Abstract
Purpose
Although ontamalimab showed promise for treatment of patients with ulcerative colitis (UC) and Crohn’s disease (CD), the Phase 3 clinical development program was terminated in 2020. Here we report the results of a long-term safety (LTS) extension study.
Patients and Methods
The study enrolled patients with UC or CD who previously participated in the randomized, placebo-controlled phase 3 induction and maintenance clinical trials that evaluated the efficacy and safety of ontamalimab. During the LTS study, patients received ontamalimab 25 mg or 75 mg once every 4 weeks or were switched from 25 mg to 75 mg. Long-term safety outcomes, including the frequency and severity of adverse events (AEs), were assessed in eligible patients for up to 6 years of treatment. Efficacy was not formally evaluated in this study.
Results
Long-term safety was evaluated in 516 patients with UC and 41 patients with CD. Across all ontamalimab dose groups in UC, 392 patients (76.0%) had AEs; 115 serious AEs occurred in 82 patients (15.9%) and 2 AEs led to patient deaths during the study. Across all ontamalimab dose groups in CD, 29 patients (70.7%) had AEs; 10 serious AEs occurred in 8 patients (19.5%) and 1 AE led to a patient death during the study. Deaths were not related to receiving ontamalimab. In patients with UC and CD, 245/253 and 18/19 who completed the study, respectively, had a treatment response at the study end.
Conclusion
Ontamalimab was well tolerated and had an acceptable long-term safety profile in patients with UC and CD.
Keywords: Crohn’s disease, long-term safety, mucosal addressin cell adhesion molecule-1, ontamalimab, ulcerative colitis
Introduction
Ulcerative colitis (UC) and Crohn’s disease (CD) are inflammatory bowel diseases (IBDs) that are prevalent in the Western world and have increasing incidence in newly industrialized countries.1 Without adequate treatment, UC and CD can result in substantial damage to the bowel and can have considerable impact on patients’ quality of life.2–4 Historically, medical treatment strategies were focused on alleviating symptoms associated with UC and CD. Modern treatment strategies also aim to achieve full symptom control and mucosal healing to reduce or prevent long-term bowel damage and reduce the need for surgery, which is often required in patients with IBD.3–6 This is achieved, in part, through the use of targeted IBD therapies.7,8
An established therapeutic mechanism for improving the inflammation associated with UC and CD is the reduction of lymphocyte trafficking from the systemic circulation into the gut. Homing T lymphocytes expressing α4β7 integrin are trafficked into the lamina propria by binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on the surface of endothelial cells. By inhibiting the binding of α4β7 integrin to MAdCAM-1, the homing of those lymphocytes to the gut can be reduced.9,10 Vedolizumab is a humanized monoclonal antibody advanced IBD therapy that binds to α4β7 integrin on circulating lymphocytes to prevent its interaction with MAdCAM-1.11 In clinical trials and real-world studies, vedolizumab has demonstrated effectiveness in the treatment of patients with UC and CD, including achieving objective mucosal healing.12–15 Because MAdCAM-1 is preferentially expressed in gut-associated lymphoid tissue and its expression is increased during the chronic inflammation associated with IBD, the action of vedolizumab is thought to be gut-selective.16 This may contribute to vedolizumab’s good tolerability and long-term safety profile.17–19
Ontamalimab is a human immunoglobulin G2 monoclonal antibody that selectively binds with high affinity to MAdCAM-1 to prevent its interaction with α4β7-expressing lymphocytes.20 By binding directly to MAdCAM-1, off-target effects with ontamalimab may be minimized.21 In Phase 2 clinical trials, ontamalimab was well tolerated with an acceptable safety profile in patients with moderate to severe UC or CD, and had promising efficacy data (although clinical endpoint differences did not reach statistical significance for CD).22–25 Efficacy and safety of ontamalimab for induction and maintenance therapy were previously evaluated in 6 phase 3 placebo-controlled clinical trials in people with UC and CD. In 2 induction studies, greater proportions of patients with UC who received 75 mg ontamalimab had clinical remission at week 12 than those who received placebo (29.8% vs 15.8% and 29.5% vs 12.5%, respectively). At week 52 of the maintenance study, 40.2% of patients with UC who received 75 mg ontamalimab had clinical remission versus 12.8% of those who received placebo.26 Ontamalimab was generally well tolerated at all doses in adult patients with UC or CD. The frequency of treatment-emergent adverse events (AEs) was similar between the ontamalimab and placebo arms with most AEs being mild to moderate in severity.
However, for business reasons related to the acquisition of Shire Pharmaceuticals plc by Takeda Pharmaceutical Company and unrelated to the efficacy and safety of the drug, on May 29, 2020, as requested by the European Commission, Takeda Pharmaceuticals announced the decision to discontinue the ontamalimab clinical development program in UC and CD.27 After the announcement of the closure of the program the ongoing long-term safety (LTS) extension study was continued for a further 3 years (until December 2023) to provide active treatment to patients who had already enrolled or who had entered from a maintenance study and had responded to treatment. Here we report the results on the long-term safety and tolerability of ontamalimab in patients with UC and CD.
Materials and Methods
Study Design and Patient Population
This was a Phase 3, multicenter extension study conducted at 225 sites in 33 countries to evaluate the long-term safety of ontamalimab in patients with moderate to severe UC and CD (NCT03283085). Eligible patients were those who were previously enrolled in 6 separate phase 3 studies that evaluated ontamalimab as an induction therapy (UC: NCT03259334 and NCT03259308; CD: NCT03559517 and NCT03566823) or maintenance therapy (UC: NCT03290781; CD: NCT03627091) in patients with UC or CD (Figure 1A). Eligibility criteria for enrollment in the induction and maintenance studies have been described previously.26
Figure 1.
Schematic illustrating (a) patient enrollment during part 1 of the LTS study and (b) enrollment or continuation into part 2 of the study following early closure of the phase 3 maintenance studies. aExcept for evaluation of treatment response, which used the baseline of the induction studies as the baseline for the LTS study. bDefined as sustained symptomatic worsening, confirmed by endoscopy. cPatients who withdrew from the study for any reason before Protocol Amendment 4, including those who did not have a treatment response as required by the protocol amendment to continue to part 2 of the LTS study. All patients who received ontamalimab 25 mg in part 1 of the study and had a treatment response were escalated to 75 mg (or withdrew) during part 2 of the study and are counted in the 25 mg – 75 mg treatment group. dPatients who received ontamalimab 25 mg at their last treatment visit before entry into the LTS study (UC induction week 12 visit; CD induction week 16 visit; UC/CD treatment failure visit; UC/CD maintenance week 52 visit; UC/CD study early termination visit) continued to receive ontamalimab 25 mg until the results of the induction studies were available. The pooled analysis of the induction studies data indicated that 75 mg was an effective dose, so all patients were switched to ontamalimab 75 mg.
Abbreviations: CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; LTS, long-term safety; RB, rectal bleeding; SES-CD, Simple Endoscopic Score for Crohn’s Disease; UC, ulcerative colitis.
