Humira vs remicade for uc

The Pros and Cons of Biologics for Ulcerative Colitis

In the last decade or so, treatment options for ulcerative colitis have expanded quite a bit. Among the new options is a class of drugs called biologics. Biologics are derived from human genes and are designed to act on the immune system, specifically parts of the immune system that play key roles in fueling inflammation.

“As inflammation is thought to be a cornerstone of the process involved in the manifestation of inflammatory bowel diseases, like Crohn’s disease and ulcerative colitis, they have proved to be very effective as treatment for certain patients,” says Donald Tsynman, MD, a gastroenterologist at Manhattan Specialty Care in New York City.

The fact that biologics target the activity of the patient’s own immune system is what sets them apart from some other medications for ulcerative colitis, Dr. Tsynman says.

How Biologics Work

“The biologics that have been approved by the FDA for Crohn’s and ulcerative colitis all involve antibodies that are developed in the lab to target a specific protein,” says Joel Pekow, MD, an assistant professor of medicine at University of Chicago Medicine and a gastroenterologist at the University of Chicago Medicine Inflammatory Bowel Disease Center in Illinois.

Four biologics in particular are FDA approved for treating ulcerative colitis: Humira (adalimumab), Simponi (golimumab), Remicade (infliximab), and Entyvio (vedolizumab). They all target a protein called tumor necrosis factor alpha (TNF-alpha), which contributes to inflammation.

A study published in January 2015 in Therapeutics and Clinical Risk Management compared adalimumab, golimumab, and infliximab and found all three drugs to be effective at inducing and sustaining disease remission in ulcerative colitis, and to be comparatively safe. It’s worth mentioning that infliximab has been around the longest, so your doctor may be more comfortable with it than with other biologics.

Vedolizumab is the new biologic on the block, having been FDA approved in 2014. A study called GEMINI, published in November 2016 in the Journal of Crohn’s and Colitis, found vedolizumab to be effective in the long term, with 88 percent of patients who responded to the drug still in remission after two years of treatment.

While biologics may be a promising option for treating your ulcerative colitis, not every drug is suited to every patient.

The Potential Downsides of Biologics

While studies and clinical information indicate that biologics are generally safe, they are relatively new drugs, so — with the exception of Remicade (infliximab) — safety information for more than a few years is not available. Moreover, because most of them are only available as name brands, they can be very expensive. Remicade is again an exception, because it has a biosimilar called Inflectra (infliximab-dyyb) — a nearly identical molecule that functions in the same manner — approved in 2016.

A person’s lifestyle, demographic factors, and the severity of the disease are also considerations in the choice of whether or not to use biologics and which of them is the best option. Some of these include:

  • Pregnancy Tsynman notes that biologics can cross the placental membrane. There is simply not enough clinical data available to determine whether biologics are safe for pregnant women and their children. But doctors in the U.S. encourage people to stay on their therapy through pregnancy.
  • Method of treatment Some biologics, such as adalimumab, can be self-administered via an at-home injection, while others, like vedolizumab, require intravenous infusion. Your level of comfort or schedule might influence your choice between biologics, or whether to take them at all.
  • Severity of disease All these drugs are prescribed for moderate to severe disease, and they all come with potential side effects, including fever and respiratory infections. If your disease is milder in nature, you might find that the side effects are not worth the benefits.

If you’re considering biologics for treatment, speak to your doctor to find out what’s best for you. As Tsynman says, “At the heart of the decision is the relationship between the patient and the physician and specifically exploring what works best for each individual.”

Efficacy of Adalimumab as a long term maintenance therapy in ulcerative colitis

Abstract

Introduction: Adalimumab is a recombinant human IgG1 monoclonal antibody to TNF-alpha. There are limited data with regard to its efficacy in ulcerative colitis. We report experience of adalimumab in ulcerative colitis in a single centre with a focus on the ability of this agent to maintain response and avoid colectomy in the medium to long-term.

Methods: Twenty-three ulcerative colitis patients (mean age 32 years; 7 female) who received adalimumab were identified from a prospectively maintained database of over 2700 IBD patients. The primary study endpoint was treatment failure defined as discontinuation of adalimumab due to lack of efficacy, as defined by requiring an alternative maintenance therapy or colectomy, or intolerance. Colectomy rate was recorded as a secondary endpoint.

Results: Most patients (96%) had received immunosuppressants prior to adalimumab therapy (infliximab 20/23 87%). Sixteen of 23 patients (70%) discontinued adalimumab. Six primary failures, 8 secondary loss of response, one had unacceptable side effects and one discontinued treatment after 6 months but remains in remission. Overall estimated cumulative treatment failure rates at 6, 12 and 24 months were 50%, 65% and 72% respectively. Median follow-up in patients continuing adalimumab is 23 months (IQR 17–31 months). Treatment failure was unrelated to patient age, gender, disease extent, smoking status or CRP. Colectomy free survival was 59% at 2 years. No patient experienced a major adverse event.

