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 with, lost response to, or were intolerant to, a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, 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 with, lost response to, or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response with, 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
   2. One of the following: 
      1. Actively inflamed joints 
      2. Dactylitis 
      3. Enthesitis 
      4. Axial disease 
      5. Active skin and/or nail involvement
   3. The individual has had an inadequate response, intolerance or contraindication to a trial of one or more conventional therapy (such as mesalamine, sulfasalazine, azathioprine, 6-mercaptopurine, methotrexate, or has demonstrated dependence on systemic corticosteroids)
   4. The individual has had an inadequate response to a trial of one or more biologic TNF antagonist
   5. Vedolizumab is used for one of the following:
      • To reduce signs or symptoms
      • 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
   2. One of the following: 
      1. Greater than 6 stools per day 
      2. Frequent blood in the stools 
      3. Frequent urgency 
      4. Presence of ulcers 
      5. Abnormal lab values (e.g., hemoglobin, ESR, CRP) 
      6. Dependent on, or refractory to, corticosteroids 
   3. The individual has had an inadequate response, intolerance or contraindication to a trial of one or more conventional therapy (such as mesalamine, sulfasalazine, azathioprine, 6-mercaptopurine, methotrexate, or has demonstrated dependence on systemic corticosteroids)
   4. The individual has had an inadequate response to a trial of one or more biologic TNF antagonist
   5. Vedolizumab is used for one of the following:
      • To reduce signs or symptoms
      • 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
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)
3. Tuberculosis or active, serious infection or a history of recurrent infections
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
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/unproven therefore considered 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's 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 3 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 6-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 6 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%, 7%, and 17.7% 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 6 (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% versus 21.6% in the vedolizumab every 8 weeks arm compared to the placebo arm, respectively (p < 0.001); and, 36.4% versus 21.6% in the vedolizumab every 4 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 6 in participants with prior tumor necrosis factor antagonist agent failure, was not met: 15% in the vedolizumab-treated group versus 12% in the placebo group (p = 0.433). At week 10, however, a higher proportion of the vedolizumab-treated participants were in remission (26.6%) than those given placebo (12.1%) (nominal p = 0.001; relative risk [RR], 2.2; 95% 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 6 than those given placebo (39.2% vs. 22.3%; nominal p = 0.001; RR, 1.8; 95% 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 2 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 6), participants with a clinical response to induction (that is, a reduction in the Mayo score of at least 3 points and a decrease of at least 30% from the baseline score, with a decrease of at least 1 point on the Rectal Bleeding subscale or an absolute rectal bleeding of at least 1 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 8 weeks (n = 122), or vedolizumab 300 mg IV every 4 weeks (n = 125) for 52 weeks.

At week 6, 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%, 25.5%, and 44.3% 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 6) 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% versus 15.9% in the vedolizumab every 8 weeks compared to the placebo arm, respectively (p < 0.001); and, 44.8% versus 15.9% in the vedolizumab every 4 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% vs. 15%) and serious infections (5% vs. 3%) compared with placebo. Serious adverse reactions reported in the combined data set in the clinical trials were 7% for vedolizumab-treated participants versus 4% 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

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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 Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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