Patients were enrolled in the LTS study under two parts (Figure 1B). During part 1 patients were enrolled as per the original study protocol (Figure 1A). Patients with UC or CD who completed the phase 3 induction studies, but did not meet the response criteria (at week 12 and 16, respectively) for entry to the maintenance studies, were eligible for the LTS study. Baseline for the LTS study was defined as week 12 and week 16 of the induction studies for those with UC and CD, respectively. Patients with UC or CD who entered and completed the maintenance studies or had treatment failure (defined as sustained symptomatic worsening, confirmed by endoscopy) during the maintenance studies were also eligible for enrollment in the LTS study. For patients who completed the maintenance studies, week 52 of the maintenance study was defined as baseline for the LTS study; for those who discontinued owing to treatment failure, their early discontinuation date was defined as baseline for the LTS study. Patients who entered the LTS study having not responded to induction therapy or having had treatment failure during maintenance therapy were randomized 1:1 to receive ontamalimab 25 mg or 75 mg subcutaneously (SC) once every 4 weeks in the LTS study. Patients who entered the LTS study having completed one of the maintenance studies continued to receive ontamalimab 25 mg or ontamalimab 75 mg SC once every 4 weeks as per their dose at completion of the maintenance studies. Part 2 of enrollment proceeded following a protocol amendment (Protocol Amendment 4, September 21, 2020) made after the closure of the ontamalimab Phase 3 clinical development program. Protocol Amendment 4 was made to permit those enrolled in the maintenance studies who had a response to ontamalimab treatment to continue to the LTS study without having completed the maintenance studies (week 52 visit) at the time of their early termination. The amendment also allowed those already enrolled in the LTS study who had a response to treatment to continue to receive treatment. To be eligible to continue into or be enrolled into part 2 of the study following Protocol Amendment 4, patients were required to have a response to treatment, as defined in Figure 1B. No further patients from the induction studies were eligible for enrollment in the LTS study under Protocol Amendment 4.
All patients enrolled in the LTS study received active study drug. Following Protocol Amendment 4, the study became a single-dose study when the results of the pooled analysis of the induction studies became available. Patients who were already enrolled in the LTS study continued to receive either ontamalimab 25 mg or 75 mg and those who enrolled from the maintenance studies under Protocol Amendment 4 received 25 mg or 75 mg as per their dose at the early termination of the maintenance studies. Based on a pooled analysis of data from the induction studies, 75 mg was found to be an effective dose and all patients who were receiving ontamalimab 25 mg were switched to the 75 mg dose. The LTS study therefore had 3 treatment groups: 25 mg (patients who dropped out before the single dose was implemented), 25 mg – 75 mg (25 mg before and 75 mg after Protocol Amendment 4), and 75 mg (Figure 1B). For brevity, the pooled treatment groups that contain all patients with UC or CD from the 25 mg, 25 mg – 75 mg, and 75 mg treatment groups are hereafter described as the “all doses” group.
Patients entered a 12-week safety follow-up period following their final dose of the study drug. The study end date was December 31, 2023, and the maximum duration of participation in the LTS study for patients enrolled under Protocol Amendment 4 was 3 years. Patients enrolled in the LTS study between the initiation and Protocol Amendment 4 had a maximum of 6 years in the study. The first patient was enrolled in the study on February 27, 2018, and the last patient was completed on December 13, 2023.
Outcomes
The primary objective of the study was to evaluate the long-term safety and tolerability of ontamalimab in patients with UC and CD. Safety was measured by the incidence and severity of AEs; the incidence and type of serious infections; and change from baseline and incidence of abnormalities in laboratory tests and vital signs. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1. Treatment-emergent AEs were defined as AEs with start dates or worsening dates at the time of, or following, the first exposure to the study drug in the LTS study.
The secondary objective was to evaluate the maintenance of response to long-term treatment with ontamalimab in patients with UC and CD. This efficacy endpoint was evaluated for patients who participated in the study under Protocol Amendment 4. At every third treatment visit (once every 12 weeks), patients were assessed for ongoing treatment response. After Protocol Amendment 4 endoscopy was optional. Therefore, for patients with UC, depending on whether an endoscopy was performed at the visit, treatment response was measured by either modified Mayo score (the Mayo score without the Physician Global Assessment subscore; range 0–9) or a clinical composite score (rectal bleeding subscore plus stool frequency score). Treatment response was defined as a decrease in modified Mayo score of ≥3 points and ≥30% (where endoscopy was performed), or a decrease in clinical composite score of ≥2 points and ≥30% with an accompanying decrease in rectal bleeding subscore of ≥1 point or a subscore for rectal bleeding of ≤1, compared with the baseline value for the induction studies. For patients with CD, depending on whether an endoscopy was performed at the visit, treatment response was defined as a decrease in Crohn’s Disease Activity Index (CDAI) of ≥100 points from the baseline value for the induction studies and/or a decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) score of ≥25% from the baseline value for the induction studies. No formal statistical testing was performed on the efficacy assessments.
Data Collection and Statistical Analysis
Under Protocol Amendment 4, a maximum of 568 patients were planned to be enrolled in the LTS study. The full analysis set comprised all patients who were randomized and received at least 1 dose of ontamalimab in the LTS study. All safety analyses were conducted in the safety set, which comprised all patients who received at least 1 dose of ontamalimab in the LTS study. All statistical analyses were performed using SAS version 9.3 or higher (SAS Institute, Cary, NC, USA). Categorical variables are presented as the number and percentage of patients within each category and continuous variables are presented as the mean and SD.
Results
Patient Disposition
Overall, safety of ontamalimab was evaluated in 516 patients with UC and 41 patients with CD. Of these, 246 patients (47.7%) with UC and 18 patients (43.9%) with CD completed the study (Supplementary Table 1). During the LTS study all patients received ontamalimab and all patients who completed the study received ontamalimab 75 mg (as described by Protocol Amendment 4). The primary reason for study withdrawal in the “all doses” groups of patients with UC or CD was withdrawal by the patient (Supplementary Table 2). Supplementary Table 3 describes the treatment that patients who were enrolled in the LTS study received during the previous induction and maintenance studies.
Baseline Demographic and Disease Characteristics
Baseline demographic and disease characteristics for patients with UC are shown by treatment group in Table 1. In the “all doses” group of patients with UC, the mean (SD) age was 41.2 (13.9) years, and 309 patients (59.9%) were male; the most common disease location was left-sided colitis, which occurred in 205 patients (39.7%). Most patients (73.6%) were antitumor necrosis factor α (anti-TNFα) treatment-naive and were not receiving a glucocorticoid (64.5%) at the study baseline. There were no marked differences between the treatment groups in the UC cohort. The baseline disease and demographic characteristics for patients with UC enrolled in the LTS study were similar to those of the patients enrolled in the previous induction and maintenance studies. In particular, across the treatment groups in the 2 induction studies and 1 maintenance study of ontamalimab in patients with UC, 56.6% to 69.0% of patients were not receiving a glucocorticoid at baseline and 68.9% to 79.1% of patients were anti-TNFα treatment-naive.26
Table 1.
