Long-term Safety of Vedolizumab for Inflammatory Bowel Disease

Edward V. Loftus Jr; Brian G. Feagan; Remo Panaccione; Jean-Frédéric Colombel; William J. Sandborn; Bruce E. Sands; Silvio Danese; Geert D'Haens; David T. Rubin; Ira Shafran; Andrejus Parfionovas; Raquel Rogers; Richard A. Lirio; Séverine Vermeire

Disclosures

Aliment Pharmacol Ther. 2020;52(8):1353-1365. 

In This Article

Results

Patient Characteristics

A total of 2243 patients (894 UC, 1349 CD) enrolled in GEMINI LTS. Of these, 1822 participated in a prior vedolizumab randomised study; 421 were de novo patients (Figure 1). The safety population consisted of all 2243 patients; 2177 patients were included in the efficacy population. Overall, 766 of 2243 (34.2%) patients completed GEMINI LTS (36.9% UC, 32.3% CD). The most common reasons for treatment discontinuation were lack of efficacy (26.6% UC, 28.3% CD), AEs (14.4% UC, 16.5% CD), and withdrawal by the patient (16.9% UC, 14.8% CD). Additional reasons for withdrawal were not captured but likely included the availability of an expanded-access programme at a local study site or the availability of commercial vedolizumab.

The mean age of patients with UC at enrolment in GEMINI LTS was 41.2 years; roughly one third were younger than 35 years and 4.7% were ≥65 years of age. At enrolment, the mean partial Mayo score of patients with UC was 6.0 and the mean disease duration was 8.1 years. For patients with CD, the mean age at enrolment was 37.8 years and almost half (47.8%) were younger than 35; only 2.5% were ≥65 years of age. The mean HBI score at enrolment was 10.9 and the mean duration of CD was 10.1 years. All patients with UC or CD had received ≥1 prior conventional therapy and approximately half of patients with UC and two-thirds of patients with CD had previously failed therapy with a TNF antagonist. At enrolment, 36.9% and 40.4% of patients with UC and CD, respectively, were taking concomitant corticosteroids (Table 1).

Inclusive of previous trials, 1350 of the 2243 patients (60.2%) completed ≥24 infusions (2 years of vedolizumab exposure), with similar proportions of patients with UC or CD (63.8% and 57.8%, respectively). More than half (51.9%) completed ≥36 infusions (3 years of exposure) and 24.8% completed ≥72 infusions (6 years of exposure). Five patients with UC received ≥116 infusions (≥9 years of exposure). The median cumulative vedolizumab exposure was 42.4 months in patients with UC and 31.5 months in patients with CD, with maximum exposure times of 9.3 and 8.4 years, respectively (Table 1).

Adverse Events

Inclusive of preceding trials (for patients who rolled over from a prior study) and GEMINI LTS, almost all patients experienced at least 1 AE (92.7% UC, 96.0% CD), the majority of which were mild or moderate in severity. The overall incidence rate of AEs was 1220.5 and 1799.2/1000 PYs for patients with UC and CD, respectively. The most frequent AEs were disease exacerbations (35.9% UC, 35.3% CD), nasopharyngitis (28.2% UC, 25.4% CD) and arthralgia (17.3% UC, 24.4% CD). Fewer than half of AEs (39.7% UC, 46.2% CD) were considered by the treating physician to be vedolizumab-related (Table 2). SAEs were less frequent (31.0% UC and 40.6% CD) with an incidence of 90.9 and 146.5/1000 PYs for patients with UC and CD, respectively. The most common SAEs were disease exacerbation (13.3% UC, 16.6% CD) and abdominal pain (1.0% UC, 3.0% CD). SAEs were deemed treatment related in 4.1% and 5.9% of patients UC and CD, respectively.

Of the 76 patients (3.4%) who were ≥65 years old, 93.0% reported an AE, comparable to 94.8% in patients <65 years old. However, patients ≥65 versus <65 years old had numerically lower rates of the most common AEs such as arthralgia (19.7% vs 21.8%), nasopharyngitis (15.5% vs 26.4%) and headache (15.5% vs 20.2%).

Patients with UC who had failed prior TNF antagonist therapy reported slightly more AEs than patients who had not (95.5% vs 90.7%). Numerically more patients with UC and prior TNF antagonist failure had treatment-related AEs and SAEs than patients with no prior TNF antagonist failure (51.3% vs 31.5% and 35.5% vs 28.2%). Patients with CD also reported slightly more AEs with prior TNF antagonist failure versus without (97.5% vs 93.5%), more treatment-related AEs (51.3% vs 36.9%), and more SAEs (42.7% vs 36.9%) (Table S1).

