Abstract
Objectives
Payer mandates have resulted in children with inflammatory bowel disease (IBD) switching from originator Remicade® (O‐Rem) to an infliximab biosimilar (B‐IFX). Patients and families are fearful of switching because disease has been well controlled on O‐Rem. Real‐world data documenting clinical outcomes after such switches in pediatric patients are limited. The aim of this project was to examine 1 year of follow‐up in a large adolescent/young adult IBD cohort who changed from O‐Rem to B‐IFX.
Methods
We identified patients with IBD at Connecticut Children's receiving O‐Rem for at least 1 year, who were either in clinical remission or had low disease activity, and who were subsequently switched to B‐IFX. An age, gender, IBD‐subtype, and duration since diagnosis cohort that continued on O‐Rem was then matched to the switch cohort and served as a comparator group (1: switch vs. 2: no‐switch). B‐IFX was Inflectra® in all cases.
Results
Two hundred and seventy‐nine patients (mean age 18.7 years, Crohn's disease = 243, ulcerative colitis = 36) were studied (switch, n = 93, no‐switch, n = 186). Mean time since diagnosis was >6 years in both groups, and mean duration of anti‐tumor necrosis factor use was >5 years. There were no significant changes in hemoglobin, albumin, C‐reactive protein, erythrocyte sedimentation rate, or disease activity in either group over 1 year. Dosing modifications as well as the frequency of low‐level antibodies to infliximab were similar in both groups over the study period.
Conclusion
Switching from O‐Rem to B‐IFX has no impact on clinical or laboratory parameters over the subsequent year. Clinicians can reliably reassure patients and families that switching is safe.
Keywords: anti‐TNF therapy, Crohn's disease, pediatrics, ulcerative colitis
What is Known
Biosimilar biologics are now increasingly being required by third‐party payers for the treatment of inflammatory bowel disease (IBD).
Pediatric data describing clinical and laboratory course following switch from originator‐Remicade® to biosimilar‐Inflectra® are limited.
What is New
Our large real‐world experience with an adolescent and young adult IBD population documents no significant difference comparing patients who remain on originator‐Remicade® to those who are switched to biosimilar‐Inflectra®.
We also demonstrate that dosing regimens and the development of antibodies to infliximab are similar between switch and nonswitch groups over a year.
Patients and families should be reassured of the safety of switching to a biosimilar.
1. INTRODUCTION
Treatment with anti‐tumor necrosis factor (TNF) agents is firmly established for the care of adults and children with inflammatory bowel disease (IBD). 1 , 2 Infliximab, a chimeric immunoglobulin G1 antibody, was approved for pediatric use in 2006 and for many years was administered as the originator drug Remicade®. In 2013, the European Medicines Agency authorized biosimilar infliximab (CT‐P13) under the brand names Remsima® and Inflectra®. The US Food and Drug Administration approved the use of Inflectra® for all relevant indications in April 2016. Ample evidence exists in adults with IBD documenting equivalent efficacy and safety of infliximab biosimilar (B‐IFX) to originator Remicade (O‐Rem). 2 , 3 , 4 , 5 Real‐world pediatric/adolescent data remain limited. 6 , 7 , 8 , 9 , 10
Third‐party payer mandates over the past several years have resulted in an increasing number of children and adolescents with IBD being switched from O‐Rem to a B‐IFX. Patients and families are often reluctant to switch because disease has been well controlled on O‐Rem and they are fearful of clinical worsening. We sought to better understand our real‐life experience in a large pediatric/adolescent and young adult IBD population who underwent a switch from O‐Rem to a B‐IFX. To our knowledge, this is the largest single‐center comparison of pediatric patients who underwent a switch from O‐Rem to B‐IFX to those who remained on O‐Rem.
2. METHODS
We conducted a retrospective single‐center case–control study that was approved by the Institutional Review Board at Connecticut Children's. We first identified patients 6–26 years of age diagnosed with IBD at Connecticut Children's by query of our IBD database. We then identified those who were either in clinical remission or had low disease activity on O‐Rem and were subsequently switched to B‐IFX. B‐IFX was Inflectra® in all cases. We identified control patients who were not switched to B‐IFX and remained on O‐Rem to serve as a comparator population. The comparator group was matched to switch patients by age, gender, IBD subtype, and time since diagnosis. Comparator controls and cases were matched at a 2:1 ratio. The minimum duration on O‐Rem was 12 months before switching to B‐IFX. A minimum follow‐up of 12 months following the switch from O‐Rem to B‐IFX was required.
The primary aim was to evaluate changes in the clinical and laboratory status of IBD patients in remission/low disease activity on O‐Rem when switched to B‐IFX and determine whether these changes differ compared to patients who remain on O‐Rem. Baseline clinical, laboratory, and demographic characteristics were recorded for all patients and included age, sex, race/ethnicity, type of IBD, time since IBD diagnosis, disease activity, concomitant medications, and Paris classification. Disease activity was described by Physician's Global Assessment (PGA), Pediatric Ulcerative Colitis Activity Index (PUCAI) for those with ulcerative colitis (UC), and Pediatric Crohn's Disease Activity Index (PCDAI) for those with Crohn's disease (CD). Need for hospitalization or surgery secondary to IBD was noted. Laboratory parameters longitudinally measured over the same period included hemoglobin, albumin, C‐reactive protein, erythrocyte sedimentation rate, anti‐TNF drug level, and antibody level to anti‐TNF. Follow‐up data were obtained at 6 and 12 months following baseline.