Baseline Demographic and Disease Characteristics of Patients with UC
| Characteristic | Ontamalimab 25 mg |
Ontamalimab 25 mg – 75 mg |
Ontamalimab 75 mg |
Ontamalimab All Doses |
|---|---|---|---|---|
| Patients, n | 89 | 159 | 268 | 516 |
| Age, y, mean (SD) | 38.6 (13.1) | 41.8 (13.0) | 41.8 (14.6) | 41.2 (13.9) |
| Age category, y, n (%) | ||||
| <18 | 0 (0.0) | 2 (1.3) | 7 (2.6) | 9 (1.7) |
| 18-64 | 87 (97.8) | 148 (93.1) | 239 (89.2) | 474 (91.9) |
| ≥65 | 2 (2.2) | 9 (5.7) | 22 (8.2) | 33 (6.4) |
| Sex, n (%) | ||||
| Male | 60 (67.4) | 92 (57.9) | 157 (58.6) | 309 (59.9) |
| Female | 29 (32.6) | 67 (42.1) | 111 (41.4) | 207 (40.1) |
| Ethnicity, n (%) | ||||
| Hispanic or Latino | 5 (5.6) | 12 (7.5) | 15 (5.6) | 32 (6.2) |
| Not Hispanic or Latino | 84 (94.4) | 146 (91.8) | 251 (93.7) | 481 (93.2) |
| Not reported | 0 (0.0) | 1 (0.6) | 2 (0.7) | 3 (0.6) |
| Unknown | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Race, n (%) | ||||
| American Indian or Alaska Native | 0 (0.0) | 2 (1.3) | 4 (1.5) | 6 (1.2) |
| Asian | 7 (7.9) | 14 (8.8) | 24 (9.0) | 45 (8.7) |
| Black or African American | 0 (0.0) | 2 (1.3) | 4 (1.5) | 6 (1.2) |
| White | 77 (86.5) | 135 (84.9) | 231 (86.2) | 443 (85.9) |
| Native Hawaiian or Other Pacific Islander | 1 (1.1) | 0 (0.0) | 0 (0.0) | 1 (0.2) |
| Multiple | 2 (2.2) | 2 (1.3) | 3 (1.1) | 7 (1.4) |
| Other | 2 (2.2) | 4 (2.5) | 2 (0.7) | 8 (1.6) |
| Disease duration, y, mean (SD) | 5.4 (5.2) | 7.7 (7.3) | 6.7 (7.4) | 6.8 (7.1) |
| Disease location, n (%) | ||||
| Proctitis | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Procto-sigmoiditis | 13 (14.6) | 46 (28.9) | 54 (20.1) | 113 (21.9) |
| Left-sided colitis | 35 (39.3) | 56 (35.2) | 114 (42.5) | 205 (39.7) |
| Extensive colitis/pancolitis | 41 (46.1) | 57 (35.8) | 99 (36.9) | 197 (38.2) |
| Missing | 0 (0.0) | 0 (0.0) | 1 (0.4) | 1 (0.2) |
| Anti-TNFα treatment status, n (%) | ||||
| Experienced | 27 (30.3) | 46 (28.9) | 63 (23.5) | 136 (26.4) |
| Naive | 62 (69.7) | 113 (71.1) | 205 (76.5) | 380 (73.6) |
| Glucocorticoid use at LTS study baseline,a n (%) | ||||
| Yes | 47 (52.8) | 45 (28.3) | 91 (34.0) | 183 (35.5) |
| No | 42 (47.2) | 114 (71.7) | 177 (66.0) | 333 (64.5) |
| Systemic glucocorticoid dose at LTS study baseline, mg, mean (SD) | 30.5 (16.7) | 22.9 (10.3) | 27.8 (14.5) | 27.5 (14.5) |
| Smoking status,b n (%) | ||||
| Never | 58 (65.2) | 114 (71.7) | 192 (71.6) | 364 (70.5) |
| Current | 4 (4.5) | 9 (5.7) | 21 (7.8) | 34 (6.6) |
| Former | 26 (29.2) | 35 (22.0) | 51 (19.0) | 112 (21.7) |
| Total Mayo score at LTS study baseline,a mean (SD) | 8.2 (2.4) | 4.7 (3.6) | 5.9 (3.7) | 5.9 (3.6) |
| Stool frequency subscore at LTS study baseline,a n (%) | ||||
| 0 | 3 (3.4) | 51 (32.1) | 64 (23.9) | 118 (22.9) |
| 1 | 16 (18.0) | 41 (25.8) | 58 (21.6) | 115 (22.3) |
| 2 | 23 (25.8) | 22 (13.8) | 45 (16.8) | 90 (17.4) |
| 3 | 45 (50.6) | 41 (25.8) | 95 (35.4) | 181 (35.1) |
| Missing | 2 (2.2) | 4 (2.5) | 6 (2.2) | 12 (2.3) |
| Rectal bleeding subscore at LTS study baseline,a n (%) | ||||
| 0 | 17 (19.1) | 87 (54.7) | 121 (45.1) | 225 (43.6) |
| 1 | 30 (33.7) | 29 (18.2) | 52 (19.4) | 111 (21.5) |
| 2 | 35 (39.3) | 31 (19.5) | 76 (28.4) | 142 (27.5) |
| 3 | 5 (5.6) | 8 (5.0) | 13 (4.9) | 26 (5.0) |
| Missing | 2 (2.2) | 4 (2.5) | 6 (2.2) | 12 (2.3) |
Notes: aBaseline is the point of entry into the LTS study defined as the value collected at week 12 of the induction study or week 52 or early termination visit of the maintenance study. bSmoking status was collected at the screening visit of the Phase 3 induction studies.
Abbreviations: Anti-TNFα, antitumor necrosis factor α; LTS, long-term safety; UC, ulcerative colitis.
Baseline demographic and disease characteristics for patients with CD are shown by treatment group in Table 2. In the “all doses” group, which contained patients with CD who received any dose of ontamalimab during the LTS study, the mean (SD) age was 38.4 (12.5) years, and 21 patients (51.2%) were male; the most common disease location was perianal disease, which occurred in 12 patients (29.3%). Most patients (56.1%) were anti-TNFα treatment-naive and were not receiving a glucocorticoid (63.4%) at the study baseline. The mean [SD] age of the patients who received ontamalimab 25 mg (48.2 [17.4] years) was higher than those who received ontamalimab 75 mg (38.1 [12.5] years); those who switched from an initial dose of 25 mg to 75 mg during the study were the youngest patients (34.2 [7.4] years).
Table 2.
