CAM 104

Vedolizumab (Entyvio™)

Category:Prescription Drug   Last Reviewed:April 2019
Department(s):Medical Affairs   Next Review:April 2020
Original Date:April 2015    

Description
Entyvio, an integrin receptor antagonist, is a humanized monoclonal antibody that binds specifically to α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thus inhibiting migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal (GI) parenchymal tissue. It is indicated in ulcerative colitis (UC), for inducing and maintaining clinical response, inducing and maintaining clinical remission, improving the endoscopic appearance of the mucosa and achieving corticosteroid-free remission in adult patients who have had an inadequate response to, lost response to or were intolerant to, a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response to, were intolerant to or demonstrated dependence on corticosteroids. Entyvio is also indicated in Crohn’s disease (CD), for achieving a clinical response, achieving clinical remission and achieving corticosteroid-free remission in adult patients with moderately to severely active CD who have had an inadequate response to, lost response to or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response to, were intolerant to or demonstrated dependence on steroids. 

Policy 
Coverage of Vedolizumab (Entyvio) is provided when the FDA-approved indications below are met and there has been a trial and failure of preferred therapy.

Vedolizumab is considered MEDICAL NECESSARY when criteria are met for either of the following indications:

  1. Crohn's Disease (CD) when each of the following criteria is met:
    1. Individual is 18 years of age or older with moderately to severely active CD; AND
    2. Individual has failed to respond to, lost response to, is intolerant of or has a medical contraindication to a tumor necrosis factor (TNF) antagonist drug or conventional therapy, such as aminosalicylates/5-ASA products (for example, mesalamine, sulfasalazine), an immunomodulator (such as azathioprine, 6-mercaptopurine [6-MP] or an immunosuppressive drug), or has demonstrated dependence on systemic corticosteroids; AND
    3. Vedolizumab is used for one of the following:
      1. To reduce signs or symptoms; OR
      2. To induce or maintain clinical response or remission.
  2. Ulcerative Colitis (UC) when each of the following criteria is met:
    1. Individual is 18 years of age or older with moderately to severely active UC; AND
    2. Individual who has failed to respond to, lost response to, is intolerant of or has a medical contraindication to a TNF antagonist drug or conventional therapy, such as aminosalicylates/5-ASA products (for example, mesalamine, sulfasalazine), an immunomodulator (such as azathioprine, 6-MP or an immunosuppressive drug) or has demonstrated dependence on systemic corticosteroids; AND
    3. Vedolizumab is used for one of the following:
      1. To reduce signs or symptoms; OR
      2. To induce or maintain clinical remission or response and mucosal healing.

Vedolizumab is considered NOT MEDICALLY NECESSARY for an individual with any of the following:

  1. In combination with a TNF antagonist; or
  2. In combination with a non-TNF antagonist immunomodulatory drug, such as natalizumab (Tysabri®, Biogen Idec Inc., Cambridge, MA; Elan Pharmaceuticals, Inc., San Diego, CA); or
  3. Tuberculosis or active, serious infection or a history of recurrent infections; or
  4. Individual has not had a tuberculin skin test (TST) or Centers for Disease Control (CDC)-recommended equivalent to evaluate for latent tuberculosis prior to initiating vedolizumab; or
  5. New or worsening neurological signs or symptoms of John Cunningham virus (JCV) infection or risk of progressive multifocal leukoencephalopathy (PML).

Vedolizumab is considered INVESTIGATIONAL and NOT MEDICALLY NECESSARY when the medically necessary criteria are not met and for all other indications.

Benefit Application
This medical policy relates only to the services or supplies described herein. Please refer to the member's benefit booklet for availability of benefits. Member benefits may vary according to benefit design; therefore, member benefit language should be reviewed before applying the terms of this medical policy. 

Rationale 
Crohn's disease and ulcerative colitis are chronic, relapsing inflammatory bowel diseases (IBD) affecting the gastrointestinal mucosa. Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin (a cell-adhesion molecule), blocks the interaction of α4β7 integrin with mucosal addressing cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal mucosa. The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been identified as an important contributor to the chronic inflammation of Crohn's disease and ulcerative colitis (Entyvio Product Information [PI] Label, 2014). On May 20, 2014, the FDA approved vedolizumab (Entyvio, Takeda Pharmaceuticals America, Inc., Deerfield, IL) for two indications: treatment of adults with either moderately to severely active Crohn's disease or moderately to severely active ulcerative colitis who have not fully responded to treatment with steroids, immunomodulators or TNF inhibitors (antagonists).

