This document addresses the U.S. Food and Drug Administration (FDA) approved indications for vedolizumab (Entyvio, Millennium Pharmaceuticals Inc., Takeda Pharmaceuticals America, Inc.), an integrin receptor antagonist used for the treatment of moderately to severely active Crohn's disease and moderately to severely active ulcerative colitis.
Note: Please see the following documents for information concerning other drugs that may be used for the treatment of Crohn's disease and ulcerative colitis:
Note: For additional information on review of clinically equivalent cost effective criteria for products addressed in DRUG.00068, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.
Vedolizumab is considered medically necessary when criteria are met for either of the following indications:
Not Medically Necessary:
Vedolizumab is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Vedolizumab is considered investigational and not medically necessary when criteria are not met and for all other indications.
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 18 years of age or older 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 in adults 18 years of age or older 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 TNF 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 ages 18 years or older 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 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.
Colombel and colleagues (2016) evaluated the safety data from six clinical trials of vedolizumab for ulcerative colitis and Crohn's disease. Adverse events were evaluated in participants who received ≥ one dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates (that is, the number of participants experiencing the event per 100 person-years of exposure). Predictors of serious infection were assessed using a Cox proportional hazards model. A total of 2830 participants had 4811 person-years of vedolizumab exposure (median exposure range, 1-1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections (n=15), sepsis (n=11), tuberculosis (n=4), and Listeria meningitis (n=1) were reported for between 1 and 15 participants (≤ 0.6% of participants). No cases of PML were observed. Independent risk factors for serious infection in participants with ulcerative colitis were prior failure of a TNF antagonist (Hazard ratio [HR], 1.99; 95% CI 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003). In Crohn's disease participants, independent risk factors for serious infection were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001) and corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Infusion-related reactions (as defined by the investigators) were reported for ≤ 5% of participants in each study. A total of 18 vedolizumab-exposed participants (< 1%) were diagnosed with a malignancy.
Several systematic reviews and meta-analyses including only placebo-controlled trials have been conducted indirectly comparing vedolizumab with other biologic agents (Chandar, 2015; Danese, 2014; Hazelwood, 2014; Lin, 2015; Singh, 2014). To date, there are no published randomized controlled clinical trials that directly compare vedolizumab to other biologic agents for the treatment of active Crohn's disease or active ulcerative colitis.
Off-Label Use of Vedolizumab in the Pediatric Population with Crohn's Disease and Ulcerative Colitis
Conrad and colleagues (2016) performed a single-center, observational, prospective cohort study of 21 children ages 13 to 21 years with severe IBD, including Crohn's disease (n=16), ulcerative colitis (n=3), or IBD unclassified (IBD-U) (n=2), who were refractory to TNF antagonist therapy. Subjects were selected for study inclusion by the treating pediatric gastroenterologist. Nearly half of the Crohn's disease subjects had complicated disease, including 3 subjects with stricturing disease, 2 subjects with penetrating disease, and 2 subjects with both stricturing and penetrating disease. All subjects were treated with at least one TNF antagonist agent before starting vedolizumab, and 13 of 21 (62%) subjects had failed treatment with two TNF antagonist agents. Vedolizumab therapy was initiated in all subjects at an induction dose of 300 mg infusions at 0, 2, and 6 weeks followed by a maintenance phase at 8-week intervals. Concomitant medications were prescribed at the discretion of the treating pediatric gastroenterologist. Disease activity, clinical response, concomitant medication use and adverse events were measured over 22 weeks. Pediatric Crohn's Disease Activity Index (PCDAI) or Pediatric Ulcerative Colitis Activity Index (PUCAI) scores were calculated at each infusion visit based on history and physical examination performed by a physician member of the study team, and laboratory data extracted from the electronic medical record. Clinical response (combined PCDAI and PUCAI disease activity) was observed in 6 of 19 (31.6%) evaluable subjects at week 6 and in 11 of 19 (57.9%) evaluable subjects by week 22. Before induction, 15 of 21 (71.4%) subjects were treated with systemic corticosteroids compared with 7 of 21 (33.3%) subjects at 22 weeks. Steroid-free remission was obtained by 1 of 20 (5.0%) subjects at 6 weeks, 3 of 20 (15.0%) subjects at 14 weeks, and 4 of 20 (20.0%) subjects at 22 weeks. A statistically significant improvement in serum albumin and hematocrit was observed; however, CRP increased by week 22 (p<0.05). No infusion reactions were reported. There were five occurrences of upper respiratory tract infections, fatigue, nausea, vomiting, headaches, dizziness, nasopharyngitis, erythema nodosum, skin infections, new perianal disease, and sinusitis at follow-up visits. A total of 12 serious adverse events resulted in hospitalization among the subjects receiving vedolizumab during the study period. Two subjects required surgery, including 1 subject with ulcerative colitis who had persistent symptoms of severe colitis and steroid dependence and required a total colectomy shortly after the week 22 infusion. The second subject with Crohn's disease had a history of recurrent acute kidney injury due to hypovolemia with disease flares and developed obstructing nephrolithiasis with associated pyonephritis. This subject required surgical intervention, antibiotic treatment, and continued on vedolizumab, subsequently achieving remission without further renal involvement. Limitations of this study include the observational design without a comparator control group, small sample size, and the short follow-up period.
