Tag Archives: Vedolizumab

Toronto Consensus: Practice Guidelines for Nonhospitalized Ulcerative Colitis

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A group of 23 experts followed a rigorous process over a 1-year period to assess the quality of evidence and develop consensus statements regarding the medical management of ulcerative colitis (UC) in adults (Bressler B, Marshall JK et al. Gastroenterol 2015; 148: 1035-58, editorial 877-80).

The need for updated guidelines has emerged due to practice variation related in part to a wider availability of treatments and diagnostic tools. It is recognized that early institution of effective therapy is associated with the best outcomes.  In addition, due to the chronic nature of ulcerative colitis and the potential for reduced durability of biologic agents, careful decision-making can improve response.

Table 4 in the article summarizes the recommendations.  I will list a few:

1. Thiopurines:

  • “In patients with UC, we recommend against the use of thiopurine monotherapy to induce complete remission.”
  • In selected patients, “we suggest thiopurine monotherapy as an option to maintain complete corticosteroid-free remission.”

2. Anti-TNF therapy:

  • “In patients with UC who fail to respond to thiopurines or corticosteroids, we recommend anti-TNF therapy to induce complete corticosteroid-free remission.”
  • “When starting anti-TNF therapy, we recommend it be combined with a thiopurine or methotrexate rather than used as monotherapy to induce complete remission.”
  • For UC patients with suboptimal response or for those who lose response to anti-TNF therapy, “we recommend dose intensification.”  Dose optimization should be informed by therapeutic drug monitoring.

3. Vedolizumab

  • Vedolizumab is recommended with primary anti-TNF failure (rather than switching to an alternative anti-TNF), whereas either a 2nd anti-TNF or vedolizumab is recommended with secondary anti-TNF failure based on therapeutic drug monitoring.

4. Fecal microbial transplant (FMT)

  • “We recommend against FMT…outside the setting of a clinical trial.”

5. 5-ASA and Corticosteroids

  • Rectal 5-ASA is recommended at 1 g daily for mild-to-moderate ulcerative proctitis.  5-ASA enemas are recommended for mild-to-moderate left-sided ulcerative colitis.
  • In patients with moderate-to-severe UC, corticosteroids are recommended as 1st line therapy for induction of remission but not for maintaining remission.  In addition, corticosteroids are recommended as 2nd-line agents for inducing remission in those with mild-to-moderate disease who do not respond to 5-ASA products.

With all of the treatments, the authors recommend followup to assure response to therapy; this followup ranges from within 2 weeks for steroids, to 4-8 weeks with 5-ASA products, to 8-14 weeks for biologic agents.

Overall, the emphasis of this consensus statement is on maximizing the response to biologic agents.  By optimizing dosing and using combination therapy, the treatment guidelines aim to lower rates of antidrug antibody formation.  This in turn should improve results and is in agreement with data from both the SONIC study and the UC-SUCCESS study.

The editorial comments that methotrexate “may be an attractive option for young male patients;” however, “the absence of data on risk of malignancy with methotrexate in IBD may reflect lower frequency of use for this indication.”

While these guidelines will be useful, there are many unanswered questions (discussed in editorial).

  • In patients on combination therapy, what is the optimal dose of the immunomodulator?
  • When or Should the immunomodulator be withdrawn?
  • For secondary failure, should a 2nd anti-TNF be used prior to vedolizumab?
  • How should these guidelines be tailored for the pediatric population (or the elderly)?
  • What is the optimal monitoring for UC patients with regard to biomarkers and endoscopy?
  • What is the appropriate role of therapeutic drug monitoring?

Bottomline: These guidelines are likely to promote the use of more combination therapy and help define the current role of vedolizumab.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Early Look At Entyvio (Vedolizumab) in Pediatrics

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From DDW 2015 and HealioGastro: Entyvio shows promise in pediatric patients

First study, abstract 321:

Namita Singh, MD, of Cedars Sinai Medical Center in New York, … presented results of a prospective observational study in which they initiated Entyvio (vedolizumab, Takeda; 6 mg/kg, maximum 300 mg) — off label — via intravenous infusion in pediatric patients…The primary clinical outcomes was clinical remission at week 6 (PUCAI ≤ 10; PCDAI ≤ 10).

The study looked at 23 patients (15 with Crohn’s; eight with ulcerative colitis) enrolled between June 2014 and October 2014; median age of vedolizumab initiation was 14 years.

At 88%, the patients with ulcerative colitis had a higher rate of remission than those with Crohn’s who were at 40% [at week 6]. This trend sustained at week 14 and Singh said all patients with ulcerative colitis were in remission at week 14.