Baseline Demographic and Disease Characteristics of Patients with CD
| Characteristic | Ontamalimab 25 mg |
Ontamalimab 25 mg – 75 mg |
Ontamalimab 75 mg |
Ontamalimab All Doses |
|---|---|---|---|---|
| Patients, n | 5 | 10 | 26 | 41 |
| Age, y, mean (SD) | 48.2 (17.4) | 34.2 (7.4) | 38.1 (12.5) | 38.4 (12.5) |
| Age category, y, n (%) | ||||
| <18 | 0 (0.0) | 1 (10.0) | 1 (3.8) | 2 (4.9) |
| 18-64 | 4 (80.0) | 9 (90.0) | 25 (96.2) | 38 (92.7) |
| ≥65 | 1 (20.0) | 0 (0.0) | 0 (0.0) | 1 (2.4) |
| Sex, n (%) | ||||
| Male | 4 (80.0) | 5 (50.0) | 12 (46.2) | 21 (51.2) |
| Female | 1 (20.0) | 5 (50.0) | 14 (53.8) | 20 (48.8) |
| Ethnicity, n (%) | ||||
| Hispanic or Latino | 0 (0.0) | 1 (10.0) | 2 (7.7) | 3 (7.3) |
| Not Hispanic or Latino | 5 (100.0) | 9 (90.0) | 24 (92.3) | 38 (92.7) |
| Not reported | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Unknown | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Race, n (%) | ||||
| American Indian or Alaska Native | 0 (0.0) | 0 (0.0) | 1 (3.8) | 1 (2.4) |
| Asian | 1 (20.0) | 0 (0.0) | 0 (0.0) | 1 (2.4) |
| Black or African American | 0 (0.0) | 0 (0.0) | 2 (7.7) | 2 (4.9) |
| White | 4 (80.0) | 9 (90.0) | 23 (88.5) | 36 (87.8) |
| Native Hawaiian or Other Pacific Islander | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Multiple | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Other | 0 (0.0) | 1 (10.0) | 0 (0.0) | 1 (2.4) |
| Disease duration, y, mean (SD) | 8.4 (10.5) | 4.1 (3.9) | 6.4 (7.1) | 6.1 (6.9) |
| Disease location, n (%) | ||||
| Small intestine only | 2 (40.0) | 2 (20.0) | 3 (11.5) | 7 (17.1) |
| Colon and/or rectum only | 2 (40.0) | 3 (30.0) | 4 (15.4) | 9 (22.0) |
| Ileo-colitis | 1 (20.0) | 1 (10.0) | 5 (19.2) | 7 (17.1) |
| Perianal | 0 (0.0) | 2 (20.0) | 10 (38.5) | 12 (29.3) |
| Other | 0 (0.0) | 2 (20.0) | 4 (15.4) | 6 (14.6) |
| Anti-TNFα treatment status, n (%) | ||||
| Experienced | 3 (60.0) | 3 (30.0) | 12 (46.2) | 18 (43.9) |
| Naive | 2 (40.0) | 7 (70.0) | 14 (53.8) | 23 (56.1) |
| Glucocorticoid use at LTS study baseline,a n (%) | ||||
| Yes | 3 (60.0) | 2 (20.0) | 10 (38.5) | 15 (36.6) |
| No | 2 (40.0) | 8 (80.0) | 16 (61.5) | 26 (63.4) |
| Systemic glucocorticoid dose at LTS study baseline, mg, mean (SD) | 30.0 (14.1) | 6.3 (5.3) | 27.1 (13.8) | 23.9 (14.6) |
| Smoking status,b n (%) | ||||
| Never | 2 (40.0) | 10 (100.0) | 14 (53.8) | 26 (63.4) |
| Current | 1 (20.0) | 0 (0.0) | 7 (26.9) | 8 (19.5) |
| Former | 2 (40.0) | 0 (0.0) | 5 (19.2) | 7 (17.1) |
| Clinical remission at LTS study baseline,a,c n (%) | ||||
| Yes | 1 (20.0) | 2 (20.0) | 7 (26.9) | 10 (24.4) |
| No | 4 (80.0) | 8 (80.0) | 19 (73.1) | 31 (75.6) |
| CDAI score at LTS study baseline,a mean (SD) | 267.0 (98.2) | 147.6 (109.0) | 164.2 (125.3) | 173.5 (121.6) |
| SES-CD at LTS study baseline,a n (%) | ||||
| ≥17 | 0 (0.0) | 0 (0.0) | 1 (3.8) | 1 (2.4) |
| <17 | 1 (20.0) | 4 (40.0) | 11 (42.3) | 16 (39.0) |
| Missing | 4 (80.0) | 6 (60.0) | 14 (53.8) | 24 (58.5) |
Notes: aBaseline is the point of entry into the LTS study defined as the value collected at week 16 of the induction study or week 52 or early termination visit of the maintenance study. bSmoking status was collected at the screening visit of the phase 3 induction studies. cClinical remission is defined by 2-item PRO subscores of average daily abdominal pain (≤ 3 on 11-point numeric rating scale) and average daily stool frequency (≤ 2 of type very soft stools/liquid stools) over the 7 most recent days before the LTS study baseline.
Abbreviations: Anti-TNFα, antitumor necrosis factor α; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; LTS, long-term safety; PRO, patient-reported outcome; SES-CD, Simple Endoscopic Score for Crohn’s Disease.
Safety
The proportions of patients who experienced AEs and serious AEs were similar between the UC and CD disease cohorts and across treatment groups. A summary of the AEs and serious AEs reported by treatment group is shown in Table 3.
Table 3.
Summary of AEs by Treatment Group in Patients with UC and CD
| UC | ||||||||
|
Ontamalimab 25 mg N=89 |
Ontamalimab 25 mg – 75 mg N=159 |
Ontamalimab 75 mg N=268 |
Ontamalimab All Doses N=516 |
|||||
| n (%) | Events, n | n (%) | Events, n | n (%) | Events, n | n (%) | Events, n | |
| Any AE | 67 (75.3) | 193 | 122 (76.7) | 811 | 203 (75.7) | 1076 | 392 (76.0) | 2080 |
| AE maximum severitya | ||||||||
| Severe | 8 (9.0) | – | 14 (8.8) | – | 24 (9.0) | – | 46 (8.9) | – |
| Moderate | 40 (44.9) | – | 65 (40.9) | – | 107 (39.9) | – | 212 (41.1) | – |
| Mild | 19 (21.3) | – | 43 (27.0) | – | 72 (26.9) | – | 134 (26.0) | – |
| Serious AE | 15 (16.9) | 18 | 21 (13.2) | 29 | 46 (17.2) | 68 | 82 (15.9) | 115 |
| Serious AE related to study drug | 3 (3.4) | 3 | 0 (0.0) | 0 | 4 (1.5) | 9 | 7 (1.4) | 12 |
| AE leading to study discontinuation | 15 (16.9) | 17 | 3 (1.9) | 3 | 14 (5.2) | 14 | 32 (6.2) | 34 |
| AE leading to deathb | 0 (0.0) | 0 | 0 (0.0) | 0 | 2 (0.7) | 2 | 2 (0.4) | 2 |
| CD | ||||||||
|
Ontamalimab 25 mg N=5 |
Ontamalimab 25 mg – 75 mg N=10 |
Ontamalimab 75 mg N=26 |
Ontamalimab All Doses N=41 |
|||||
| n (%) | Events, n | n (%) | Events, n | n (%) | Events, n | n (%) | Events, n | |
| Any AE | 4 (80.0) | 9 | 8 (80.0) | 50 | 17 (65.4) | 76 | 29 (70.7) | 135 |
| AE maximum severitya | ||||||||
| Severe | 2 (40.0) | – | 2 (20.0) | – | 1 (3.8) | – | 5 (12.2) | – |
| Moderate | 0 (0.0) | – | 4 (40.0) | – | 11 (42.3) | – | 15 (36.6) | – |
| Mild | 2 (40.0) | – | 2 (20.0) | – | 5 (19.2) | – | 9 (22.0) | – |
| Serious AE | 2 (40.0) | 2 | 2 (20.0) | 4 | 4 (15.4) | 4 | 8 (19.5) | 10 |
| Serious AE related to study drug | 1 (20.0) | 1 | 0 (0.0) | 1 | 1 (3.8) | 1 | 2 (4.9) | 2 |
| AE leading to study discontinuation | 1 (20.0) | 1 | 0 (0.0) | 0 | 4 (15.4) | 4 | 5 (12.2) | 5 |
| AE leading to death | 1 (20.0) | 1 | 0 (0.0) | 0 | 0 (0.0) | 0 | 1 (2.4) | 1 |
Notes: aPatients are counted only once, according to the maximum severity of any event they experienced. If severity was missing for an event before the first dose of the study drug, the event was assigned mild. If severity was missing for an event after the first dose of the study drug, the event was assigned severe. bOne patient in the 75 mg treatment group died owing to COVID-19. This was not considered to be a treatment-emergent AE and is not counted in this table.
