Gastroenterology · Medical Literature
Impact of Immunogenicity on Clinical Outcomes in Patients With Moderate-to-Severe Inflammatory Bowel Disease Receiving Subcutaneous Infliximab: A Post Hoc Analysis of the LIBERTY Trials.
Abstract
LIBERTY-CD and LIBERTY-UC demonstrated superior efficacy of subcutaneous infliximab (IFX SC) to placebo in patients with Crohn's disease (CD) or ulcerative colitis (UC). Here, we investigated the impact of anti-drug antibodies (ADAs) on clinical outcomes. Patients randomized to IFX SC maintenance treatment in the LIBERTY trials were included (CD, n = 231; UC, n = 294). ADAs were tested using a highly sensitive, drug-tolerant assay. Patients were grouped by ADA occurrence and titer and evaluated for outcomes up to Week (W) 54. Among patients with CD and UC, 150 (64.9%) and 187 (63.6%) were ADA-positive, respectively. No statistically significant differences were observed between the ADA-positive and ADA-negative groups in W54 efficacy (CD: clinical remission, 69.5% [95% confidence interval: 61.6-77.5] vs. 79.7% [70.2-89.2], p = 0.134; endoscopic response, 57.5% [48.9-66.1] vs. 65.2% [54.0-76.5], p = 0.359; UC: clinical remission, 49.1% [41.3-56.8] vs. 57.0% [46.5-67.4], p = 0.284), drug persistence (CD: 84.7% [79.1-90.6] vs. 85.2% [77.8-93.3]; UC: 84.5% [79.5-89.8] vs. 77.6% [70.1-85.9]), and safety (patients with ≥ 1 treatment-emergent adverse event; CD: 71.2% [64.0-78.3] vs. 74.4% [64.9-83.8]; UC: 69.5% [62.9-76.0] vs. 64.2% [55.0-73.3]), despite lower drug concentrations in ADA-positive patients at W54 (CD: 10.6 μg/mL [9.1-12.2] vs. 17.9 μg/mL [15.8-20.1]; UC: 12.2 μg/mL [10.8-13.5] vs. 21.0 μg/mL [18.4-23.6]). No significant relationship between ADA titer and efficacy or persistence was noted. Although ADAs affected drug levels, no significant differences by ADA occurrence were observed in W54 efficacy or safety among patients receiving IFX SC maintenance treatment. While high ADA titers were associated with lower drug levels, effectiveness was not diminished within 1 year. ClinicalTrials.gov identifiers NCT03945019 (LIBERTY-CD) and NCT04205643 (LIBERTY-UC).
Clinical relevance
In patients with moderate-to-severe Crohn's disease (CD) or ulcerative colitis (UC) receiving subcutaneous infliximab (IFX SC) maintenance therapy, do anti-drug antibodies (ADAs) adversely affect clinical efficacy, drug persistence, or safety outcomes through Week 54? __SNAPSHOT__ {"studyDesign":"Post hoc analysis of two randomized, placebo-controlled, Phase 3 trials (LIBERTY-CD [NCT03945019] and LIBERTY-UC [NCT04205643])","setting":"Multinational; academic and clinical centers across multiple countries (specific sites not reported in abstract)","sampleSize":"n=525 (CD: n=231; UC: n=294); all randomized to IFX SC maintenance arm","population":"Adults with moderate-to-severe CD or UC who responded to IV infliximab induction (CT-P13 5 mg/kg at Weeks 0, 2, 6) and were randomized to IFX SC maintenance at Week 10","intervention":"Subcutaneous infliximab (CT-P13 SC) 120 mg every two weeks maintenance therapy; patients classified post hoc by ADA occurrence and titer using a highly sensitive, drug-tolerant assay","comparator":"ADA-negative patients within the IFX SC arm (intra-arm comparison); placebo was the comparator in the parent trials but not in this post hoc analysis","primaryOutcome":"Clinical remission at Week 54; secondary outcomes included endoscopic response (CD), drug persistence, and safety through Week 54","followUp":"54 weeks","fundingSource":"Industry (Celltrion, Inc.; authors include Celltrion employees [Kang A, Kim DH, Lee YN])"}
Key findings
Among patients receiving IFX SC maintenance, ADA positivity was highly prevalent: 150/231 (64.9%) in CD and 187/294 (63.6%) in UC. Despite this high ADA prevalence, no statistically significant differences were observed between ADA-positive and ADA-negative groups across all primary and secondary efficacy outcomes at Week 54. In CD, clinical remission rates were 69.5% (95% CI: 61.6–77.5) in ADA-positive vs. 79.7% (95% CI: 70.2–89.2) in ADA-negative patients (p=0.134); endoscopic response was 57.5% (95% CI: 48.9–66.1) vs. 65.2% (95% CI: 54.0–76.5) (p=0.359). In UC, clinical remission was 49.1% (95% CI: 41.3–56.8) in ADA-positive vs. 57.0% (95% CI: 46.5–67.4) in ADA-negative patients (p=0.284). Drug persistence was similarly comparable: CD 84.7% (95% CI: 79.1–90.6) in ADA-positive vs. 85.2% (95% CI: 77.8–93.3) in ADA-negative; UC 84.5% (95% CI: 79.5–89.8) vs. 77.6% (95% CI: 70.1–85.9). No statistically significant between-group differences were observed in the proportion of patients experiencing ≥1 treatment-emergent adverse event. Absolute differences in remission rates trended numerically lower in ADA-positive patients (CD: −10.2 percentage points [calculated]; UC: −7.9 percentage points [calculated]), but these did not reach statistical significance. NNH for loss of clinical remission attributable to ADA positivity was not calculable from reported data. Specific adverse event rates and ADA titer-stratified subgroup results are not fully reproduced in the available abstract.