Week 6 and week 14 remission rates overall were 46.6% and 54.5%, respectively, and week 6 remission predicted week 14 remission (P < .05).

“Week 6 remission is associated with week 14 remission,” Singh said. “This suggests that we can determine early in therapy whether a patient will be a primary responder to therapy. If not, then perhaps we should move on to another therapy.”

“Longer duration from last anti-TNF exposure is associated with higher remission rates,” Singh said.

Second study, abstract 322:

Ronen Stein, MD, from the Perelman School of Medicine at the University of Pennsylvania, also presented data on vedolizumab therapy in patients with severe pediatric IBD…In this single center, prospective observational cohort study, the primary endpoint was a decrease in PCDAI/PUCAI from baseline to weeks 6, 14 and 22 and secondary endpoints were changes in albumin, hematocrit and CRP as well as remission at the same time points.

Patients received vedolizumab infusions (300 mg) at weeks 0, 2 and 6 for induction and maintenance through week 22.

The researchers included children aged 13 years to 21 years (n = 17) with IBD who weighed 40 kg or more and had a past failure on TNF-alpha inhibitor therapy. Of these patients, 15 had Crohn’s disease and two had unclassified IBD (IBD-U).

More than three-quarters started on systemic corticosteroids at baseline; more than one quarter were on immunomodulators. Seven patients had previous abdominal surgery and 59% of patients had failed more than one biologic therapy…

At each time point in question, this study saw improvement of PCDAI (P < .001 at week 6; P < .05 at week 14; P < .0001 at week 22).

“Starting at week 6, there was a significant decrease in PCDAI that was sustained for weeks 14 and 22.”

Five patients reached remission at week 6.

“There really is no pattern to tell us which patients will be in remission at week 6. They have pretty different characteristics,” Stein said.

Briefly noted:

Link: Case description/images of 9 year old with gastric Crohn’s

Related blog posts:

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Enthusiasm for Vedolizumab

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A recent GI & Hepatology News article quoted several leading IBD researchers stating that they consider Vedolizumab a first-line biologic therapy for ulcerative colitis.  Here’s the link:

Vedolizumab for UC

Here’s an excerpt:

Dr. Feagan presented outcome results after 80 and 104 weeks of vedolizumab treatment of 278 patients with ulcerative colitis who had completed a full year of treatment during the GEMINI 1 trial [Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab in Patients with Moderate to Severe Ulcerative Colitis] (N. Engl. J. Med. 2013;369:699-710). He reported that the percentage of patients in clinical remission grew from 66% after 52 weeks on treatment (the time of entry into the long-term phase of the study), to 77% after 80 weeks, which then dropped to 73% after 104 weeks. Patients with a clinical response increased from 78% after 52 weeks to 88% after 80 weeks, and then dropped to 83% after 104 weeks.

During weeks 53-104 on treatment the rates of adverse events, serious adverse events, serious infections, adverse events resulting in treatment discontinuation, enteric infections, and malignancies were all low and similar to the event rates seen among the patients randomized to placebo in the GEMINI 1 study.

The results suggest that with vedolizumab treatment of inflammatory bowel disease “once you achieve an effect it is long-lasting,” Dr. Rutgeerts said in an interview. But he cautioned that the long-lasting efficacy was achieved with treatment every 4 weeks. While this approach was safe, it would also be expensive in routine practice, he noted. “The safety looks good, but the cost would be very high.”

“A key concept of vedolizumab is that it builds efficacy over time,” commented Dr. Silvio Danese during a talk at the meeting. “Vedolizumab is not the fastest runner, but [treating inflammatory bowel disease] is a marathon, and the important thing is getting to the finish”

Bottomline: Head-to-head trials would be helpful to determine which biologic agent should be considered first-line.

Related blog posts:

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Podcast on Vedolizumab Efficacy for Crohn’s Disease

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According to AGA Journals blog, one may need to wait up to 10 weeks to determine whether vedolizumab is effective for Crohn’s disease. Here’s the link: Vedolizumab for Crohn’s.

Here’s an excerpt: (re: Bruce Sands’ article in the September issue of Gastroenterology)

Sands et al. report that vedolizumab, an antibody against the integrin α4β7, is no more effective than placebo in inducing clinical remission at week 6 in patients with Crohn’s disease in whom previous treatment with tumor necrosis factor antagonists had failed.