Efficacy of Vedolizumab for Crohn's Disease
The FDA approval of vedolizumab for active Crohn's disease was confirmed in two pivotal trials, GEMINI 2 and GEMINI 3. The GEMINI 2 trial (Sandborn, 2013) is a placebo-controlled, induction-maintenance phase 3 trial in adults with active Crohn's disease for at least three months with a Crohn's Disease Activity Index (CDAI) score of 220 to 450 (that is, moderate to severe disease). GEMINI 3 (Sands, 2014) is a randomized, placebo-controlled, double-blind six-week trial of induction therapy only in individuals with moderately to severely active Crohn's disease who failed to respond to, or were intolerant to, prior therapy.

At week six in the induction phase of GEMINI 2, rates of clinical remission (primary induction end point defined as CDAI score ≤ 150) differed significantly (p=0.02) in the vedolizumab- versus placebo-treated participants (15 percent, 7 percent and 17.7 percent in the vedolizumab arm of cohort 1, placebo arm of cohort 1 and cohort 2 [all participants received vedolizumab], respectively). There were no statistical differences in CDAI-100 response (that is, ≥ 100-point decrease in CDAI score, primary induction end point) or change in C-reactive protein (CRP) levels from baseline to week six (a secondary induction end point). At week 52 in the maintenance phase of GEMINI 2, rates of clinical remission (primary maintenance end point) differed significantly in participants treated with both regimens of vedolizumab versus those treated with placebo. Rates of clinical remission were 39.0 percent versus 21.6 percent in the vedolizumab every eight weeks arm compared to the placebo arm, respectively (p<0.001); and 36.4 percent versus 21.6 percent in the vedolizumab every four weeks arm compared to the placebo arm, respectively (p=0.004). Secondary maintenance end points such as CDAI-100 response at 52 weeks and glucocorticoid-free remission (but not durable remission) met the statistical threshold of < 0.05. In the induction phase only in GEMINI 3 (Sands, 2014), the primary end point, that is, clinical remission at week six in participants with prior tumor necrosis factor antagonist agent failure, was not met: 15 percent in the vedolizumab-treated group versus 12 percent in the placebo group (p=0.433). At week 10, however, a higher proportion of the vedolizumab-treated participants were in remission (26.6 percent) than those given placebo (12.1 percent) (nominal p=0.001; relative risk [RR], 2.2; 95 percent confidence interval [CI], 1.3-3.6). A higher proportion of participants with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (≥ 100-point decrease in CDAI score from baseline) at week six than those given placebo (39.2 percent vs. 22.3 percent; nominal p=0.001; RR, 1.8; 95 percent CI, 1.2-2.5). Exploratory analyses of planned secondary end points suggested a beneficial effect of vedolizumab in clinical remission at 10 weeks. Adverse event results were similar among all groups.

Efficacy of Vedolizumab for Ulcerative Colitis
The FDA approval of vedolizumab for ulcerative colitis was confirmed in a placebo-controlled, induction-maintenance phase 3 trial of adults with active disease (Feagan, 2013). The study design of the GEMINI 1 UC trial was similar to GEMINI 2 (CD trial) in that participants were recruited from two cohorts in the induction phase, a double-blind cohort 1 phase (vedolizumab, n=225; placebo, n=149) and an open-label cohort 2 phase (n=521) of participants who received vedolizumab induction therapy. In the maintenance phase (at week six), participants with a clinical response to induction (that is, a reduction in the Mayo score of at least three points and a decrease of at least 30 percent from the baseline score, with a decrease of at least one point on the Rectal Bleeding subscale or an absolute rectal bleeding of at least one point on the Rectal Bleeding subscale or an absolute rectal bleeding score of 0 or 1) from both cohorts were re-randomized to placebo (n=126), vedolizumab 300 mg intravenous (IV) every eight weeks (n=122) or vedolizumab 300 mg IV every four weeks (n=125) for 52 weeks.

At week six, rates of clinical response (primary induction end point) in the induction phase differed significantly (p<0.001) in vedolizumab- versus placebo-treated participants; that is, 47.1 percent, 25.5 percent and 44.3 percent in the vedolizumab arm of cohort 1, placebo arm of cohort 1 and cohort 2 [all participants received vedolizumab], respectively). Both secondary induction end points (clinical remission and mucosal healing at week six) were statistically and significantly higher in vedolizumab- versus placebo-treated participants. At week 52, rates of clinical remission (primary maintenance end point) differed significantly in participants treated with both regimens of vedolizumab versus those treated with placebo. Rates of clinical remission were 41.8 percent versus 15.9 percent in the vedolizumab every eight weeks compared to the placebo arm, respectively (p<0.001); and, 44.8 percent versus 15.9 percent in the vedolizumab every four weeks compared to the placebo arm, respectively (p<0.001). At 52 weeks, durable clinical response and remission, mucosal healing and glucocorticoid-free remission met the statistical threshold (< 0.05).