Abbreviations: AE, adverse event; CD, Crohn’s disease; UC, ulcerative colitis.
The mean (SD) length of exposure to the study drug in the LTS study by treatment group for patients with UC was 258.0 (179.6) days, 1201.9 (315.3) days, and 886.5 (507.6) days, for the 25 mg, 25 mg – 75 mg, and 75 mg treatment groups, respectively. The treatment duration for “all doses” was 875.3 (518.1) days. As a result of the changes introduced by Protocol Amendment 4, the duration of exposure to the study drug in the 25 mg group is considerably shorter than other groups because these patients either discontinued before Protocol Amendment 4 or were switched to the 75 mg dose and subsequently counted in the 25 mg – 75 mg group. This applies to patients with UC or CD. In patients with UC in the “all doses” group, 2080 AEs were reported to have occurred in 392 patients (76.0%); the proportions of patients who had an AE was similar across the treatment groups. For patients with UC, 46 patients (8.9%) in the “all doses” group had an AE with a maximum severity considered severe; a similar proportion of patients experienced a severe AE across all treatment groups. A total of 115 serious AEs occurred in 82 patients (15.9%) in the “all doses” group. Twelve serious AEs in 7 patients (1.4%) were related to the study drug; 9 of these events occurred in the 75 mg treatment group. Two patients (0.4%) with UC, who were in the 75 mg treatment group, had an AE that led to their death during the study. The cause of death for a 58-year-old patient was bronchiectasis, and for a 37-year-old patient the cause of death was unknown; neither death was considered related to ontamalimab. One further patient in the 75 mg treatment group died of cardiorespiratory failure due to COVID-19 that was not considered related to ontamalimab; the event was not considered treatment-emergent because the start date was not provided.
The mean (SD) length of exposure to the study drug in the LTS study by treatment group for patients with CD was 225.2 (149.2) days, 921.7 (445.4) days, and 637.6 (461.2) days, for the 25 mg, 25 mg – 75 mg, and 75 mg treatment groups, respectively. The mean treatment duration for “all doses” was 656.6 (470.0) days. In patients with CD in the “all doses” group, 29 patients (70.7%) had a total of 135 AEs; the proportion of patients with AEs was higher in the 25 mg (80.0%) and 25 mg – 75 mg (80.0%) groups than in the 75 mg (65.4%) treatment group, but this was confounded by relatively low numbers of patients in each group (5, 10, and 26 patients, respectively). For most patients with CD who had an AE, the maximum event severity was mild or moderate, although 5 patients (12.2%) had an AE that was considered severe. Ten serious AEs were reported in 8 patients (19.5%) in the “all doses” group with 2 events in 2 patients being considered related to the study drug. Among those with CD, 5 patients (12.2%) had an AE that led to study discontinuation. One 72-year-old patient in the 25 mg group had an AE that led to death during the study, the cause of which was unknown but was not considered to be related to the study drug.
The most frequently occurring AEs in patients with UC and CD are shown in Table 4. In patients with UC in the “all doses” group, other than coronavirus infection and UC, the most frequently occurring AE was nasopharyngitis (52 AEs in 40 patients [7.8%]); for CD in the “all doses” group, other than coronavirus infection and CD, the most frequent AE was headache, which was reported 5 times in 5 patients (12.2%). In the larger UC patient cohort, 538 infections were reported in 244 patients (47.3%) in the “all doses” group. Infections that occurred in more than 2% of patients in the “all doses” groups are shown in Supplementary Table 4. In patients with UC, there were 31 serious infections in 26 patients; the 3 most frequent serious infections were appendicitis (6 events in 6 patients), viral pneumonia (6 events in 5 patients), and coronavirus infection (3 events in 3 patients). A total of 40 infections occurred in 17 patients (41.5%) with CD in the “all doses” group; there were no serious infections reported in patients with CD.
Table 4.
Most Frequently Occurring AEs by Treatment Group in Patients with UC or CD
| UC | ||||||||
|
Ontamalimab 25 mg N=89 |
Ontamalimab 25 mg – 75 mg N=159 |
Ontamalimab 75 mg N=268 |
Ontamalimab All Doses N=516 |
|||||
| n (%) | Events, n | n (%) | Events, n | n (%) | Events, n | n (%) | Events, n | |
| Coronavirus infection | 2 (2.2) | 2 | 40 (25.2) | 47 | 59 (22.0) | 64 | 101 (19.6) | 113 |
| UC | 27 (30.3) | 37 | 21 (13.2) | 30 | 35 (13.1) | 51 | 83 (16.1) | 118 |
| Nasopharyngitis | 2 (2.2) | 2 | 18 (11.3) | 23 | 20 (7.5) | 27 | 40 (7.8) | 52 |
| Anemia | 7 (7.9) | 7 | 14 (8.8) | 24 | 18 (6.7) | 27 | 39 (7.6) | 58 |
| Diarrhea | 3 (3.4) | 4 | 17 (10.7) | 25 | 10 (3.7) | 17 | 30 (5.8) | 46 |
| Headache | 3 (3.4) | 3 | 16 (10.1) | 23 | 10 (3.7) | 22 | 29 (5.6) | 48 |
| Hypertension | 3 (3.4) | 3 | 12 (7.5) | 12 | 13 (4.9) | 14 | 28 (5.4) | 29 |
| Upper respiratory tract infection | 3 (3.4) | 3 | 9 (5.7) | 15 | 16 (6.0) | 19 | 28 (5.4) | 37 |
| Arthralgia | 3 (3.4) | 3 | 10 (6.3) | 14 | 13 (4.9) | 20 | 26 (5.0) | 37 |
| Pyrexia | 4 (4.5) | 8 | 9 (5.7) | 10 | 13 (4.9) | 23 | 26 (5.0) | 41 |
| CD | ||||||||
|
Ontamalimab 25 mg N=5 |
Ontamalimab 25 mg – 75 mg N=10 |
Ontamalimab 75 mg N=26 |
Ontamalimab All Doses N=41 |
|||||
| n (%) | Events, n | n (%) | Events, n | n (%) | Events, n | n (%) | Events, n | |
| Coronavirus infection | 0 (0.0) | 0 | 2 (20.0) | 2 | 4 (15.4) | 4 | 6 (14.6) | 6 |
| Headache | 1 (20.0) | 1 | 1 (10.0) | 1 | 3 (11.5) | 3 | 5 (12.2) | 5 |
| CD | 0 (0.0) | 0 | 1 (10.0) | 1 | 3 (11.5) | 4 | 4 (9.8) | 5 |
| Anal fistula | 0 (0.0) | 0 | 0 (0.0) | 0 | 3 (11.5) | 5 | 3 (7.3) | 5 |
| Arthralgia | 0 (0.0) | 0 | 2 (20.0) | 3 | 1 (3.8) | 1 | 3 (7.3) | 4 |
| Back pain | 0 (0.0) | 0 | 2 (20.0) | 3 | 1 (3.8) | 1 | 3 (7.3) | 4 |
| Nasopharyngitis | 0 (0.0) | 0 | 0 (0.0) | 0 | 3 (11.5) | 6 | 3 (7.3) | 6 |
| Sinusitis | 0 (0.0) | 0 | 2 (20.0) | 2 | 1 (3.8) | 1 | 3 (7.3) | 3 |
Notes: Table lists AEs that occurred in ≥5% of patients in the “all doses” groups. AEs were classified using version 19.1 of MedDRA.
