Vedolizumab was introduced in 2014 as a therapy for Inflammatory Bowel Disease (IBD). Although recommendations from the National Institute for Health and Care Excellence were based on a maintenance dose of 300 mg administered intravenously every 8 weeks, the Summary of Product Characteristics includes an option of increasing the frequency of dosing for patients who initially respond but later experience a decrease in response. In this literature review of the evidence for a shorter duration between doses we identified seven studies which report that dose interval shortening recaptures response in around 50% of cases with remission rates of 11% to 34% between 4 and 52 weeks. A sustained response was seen in the majority of patients for up to 1 year, however, patients continued to receive escalated dosing for up to 100 weeks, which does not reflect clinical practice where short-term escalation is usually prescribed. There is a lack of randomised controlled trials and a lack of trials reporting endoscopic remission, which is the goal of care in IBD. The use of therapeutic drug monitoring (TDM) to guide dose escalation is uncertain and further studies are required to help clarify the role of TDM.
- Gastrointestinal diseases
- Evidence-Based Medicine
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Key learning points
Vedolizumab is licensed for the treatment of ulcerative colitis and Crohn’s disease with a recommended maintenance dose of 300 mg administered intravenously every 8 weeks.
The Summary of Product Characteristics includes the option that some patients who experience a loss of response may benefit from dose escalation to vedolizumab administered intravenously every 4 weeks.
Data from observational and single-arm open-label studies show that between 32% and 63% of patients who had lost response to vedolizumab, regained response after an increase in dose frequency with intravenous vedolizumab.
The main limitations of the evidence regarding the efficacy of dose escalation include the use of clinical remission alone without endoscopic assessment pre-escalation and post-escalation and the absence of randomised controlled trial data.
The goal of modern inflammatory bowel disease management is concurrent endoscopic and symptomatic remission, and therefore, the studies fall short of determining the desired end point.
Vedolizumab (Entyvio) is a humanised monoclonal antibody directed against the α4β7 integrin on T helper cells; this integrin is expressed on certain white blood cells found in the gut and is responsible for recruitment of white cells to inflamed bowel tissue.1–3 Vedolizuab, therefore, reduces inflammation specifically in the gastrointestinal tract. Its introduction in May 2014 provided another therapeutic option for people with inflammatory bowel disease (IBD). The National Institute for Health and Care Excellence (NICE) technology appraisals (TAs) of vedolizumab for treating ulcerative colitis (UC) and Crohn’s disease (CD) refer to a dosing schedule of vedolizumab 300 mg given by intravenous infusion at 0, 2 and 6 weeks and then every 8 weeks, with the option of an additional dose at week 10 for people with CD who have not shown a response.1 2 However, the dosing regimen in the summary of product characteristics (SPC) includes an option of increasing the dose frequency to every 4 weeks for patients who experience a decrease in response.3 This may have a significant impact on the way vedolizumab is used as there will be a loss of response (LOR) in around one-third of patients who initially responded.4 5 In this article, we explore the evidence for a shorter dose interval and consider the implications. The data in this article refer to treatment with intravenous vedolizumab and not subcutaneous vedolizumab.
Vedolizumab is licensed for use in adults with moderately to severely active UC or CD who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumour necrosis factor-alpha (TNFα) inhibitor.3 It also has a licence for the treatment of pouchitis.
The recommended dose for UC and CD is vedolizumab 300 mg administered by intravenous infusion at 0, 2 and 6 weeks and then every 8 weeks.3 Patients with CD, who have not shown a response, may benefit from a dose of vedolizumab at week 10. Treatment should be discontinued if there is no therapeutic benefit by week 10 (for people with UC) and by week 14 (for people with CD). The SPC also states that some patients who have experienced a decrease in their response may benefit from an increase in dosing frequency to intravenous vedolizumab 300 mg every 4 weeks.3
Summary of national recommendations
Vedolizumab is recommended by NICE ‘within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults…until it stops working or surgery is needed’.1 NICE also recommends vedolizumab ‘as an option for treating moderately to severely active Crohn’s disease only if a tumour necrosis factor-alpha inhibitor has failed…or a tumour necrosis factor-alpha inhibitor cannot be tolerated or is contraindicated…until it stops working or surgery is needed, or until 12 months after the start of treatment, whichever is shorter’.2 When NICE developed its TAs in 2015 its documentation noted that the recommended dose of vedolizumab was 300 mg at 0, 2 and 6 weeks followed by maintenance dosing every 8 weeks, with the option of an additional dose at week 10 for people with CD who have not shown a response. NICE based its decision on evidence from the GEMINI trials.4–6 The NICE TA guidance has not been updated since 2015.