However, at week 10, a higher proportion of patients given vedolizumab were in remission (26.6%) than of those given placebo (12.1%)… Adverse events were similar between groups.

Related blog post:

Comparing Biologics for Ulcerative Colitis

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A recent study has reviewed biologic therapies for ulcerative colitis (Ann Intern Med. 2014;160(10):704-711). Here’s the abstract link: bit.ly/1o5PpRX.

Data Synthesis: ..There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo.

Limitation: Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials.

Conclusion: Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option.

Related blog posts:

 

What you might not know about anti-TNF monitoring…

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At a recent group dinner meeting, we had the opportunity to review therapeutic anti-TNF monitoring. In addition, we discussed emerging treatments for inflammatory bowel disease, like golimumab, tofacintinib and vedolizumab.

As noted in previous blog entries (see below), therapeutic anti-TNF monitoring can help adjust treatment.  Namely, if a patient loses response to therapy and has low trough levels of anti-TNF (Infliximab ❤ μg/mL, Adalimumab <8 μg/mL, or certolizumab <27.5 μg/mL) without antidrug antibodies (ADAs), then increasing the dose is likely to be effective.  However, if a patient has a therapeutic level and is not responding, changing to another agent and/or further investigation is worthwhile.

So, what information is new?

  • Only about 20% of patients who lose clinical response develop ADAs.  So, drug level, rather than ADAs, is most helpful.
  • For infliximab, adjusting dose 14 weeks into therapy to achieve a target trough level between 3-7 mcg/mL may be helpful.
  • Severe colitis patients may need higher initial doses (?as high as 20 mg/kg) due to potential for ‘antigen sink.’  This is due to notably higher clearance in the presence of low albumin, and high CRP.  Other factors that increase clearance include higher BMI and male gender.
  • About 1/2 of patients who receive higher doses due to severe disease may be able to deescalate dosage when improved. (?which half)
  • Currently, a reactive approach to checking levels is common in U.S. in part due to costs associated with checking trough levels and ADAs (as much as $2500).  That is, most commonly checking levels is undertaken in patients with suboptimal clinical response.  A proactive approach to achieve target levels may be shown to be helpful.
  • While studies have not shown higher adverse reactions with higher trough levels, there are a few clinical situations in which lower trough levels can be important.  In patients with psoriatic skin lesions and arthralgias, if trough levels are elevated, lowering the dose may be helpful.

Outstanding questions?

  • Should patients have drug levels checked when they are asymptomatic?
  • How does a practitioner account for variability among different laboratory assays?
  • What is the optimal target level for each anti-TNF agent? Is this different in Crohn disease compared with ulcerative colitis? Is the trough target level different in adults than children?
  • Is there a toxic level?
  • If a rapid test response were available, would checking drug levels be needed for hospitalized patients to assess anti-TNF rescue therapy?

Related blog links:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

Coming Soon to a Pharmacy Near You (part 2)…

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While yesterday’s post reviewed the data that indicate that vedolizumab is likely to be helpful for ulcerative colitis, only small improvements were noted for patients with Crohn’s disease (NEJM 2013; 369: 711-21, GEMINI 2 studies).

Vedolizumab, “a humanized immunoglobulin G1 monoclonal antibody to α4β7 integrin, modulates gut, but not brain, lymphocyte trafficking.”  The GEMINI 2 studies for Crohn’s disease were similar to the GEMINI 1 studies for UC.  However, even more medical centers (n=285) in more countries (n=39) and more patients (n=1115 with 967 receiving study drug) participated.

Baseline characteristics:

  • Median age: 36.1 years
  • Current Smokers: 26.7%
  • Disease location: 16.2% ileum only, 28.3% colon only, 55.4% ileum/colon
  • Median fecal calprotectin: 686 mcg/gram
  • Concomitant medications: 34.2% steroids only, 16.2% immunosuppressives only, 17% both steroids and immunosuppressives, 32.6% neither steroids or immunosuppressives
  • Median steroid dosage: 20 mg
  • Prior TNF antagonist ≥1:  61.8%
  • Prior surgery for Crohn’s disease: 41.8%
  • Prior fistulizing disease: 36.8%

Results:

  • At week 6, 14.5% of vedolizumab-treated patients and 6.8% of placebo-treated patients were in clinical remission (CDAI ≤150).
  • At week 6, 31.4% of study drug group and 25.7% of placebo group had a CDAI-100 response (≥ 100 point decrease in CDAI score).
  • Among patients with an induction response, 39% and 36.4% of vedolizumab every 8 weeks and every 4 weeks, respectively were in clinical remission at week 52, compared with 21.6% of patients assigned to placebo.
  • Vedolizumab-treated patients had increased serious adverse effects including serious infections.  Nasopharyngitis occurred more frequently.
  • Five deaths were noted during the study, four among the treatment group (Crohn’s/sepsis, intentional overdose, myocarditis, and septic shock).
  • No PML cases have been reported among the 3000 patients exposed to vedolizumab

