Tag Archives: Vedolizumab

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