In the GEMINI 1 study, 373 patients with UC, who had responded to two doses of vedolizumab 300 mg in an induction phase, were randomised to receive vedolizumab every 8 weeks, every 4 weeks or placebo for 52 weeks.4 The clinical remission rates (primary outcome) at 52 weeks for vedolizumab given every 8 weeks, vedolizumab given every 4 weeks and placebo were 42%, 45% and 16%, respectively.
The GEMINI 2 study was similar in design to GEMINI 1 but involved 461 people with CD in the maintenance phase.5 The clinical remission rates (primary outcome) at 52 weeks for patients who received vedolizumab every 8 weeks, every 4 weeks or placebo were 39%, 36% and 22%, respectively.
The GEMINI 1 and 2 studies showed that there was no advantage of a maintenance dose given every 4 weeks over a maintenance dose every 8 weeks in patients who had responded to vedolizumab during the induction phase.4 5
NICE also took into account the GEMINI 3 study, which assessed the effect of vedolizumab or placebo as induction therapy in adults with moderately to severe CD in whom treatment with a TNFα inhibitor had failed.6 There was no difference in the primary outcome of inducing clinical remission at week 6 (15.2% vs 12.1%, p=0.433). Exploratory analysis of a secondary outcome showed a greater clinical remission rate at week 10 with vedolizumab (27.6% vs 12.1%).
The NICE TA assessments for vedolizumab for UC and CD appear to be based on an assumption that the cycle length of the maintenance phases of treatment was 8 weeks with no specific reference to a dosing regimen of every 4 weeks for people who experience a decrease in their response to vedolizumab treatment.1 2
The advice published by the Scottish Medicines Consortium (SMC) in 2015 included the same dosing schedule as the NICE TAs, however, the SMC guidance also included the SPC recommendation that ‘some patients who have experienced a decrease in their response may benefit from an increase in dosing frequency to 300 mg every 4 weeks’.7 8 Nevertheless, the costing information in the SMC guidance for vedolizumab in the treatment of UC and CD, was based on an intravenous dose of 300 mg administered at week 0, 2 and 6, then every 8 weeks. The cost–utility analysis was based on a 6-week induction phase, followed by long-term maintenance with a cycle length of 8 weeks.
Evidence to support dose escalation in patients with asecondary loss of response
The GEMINI 1 and GEMINI 2 trials found no difference between 4 weekly and 8 weekly maintenance dosing.4 5 Neither trial assessed the efficacy of dose escalation for patients experiencing a secondary LOR. A meta-analysis published in 2019 examined vedolizumab dose intensification in people with UC or CD and secondary LOR.9 The authors reported data from four studies with 111 patients with a secondary LOR that showed that dose escalation recaptured response in 54% (95% CI 22 to 83) of patients.9
A literature review (box 1) identified seven studies (four observational studies and three single arm open-label studies), with 411 patients with IBD, that examined the effect of dose escalation for patients experiencing a LOR (table 1).10–16 The criteria for dose escalation for LOR varied between studies, particularly in patients with UC. The definition for response and remission were also heterogeneous with different scoring systems being used and some using a physician’s assessment (table 1). For CD, the definitions were more uniform and were based on the Harvey Bradshaw Index. Vedolizumab dose escalation for a primary non-response is currently not recommended, however, four of the studies included in the analysis (table 1) combined the results for patients with LOR and primary non-response, but the majority had LOR.10–13
Search strategy for literature review
A literature search was conducted of PubMed and OVID MEDLINE using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses on 15 April 2022 using the following search terms: ‘Vedolizumab’, ‘dose intensification’ or ‘dose frequency’ or ‘escalation’ or ‘interval shortening’ or ‘4*week*’ or 4 week*’. Studies with adult participants were included. The search strategy identified 303 citations of which 56 were included for full text review. Finally, seven studies were eligible for inclusion. A further 12 studies were included for qualitative information (online supplemental material).