While the response rate to vedolizumab was modest in Crohn’s disease patients, there are some factors that need to be considered in interpreting this data. Unlike in many trials (According to the study which you would never … – gutsandgrowth), this trial included patients with more disease severity.  The authors note that the effects of anti-integrin therapy could be relatively slower acting in Crohn’s disease due to the transmural nature of the disease.  An alternative explanation would be that the gut-selective targeting by vedolizumab is ineffective in most patients with Crohn’s disease due to the need for a more systemic inhibition with transmural disease.

Bottom-line: Among the small percentage of patients who have a response to vedolizumab at week 6, the rates of clinical remission at week 52 were significantly higher than those who received placebo.

Coming Soon to a Pharmacy Near You (part 1)…

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Vedolizumab!

Two articles indicate that Vedolizumab will be an important agent for treating Ulcerative Colitis (UC).  The first article, NEJM 2013; 369: 699-710, describes two integrated studies (GEMINI 1 studies) in the use of this agent for induction and then for maintenance therapy of UC.

Background: Vedolizumab is a gut-selective blocker of lymphocyte trafficking (see previous post: Vedolizumab -another new IBD treatment | gutsandgrowth).  It is similar to natalizumab which was approved in 2008 for Crohn’s disease.  In phase 3 trials, natalizumab was demonstrated a response in 48% of patients with moderate-to-severe disease, but its large-scale use has been precluded by the potential for reactivation of the John Cunningham (JC) virus and progressive multifocal leukoencephalopathy (PML).

Study design: this study was a phase 3, randomized, double-blind, placebo-controlled study conducted at 211 medical centers in 34 countries from 2008-2012.  At baseline some of the assessments included blood tests, stool for enteric pathogens, chest radiography, stool calprotectin, QuantiFERON-TB Gold assay and sigmoidoscopy.  Intravenous vedolizumab was administered at a dose of 300 mg or placebo at days 1 and 15 during induction; also patients were stratified for glucocorticosteroids, use of immunosuppressives and prior use of TNF antagonists.  In total, 746 patients received vedolizumab and 149 received placebo.

Some of the baseline patient characteristics:

  • Mean age: 40.3 yrs
  • Median prednisone dose: 20 mg
  • Average fecal calprotectin: 899 mcg/gr.
  • Site of disease: 37% pancolitis, 13% rectum/sigmoid only, 37.9% left-sided disease, 12.2% disease proximal to splenic flexure.
  • Prior anti-TNF therapy: 48.2%

Results:

  • Induction: at week 6, 47.1% of vedolizumab and 25.5% of placebo-treated patients had a clinical response
  • Maintenance: at week 52, of patients randomly assigned to continue receiving vedolizumab, 44.8% every 4 weeks, 41.8% every 8 weeks were in clinical remission compared with 15.9% receiving placebo
  • Glucocorticoid-free remission at 52 weeks in 45.2% of patients receiving vedolizumab every 4 weeks, 31.4% receiving every 8 week treatment, and 13.9% of placebo-treated patients.
  • Figure 1 details important changes in Partial Mayo score, IBDQ score, Fecal calprotectin, and prednisone dose changes.  With regard to fecal calprotectin, at week 6 the median calprotectin level had dropped approximately 70%.  Smaller decreases were noted in patients continuing vedolizumab at week 52.
  • Safety: “no important differences” according to the authors between vedolizumab and placebo.  Specifically, there were no cases of PML; however, routine JC virus testing was not performed in this study.  Infusion reactions were seen in three cases (two with detectable antibody). a mild increase in nasopharyngitis was noted.
  • Cancer: 1.1% of placebo-treated patients developed a malignancy (1 colon cancer, 1 transitional-cell carcinoma, 1 squamous-cell carcinomas of skin) and 0.2% of vedolizumab (1 colon cancer)
  • Drug levels: mean vedolizumab concentrations at every 4 week dosing: 38.3 mcg/mL and at every 8 week dosing: 11.2 mcg/mL
  • Antibodies: 3.7% had samples that were positive for anti-vedolizumab antibodies at any time.  1% developed persistent antibody positivity.