Conclusion: Adalimumab shows some efficacy as a maintenance strategy in Ulcerative Colitis, but only a limited proportion of patients remain well on continued treatment at 2 years.

1 Introduction

Inflammatory Bowel Diseases are chronic inflammatory disorders of the gastrointestinal tract, which comprise two main disease types, Crohn’s Disease and ulcerative colitis. While these are distinct disease entities, their pathogenesis and treatment show considerable overlap.1,2 Tumour necrosis factor (TNF-alpha) is an important pro-inflammatory cytokine involved in the pathogenesis of both disorders and has emerged as an important therapeutic target.3 Infliximab, a chimeric antibody to TNF-alpha, has demonstrated efficacy in the treatment of ulcerative colitis.4 Adalimumab is a recombinant human IgG1 monoclonal antibody to TNF-alpha that is licensed for use in Crohn’s disease.5 Given the efficacy of infliximab for ulcerative colitis, there has been considerable interest in whether a subcutaneously delivered anti-TNF agent could be employed for maintenance therapy. A randomised controlled trial assessing the efficacy of adalimumab in ulcerative colitis has been completed and preliminary reports suggest adalimumab is effective for induction of remission in this disease.6 Although adalimumab has been used on an unlicensed basis as a treatment for ulcerative colitis, there are limited data on its long-term effectiveness as part of a maintenance strategy. We report a single centre experience of adalimumab in ulcerative colitis with a focus on the ability of this agent to maintain long-term clinical response and avoid colectomy in clinical practice.

2 Materials and methods

Thirty-nine patients with biopsy proven ulcerative colitis who received adalimumab were identified from a prospectively maintained database of over 2734 IBD patients. Sixteen patients were excluded as they were receiving adalimumab for an indication other than active ulcerative colitis (Pyoderma gangrenosum post colectomy (n = 4), Ankylosing Spondylitis with long-standing quiescent colitis (n = 2), Ankylosing Spondylitis post colectomy (n = 2), Subsequent diagnosis of Crohn’s Disease (n = 7), Insufficient data (n = 1)). Patients with indeterminate colitis were excluded.

Twenty-three patients who received adalimumab for treatment of ulcerative colitis were included in the final analysis. Patient data were retrieved from a prospectively maintained IBD Database. In addition, all histopathology records, electronic laboratory, radiological and endoscopic databases were retrieved and were cross checked against both the patients’ clinical notes and database to ensure accuracy. All patients received a standard induction protocol of 160 mg, 80 mg and 40 mg at weeks 0, 2 and 4 respectively. Patients were maintained on 40 mg every other week and dose escalation to 40 mg every week was used if deemed necessary, by the treating consultant gastroenterologist, to achieve clinical response, in a patient inadequately controlled on 40 mg every other week. The primary endpoint analysed was treatment failure defined as discontinuation of adalimumab due to i) intolerance, ii) requirement for additional therapies including systemic corticosteroids or an alternative maintenance therapy or iii) listing for colectomy. Secondary endpoints included median time to colectomy and colectomy-free survival. Data were recorded in Microsoft Excel and analysed using SPSS version 18.

3 Results

Patient characteristics are shown in Table 1. Median age at starting adalimumab was 35.4 years, with a median of 4.3 years from date of diagnosis to adalimumab treatment. Most patients had a pancolitis (74%) while the remainder (26%) had left sided disease. There were 17 (71%) non-smokers. Twenty-two patients (96%) had received prior immunomodulatory therapy. Most patients had received more than one immunosuppressive agent (mean 2.4; range 0–4) including azathioprine (n = 20), mercaptopurine (n = 6), ciclosporin (n = 6), and mycophenolate mofetil (n = 5). In addition, 20 patients (86%) had previously been treated with infliximab. Three of these patients were infliximab primary non-responders, 11 had secondary loss of response to infliximab and a further 6 discontinued infliximab due to side-effects.