Safety of Vedolizumab for Crohn's Disease and Ulcerative Colitis
In the clinical trials of vedolizumab for active Crohn's disease and active ulcerative colitis, participants were monitored for progressive multifocal leukoencephalopathy (PML). Although no cases were observed in the trials, John Cunningham virus (JCV) infection resulting in PML and death has occurred in individuals treated with another integrin receptor antagonist (that is, natalizumab). According to the PI label, a risk of PML cannot be ruled out; therefore, individuals treated with vedolizumab for Crohn's disease and ulcerative colitis should be monitored for any new or worsening neurological signs or symptoms. In the CD trials, vedolizumab was associated with a higher rate of serious adverse events (24 percent vs. 15 percent) and serious infections (5 percent vs. 3 percent) compared with placebo. Serious adverse reactions reported in the combined data set in the clinical trials were 7 percent for vedolizumab-treated participants versus 4 percent for placebo-treated participants. The most common adverse reactions to vedolizumab were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritis, sinusitis, oropharyngeal pain and pain in the extremities. 

Other Proposed Uses of Vedolizumab
To date, a search of the ClinicalTrials.gov database does not identify any ongoing clinical trials evaluating the safety and effectiveness of vedolizumab beyond the current FDA approved indications for moderately to severely active Crohn's disease and moderately to severely active ulcerative colitis.

References

  1. Bickston SJ, Behm BW, Tsoulis DJ, et al. Vedolizumab for induction and maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2014;(8):CD007571.
  2. Crohn's and Colitis Foundation of America (CCFA). The facts about inflammatory bowel diseases. Available at: http://www.ccfa.org/assets/pdfs/ibdfactbook.pdf. Accessed on August 28, 2014.
  3. Danese S, Fiorino G, Peyrin-Biroulet L, et al. Biological agents for moderately to severely active ulcerative colitis: a systematic review and network meta-analysis. Ann Intern Med. 2014; 160(10):704-711.
  4. Entyvio [Product Information], Deerfield, IL. Takeda Pharmaceuticals America, Inc; May 20, 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125476s000lbl.pdf. Accessed on August 28, 2014.
  5. Entyvio for intravenous injection (prescribing information).  Deerfield, IL:  Takeda Pharmaceuticals America, Inc.; May 2014
  6. Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol. 2008; 6(12):1370-1377. Erratum in: Clin Gastroenterol Hepatol. 2009; 7(4):494.
  7. Feagan BG, Rutgeerts P, Sands BE, et al.; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013; 369(8):699-710.
  8. Kawalec P, Mikrut A, Łopuch S. Systematic review of the effectiveness of biological therapy for active moderate to severe ulcerative colitis. J Gastroenterol Hepatol. 2014; 29(6):1159-1170.
  9. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010; 105(3):501-523. Erratum in: Am J Gastroenterol. 2010; 105(3):500.
  10. Lichtenstein GR, Hanauer SB, Sandborn WJ. Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults. Am J Gastroenterol. 2009; 104(2):465-483.
  11. National Digestive Diseases Information Clearinghouse (NDDIC). National Institute of Health (NIH). Digestive Diseases: A-Z List of Topics and Titles. Available at: http://digestive.niddk.nih.gov/ddiseases/a-z.aspx. Accessed on August 28, 2014.
  12. Parikh A, Fox I, Leach T, et al. Long-term clinical experience with vedolizumab in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013; 19(8):1691-1699.
  13. Parikh A, Leach T, Wyant T, et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel Dis. 2012; 18(8):1470-1479.
  14. Sandborn WJ, Feagan BG, Rutgeerts P, et al.; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013; 369(8):711-721.
  15. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014 May 21; 147(3):618-627.e3.

Coding Section

Codes Number Description
ICD-9 Diagnosis 555.0-555.9 Regional enteritis
  556.0-556.9 Ulcerative colitis
HCPCS C9026 Injection, vedolizumab, 1 mg
  J3590 Unclassified biologics (when specified as Vedolizumab (Entyvio))
  J3490 Unclassifed drug
  J3380  Injection, vedolizumab, 1 mg 
ICD-10 Diagnosis (effective 10/01/15) K50.00-K50.919 Crohn's disease (regional enteritis)
  K51.00-K51.919 Ulcerative colitis

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2015 Forward     

04/01/2019 

Annual review, no change to policy intent. 

06/04/2018

Interim review adding the following:  Coverage of Vedolizumab (Entyvio) is provided when the FDA-approved indications below are met and there has been a trial and failure of preferred therapy.

04/02/2018

Annual review, no change to policy intent. 

04/20/2017 

Annual review, no change to policy intent. 

04/20/2016 

Annual review, no change to policy intent. Updating coding to include J3380. 

04/09/2015

NEW POLICY


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