1X Bio; shareowner of Exact Sciences and Moderna. Ae Lee Jeong, Dong-Hyeon Kim, and Young Nam Lee are employees of Celltrion Inc. Dong-Hyeon Kim and Young Nam Lee are stockholders of Celltrion Inc. Jean-Frédéric Colombel – research grants from AbbVie, Janssen Pharmaceuticals, Takeda, Prometheus, and Bristol Myers Squibb; lecturer – AbbVie and Takeda; consultant fees from AbbVie, Amgen, AnaptysBio, Allergan, Arena Pharmaceuticals, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Celltrion, Eli Lilly, Envision Pharma, Ferring Pharmaceuticals, Galmed Research, GlaxoSmithKline, Genentech (Roche), Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Iterative Scopes, Merck, Landos, Microba Life Science, Novartis, Otsuka Pharmaceutical, Pfizer, Protagonist Therapeutics, Sanofi, Sun, Takeda, TiGenix, and Vifor; stock options, Intestinal Biotech Development. Ethical Approval The study was performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki. Prior to study initiation, the study protocol was approved by an independent ethics committee or institutional review board at each participating site. The full list of study sites is reported in the primary manuscript supplementary materials [ 15 ]. All participants provided written informed consent prior to enrolment in the study. Footnotes Prior Presentation: Selected data were presented as posters at the Congress of the European Crohn’s and Colitis Organization 2024 (Stockholm, Sweden; February 21–24, 2024; Poster number, P734) and at Digestive Disease Week 2024 (Washington, DC, USA; May 18–21, 2024; Poster number, Su1767). Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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