The median follow up for all patients was 22 months, IQR 8–32 months. Overall estimated cumulative treatment failure rates (Fig. 1) at 6, 12 and 24 months respectively were 50%, 65% and 72%. Sixteen patients discontinued ADA during follow up of which 15/23 (65%) were classified as treatment failures. The indication for discontinuing adalimumab treatment was primary non-response in 6 patients (37%), secondary non-response in 8 patients (50%) and side-effects in 1 patient (6%). 1 patient stopped adalimumab at 6 months when well and remains in steroid free remission at 28 months follow-up. The patient who discontinued adalimumab secondary to side effects reported feeling systemically unwell and developed a rash and had also experienced a poor response to treatment. Two other patients experienced mild side effects that did not necessitate cessation of therapy. One had transient neurological symptoms, queried mononeuritis multiplex, which resolved spontaneously and the patient continued on adalimumab. The other had a mild injection site reaction. All three patients who were primary infliximab failures also failed to respond to adalimumab. Treatment failure was unrelated to patient age, gender, disease extent, smoking status, C Reactive Protein (CRP) or prior immunosuppressant exposure.

Eight of 23 patients (35%) were deemed not to have failed adalimumab therapy after a median follow up of 23 months, of which seven continue treatment. Dose escalation was required in two of the seven. Endoscopic data available in 4 of the 8 responders confirms both clinical and endoscopic response. Colectomy free survival (Fig. 2) was 78% at 6 months, 70% at 12 months and 59% at 2 years. Nine of 15 patients (60%) who failed treatment required a colectomy with a median time to colectomy of 5 months from commencing adalimumab. Three of 15 patients (20%) were referred for surgery for active disease but refuse surgery. One patient improved while on chemotherapy for breast cancer and 1 patient is maintained on low dose oral steroid and azathioprine. A further patient was lost to follow-up (1 month) after failing adalimumab treatment.

4 Discussion

Inhibition of TNF-alpha with infliximab has been shown to be effective for both induction and maintenance of remission in ulcerative colitis.4,7 There has also been considerable interest in the use of a subcutaneous TNF-alpha antagonist in this condition. The results of a recently published randomised controlled trial by Reinisch et al.6 show that adalimumab is superior to placebo for induction of remission in ulcerative colitis, with clinical response rates of 55% at 8 weeks. Smaller observational studies have also suggested that adalimumab may be an effective maintenance strategy (clinical response rates of 60% at 12 weeks in Taxonera et al.,8 50% at 24 weeks in Afif et al.9 and 60% at 24 weeks in Oussalah et al.10 Indeed, our data are remarkably similar to the Spanish data8 with regard to immunosuppressant exposure, extent of colitis and response rates at 12 weeks. Our data are also similar to the existing data up to 52 weeks from Sandborn et al.’s RCT11 who report a response rate of 30.2% at 52 weeks. Gies et al. reported a 56% 1 year maintenance response for a cohort of 25 patients treated with adalimumab,12 which is higher than our corresponding figure, but of note in the Gies population all patients were infliximab naive, thus significantly different from our patient cohort. However, overall, our 23 month follow-up has allowed us to identify a progressive increase in treatment failure over time, with an estimated cumulative treatment failure rate of 72% at 24 months.

The observation of a positive trend in terms of initial response reflects the patient population in which adalimumab has been employed. None of our patients had acute severe colitis; all were at least partially steroid responsive and most could probably be best characterised as steroid dependent, having failed conventional steroid sparing strategies with immunomodulators or infliximab. The gap between the rates of cumulative treatment failure and colectomy is also probably explained by the fact that many patients resumed corticosteroid therapy in order to further temporise a definitive surgical solution. The success of the use of adalimumab as a definitive steroid sparing maintenance strategy therefore requires long term follow up and our data adds to current knowledge about the real world clinical effectiveness of this strategy. With regard to prior infliximab use, our data replicate previous observations8 that primary non-response to infliximab is associated with failure to respond to adalimumab. Two of three infliximab naive patients demonstrated sustained clinical response and remain steroid free on adalimumab. Data from Sandborn’s RCT11 suggests that patients previously exposed to an anti-tnf agent do not do as well on adalimumab as those who are anti-tnf naïve, but the study was underpowered to detect a statistically significant difference and they did not include primary infliximab nonresponders. Our numbers show a trend but are too small to detect a statistically significant difference between either infliximab primary non-responders versus secondary failures or infliximab naive patients versus prior infliximab use.

Our observed colectomy free survival was 78% at 6 months, which is comparable to Spanish data.8 As with the treatment failure data, there is a continued decline in colectomy free survival after this point to 59% at two years. Colectomy free survival is also falsely elevated as two patients who have ongoing active disease have declined surgery. Successful treatment at three months has previously been shown to be associated with a lower incidence of colectomy.8 Five of 9 patients (55%) who failed adalimumab within 3 months underwent colectomy, compared to a colectomy rate of 28% in the remainder. This difference was not statistically significant, and probably reflects disease severity. We did not identify this or any other factors that were significantly associated with either colectomy free survival or treatment failure.