The time to LOR was not reported in all of the studies, but Samaan et al reported a median duration of 7 months (range 3–21 months) before dose escalation.10 The exact number of escalated doses given was not reported for all studies but Samaan et al reported dose escalation for a median duration of 7 months (range 2–25).10
The results from six studies of dose escalation for LOR in people with CD show an overall response rate of 47%–61% and remission rate of 14%–34% reported for various time-points from 8 to 52 weeks.10 12–16 In UC, the response rate was 32%–63% and remission rate was 11%–34% reported for timepoints between 4 and 52 weeks.11 13–16 These findings suggest that some patients who experience LOR during maintenance treatment, benefited from dose escalation. It should be noted that 53%–100% of participants had prior TNFα inhibitor use.10–15
It is worth noting that much of the data comes from studies that were coauthored or supported by the company that markets vedolizumab in the UK. Also, some of the data is only available from brief conference reports or posters.
Therapeutic drug monitoring
In a study of 45 patients with IBD, those who were receiving vedolizumab every 4 weeks had higher blood levels than those who were receiving vedolizumab every 8 weeks.17 In addition, patients in remission, as defined by steroid-free remission and either a normal intestinal ultrasound or faecal calprotectin level, had higher median drug levels. In a small study of 21 patients with IBD that assessed proactive therapeutic drug monitoring (TDM), vedolizumab levels at week 14 were not able to predict patients who achieved disease remission at week 52.18 In an observational study (47 consecutive patients with IBD) that assessed response to vedolizumab after 6 weeks, 30 patients required additional doses.19 Trough levels of vedolizumab at week 2 were lower in patients who required additional doses compared with those who did not need additional doses (23.0 µg/mL vs 42.5 µg/mL). A systematic review and meta-analysis of 5 studies with 558 participants showed that vedolizumab trough levels of >20 µg/mL at week 6 and >12 µg/mL during maintenance may be associated with better outcomes.20
However, there is no consensus about the utility of trough levels to guide treatment escalation.15 19 21 Outtier et al found baseline vedolizumab levels, in patients with LOR did not predict who would respond to dose escalation.15 Vaughn et al examined 58 patients whose dose was escalated to see if vedolizumab trough levels could predict who would subsequently respond to dose escalation; 74% of those with a trough levels <7.4 µg/mL prior to escalation responded compared with only 52% of those with a vedolizumab trough concentration ≥7.4 µg/mL (p=0.08).21 The authors concluded that those with a trough level >7.4 µg/mL may be less likely to respond to dose escalation, however this was not statistically significant. A study by Ungar et al suggests that TDM may not be very useful at guiding escalation; preintensification vedolizumab levels were higher among patients who regained response compared with non-remitters.13 The authors concluded that the mechanism of LOR to vedolizumab is unlikely to be related to the pharmacokinetics.
With conflicting results, the role of TDM to guide escalation is not established and escalation is often guided clinically. The immunogenicity is much lower than with anti-TNFα medications, with only 2%–4% developing antibodies, which can explain the heightened usefulness of drug monitoring with anti-TNFα medications. Further prospective studies may help clarify the role of TDM.
Safety of dose interval shortening
The safety of a shorter dose interval has been studied in the GEMINI long-term safety trial and rates of adverse reactions were similar to those seen in patients receiving a dose of vedolizumab every 8 weeks. In patients with UC who were receiving vedolizumab every 4 weeks, the most common adverse events were exacerbation of UC and nasopharyngitis, serious infections occurred in 5%, infusion-related reactions occurred in 3%, and adverse events led to discontinuation in 10% .11 Among patients with CD, the most common adverse events were exacerbation of CD, nasopharyngitis and arthralgia.12 Adverse events led to discontinuation in 12% and infusion-related reactions occurred in 4%.
Durability of response
The durability of dose escalation has been studied. In UC, remission was mostly maintained up to 100 weeks with remission in 25% at week 28, 28% at week 52 and 22% at week 100 which was the end of the study.11 The response rate, however, did decrease from 53% at week 28, to 41% at week 52 and 28% at week 100. In CD, remission was mostly maintained, with remission in 23% at week 28, 32% at week 52 and 19% at week 100; response rates decreased slightly (54% and 47% and 35%, respectively).12 However, in these studies, patients were kept on escalated dosing, which does not reflect real world practice.
A meta-analysis of 6 studies (297 participants) of dose escalation for LOR showed that the rate of recapture of response in the first 30 weeks was 63% and but dropped to 50% after 30 weeks.22
When should different dose regimens be used?