Abbreviations: AE, adverse event; CD, Crohn’s disease; MedDRA, Medical Dictionary for Regulatory Activities; UC, ulcerative colitis.
Potentially clinically significant abnormalities in laboratory results are shown in Supplementary Table 5. Overall, patients with UC and CD did not have clinically significant abnormalities in hematology, chemistry, or urinalysis results during the study. There were no discernible changes in mean vital signs over time and no notable differences were observed between treatment groups. No patient in either the UC cohort or the CD cohort experienced progressive multifocal leukoencephalopathy (PML) and there were no immunotoxicity-related or immunogenicity-related AEs. No hypersensitivity events were reported.
Efficacy
Efficacy was not formally evaluated in the LTS study. Under Protocol Amendment 4, efficacy was evaluated for patients in the 25 mg – 75 mg and 75 mg treatment groups by treatment response over time. The total number of patients who participated in the study under Protocol Amendment 4 and the proportion of those who completed the study treatment period are shown in Figure 2A. In the “all doses” groups, 72.3% of patients with UC and 63.3% of patients with CD who entered as responders under Protocol Amendment 4 completed 3 years of treatment. In patients with UC and CD, 96.8% and 94.7% of those who completed the study treatment period had a treatment response at the study exit (Figure 2B). Treatment duration for patients eligible for efficacy assessment was similar between the 25 mg – 75 mg and 75 mg treatment groups for those with UC and CD (Figure 2C).
Figure 2.
Summary of (a) the proportion of patients who entered the study under Protocol Amendment 4 and completed study treatment, (b) the proportion of patients who had a treatment response (UC: a decrease in modified Mayo score of ≥3 points and ≥30%, or a decrease in clinical composite score of ≥2 points and ≥30% with an accompanying decrease in rectal bleeding subscore of ≥1 point or a subscore for rectal bleeding of ≤1, compared with the baseline value for the induction studies; CD: a decrease in CDAI of ≥100 points from the baseline value for the induction studies and/or a decrease in SES-CD score of ≥25% from the baseline value for the induction studies) at study exit for those with UC or CD, respectively, and (c) the mean (SD) treatment duration of patients who entered the LTS study under Protocol Amendment 4. aPatients who were enrolled under Protocol Amendment 4 and completed the study treatment. Denominator (N) is the total number of patients who participated in the study under Protocol Amendment 4. bTreatment duration is the number of days between the first and last dose of ontamalimab received during the LTS study by those who participated under Protocol Amendment 4 plus 29 days. cDenominator (N) is the number of patients who were enrolled under Protocol Amendment 4 and completed the study treatment.
Abbreviations: CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; LTS, long-term safety; SES-CD, Simple Endoscopic Score for Crohn’s Disease; UC, ulcerative colitis.
Discussion
In this LTS study, ontamalimab was found to have an acceptable long-term tolerability and safety profile in patients with UC or CD who received treatment for up to 6 years. The safety profile was similar to that reported during the previous placebo-controlled studies and no new safety signals were observed during the longer treatment period. Among the groups who received the maximum dose of ontamalimab 75 mg throughout the LTS study, 17.2% of patients with UC and 15.4% of patients with CD had a serious AE but only 1.5% and 3.8%, respectively, had a serious AE that was related to ontamalimab treatment. Except for coronavirus infection, or ongoing activity of UC and CD, the most frequently occurring AEs in the “all doses” group were nasopharyngitis in patients with UC and headache in patients with CD. Most AEs reported in the UC and CD cohorts were of mild or moderate severity. These safety results are similar to those previously reported in the Phase 3 induction and maintenance studies.26
Although the clinical development program was terminated early, in previous induction and maintenance studies, ontamalimab showed promising efficacy and safety for treatment of patients with moderate to severe UC and CD (although the results for CD were limited by the low number of patients enrolled).22–26 In the larger UC cohort, efficacy and safety could be more reliably characterized. In the induction studies for UC, which enrolled a total of 659 patients, at week 12 compared with placebo, ontamalimab 75 mg produced significantly better clinical response, clinical remission, endoscopic improvement, and mucosal healing.26 Consequently, this dose was chosen as the effective dose for the LTS study when the decision was taken to change to a single-dose study, and all patients received the higher dose for all or a portion of their time in the LTS study. The incidence and severity of AEs were broadly similar across the treatment groups in the LTS study, including those who received the highest dose (75 mg). In the UC cohort, approximately 75% of patients in each treatment group had an AE and approximately 9% of AEs were considered severe. The efficacy and safety results for the CD cohort in the previous induction and maintenance studies, and in the present LTS study, are confounded by the relatively low number of patients with CD who were enrolled in the studies at the time of their early termination.26 Among patients with CD who were enrolled in the LTS study there were no apparent signs of new safety considerations with ontamalimab treatment.
Although no direct head-to-head comparisons have been performed and study populations, follow-up durations, and other factors may differ, these new long-term data show that the tolerability and safety profile of ontamalimab is broadly similar to that of vedolizumab: a biologic approved for the treatment of patients with moderate to severe UC and CD that has a similar mechanism of action.17–19 By targeting the interaction between α4β7 integrin-positive lymphocytes and MAdCAM-1,9,11 and not directly targeting cytokine pathways, ontamalimab and vedolizumab appear to avoid some of the safety drawbacks associated with other biologic drugs that act systemically or on multiple targets to reduce inflammation. The effect of the selective binding of vedolizumab and ontamalimab to α4β7 integrin and MAdCAM-1, respectively, is illustrated by comparison with the biologic natalizumab, which binds to both α4β7 and α4β1 integrins. Although it was shown to be effective for the treatment of CD, the lower selectivity of natalizumab was associated with the development of the serious opportunistic infection PML.28 In this LTS study, no incidences of PML were observed with ontamalimab in patients from the UC or CD cohorts.
Infections are one of the most significant safety considerations with biologic drugs such as ontamalimab.29 Anti-TNFα treatments have been associated with increased opportunistic infections of bacterial and fungal etiology.29 For example, a univariate analysis of opportunistic infection risk in patients with IBD identified an odds ratio of 4.4 (95% CI, 1.2–17.1) for those receiving infliximab versus those not receiving the biologic drug.30 In the present LTS study of ontamalimab, the incidence of serious infections was low in both the UC and CD patient cohorts. The most commonly occurring serious infections in patients with UC were appendicitis and viral pneumonia.
The present study had several important limitations. First, the number of patients with CD who were enrolled in the LTS study was low. The safety results reported for patients with CD must be considered in this context because the study may not have sufficient power to detect potential rare long-term safety signals. Second, because of the early termination of the phase 3 studies, the range of data collected in the LTS study was limited. Thus, during the LTS study patients were not assessed for biomarker concentrations (eg, fecal calprotectin or C-reactive protein) or the presence of antidrug antibodies. Third, Protocol Amendment 4 required all patients to switch to ontamalimab 75 mg which limited the ability to characterize any difference between dose groups. Fourth, Protocol Amendment 4 did not allow those who did not have a treatment response to continue in the study which limited the ability to assess long-term treatment compliance. Finally, two patients, one with CD and one with UC, died during the study from unknown causes. Although investigators assessed that the deaths were unrelated to the study drug, the unknown causes of death introduce some uncertainty and represent a limitation of the study.