Our study has significant limitations, including its retrospective design and small patient numbers. While data on outcomes such as surgery and changes to maintenance therapy were captured prospectively in our database, we lack universal documentation of disease activity scores such as mayo index and endoscopic data in order to comment on remission. However, our data do provide information on the effectiveness of adalimumab in day-to-day clinical practice that cannot be extrapolated from tightly structured controlled trials. Thus, when examining a maintenance strategy, outcomes such as treatment failure and colectomy serve well as useful ‘hard’ endpoints. While the results with adalimumab maintenance are disappointing, we also recognise that our patient cohort represents a relatively treatment refractory population with a median disease duration of greater than four years. Patient selection is important and it is possible that the use of adalimumab earlier in the course of disease, avoiding its use in patients with known history of primary non-response to other anti-TNF therapies and administration in combination with an immunomodulator13 might all improve longer term outcomes.

The economic implications of using multiple biologic agents in ulcerative colitis are significant,14 with potential opportunity costs for these and other patients. In most of our patient cohort, colectomy was merely postponed rather than avoided. Surgery is a definitive steroid sparing treatment strategy for these patients and represents the closest thing to a cure that we can offer at present. With an estimated treatment failure rate of 72% at 2 years adalimumab demonstrates limited long-term efficacy as a maintenance strategy. However, a sustained treatment response was observed in a minority of patients and if these individuals could be identified in advance, its use in this targeted group might offer a durable solution. Future prospective studies might reasonably focus on identifying patient factors and biomarkers that predict long-lasting treatment response in order to minimise risks of toxicity, cost and treatment futility.

Conflict of interest

There is no conflict of interest for any of the authors.

Acknowledgements

Author’s contribution: SM, HM and GD designed the study. EMD, DK and DOD contributed to data collection. HM performed the statistical analysis. EMD wrote the manuscript. GD and HM revised critically the manuscript. All authors have read and approved the final version of the manuscript.

1 Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis Gastroenterology 115 1 1998 Jul 182 205 2 Khor B. Gardet A. Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease Nature 474 7351 2011 Jun 16 307 317 3 Bosani M. Ardizzone S. Porro G.B. Biologic targeting in the treatment of inflammatory bowel diseases Biologics Targets Ther 3 2009 77 97 4 Rutgeerts P. Sandborn W.J. Feagan B.G. Reinisch W. Olson A. Johanns J. et al. Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 353 23 2005 Dec 8 2462 2476 5 Sandborn W.J. Hanauer S.B. Rutgeerts P. Fedorak R.N. Lukas M. MacIntosh D.G. et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial CLASSIC-I study the efficacy of adalimumab Gut 56 9 2007 1232 1239 Sep May 6 Reinisch W. Sandborn W.J. Hommes D.W. D’Haens G. Hanauer S. Schreiber S. et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial Gut 60 6 2011 Jun 780 787 7 Wilhelm S.M. McKenney K.A. Rivait K.N. Kale-Pradhan P.B. A review of infliximab use in ulcerative colitis Clin Ther 30 2 2008 Feb 223 230 8 Taxonera C. Estelles J. Fernandez-Blanco I. Merino O. Marin-Jimenez I. Barreiro-de Acosta M. et al. Adalimumab induction and maintenance therapy for patients with ulcerative colitis previously treated with infliximab Aliment Pharmacol Ther 33 3 2011 Feb 340 348 9 Afif W. Leighton J.A. Hanauer S.B. Loftus E.V.Jr. Faubion W.A. Pardi D.S. et al. Open-label study of adalimumab in patients with ulcerative colitis including those with prior loss of response or intolerance to infliximab Inflamm Bowel Dis 15 9 2009 Sep 1302 1307 10 Oussalah A. Laclotte C. Chevaux J.B. Bensenane M. Babouri A. Serre A.A. et al. Long-term outcome of adalimumab therapy for ulcerative colitis with intolerance or lost response to infliximab: a single-centre experience Aliment Pharmacol Ther 28 8 2008 Oct 15 966 972 11 Sandborn W.J. van Assche G. Reinisch W. Colombel J.Ä. D’Haens G. Wolf D.C. et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 142 2 2012 Feb 257 265.e1-3 12 Gies N. Kroeker K.I. Wong K. Fedorak R.N. Treatment of ulcerative colitis with adalimumab or infliximab: long-term follow-up of a single-centre cohort Aliment Pharmacol Ther 32 4 2010 Aug 522 528 13 Panccione R. Ghosh S. Middleton S. Marquez J. Khalif I. Flint L. et al. Infliximab, Azathioprine, or Infliximab plus Azathioprine for Treatment of Moderate to Severe Ulcerative Colitis: The UC Success Trial . 2011 May Gastroenterology 140 5 2011 S134-S 14 Xie F. Blackhouse G. Assasi N. Gaebel K. Robertson D. Goeree R. Cost-utility analysis of infliximab and adalimumab for refractory ulcerative colitis Cost Effectiveness and Resource Allocation: C/E 7 2009 20 Figure 1

Proportion of UC patients continuing Adalimumab therapy without treatment failure.