Practice implications
This post hoc analysis suggests that ADA formation—detected in approximately two-thirds of IFX SC-treated patients using a highly sensitive drug-tolerant assay—did not translate into statistically significant impairment of clinical remission, endoscopic response, drug persistence, or safety through one year. This is a clinically important and reassuring signal that partially distinguishes IFX SC from historical IV infliximab data, where immunogenicity is well established as a driver of loss of response and treatment discontinuation. The relatively stable trough concentrations associated with the SC route (resulting in fewer low-level drug trough periods, which are known to prime immunogenicity) may partially explain the attenuated clinical impact of ADA positivity observed here. However, several important limitations constrain interpretation: (1) this is a post hoc, non-prespecified analysis and is therefore hypothesis-generating only; (2) the parent trials enrolled only IV-induction responders, excluding primary non-responders, which limits generalizability to all IBD patients; (3) the analysis is restricted to the IFX SC arm and does not compare ADA rates or clinical consequences against an IFX IV arm; (4) ADA titer-stratified subgroup results are only partially reported in the abstract; (5) longer-term consequences of ADA positivity beyond Week 54 are unknown; and (6) concomitant immunosuppressant use, a key modifier of immunogenicity, is not characterized in the available abstract. The finding that approximately 65% of patients developed ADAs yet maintained high rates of clinical remission and drug persistence is clinically noteworthy, but whether this reflects truly clinically inert immunogenicity or a window-period effect requiring longer follow-up cannot be determined from this analysis alone. IMPORTANT NOTE: Only the abstract was available for this summary; full-text data, including titer-stratified subgroups and complete adverse event tables, were not accessible and may alter interpretation. __LIMITATIONS__ Post hoc, non-prespecified design: results are exploratory and hypothesis-generating only; no adjustment for multiple comparisons is reported.,Restricted to IV induction responders randomized to IFX SC; primary non-responders and patients who did not complete induction are excluded, introducing selection bias and limiting generalizability.,No IV infliximab comparator arm in this analysis; cannot directly compare ADA rates or clinical impact of ADA positivity between SC and IV routes.,High ADA prevalence (~64%) detected by a highly sensitive drug-tolerant assay may overestimate clinically relevant immunogenicity; the clinical significance of low-titer or transient ADAs is not differentiated in the abstract.,ADA titer-stratified subgroup results and full adverse event data are not completely reproducible from the abstract alone; full-text review is required for complete characterization.,Follow-up limited to 54 weeks; longer-term clinical consequences of sustained ADA positivity are unknown.,Industry funding with Celltrion employees as co-authors; potential for sponsorship bias in analysis design, assay selection, and reporting.,Concomitant immunosuppressant use—a critical effect modifier of immunogenicity—is not characterized in the available abstract.,Sample sizes within ADA subgroups may be underpowered to detect clinically meaningful differences, particularly for less common outcomes.,Patients enrolled in the parent LIBERTY trials may not represent real-world IBD populations, including those with prior biologic failure or immunogenic failure on IV infliximab. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ In this post hoc analysis of the LIBERTY trials, approximately two-thirds of IFX SC-treated patients developed ADAs by Week 54, yet ADA positivity was not associated with statistically significant reductions in clinical remission, endoscopic response, drug persistence, or safety compared to ADA-negative patients. These exploratory findings suggest that the pharmacokinetic profile of IFX SC may attenuate the clinical impact of immunogenicity relative to historical IV infliximab data, but given the post hoc design, industry funding, and abstract-only availability, these results should be considered hypothesis-generating and confirmatory prospective studies with prespecified immunogenicity endpoints are needed before practice change.