Infliximab levels and antibody‐to‐infliximab levels were determined by commercial laboratories using drug tolerant assays (Labcorp and Quest). Our therapeutic goal is to maintain through infliximab levels between 8 and 20 µg/mL.
Descriptive analysis was used to report patient age, sex, diagnosis, medications, and time since diagnosis. Two‐sample t test was used to estimate the difference between the cases to the controls, while paired t test was used for comparing cases to cases. Chi‐square test was used for equivalent proportions, while Fisher test was used where the sample size was small.
3. RESULTS
Demographics and clinical characteristics of the two study groups are shown in Table 1. The two groups (O‐Rem to B‐IFX: n = 93; O‐REM to O‐REM: n = 186) were well‐matched using patient age, gender, and time of switch from O‐Rem to B‐IFX. Our study cohort ranged from 8 to 26 years of age and 20%–25% were less than 10 years of age. There were significantly more patients with CD compared to UC. The mean time since diagnosis was >6 years in both groups and the mean duration of anti‐TNF use was >5 years. Use of concomitant methotrexate was similar in both groups (17% switch group and 11% nonswitch group). Both groups had similar rates of missing clinical information (PGA, PUCAI, and PCDAI) throughout the 12‐month study period. Five control patients were removed from the study at 12 months as they were switched from Remicade® to biosimilar Inflectra®.
Table 1.
Demographic and clinical characteristics of patients.
| Switch cases (n = 93) | Nonswitch controls (n = 186) | |
|---|---|---|
| Age; mean, range (years) | 18.8 [9–26] | 18.6 [8–26] |
| Diagnosis <10 years of age (CD) | 20 (25%) | 24 (15%) |
| Sex (male) | 58 (62%) | 117 (63%) |
| IBD type | ||
| CD | 81 (87%) | 162 (87%) |
| UC | 12 (13%) | 24 (13%) |
| Disease location (CD) | ||
| L1a | 23 (28%) | 34 (21%) |
| L2a | 6 (7.4%) | 22 (14%) |
| L3a | 50 (62%) | 102 (63%) |
| L4a | 2 (2.5%) | 4 (2.5%) |
| Disease behavior (CD) | ||
| B1b | 71 (88%) | 140 (86%) |
| B2b | 6 (7.4%) | 4 (2.5%) |
| B2 B3b | 3 (3.7%) | 7 (4.3%) |
| B3b | 1 (1.2%) | 11 (6.8%) |
| Disease location (UC) | ||
| E3/E4c | 9 (75%) | 21 (88%) |
| Duration since diagnosis, mean (months) | 94 | 77 |
| Duration of anti‐TNF use, mean (months) | 76 | 61 |
| Concomitant methotrexate | 16 (17%) | 21 (11%) |
Note: No significant demographic differences between cases and controls except IBD type. Significantly more CD than UC among cases (p < 0.001) and controls (p < 0.001).
Abbreviations: CD, Crohn's disease; IBD, inflammatory bowel disease; TNF, tumor necrosis factor; UC, ulcerative colitis.
L1: Distal 1/3 ileal ± limited cecal disease, L2: Colonic, L3: Ileocolonic, L4: Upper disease distal to Ligament of Treitz or upper disease distal to Ligament of Treitz and proximal to distal 1/3 ileum.
B1: Nonstricturing nonpenetrating, B2: Stricturing, B3: Penetrating, B2B3: Both penetrating and stricturing disease.
E3: Extensive (hepatic flexure distally), E4: Pancolitis (proximal to hepatic flexure).
For the O‐Rem to B‐IFX group, a difference from time of change to 6 months and 12 months after switch was calculated and compared to the difference for the same interval for their assigned controls in the nonswitch group. As noted in Table 2, there were no significant changes in key laboratory markers or disease activity in either the switch group or the control group over the 6 and 12‐month observation period. The difference in values was not statistically significant, with a p level of p < 0.05 used as a marker for a significant change. Similar rates of hospitalization (2.2%) during the 12‐month observation period were seen in both study groups.
Table 2.