Bottom-line: This large study shows that vedolizumab is effective in a large number of patients with UC, many who were refractory to other treatments, including anti-TNF agents.

Related blog posts:

Running out of options

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A series of articles on natalizumab were published which give practical advice for this drug which clinicians often turn to when ‘running out of options’ (Gastroenterol Hepatol 2012; 8: 4-17).

Slides from these articles should be available soon (not online on 1/2/13):

http://www.clinicaladvances.com/index.php/our_publications/gastro_hep-issue/gh_november_2012/

According to an algorithm on page 7, in patients with moderate-severe Crohn’s disease who have failed conventional therapies and anti-TNF drugs (or unable to tolerate), the next step is to obtain anti-JCV (John Cunningham Virus) antibody status.  Patients who test negative are ‘Okay to treat with natalizumab’ due to very low risk of progressive multifocal leukoencephalopathy (PML).  Repeated testing at least once a year is then recommended.

For patients who test positive for anti-JCV at any time point, natalizumab can be considered if no other treatment options are available, but the risk of PML is much greater. Previous blog entries (below) have discussed this in greater detail and have provided additional references:

Another article published the experience in 36 Mayo clinic patients between April 2008-September 2010 (Inflamm Bowel Dis 2012; 18: 2203-08).  Consecutive patients who received natalizumab were prospectively followed.  Of the 36 treated with natalizumab, 30 agreed to participate in the study.  23 patients had failed two anti-TNF agents and 7 had failed one anti-TNF agent.  Median age was 35 years.

Results:

  • 14 (46%) had a complete clinical response, 12 had a partial response, and four had no response.  Cumulative probability of a complete response within 1 year was 56%.
  • Time to response: 10% after 1st dose, 50% of patients had complete response after 4th dose
  • Adverse events were common –though this rarely caused drug cessation. Common events included headache and infections (listed in Table 4 of article).  Some infections prompted holding natalizumab for up to 8 weeks.
  • 11 stopped natalizumab due to lack of improvement.

Vedolizumab -another new IBD treatment

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Occasionally a parent will express concern that their child may run out of effective treatments for inflammatory bowel.  At this time, there are a limited number of effective therapies. If a patient develops reactions or antibodies to medications and/or does not have a clinical response, then the options become quite limited.

Against this backdrop, it is encouraging that new medical treatments are being tested, including Vedolizumab (Inflamm Bowel Dis 2012; 18: 1470-79).

The cited study reports the experience of using Vedolizumab in a randomized controlled phase 2 dose-ranging study in 46 patients (9 placebo, 37 vedolizumab).

Vedolizumab is “a gut-selective monoclonal antibody that antagonizes α4β7 integrin on select subsets of leukocytes binding to MAdCAM-1 on gut vascular endothelium.”  Many have considered vedolizumab to be similar to natalizumab, except it is considered  gut-specific and therefore should not increase the risk of progressive multifocal leukoencephalopathy (PML).  By altering the immune surveillance/lymphocyte tracking of the GI tract and not the brain, theoretically there should not be an increased risk of PML.

Another previous limitation of vedolizumab in small studies was the development of human antihuman antibodies (HAHA) –no joke!  HAHA occurred in up to 44% of patients in previous studies and were associated with reduced efficacy.  As a consequence, a new formulation of vedolizumab has been developed with presumably reduced  immunogenicity.

In the cited study, patients between 18-70 were recruited to receive one to three doses of vedolizumab (2, 6, or 10 mg/kg) or placebo.

Results:

  • Over 50% of vedolizumab-treated patients maintained a clinical response between days 29-253 whereas placebo response ranged between 22-33%.
  • This study was not powered for efficacy; however, the treated patients did have reduced fecal calprotectin.  At baseline, the calprotectin in the treatment groups averaged 405 μg/g and by day 113 had reduced to 54 μg/g.  In contrast, placebo group started with calprotectin of 310 μg/g and dropped to 192 μg/g during same time period.
  • HAHA were detected in 4 (11%)

According to a presentation at DDW (GEMINI I trial), more than 2500 patients have been treated in trials with vedolizumab.  None has developed PML. Encouraging results for efficacy (dosing 300mg IV q4weeks) were also noted; 1 year clinical remission noted in 45% of treated patients compared with 14% of placebo group. Digestive Disease Week 2012 – Vedolizumab Scores on Safety …)

Results of vedolizumab for Crohn’s disease are expected soon as well.

Related blog entries:

Quantifying Risk of PML with Natalizumab

Tofacitinib –a JAK Inhibitor for UC