At enrolment, 299 patients with UC (34.6%) and 1124 patients with CD (83.8%) had a history of prior extraintestinal manifestations (EIM; Table 1). More patients with prior TNF antagonist failure had arthralgia/arthritis versus those without (36.3% vs 22.3% UC, 70.3% vs 60.0% CD). The most common EIM was arthralgia/arthritis (28.4% UC, 66.5% CD). More patients with UC who had previously failed prior TNF antagonist therapy reported a history of EIMs compared with those who had not failed TNF antagonist therapy (41.8% vs 28.9%). Similarly, more patients with CD and prior TNF antagonist failure had a prior history of EIMs than those with no prior failure (87.0% vs 78.3%).

Inclusive of prior vedolizumab trials and GEMINI LTS, treatment-emergent EIMs occurred in 172 patients with UC (19.2%; 70.6/1000 PYs) and 443 patients with CD (32.8%; 157.5/1000 PYs). Arthralgia was the most common event, reported by 13.4% of patients with UC (47.0/1000 PYs) and 19.9% of patients with CD (84.1/1000 PYs), followed by arthritis (1.9% UC, 3.5% CD), anal fissure (1.7% UC, 3.0% CD) and anal fistula (<1% UC, 7.0% CD). Among patients with treatment-emergent EIMs of arthralgia or arthritis, 39.5% of those with UC and 74.8% of those with CD had a history of arthralgia or arthritis. Additional treatment-emergent EIMs are reported in Table 3.

Vedolizumab was discontinued because of an AE by 137 patients with UC (15.3%) and 229 patients with CD (17.0%) (Table 2); UC or CD exacerbations (8.8% and 8.0%, respectively) were the most frequent reasons for discontinuation. All other AEs that led to discontinuation were reported in <1% of patients. There was a total of 10 deaths (4 UC, 6 CD). Two deaths were considered related to treatment by local investigators (Table 2), one patient who died of West Nile virus infection-related encephalitis and a second who died of hepatocellular carcinoma. Narratives for these 10 patient deaths can be found in the Supporting Information.

Infections

Infections were reported in 591 patients with UC (66.1%; 388.9/1000 PYs) and 937 patients with CD (69.5%; 492.1/1000 PYs). Serious infections occurred in 6.8% of patients with UC (18.0/1000 PYs) and 10.8% of patients with CD (33.6/1000 PYs; Table 2). The most common serious infections were anal abscess (0 UC, 33 CD), pneumonia (9 UC, 12 CD), gastroenteritis (5 UC, 14 CD) and appendicitis (9 UC, 8 CD). In patients with UC and CD, 17.9% and 21.6% of infections, respectively, were considered treatment-related by the investigator.

Among gastrointestinal infections of special interest, pathogen-unspecified abdominal or gastrointestinal infections were experienced by 92 patients with UC (10.3%; 34.9/1000 PYs) and 141 patients with CD (10.5%; 39.6/1000 PYs; Table 4). Opportunistic infections were reported in 61 patients (31 UC, 30 CD), the most common of which were clostridia infections. Most opportunistic infections were mild (22 of 61) or moderate in severity (35 of 61). One or more clostridial infections were reported in 26 patients with UC (2.9%) and 21 patients with CD (1.6%). Of clostridial events, 12 were severe, while the remainder were moderate (23 events) or mild (15 events); 4 patients (2 UC, 2 CD) discontinued the study because of clostridial infections. Fourteen patients with UC and 14 with CD developed Clostridium difficile infections (Table S2); 11 patients (4 UC, 7 CD) were hospitalised.

Of the 2243 patients, 294 (13.1%) were enrolled from countries with high rates of tuberculosis (TB) infection (>20 cases/100 000 people) (Table S3). Over the course of the study, 4 patients (1 UC, 3 CD), all living in countries with higher endemic rates of TB, were diagnosed with primary pulmonary TB; 3 of the 4 patients discontinued the study because of this event. Three of the cases of primary pulmonary TB were considered SAEs. One additional patient developed TB from an undetected latent infection and discontinued the study. No cases of gastrointestinal TB were reported.

Nine patients (5 UC, 4 CD) reported salmonella infections and 7 patients (5 UC, 2 CD) experienced giardiasis; no patient discontinued due to these infections. Meningitis, cryptosporidiosis and alveolar osteitis were each reported in one patient but did not lead to study discontinuation. Finally, there were no cases of herpes encephalitis, disseminated herpes zoster or PML.

Neoplasms

Benign or malignant neoplasms occurred in 58 patients with UC (6.5%; 17.2/1000 PYs) and 92 patients with CD (6.8%; 20.8/1000 PYs; Table 2). The most common benign neoplastic events were skin papillomas (<1% UC, 1.2% CD), and melanocytic naevus (<1% in UC and CD) (Table S4).