Conclusion
Accounting for limitations imposed by the decision to discontinue the clinical development program, in this LTS study, the MAdCAM-1 inhibitor ontamalimab demonstrated an acceptable tolerability and long-term safety profile in patients with UC and CD. Among patients who entered following Protocol Amendment 4 and completed the study treatment, approximately 95% had a response to treatment at the end of the study indicating that many patients continue to receive long-term benefit from ontamalimab without safety concerns. These data support the suggestion that, despite the discontinuation of the Phase 3 clinical development program, ontamalimab may be a suitable treatment for patients with UC and that MAdCAM-1 is an appropriate target for therapeutic intervention.
Acknowledgments
The authors and sponsor would like to recognize and thank the late Péter Nagy for his lifelong dedication to advancing the field of gastrointestinal medicine and the care of patients with digestive diseases. Medical writing support was provided by Adam Errington, PhD of Oxford PharmaGenesis, part of the Klick Health family and funded by Takeda Pharmaceuticals.
Present affiliations are as follows: Caleb Bliss, Apellis Pharmaceuticals, Waltham, MA, USA; Fabio Cataldi, Landos Biopharma, Blacksburg, VA, USA; Martina Goetsch, Arena Pharmaceuticals, a wholly owned subsidiary of Pfizer, Zurich, Switzerland.
Funding Statement
The study was initiated by Shire Pharmaceuticals. After the purchase of Shire Pharmaceuticals, funding continued through the new owner, Takeda Pharmaceuticals, Takeda Development Center of Americas. The study was abandoned following a decision taken by Takeda owing to not finding a licensee for ontamalimab. A further decision was made to donate data and biomaterials to the Crohn’s & Colitis Foundation of America. The investigators were informed of this decision.
Abbreviations
AE, adverse event; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; IBD, inflammatory bowel disease; LTS, long-term safety; MAdCAM-1, mucosal addressin cell adhesion molecule-1; MedDRA, Medical Dictionary for Regulatory Activities; PML, progressive multifocal leukoencephalopathy; PRO, patient-reported outcome; RB, rectal bleeding; SD, standard deviation; SES-CD, Simple Endoscopic Score for Crohn’s Disease; TNF, tumor necrosis factor; UC, ulcerative colitis.
Data Sharing Statement
The data sets, including the redacted study protocol, redacted statistical analysis plan, and individual participants’ data supporting the results reported in this article, will be made available within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. Individual data and relevant materials for those patients who have consented have been transferred to and can be accessed at the Crohn’s and Colitis Foundation of America.
Ethical Approval and Informed Consent
This prospective, multicenter, multinational study (ClinicalTrials.gov NCT03283085) was approved by local Institutional Review Boards or Ethics Committees at each of the 225 study locations in 33 countries (Primary approval for Prof. Geert D’Haens - Brabant Medical Ethics Committee, Tilburg, Netherlands, IRB reference: NL62887.028.17/P1755). All participants provided written informed consent for participation. The study was conducted in accordance with the principles described in the Declaration of Helsinki (7th revision, 2013), currently applicable local ethical and legal requirements, the International Council for Harmonisation Good Clinical Practice E6 guidelines, and EU Directive 2001/20/EC and its updates.
Consent for Publication
Consent for publication was not applicable.
Author Contributions
All authors made a significant contribution to the work reported, whether that was in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas. All authors contributed to drafting, revising, or critically reviewing the article; approved the final version for publication; agreed on the journal to which the article was submitted; and accepted accountability for all aspects of the work.
Disclosure
GDH has received consulting and/or advisory board fees from AbbVie, Abivax, Agomab, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Exeliom Biosciences, GSK, Immunic, Index Pharmaceuticals, Johnson & Johnson, Lilly, Pfizer, Polpharma, ProciseDx, Progenity, Protagonist, Takeda, and Ventyx; has served on speaker’s bureaus for AbbVie, Arena, Bristol Myers Squibb, Galapagos, Gilead, Pfizer, and Takeda; and has served on data monitoring boards for AstraZeneca, Galapagos, and Seres Health. SV has received grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer, and Takeda; and has received consulting and/or advisory board and/or speaking fees from AbbVie, Abivax, AbolerIS Pharma, Agomab, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, IMIDomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma AG, and Zealand Pharma. WR has served as a speaker for AbbVie, Celltrion, Ferring, Galapagos, Janssen, Medice, MSD, Roche, Pfizer, Sobi, and Takeda; has received consulting from AbbVie, Agomab, Alfasigma, Amgen, Anaptys Bio, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Galapagos, Gilead, Index Pharma, Inova, Janssen, Lilly, MedAhead, Merck, Microbiotica, Pfizer, Takeda, and Teva Pharma; has served as an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, Pfizer, and Teva Pharma; and has received research funding from AbbVie, Janssen, Sandoz, Sanofi, and Takeda. SD has received consulting and/or advisory board fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Lilly, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, and Vifor; and has served as a lecturer for AbbVie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, and Takeda. WJS has received consulting fees from AbbVie, Abivax, Alfasigma, Alimentiv, BeiGene, Biora (Progenity), Celltrion, Forbion, Genentech, Gossamer Biosciences, Index Pharmaceuticals, Lilly, Oppilan Pharma (now Ventyx Biosciences), Prometheus Biosciences, Protagonist Therapeutics, Shoreline Biosciences, Vedanta Biosciences, Ventyx Biosciences, Zealand Pharma; has stock or stock options in BeiGene, Biora (Progenity), Gossamer Biosciences, Lilly, Oppilan Pharma (now Ventyx Biosciences), Prometheus Biosciences, Prometheus Laboratories, Shoreline Biosciences, and Ventyx Biosciences; and has served as an employee for Mirador Therapeutics, Shoreline Biosciences, and Ventyx Biosciences. WJS’s spouse has stock or stock options in Lilly, Mirador Therapeutics, Prometheus Biosciences, Prometheus Laboratories, Ventyx Biosciences, and Vimalan Biosciences; has served as an employee at Mirador Therapeutics and Prometheus Biosciences; and has served as a consultant for Prometheus Laboratories. SS has received consulting and/or advisory board fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Fresenius, Galapagos, Genentech, Gilead, GlaxoSmithKline, I-Mab Biopharma, Janssen, Lilly, Merck, Novartis/Sandoz, Pfizer, Protagonist, Shire, Takeda, and Theravance. SH has received consulting and/or advisory board fees from Takeda; has served as a lecturer for AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Takeda; has served as a consultant for AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Prometheus; and has served on a Data Monitoring Safety Board for Bristol Myers Squibb, Boehringer Ingelheim, and Prometheus. CB was an employee of Takeda at the time of the study; and is an employee of and receives stock and/or stock options in Apellis Pharmaceuticals. FC was an employee of Takeda at the time of the study; and is an employee of and receives stock and/or stock options in Landos Biopharma. MG was an employee of Takeda at the time of the study; and is an employee of and receives stock and/or stock options in Arena Pharmaceuticals, a wholly owned subsidiary of Pfizer, Zurich, Switzerland. KJG was previously a consultant for Arena Pharmaceuticals, ICON, Pfizer, Shire, and Takeda; and is currently a consultant to Abivax and Monte Rosa. MM is an employee of Takeda and has stock and/or stock options in Takeda. PN was a former employee of Takeda and had stock and/or stock options.