Figure 1

Proportion of UC patients continuing Adalimumab therapy without treatment failure.

Figure 2

Colectomy free survival for all UC patients treated with Adalimumab.

Figure 2

Colectomy free survival for all UC patients treated with Adalimumab.

Table 1

Clinical features of 23 patients receiving Adalimumab (ada) for UC.

Variable Number
Age receiving ada (median ) 35.4 years
Time from diagnosis to ada Rx 4.3 years
Gender: male 16 (70%)
Female 7
Disease extent: pancolitis 16
Left sided 7
Non-smokers 17
Smokers 6
Prior immunosuppression 22 (96%)
Infliximab 20
Thiopurine 21
Variable Number
Age receiving ada (median ) 35.4 years
Time from diagnosis to ada Rx 4.3 years
Gender: male 16 (70%)
Female 7
Disease extent: pancolitis 16
Left sided 7
Non-smokers 17
Smokers 6
Prior immunosuppression 22 (96%)
Infliximab 20
Thiopurine 21

Table 1

Clinical features of 23 patients receiving Adalimumab (ada) for UC.

Variable Number
Age receiving ada (median ) 35.4 years
Time from diagnosis to ada Rx 4.3 years
Gender: male 16 (70%)
Female 7
Disease extent: pancolitis 16
Left sided 7
Non-smokers 17
Smokers 6
Prior immunosuppression 22 (96%)
Infliximab 20
Thiopurine 21
Variable Number
Age receiving ada (median ) 35.4 years
Time from diagnosis to ada Rx 4.3 years
Gender: male 16 (70%)
Female 7
Disease extent: pancolitis 16
Left sided 7
Non-smokers 17
Smokers 6
Prior immunosuppression 22 (96%)
Infliximab 20
Thiopurine 21

© 2012 European Crohn’s and Colitis Organisation

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced results from the Phase 3b head-to-head VARSITY study which demonstrated that the gut-selective biologic vedolizumab (Entyvio®) was superior to the anti-tumor necrosis factor-alpha (anti-TNFα) biologic adalimumab (Humira®) in achieving clinical remission* in patients with moderately to severely active ulcerative colitis at week 52. Data showed that 31.3% (n=120/383) of patients receiving vedolizumab intravenous (IV) achieved the primary endpoint of clinical remission compared to 22.5% (n=87/386) of patients treated with adalimumab subcutaneous (SC) at week 52, with the difference being statistically significant (p=0.0061). These results were announced as an oral presentation (OP34) on Saturday March 9, 2019 from 09:40-09:50, at the 14th Congress of the European Crohn’s and Colitis Organisation (ECCO) in Copenhagen, Denmark.1

Furthermore, treatment with vedolizumab was associated with significantly higher rates of mucosal healing** at week 52, with 39.7% of patients receiving vedolizumab achieving mucosal healing compared to 27.7% treated with adalimumab (p=0.0005). A non-statistically significant difference in favor of adalimumab was seen in the percentage of patients using oral corticosteroids at baseline who discontinued corticosteroids and were in clinical remission*** at week 52. While the study was not powered to compare the safety of the two biologics, patients treated with vedolizumab (62.7%) had a lower rate of overall adverse events over 52 weeks than patients treated with adalimumab (69.2%), with a lower rate of infections reported in patients treated with vedolizumab (33.5%) as compared to adalimumab (43.5%). The rate of serious adverse events was also lower in vedolizumab-treated patients than adalimumab (11.0% vs. 13.7% respectively).1

“The VARSITY study addresses critical questions concerning the selection of biologic therapy in ulcerative colitis,” said Dr. Bruce E. Sands, primary investigator of the VARSITY study and Chief of the Dr. Henry D. Janowitz Division of Gastroenterology at Mount Sinai Hospital and the Icahn School of Medicine at Mount Sinai in New York. “The goal of treatment in ulcerative colitis is to achieve clinical remission and mucosal healing, and these results clearly highlight the benefits seen with vedolizumab versus adalimumab on these important outcomes. The results also showed lower rates of overall and serious adverse events including infections in patients treated with vedolizumab than adalimumab.”