Escalated vedolizumab dosing is an option for patients who, after an initial response, experience LOR while on maintenance therapy.3 Escalation is not indicated for patients who are responding to a dose given every 8 weeks.1–3 Another group of patients who sometimes undergo dose escalation, but in whom dose escalation is currently not recommended are those with a primary non-response. There is limited published data on the effect of vedolizumab in primary non-response. In one retrospective study of 22 patients with a partial response and 2 patients with a non-response who underwent dose escalation, 10/22 (45%) of partial responders and 0/2 non responders achieved remission after an average of 56 weeks.23 In a study of 70 non-responders who received escalated dosing, 52% achieved clinical response and 42% achieved clinical remission.24
Response rate of escalated doses of vedolizumab in patients who have failed other biologics
A post hoc analysis of the GEMINI II trial showed that patients with prior anti-TNFα treatment failure were less likely to be in remission at 52 weeks with vedolizumab.25 It appears that this does not hold true for dose escalation for LOR. In a retrospective cohort study, prior anti-TNFα use did not predict success of dose escalation for LOR.10 In the GEMINI II extension study, similar improvements were seen regardless of prior anti-TNFα use and an open-label prospective study with 59 participants found that there was no difference in response to dose escalation to 4 weekly dosing, among those who had and had not previously received anti-TNFα treatment.12 15 As the majority of patients in the studies of our literature review had previously received anti-TNFα medicines, a trial of dose escalation in patients with LOR, regardless of prior anti-TNFα treatment, may be a reasonable clinical approach.
There is a lack of randomised controlled trials investigating dose escalation with vedolizumab. In the studies identified, the criteria for dose escalation and definition of response and remission were heterogeneous and many have only been published as short, summarised conference reports. The role of TDM is still under investigation and currently dose escalation is based on clinical LOR. Not all studies reported the duration for which 4-weekly dosing was administered but if there is no improvement after three doses, further dosing is not likely to be useful, especially given the high cost of vedolizumab and the inconvenience for the patient. The majority of studies were based on clinical outcomes and very few patients had endoscopic or biomarker remission, which, in conjunction with symptomatic remission is the goal of IBD management. Clinical remission alone, without reporting on endoscopic remission, falls short of the desired endpoint. In the GEMINI extension study, participants received dose escalation for up to 100 weeks, which is longer than is usual in the clinical practice, where patients are often are approved for a few months of escalated dosing, before having to reapply.11 12 Despite numerous limitations of the evidence, there are some data that suggest a benefit for dose escalation for some patients. Vedolizumab is more expensive than other biologics. Some local health systems allow dose escalation of vedolizumab, others require individual funding requests while others do not approve it.
We are not aware of evidence for the cost-effectiveness of dose escalation for LOR.
The introduction of vedolizumab in 2014 provided an additional treatment option for patients with IBD. The SPC’s recommendation that ‘some patients who have had a decrease in their response may benefit from dose escalation to 4-weekly’ is supported by evidence from observational and single-arm open-label studies identified in our literature review. The data we present in this review focus only on the use of intravenous vedolizumab. There have been no double-blind randomised controlled trials examining the efficacy of dose escalation, however, the non-randomised trials show that in patients with an LOR, around 50% of patients recaptured response with dose escalation. Most of the patients had previous biological exposure and subgroup analysis showed that prior anti-TNFα failure did not reduce the efficacy of dose escalation in the few studies which examined this. The question of whether those with a primary non-response may benefit from dose escalation remains unanswered. While dose escalation for LOR appears to offer a benefit for patients with IBD, we were unable to find a cost-effectiveness assessment of the effect of dose-escalation. It is unclear how this might affect national recommendations. There is some evidence to suggest that dose escalation is associated with an increase in vedolizumab trough levels. There are, however, conflicting results about the role of TDM to predict who might respond to dose escalation for LOR. The role for TDM in guiding escalation may become clearer with further studies.
Information for patients
When people with inflammatory bowel disease start vedolizumab treatment, around 44% of those with Crohn’s disease and 57% with ulcerative colitis will improve and around 39% of those with Crohn’s disease and 42% with ulcerative colitis will be in remission at 1 year.
One-third of patients who initially improve with vedolizumab will experience worsening of symptoms.
For patients treated with intravenous vedolizumab, there is some evidence that shortening the interval between doses from 8 weeks to 4 weeks will help up to 50% of those patients who initially responded to vedolizumab, but later experienced a loss of response.
Patients whose symptoms do not improve when the dose frequency is increased to every 4 weeks, might need an alternative medication or treatment.
Competing interests None declared. Refer to the online supplementary files to view the ICMJE form(s).
Provenance and peer review Commissioned; externally peer reviewed.
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