Singh and colleagues (2016) retrospectively described the clinical experience of vedolizumab in a pediatric population with IBD at three tertiary IBD centers. A total of 52 subjects younger than 18 years of age (mean age 14.9, range 7-17 years) with Crohn's disease (n=30; 58%) and ulcerative colitis (n=22; 42%) were prescribed vedolizumab at the discretion of the treating physician. On initiation of vedolizumab, 15 subjects were on concomitant immunomodulator therapy (6-MP, azathioprine, or methotrexate). A total of 47 of 52 (90%) subjects had failed at least one TNF antagonist agent (adalimumab, certolizumab pegol, or infliximab) and 23 of 52 (44%) had failed at least two TNF antagonist agents. Eleven subjects (21%), all with Crohn's disease, had IBD-related operations before initiation of vedolizumab with a median time from operation to vedolizumab initiation of 10 (range 1-31) months. All subjects received vedolizumab intravenously at 0, 2, and 6 weeks and then approximately every 8 weeks. The dose of vedolizumab was 300 mg in 39 (75%) subjects and smaller subjects were dosed by weight (6 mg/kg in 11 subjects; 5 mg/kg in 2 subjects). At the time of vedolizumab initiation, 29 of 52 (56%) subjects received a corticosteroid (prednisone or oral budesonide). By week 6, 18 of 50 (36%) subjects received a corticosteroid, and by week 14, 8 of 42 (19%) subjects received prednisone (no subject was on budesonide). The primary outcome measure was clinical remission at week 14 defined as PUCAI < 10 or weighted PCDAI < 12.5. Secondary outcomes included clinical remission rates at weeks 6, 22, and 30, CRP responsiveness, and steroid-free remission. By week 6, the median weighted PCDAI was 15 (IQR, 5.6-27.5), with 9 of 26 (35%) subjects in remission. At week 14, median weighted PCDAI was 20 (IQR, 0-35), with 10 of 24 (42%) subjects being in remission. At baseline, the median PUCAI for the 22 subjects with ulcerative colitis was 30 (IQR, 10-55) with 4 of 22 (18%) subjects in remission. By week 6, the median PUCAI was 2.5 (IQR, 0-15), with 14 of 22 (63%) subjects in remission, and week 14 median PUCAI was 0 (IQR, 0-10), with 13 of 17 (76%) subjects being in remission. At week 14, remission rates for subjects with ulcerative colitis and Crohn's disease were 76% and 42%, respectively (p< 0.05). A total of 80% of subjects who were treatment- naive to TNF antagonist therapy experienced remission at week 14. At week 22, TNF antagonist-naive subjects had higher remission rates than TNF antagonist-exposed subjects (100% vs. 45%; p=0.04). A total of 40 (77%) subjects remained on vedolizumab at the time of last follow-up (median follow-up time, 22 weeks). Three Crohn's disease subjects discontinued vedolizumab between weeks 22 and 30 due to lack of efficacy, and 4 ulcerative colitis subjects and 2 Crohn's disease subjects underwent an IBD-related operation within the first 30 weeks of treatment with vedolizumab. Four of these subjects underwent colectomy and 2 subjects underwent ileocecectomy. Two subjects who underwent operation remained on vedolizumab postoperatively and were in clinical remission at the time of last follow-up. There were no infusion reactions or serious adverse events reported at last follow-up and no cases of PML or infections. Limitations of this study include the retrospective design, small sample size, heterogeneous population, and lack of a standard set of inclusion or exclusion criteria. In addition, the authors noted that lack of standardized dosing in this pediatric population led to variation of dosing, which introduces this as a potentially confounding factor.
In summary, based on the available peer-reviewed published medical literature and views of relevant medical specialists practicing in pediatrics and pediatric gastroenterology, the use of vedolizumab to induce or maintain remission may be considered a treatment option in a subset of the pediatric population 6 years of age or older with Crohn's disease or ulcerative colitis who are refractory to treatment with conventional drug therapy or TNF antagonist agents, or in those who have failed to respond to, are intolerant of, or have demonstrated dependence on systemic corticosteroids.
Other Proposed Uses of Vedolizumab
To date, a search of the ClinicalTrials.gov database has identified early phase 2 clinical trials evaluating vedolizumab for conditions other than for the FDA approved indications, including use for graft-versus-host disease in individuals undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and in combination with other agents for advanced melanoma. Two phase 3 clinical trials are currently evaluating the efficacy, safety, and pharmacokinetics of intravenous vedolizumab in the induction and maintenance therapy of individuals 15 years of age and older with moderately or severely active Crohn's disease (NCT02038920) and moderately or severely active ulcerative colitis (NCT02039505). The estimated completion date for both studies is April 2018.