“As the first clinical study to directly compare the efficacy and safety of two commonly used biologic therapies in patients with ulcerative colitis, VARSITY provides invaluable knowledge to help inform physicians’ treatment decisions when initiating biologic therapy,” said Jeff Bornstein, M.D., Executive Medical Director, Takeda. “This is also the first time we have seen a direct comparison between two medicines with distinct modes of action in ulcerative colitis, the gut-selective anti-alpha4beta7 integrin vedolizumab and the anti-TNFα adalimumab. This is an exciting time in the landscape of ulcerative colitis treatment, as head-to-head clinical data has not previously been available to guide treatment decisions around biologic therapies.”

VARSITY is a phase 3b, randomized, double-blind, double-dummy, multi-center, active-controlled study to evaluate the efficacy and safety of vedolizumab IV compared to adalimumab SC at week 52 in patients with moderately to severely active ulcerative colitis. The study randomized 769 patients (vedolizumab n=383 or adalimumab n=386), all of whom had inadequate response with, loss of response to, or intolerance to corticosteroids, immunomodulators, or one TNFα-antagonist other than adalimumab prior to being enrolled. Patients were randomized into one of two treatment groups, vedolizumab IV and placebo SC or adalimumab SC and placebo IV. Patients in the vedolizumab group were administered vedolizumab IV 300 mg at weeks 0, 2, 6 and every 8 weeks thereafter until week 46, along with placebo SC at week 0 and every 2 weeks until week 50. The adalimumab group were administered adalimumab SC 160 mg at week 0, 80 mg at week 2 and 40 mg every 2 weeks until week 50, along with placebo IV at weeks 0, 2, 6 and every 8 weeks thereafter until week 46. Dose escalation was not permitted in either treatment arm during the study.1,2

* Primary endpoint: Clinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore ˃1 point.

** Secondary endpoint: Mucosal healing is defined as Mayo endoscopic subscore of ≤1 point. Mayo score: instrument designed to measure disease activity of ulcerative colitis.

*** Secondary endpoint: Corticosteroid-free clinical remission is defined as patients using oral corticosteroids at baseline (week 0) who have discontinued oral corticosteroids and are in clinical remission at week 52.

About Ulcerative Colitis

Ulcerative colitis (UC) is one of the most common forms of inflammatory bowel disease (IBD).3 UC is a chronic, relapsing, remitting, inflammatory condition of the gastrointestinal tract that is often progressive in nature, and involves the innermost lining of the large intestine.4,5 UC commonly presents with symptoms of abdominal discomfort and loose bowel movements, including blood or pus.5,6 The cause of UC is not fully understood; however, recent research suggests hereditary, genetics, environmental factors, and/or an abnormal immune response to microbial antigens in genetically predisposed individuals can lead to the condition.5,7,8

About Entyvio® (vedolizumab)

Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation.9 It is a humanized monoclonal antibody designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but not vascular cell adhesion molecule 1 (VCAM-1).10 MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.11 The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.10 These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD).10,12,13 By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.10

Vedolizumab IV is approved for the treatment of adult patients with moderately to severely active UC and CD, who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNFα) antagonist.9 Vedolizumab IV has been granted marketing authorization in over 60 countries, including the United States and European Union, with more than 260,000 patient years of exposure to date.14

Therapeutic Indications

Ulcerative colitis

Vedolizumab is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNFα) antagonist.

Crohn’s disease

Vedolizumab is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNFα) antagonist.

Important Safety Information

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Special warnings and special precautions for use

Vedolizumab should be administered by a healthcare professional prepared to manage hypersensitivity reactions, including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use when administering vedolizumab. Observe patients during infusion and until the infusion is complete.

Infusion-related reactions

In clinical studies, infusion-related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity. If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of vedolizumab must be discontinued immediately and appropriate treatment initiated (e.g., epinephrine and antihistamines). If a mild to moderate IRR occurs, the infusion rate can be slowed or interrupted and appropriate treatment initiated (e.g., epinephrine and antihistamines). Once the mild or moderate IRR subsides, continue the infusion. Physicians should consider pre-treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) prior to the next infusion for patients with a history of mild to moderate IRR to vedolizumab, in order to minimize their risks.

