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


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

In This Article


GEMINI LTS is the largest and longest clinical study yet performed to evaluate the risks and benefits of long-term vedolizumab therapy in patients with moderately to severely active UC or CD. Previous interim analyses reported interim safety summaries, while this final report presents in-depth safety over a median cumulative vedolizumab exposure period of 42.4 months (range: 0.03–112.2 months) for patients with UC and 31.5 months (range: 0.03–100.3 months) for patients with CD.[8,9] Study patients, all of whom had previously responded to vedolizumab induction therapy, had in total 7999 PYs (3451 PYs [UC] and 4548 PYs [CD]) of vedolizumab exposure. The large number of patients (N = 2243) and long cumulative duration of vedolizumab treatment provides valuable information to clinicians regarding the expected incidence of AEs with long-term vedolizumab treatment in responding patients.

In this final data analysis, we were able to closely evaluate the potential for systemic infections with the gut-selective vedolizumab and contrast that with previous reports of biologics with a broader mechanism of action. An analysis utilising the HealthCore Integrated Research Database (HIRD) reported that the incidence rates of a range of infections including C difficile(HR 1.39), TB (HR, 2.43), rectal or peritoneal abscesses (HR 3.12) were higher in patients currently taking TNF antagonist therapies compared with TNF antagonist naïve patients.[14] In GEMINI LTS, vedolizumab treatment was associated with relatively low rates of serious infections (18.0 and 33.6/1000 PYs in UC and CD, respectively). In a pivotal trial of adalimumab, rates of serious infection were roughly double with 35 and 67/1000 PYs, respectively.[15] In VARSITY, a double-blind, head-to-head study of patients treated with vedolizumab or adalimumab, vedolizumab was associated with lower rates of overall and serious infections than adalimumab (23.4 vs 34.6/100 PYs and 1.6 vs 2.2/100 PYs, respectively).[16]

While these data suggest a decreased risk of systemic infections with vedolizumab, an increased risk of gastrointestinal infections is plausible given the gut-selective mechanism of action and evidence for reduced immune response in the gastrointestinal tract.[17] In this study, gastrointestinal infections were infrequent during long-term vedolizumab exposure (34.9 and 39.6/1000 PYs for UC and CD, respectively), and the rate of C difficile (4.9 and 3.6/1000 PYs for UC and CD, respectively) was consistent with recent reports from other clinical studies including the HIRD, which reported rates of 3.14/1000 PY for patients with moderate to severe IBD.[14] The potential for increased risk of gastrointestinal infections continues to be evaluated.

GEMINI LTS identified no cases of PML with 7999 PYs of vedolizumab exposure. There have also been no confirmed cases of PML reported in vedolizumab clinical trials (>6000 patients treated with vedolizumab). In over 470 000 PYs of postmarketing exposure, only a single confirmed case of PML has been reported. This patient had multiple contributory factors for developing PML, specifically human immunodeficiency virus (HIV) infection with a CD4 count of 300 cells/mm3 and prolonged prior and concomitant immunosuppression use. The case was adjudicated by an Independent PML Adjudication Committee which concluded that the most likely cause of PML in this patient was their HIV diagnosis and prolonged immunosuppression. A PML risk estimation model explored the expected number of vedolizumab-associated PML cases up to 2034.[18] The model showed that assuming the risk is the same as in the general population, the first PML case would have most likely occurred by 2018 (55% probability). Assuming the risk is the same as in rheumatoid arthritis (an inflammatory condition), the first PML case would have most likely occurred by 2018 (≥90% probability). The occurrence of this case is consistent with the predictions of the model.