Outcomes after 6 and 12 months.
| Baseline | After 6 months | After 12 months | |
|---|---|---|---|
| Remicade® to Biosimilar IFX (n = 93) | |||
| Albumin (g/dL) | 4.37 | 4.4 | 4.4 |
| Hemoglobin (g/dL) | 13.67 | 13.71 | 13.79 |
| ESR (mm/h) | 6.82 | 7.4 | 7.42 |
| CRP (mg/L) | 3.149 | 2.74 | 3.51 |
| PGA | |||
| Quiescent | 75 | 67 | 67 |
| Mild | 12 | 8 | 6 |
| Moderate | 0 | 1 | 0 |
| Severe | 0 | 0 | 0 |
| PCDAI < 10 | 78/80 (98%) | 65/71 (92%) | 59/62 (95%) |
| PUCAI < 10 | 11/11 (100%) | 11/11 (100%) | 10/11 (91%) |
| Remicade® to Remicade® (n = 186) | |||
| Albumin (g/dL) | 4.46 | 4.45 | 4.4 |
| Hemoglobin (g/dL) | 13.35 | 14.07 | 13.61 |
| ESR (mm/h) | 6.18 | 5.87 | 6.2 |
| CRP (mg/L) | 1.81 | 2.32 | 2.95 |
| PGA | |||
| Quiescent | 157 | 162 | 139 |
| Mild | 20 | 8 | 12 |
| Moderate | 0 | 2 | 2 |
| Severe | 0 | 0 | 0 |
| PCDAI < 10 | 149/157 (95%) | 149/154 (97%) | 125/134 (93%) |
| PUCAI < 10 | 20/20 (100%) | 17/18 (94%) | 16/19 (84%) |
Abbreviations: CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; PCDAI, Pediatric Crohn's Disease Activity Index; PGA, Physician's Global Assessment; PUCAI, Pediatric Ulcerative Colitis Activity Index.
During the 1‐year observation period, we examined dosing changes in both the switch and nonswitch groups. For the switch group, 4% required a decrease in dose, 30% required an increase in dose, and 66% had no change when compared to initial dosing. For the nonswitch group, 17% of patients required a decrease in dose, 34% required an increase in dose, and 49% had no change when compared to initial dosing. A small number of patients developed clinically insignificant low‐level antibodies to infliximab during the study period, which occurred at a slightly lower proportion among the switch group, with 11.7% of patients developing detectable antibodies versus 16.9% for the nonswitch group.
4. DISCUSSION
With this large, real‐world experience cohort of patients with IBD, we add to the growing pool of evidence that switching pediatric/adolescent and young adult patients with IBD from O‐Rem to B‐IFX does not result in a change in clinical status. A similar study by Hinshaw et al. 7 showed that pediatric patients with IBD who were switched from O‐Rem to a biosimilar maintained the same level of disease activity by following their biochemical markers over 12 months; however, their study had a sample size of 12. To our knowledge, this is the largest single‐center comparison of pediatric/adolescent and young adult patients who underwent a switch from O‐Rem to B‐IFX with those who remained on O‐Rem.
Our data convincingly show that there are no changes in clinical course following switch from O‐Rem to biosimilar Inflectra®. To us, the implication is that biosimilar use would be appropriate at any time during the use of infliximab therapy. We realize that different geographic locations may be subject to the rules of local payers and may or may not be able to use the biologic of their choice. Our data give us assurance that the biosimilar Inflectra® is no less effective than O‐Rem.
In our study group, similarly to the survey results of Maltz et al., 8 the primary reason for pediatric gastroenterologists to switch to a biosimilar was an insurance‐mandated change. As per a recent study from Nationwide Children's Hospital, the authors show that there was an estimated cost savings of $11,260 average sales price and $566,223 wholesale acquisition cost for 53 pediatric and young adult patients with IBD who underwent a switch from infliximab originator to a biosimilar. 11 With the growing body of evidence that biosimilar use is safe and effective for disease and growth in pediatric patients with IBD, in addition to the cost–benefit that comes with the switch, institutions may consider increasing their use.
Limitations to our study include its retrospective nature and unavoidable missing data during the duration of the 12 month review. Unfortunately, there is a lack of uniformity of practice amongst providers in obtaining routine fecal markers of inflammation. Patients would not necessarily have repeat endoscopic evaluation simply because of change of O‐Rem to biosimilar. Additionally, only one biosimilar (Inflectra®) was studied. It is likely that other B‐IFXs will work similarly, but that may require additional study. All of our patients were in clinical remission at the time of switch. Thus, we do not know whether switching during active disease would affect clinical course.
Future studies on patient course following switch from originator medication to biosimilars should at minimum include fecal markers of inflammation, as well as endoscopic evaluation when appropriate. As safety can never be predicted, multicenter registries of patients switching therapy would be helpful. It will also be important to obtain reliable and independent information on actual cost savings.
It is imperative that providers anticipate patient and family concerns about therapy switches. Our data should be reassuring to providers, patients, and their families that switching from O‐Rem to the biosimilar Inflectra® is not associated with change in clinical course among IBD patients who are in remission.
CONFLICTS OF INTEREST STATEMENT
Jeffrey S. Hyams serves on Advisory Boards for Janssen, Abbvie, Lilly, Boehringer‐Ingelheim, and Pfizer. The remaining authors declare no conflict of interest.
Solomon V, Kuzoian S, Michel G, Brimacombe M, Hyams JS. Change from originator infliximab to biosimilar does not affect 1‐year outcome in children with inflammatory bowel disease. JPGN Rep. 2024;5:442‐446. 10.1002/jpr3.12134
Dr. Viven Solomon, Dr. Sydney Kuzoian, and Dr. Jeffrey Hyams are NASPGHAN members.
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