Infections

Vedolizumab is a gut-selective integrin antagonist with no identified systemic immunosuppressive activity. Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier. Vedolizumab treatment is not to be initiated in patients with active, severe infections such as tuberculosis, sepsis, cytomegalovirus, listeriosis, and opportunistic infections until the infections are controlled, and physicians should consider withholding treatment in patients who develop a severe infection while on chronic treatment with vedolizumab. Caution should be exercised when considering the use of vedolizumab in patients with a controlled chronic severe infection or a history of recurring severe infections. Patients should be monitored closely for infections before, during and after treatment. Before starting treatment with vedolizumab, screening for tuberculosis may be considered according to local practice. Some integrin antagonists and some systemic immunosuppressive agents have been associated with progressive multifocal leukoencephalopathy (PML), which is a rare and often fatal opportunistic infection caused by the John Cunningham (JC) virus. By binding to the α4β7 integrin expressed on gut-homing lymphocytes, vedolizumab exerts an immunosuppressive effect specific to the gut. Although no systemic immunosuppressive effect was noted in healthy subjects, the effects on systemic immune system function in patients with inflammatory bowel disease are not known. Healthcare professionals should monitor patients on vedolizumab for any new onset or worsening of neurological signs and symptoms, and consider neurological referral if they occur. If PML is suspected, treatment with vedolizumab must be withheld; if confirmed, treatment must be permanently discontinued. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months.

Malignancies

The risk of malignancy is increased in patients with ulcerative colitis and Crohn’s disease. Immunomodulatory medicinal products may increase the risk of malignancy.

Prior and concurrent use of biological products

No vedolizumab clinical trial data are available for patients previously treated with natalizumab. No clinical trial data for concomitant use of vedolizumab with biologic immunosuppressants are available. Therefore, the use of vedolizumab in such patients is not recommended.

Vaccinations

Prior to initiating treatment with vedolizumab all patients should be brought up to date with all recommended immunizations. Patients receiving vedolizumab may receive non-live vaccines (e.g., subunit or inactivated vaccines) and may receive live vaccines only if the benefits outweigh the risks.

Adverse reactions include: nasopharyngitis, headache, arthralgia, upper respiratory tract infection, bronchitis, influenza, sinusitis, cough, oropharyngeal pain, nausea, rash, pruritus, back pain, pain in extremities, pyrexia, fatigue and anaphylaxis.

Please consult with your local regulatory agency for approved labeling in your country.

For U.S. audiences, please see the full Prescribing Information including Medication Guide for ENTYVIO®.
For EU audiences, please see the Summary of Product Characteristics (SmPC) for ENTYVIO®.

Takeda’s Commitment to Gastroenterology

Gastrointestinal (GI) diseases can be complex, debilitating and life-changing. Recognizing this unmet need, Takeda and our collaboration partners have focused on improving the lives of patients through the delivery of innovative medicines and dedicated patient disease support programs for over 25 years. Takeda aspires to advance how patients manage their disease. Additionally, Takeda is leading in areas of gastroenterology associated with high unmet need, such as inflammatory bowel disease, acid-related diseases and motility disorders. Our GI Research & Development team is also exploring solutions in celiac disease and liver diseases, as well as scientific advancements through microbiome therapies.

About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience, and Rare Diseases. We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions.

For more information, visit https://www.takeda.com

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1 Schreiber S, Peyrin-Biroulet L, Loftus EV Jr, et al. VARSITY: A double-blind, double-dummy, randomised, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis. Presented at the 14th Congress of the Crohn’s and Colitis Organisation (ECCO), Copenhagen, Denmark. Oral presentation #OP34 (Saturday March 9, 2019, 09:40-09:50).

2 An efficacy and safety study of vedolizumab intravenous (IV) compared to adalimumab subcutaneous (SC) in participants with ulcerative colitis. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02497469. Last updated: February 28, 2019. Last Accessed: February 2019.

3 Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.

4 Torres J, Billioud V, Sachar DB, et al. Ulcerative colitis as a progressive disease: the forgotten evidence. Inflamm Bowel Dis. 2012;18:1356-1363.

5 Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380:1606-1619.

6 Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126:1518-1532.

7 Henckaerts L, Pierik M, Joossens M, et al. Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease. Gut. 2007;56:1536-1542.

8 Kaser A, Zeissig S, Blumberg RS. Genes and environment: How will our concepts on the pathophysiology of IBD develop in the future? Dig Dis. 2010;28:395-405.

10 Soler D, Chapman T, Yang LL, et al. The binding specificity and selective antagonism of vedolizumab, an anti-α4β7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330:864-875.

11 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;151:97‑110.

12 Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298‑1312.

13 Wyant T, Fedyk E, Abhyankar B. An overview of the mechanism of action of the monoclonal antibody vedolizumab. J Crohns Colitis. 2016;10:1437-1444.

14 Takeda Data on File. 2019.

My Experience with Humira

During a colonoscopy, samples will also be taken. Mine didn’t present with the chronic inflammation results gastroenterologist look for when diagnosing Crohn’s.

  • Computerized tomography (CT).