References
- 1.Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390(10114):2769–15. doi: 10.1016/S0140-6736(17)32448-0 [DOI] [PubMed] [Google Scholar]
- 2.Ghosh S, Mitchell R. Impact of inflammatory bowel disease on quality of life: results of the European federation of Crohn’s and ulcerative colitis associations (EFCCA) patient survey. J Crohns Colitis. 2007;1(1):10–20. doi: 10.1016/j.crohns.2007.06.005 [DOI] [PubMed] [Google Scholar]
- 3.Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn’s disease. Lancet. 2017;389(10080):1741–1755. doi: 10.1016/S0140-6736(16)31711-1 [DOI] [PubMed] [Google Scholar]
- 4.Gros B, Kaplan GG. Ulcerative colitis in adults: a review. JAMA. 2023;330(10):951–965. doi: 10.1001/jama.2023.15389 [DOI] [PubMed] [Google Scholar]
- 5.Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324–1338. doi: 10.1038/ajg.2015.233 [DOI] [PubMed] [Google Scholar]
- 6.Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the international organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology. 2021;160(5):1570–1583. doi: 10.1053/j.gastro.2020.12.031 [DOI] [PubMed] [Google Scholar]
- 7.Feuerstein JD, Ho EY, Shmidt E, et al. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn’s disease. Gastroenterology. 2021;160(7):2496–2508. doi: 10.1053/j.gastro.2021.04.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Feuerstein JD, Isaacs KL, Schneider Y, Siddique SM, Falck-Ytter Y, Singh S. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1450–1461. doi: 10.1053/j.gastro.2020.01.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Mehandru S, Colombel JF, Juarez J, Bugni J, Lindsay JO. Understanding the molecular mechanisms of anti-trafficking therapies and their clinical relevance in inflammatory bowel disease. Mucosal Immunol. 2023;16(6):859–870. doi: 10.1016/j.mucimm.2023.08.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Dotan I, Allez M, Danese S, Keir M, Tole S, McBride J. The role of integrins in the pathogenesis of inflammatory bowel disease: approved and investigational anti-integrin therapies. Med Res Rev. 2020;40(1):245–262. doi: 10.1002/med.21601 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wyant T, Fedyk E, Abhyankar B. An overview of the mechanism of action of the monoclonal antibody vedolizumab. J Crohns Colitis. 2016;10(12):1437–1444. doi: 10.1093/ecco-jcc/jjw092 [DOI] [PubMed] [Google Scholar]
- 12.Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711–721. doi: 10.1056/NEJMoa1215739 [DOI] [PubMed] [Google Scholar]
- 13.Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699–710. doi: 10.1056/NEJMoa1215734 [DOI] [PubMed] [Google Scholar]
- 14.Danese S, Sandborn WJ, Colombel JF, et al. Endoscopic, radiologic, and histologic healing with vedolizumab in patients with active Crohn’s disease. Gastroenterology. 2019;157(4):1007–1018.e1007. doi: 10.1053/j.gastro.2019.06.038 [DOI] [PubMed] [Google Scholar]
- 15.Schreiber S, Dignass A, Peyrin-Biroulet L, et al. Systematic review with meta-analysis: real-world effectiveness and safety of vedolizumab in patients with inflammatory bowel disease. J Gastroenterol. 2018;53(9):1048–1064. doi: 10.1007/s00535-018-1480-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Briskin M, Winsor-Hines D, Shyjan A, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol. 1997;151(1):97–110. [PMC free article] [PubMed] [Google Scholar]
- 17.Cohen RD, Bhayat F, Blake A, Travis S. The safety profile of vedolizumab in ulcerative colitis and Crohn’s disease: 4 years of global post-marketing data. J Crohns Colitis. 2020;14(2):192–204. doi: 10.1093/ecco-jcc/jjz137 [DOI] [PubMed] [Google Scholar]
- 18.Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2017;66(5):839–851. doi: 10.1136/gutjnl-2015-311079 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Loftus EV, Feagan BG, Panaccione R, et al. Long-term safety of vedolizumab for inflammatory bowel disease. Aliment Pharmacol Ther. 2020;52(8):1353–1365. doi: 10.1111/apt.16060 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Pullen N, Molloy E, Carter D, et al. Pharmacological characterization of PF-00547659, an anti-human MAdCAM monoclonal antibody. Br J Pharmacol. 2009;157(2):281–293. doi: 10.1111/j.1476-5381.2009.00137.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.D’Haens G, Vermeire S, Vogelsang H, et al. Effect of PF-00547659 on central nervous system immune surveillance and circulating β7+ T cells in Crohn’s disease: report of the TOSCA study. J Crohns Colitis. 2018;12(2):188–196. doi: 10.1093/ecco-jcc/jjx128 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Reinisch W, Sandborn WJ, Danese S, et al. Long-term safety and efficacy of the anti-MAdCAM-1 monoclonal antibody ontamalimab [SHP647] for the treatment of ulcerative colitis: the open-label study TURANDOT II. J Crohns Colitis. 2021;15(6):938–949. doi: 10.1093/ecco-jcc/jjab023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Wang Y, Marier JF, Lavigne J, Kassir N, Martin P. Population pharmacokinetics and pharmacodynamics of ontamalimab (SHP647), a fully human monoclonal antibody against mucosal addressin cell adhesion molecule-1 (MAdCAM-1), in patients with ulcerative colitis or Crohn’s disease. J Clin Pharmacol. 2020;60(7):903–914. doi: 10.1002/jcph.1590 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.D’Haens GR, Reinisch W, Lee SD, et al. Long-term safety and efficacy of the anti-mucosal addressin cell adhesion molecule-1 monoclonal antibody ontamalimab (SHP647) for the treatment of Crohn’s disease: the OPERA II study. Inflamm Bowel Dis. 2022;28(7):1034–1044. doi: 10.1093/ibd/izab215 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Vermeire S, Sandborn WJ, Danese S, et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10090):135–144. doi: 10.1016/S0140-6736(17)30930-3 [DOI] [PubMed] [Google Scholar]
- 26.Vermeire S, Danese S, Sandborn WJ, et al. Efficacy and safety of the anti-mucosal addressin cell adhesion molecule-1 antibody ontamalimab in patients with moderate-to-severe ulcerative colitis or Crohn’s disease. J Crohns Colitis. 2024;18(5):708–719. doi: 10.1093/ecco-jcc/jjad199 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.European commission releases Takeda from commitment to divest Shire’s pipeline compound SHP647. Takeda Pharmaceuticals. 2020. Available from: https://www.takeda.com/newsroom/newsreleases/2020/european-commission-releases-takeda-from-commitment-to-divest--shires-pipeline-compound-shp647/. Accessed January 10, 2025.
- 28.Berger JR. Natalizumab and progressive multifocal leucoencephalopathy. Ann Rheum Dis. 2006;65 Suppl 3(Suppl 3):iii48–53. doi: 10.1136/ard.2006.058404 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Click B, Regueiro M. A practical guide to the safety and monitoring of new IBD therapies. Inflamm Bowel Dis. 2019;25(5):831–842. doi: 10.1093/ibd/izy313 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Toruner M, Loftus EV, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134(4):929–936. doi: 10.1053/j.gastro.2008.01.012 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data sets, including the redacted study protocol, redacted statistical analysis plan, and individual participants’ data supporting the results reported in this article, will be made available within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. Individual data and relevant materials for those patients who have consented have been transferred to and can be accessed at the Crohn’s and Colitis Foundation of America.