Description of the Conditions
Crohn's disease, also referred to as regional enteritis, is an IBD generally accepted as an autoimmune disease that occurs in genetically predisposed individuals; clinical presentation is primarily determined by the anatomic location of the disease. The most common presenting symptoms are fever, abdominal pain, and diarrhea with or without blood. Fistula formation, fissuring, discontinuous intestinal and transmural involvement with bowel-wall thickening and extraintestinal manifestations such as arthritis, skin and eye manifestations, metabolic deficiencies, hypercoagulation, and hepatobiliary disease are frequent complications. The clinical course of Crohn's disease is chronic and intermittent and there is no known cure. Medical therapy includes the use of 5-ASA products such as mesalamine, sulfasalazine, or olsalazine, glucocorticoids such as prednisone or budesonide, antibiotics, immunosuppressive drugs (6-MP/AZA), methotrexate and other anti-inflammatory agents.
Ulcerative colitis is a chronic disease characterized by diffuse mucosal inflammation limited to the colon, may affect any age group, although there are peaks at ages 15 to 30 and then again at ages 50 to 70. Besides the primary clinical symptom of bloody diarrhea, ulcerative colitis is often accompanied by symptoms of rectal urgency and painful, unsuccessful attempts to have a bowel movement. The clinical course is marked by intermittent worsening or slowing of disease symptoms. Medical therapy is indicated for the reduction in signs and symptoms of active ulcerative colitis. Conventional treatment options for individuals with severe corticosteroid-refractory ulcerative colitis include intravenous cyclosporine, which is frequently limited by toxicity, certain TNF antagonist agents, or in ulcerative colitis unresponsive to pharmacologic agents, surgical resection (for example, colectomy).
FDA PI Label Warnings and Precautions with Use of Vedolizumab
Vedolizumab has the following Warnings and Precautions (Entyvio PI Label, 2014):
5-Aminosalicylic acid (5-ASA) products: A class of anti-inflammatory drugs used to treat bowel inflammation, diarrhea, rectal bleeding, and abdominal pain in Crohn's disease and ulcerative colitis; includes mesalamine or mesalamine converting products such as balsalazide, olsalazine, and sulfasalazine.
Conventional therapy: Treatments that are widely accepted and practiced by the medical community.
Corticosteroids (systemic): A class of drugs, also referred to as glucocorticoids, which reduce inflammation and are synthetic derivatives of the natural steroid, cortisol, which is produced by the adrenal glands; includes prednisone, methylprednisone, and hydrocortisone.
Immunomodulator drugs: A class of drugs that modifies or influences the immune system.
Immunosuppressive drugs: A subclass of immunomodulator drugs that reduce inflammation by affecting the immune system; includes 6-MP, azathioprine, cyclophosphamide, cyclosporine, methotrexate, and tacrolimus; also referred to as immunosuppressant drugs.
Induction: Treatment designed as a first step toward treatment of a given condition.
Refractory disease: Illness or disease that is unresponsive to conventional treatment.
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services may be Medically Necessary when criteria are met:
|J3380||Injection, vedolizumab, 1 mg [Entyvio]|
|K50.00-K50.919||Crohn's disease (regional enteritis)|
When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above for those situations described in the Position Statement as not medically necessary.
When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
Integrin Receptor Antagonist
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|09/27/2017||Added Note to the Description section regarding CG-ADMIN-02.|
|Revised||02/02/2017||Medical Policy & Technology Assessment Committee (MPTAC) review. Revised NMN criteria, removing criteria regarding tuberculosis infections and testing for latent tuberculosis. Updated Rationale, References, and Websites for Additional Information sections.|
|12/21/2016||Clarified Description/Scope section, removing FDA approved age for use.|
|Revised||11/03/2016||MPTAC review. Updated formatting in Position Statement section and other changes to abbreviations. Revised MN criteria to include use of vedolizumab in the pediatric population 6 years of age or older with Crohn's disease and ulcerative colitis when criteria are met. Revised "immunomodulatory" to "immunomodulator" in the NMN statement. Updated Description, Rationale, Background, Definitions, References, and Websites for Additional Information sections.|
|Revised||05/05/2016||MPTAC review. Format changes and clarifications to the MN statements. Updated the Rationale, References, and Websites for Additional Information sections.|
|Revised||11/05/2015||MPTAC review. Changed registered trademark to Entyvio® . Minor change to the not medically necessary criterion #4: adding "and Prevention" to CDC. Minor change to investigational and not medically necessary statement, removing "...the medically necessary..." Updated Rationale, References, and Websites for Additional Information sections. Updated Coding section with 01/01/2016 HCPCS changes, removing C9026 deleted 12/31/2015; also removed ICD-9 codes.|
|New||11/13/2014||MPTAC review. Initial document development.|