Some treatments that suppress the immune system, including treatments for IBD, increase the risk of cancer.[19] Previous reports indicate that rates of lymphoma, skin cancers, head and neck cancers and cervical cancer may be increased with immunosuppressive regimens while the rates of other tumours including lung and breast cancers are less affected.[20] In the HIRD analysis, the incidence of solid tumours overall was similar between TNF antagonist exposed and TNF antagonist naïve patients, 8.21 and 9.95/1000 PYs (HR 0.80), but rates of colon cancer (1.45 vs 1.08/1000 PYs [HR 1.25]), rectal cancer (1.74 vs 0.64/1000 PYs [HR 2.81]) and cervical dysplasia (8.91 vs 4.07/1000 PYs [HR 1.93]) were increased in patients on TNF antagonist therapy.[14] A meta-analysis of malignancies following TNF antagonist therapy reported similar rates for all-site malignancies ranging from 3.88 to 9.34/1000 PYs.[21] The rate of all-site malignancies in GEMINI LTS patients was also in line with these reports in patients with UC or CD (9.8 and 8.3/1000 PY, respectively) suggesting that vedolizumab, like TNF antagonist therapies, does not impact the overall rate of malignancies. However, in GEMINI LTS, vedolizumab was associated with lower rates of colon and rectal cancers (1.0 and 0.3/1000 PYs for UC and 0.3 and 0.5/1000 PYs for CD).

EIM such as arthralgia and arthritis are common in IBD. In this final analysis of GEMINI LTS, arthralgia was the most common treatment-emergent EIM (13.4% of patients with UC [47.0/1000 PYs] and 19.9% of patients with CD [84.1/1000 PYs]). Although this analysis includes longer cumulative exposure to vedolizumab, the rate of arthralgia is similar to a previous post-hoc analysis of the GEMINI trials (9% UC, 28% CD).[22] Likewise, the pivotal GEMINI studies reported that arthralgia was the most common treatment-emergent AE in the first 52 weeks of vedolizumab treatment (9% UC, 13.5% CD).[8,9] The GEMINI LTS interim analyses with approximately 4 years of follow-up was slightly higher (14% UC, 20% CD)[8,9] but consistent with this final analysis (17% UC, 24% CD).

Long-term vedolizumab therapy maintained or improved HRQOL in patients with moderately to severely active UC or CD. The range of validated assessment tools used to demonstrate improvements in HRQOL in GEMINI LTS provides further evidence of the consistent positive benefits provided by long-term vedolizumab therapy in terms of both disease-specific and global measures of patient well-being.[11–13] In addition, GEMINI LTS demonstrated that continuous vedolizumab treatment was efficacious over the long-term (in some patients for as long as 9 years) in patients with UC or CD. The previous interim analyses also reported that patients with UC or CD experienced clinical improvements with continuous vedolizumab treatment.[8,9]

Study limitations include potential bias that may be associated with non-blinded, non-randomised, uncontrolled studies. In addition, per the study design, only patients up to 65 years of age were initially enrolled, skewing the population younger than what is observed in clinical practice. The frequency of maintenance dosing in GEMINI LTS (Q4W) was determined prior to regulatory approval and is thus more frequent than the approved Q8W dosing used in clinical practice in the US. A further consideration is that endoscopy was not prospectively conducted in GEMINI LTS, precluding evaluation of mucosal healing and changes with long-term vedolizumab treatment. Finally, GEMINI LTS efficacy analyses were limited by the loss of patients over time primarily due to vedolizumab approval or expanded-access programme availability at the local study site, with 378/2243 patients receiving vedolizumab for ≥6 years. The rate of patient dropout (1477/2243) should be interpreted with caution, as the study period was extended well beyond the original duration through the addition of study protocol amendments to enable continued patient access to vedolizumab in countries where commercial or extended access to vedolizumab was not otherwise available. Consequently, to approximate patient numbers, LOCF analyses were performed to assess clinical efficacy. The data show a steady rate of both clinical remission and response.

In conclusion, the final analysis of GEMINI LTS comprehensively demonstrates that vedolizumab therapy has a safety and tolerability profile suitable for long-term treatment of patients with moderately to severely active UC or CD. This is a key consideration in the management of IBDs given that they are chronic conditions that typically require lifelong therapy.