The most common malignant neoplasm in patients with UC or CD was basal cell carcinoma with <1% in UC and CD. The next most common neoplasms were lung neoplasm in <1% of patients with UC and CD and colon carcinomas in <1% of patients with UC and CD (Table S4). One patient developed a malignant hepatic neoplasm, which was considered by the investigator to be related to vedolizumab. No trend was observed between the development of malignancy and age, sex, type of malignancy or duration of vedolizumab exposure.

Infusion-related Reactions

Investigator-defined infusion-related reactions were reported in 36 patients with UC (4.0%) and 67 patients with CD (5.0%) (Table 2). Two patients discontinued treatment because of infusion reactions. The most common infusion-related reactions were nausea (3 UC, 11 CD), dizziness (3 UC, 8 CD) and headache (4 UC, 7 CD). Each infusion-related reaction event (cumulative over the patients' previous study and GEMINI LTS) occurred in <1% of patients overall.

Other AEs

Overall, hepatobiliary events were reported for 29 patients with UC (3.2%) and 63 patients with CD (4.7%) (Table 2). All events occurred in <1% of patients except for cholelithiasis, which occurred in 25 patients (1.1%). Three patients (2 UC, 1 CD) discontinued the study because of a hepatobiliary disorder.

Thromboembolic events were reported for 5 patients with UC (<1%) and 20 patients with CD (1.5%). Three events (deep vein thrombosis, thrombophlebitis, and venous thrombosis in a limb in 1 patient each) were considered related to study drug.

Efficacy Outcomes

Clinical response rates and clinical remission rates were likewise maintained long-term. At 400 weeks of treatment, 217 of 658 (33.0%) patients with UC and 197 of 700 (28.1%) patients with CD were in clinical remission and 230 of 657 (35.0%) and 232 of 700 (33.1%), respectively, had a clinical response (Figures 2 and 3). Clinical response and clinical remission rates trended lower in both patients with UC and CD who had failed TNF antagonist therapy relative to patients who had not (Figures S1 and S2).

Figure 2.

Clinical response over time in patients with UC or CD. Clinical response was assessed at baseline, weeks 4, 8, 12 and every 8 weeks thereafter. For patients with UC, clinical response was defined as a decrease in the partial Mayo score of ≥2 points and ≥25% from baseline, with an accompanying decrease in rectal bleeding subscore of ≥1 point from baseline or absolute rectal bleeding subscore of ≤1 point. For patients with CD, clinical response was defined as a ≥3-point decrease from baseline in the HBI score. Baseline was defined as the last assessment prior to the first dose of study drug administration in GEMINI 1 for patients with UC and GEMINI 2 for patients with CD. For patients who discontinued the study, the final assessed value of clinical response was carried forward to the end of the study. CD, Crohn's disease; HBI, Harvey-Bradshaw Index; UC, ulcerative colitis

Figure 3.

Clinical remission over time in patients with UC or CD. Clinical remission was assessed at baseline, Weeks 4, 8, 12 and every 8 weeks thereafter. For patients with UC, clinical remission was defined as a partial Mayo score of ≤2 with no individual subscore >1. For patients with CD, clinical remission was defined as an HBI score ≤4. For patients who discontinued the study, the final assessed value of clinical response was carried forward to the end of the study. CD, Crohn's disease; HBI, Harvey-Bradshaw Index; UC, ulcerative colitis

HRQOL estimates, based upon IBDQ, SF-36, EQ-5D and EQ-5Q VAS scores remained stable in patients with UC and CD over the duration of GEMINI LTS (Figure 4A-D). HRQOL was comparable between patients with UC or CD who had failed prior TNF antagonist therapy versus those who had not (Figures S3 and S4).

Figure 4.

Health-related quality of life (HRQOL) by indication and assessment tool in patients with UC or CD. HRQOL was assessed at baseline and week 26 and then every 24 weeks for the first 4 years, and yearly from Year 5 onward. Assessments tools included A. IBDQ total score, B. SF-36 total score, C. EQ-5D total score, and D. EQ-5D VAS

Finally, 142 patients with UC (16.8%) experienced ≥1 UC-related hospitalisation, colectomy or UC-related procedure and 365 patients with CD (28.1%) experienced ≥1 CD-related hospitalisation, bowel resection or CD-related procedure. These events were more frequent among patients who had previously failed TNF antagonist therapy versus those who had not (23% vs 12% UC, 30% vs 24% CD). Of all hospitalisations, the most common reasons for admission of patients with UC were UC (34.4%), abdominal/gastrointestinal infection (4.5%) and abdominal/gastrointestinal pain (3.0%). Among patients with CD, the most common reasons for hospitalisation included CD (29.1%), abdominal/gastrointestinal infection (7.4%), and abdominal/gastrointestinal pain (6.2%) (Table S5). A total of 8 patients (<1%) with UC and 33 (2.4%) with CD developed postoperative complications. The most common postoperative event was intestinal anastomosis complication (1 UC, 8 CD). Additional complications are summarised in Table S6.

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