I’ve had so many of these damnable things, I can’t even remember them all. CT scans are not sensitive enough to pick up minute inflammation. In the beginning, all my CT scans showed were swollen small bowels. I was asked many times if I had been struck in the abdominal area because my colonoscopy results didn’t have the classic signs my doctors were looking for. Around March, 2018, after I’d been formally diagnosed with Crohn’s (I’ll get to how shortly), I went back to the hospital with rapidly worsening symptoms only to be told that the CT scan picked up no trace signs of inflammation, and was sent home. A second colonoscopy showed that the Crohn’s was, in fact, spreading up my duodenum, which the CT scan failed to detect.

  • Magnetic resonance imaging (MRI).

This isn’t a bad method, because it’s more sensitive than a traditional CT scan. However, it just showed more of the same; inflammation with no scarring, abscesses, strictures, or fistulas. They didn’t know why, and I was sent home. Again.

  • Capsule Endoscopy.

More of the same, here. This is great for scanning parts of your bowels not reachable by traditional endoscopy or colonoscopy methods, but it’s just as useless if you lack chronic symptoms and scarring.

So, what will work for a prospective patient who has all the symptoms of Crohn’s but lacks its hallmark scarring and fistulae formation?

  • Anti-Saccharomyces cerevisiae Antibodies (ASCA) blood test.

After three colonoscopies, countless CT scans, two MRIs and one capsule endoscopy, my then newest gastroenterologist ordered this test. Anti-Saccharomyces cerevisiae antibodies (ASCA) are a specific and sensitive diagnostic marker for the Crohn’s disease phenotype. To understand how this test works, you need to know how Crohn’s works.

Everybody produces a protein cell called Tumor Necrosis Factor Alpha (TNFα). It aids in inducing fevers, inflammation, and the inhibition of viral replication, to name a few. To put it simply, it regulates your immune system’s response to illness and disease. It can also signal a protective immune response to help block certain infections.

TNFα, in healthy folks, regulates immune cells and inflammation in the body. However, if you produce too much of it, your body begins to suffer systemic inflammation—e.g., Crohn’s Disease, and a number of other inflammatory conditions inflicted by an overactive immune system. Excess amounts of TNFα cause your immune system to mistakenly attack healthy cells in the GI tract, leading to the systemic inflammation typical to Crohn’s.

Basically, immunoglobulin (Ig)A and IgG antibodies against Saccharomyces cerevisiae (ASCA) are higher among patients with Crohn’s than those without. TNFα influences the development of IgA-ASCA antibodies in people with Crohn’s Disease.

For reference, these were my ASCA antibodies test results:

Modestly elevated, but this modest elevation got me my diagnosis and treatment after hemming and hawing from professional’s for months who claimed I was simply an attention-seeking hypochondriac because I had acute aggressive symptoms.

If you have any questions about me, Crohn’s, or Humira, please feel free to ask; I am not a medical professional, but I can give you information based on my experience in hopes that it will help you.

ADDITIONAL READING

I have compiled a list of additional resources regarding this entry and its contents for researching the topics therein:

Humira (Adalimumab): if you’re curious about Humira and want to know more, visit their homepage.

Humira Cost Savings Card: a direct link to one of the most important components of your Humira care.

Support for Humira: for a sharps container, travel case, and more.

Crohn’s Colitis Foundation: the leader in research, education, and support for IBD sufferers and their families.

The Crohn’s & Colitis Foundation of America: a non-profit, volunteer-driven organization dedicated to finding a cure for those living with IBD-related chronic illness.

Crohn’s and Colitis Foundation Forum: a place to share your experiences with Crohn’s and Colitis.

Click the ❤︎ below if you enjoyed this piece and share it with your friends by posting it on your social media! All comments are held in a moderation queue and must be accepted by the administrator.

Gastroenterology / Irritable Bowel Disease

If you’re looking for general information about Crohn’s treatment or support, the following links may be helpful.

Crohn’s & Colitis Foundation of America

The Crohn’s & Colitis Foundation of America (CCFA) is a non-profit, volunteer-driven organization dedicated to finding the cures for Crohn’s Disease and ulcerative colitis.

Crohn’s Online

This web page provides individuals who have Crohn’s with education, support and treatment options. It gives Crohn’s patients access to their Crohn’s Patient Advocate Program which will provide them or their loved one with one-on-one education and free support. Crohn’s online will also help optimize time with a gastroenterologist and provide a Q&A book.

Crohn’s Forum

Crohn’s Forum is a support group and forum for people who are personally affected or who know someone who is affected by Crohn’s Disease, Ulcerative Colitis and other IBDs. The forum is a community that offers support, friendship and understanding. Crohn’s Forum also has a Twitter page where you can get instant updates and news articles about Crohn’s.

Note: These links are provided for reference and informational purposes only and do not constitute any form of endorsement by Benevere.

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