Note: REQUIRES PRECERTIFICATION.*

Aetna considers vedolizumab (Entyvio) medically necessary for the treatment of adult members 18 years of age or older with active ulcerative colitis who meet either of the following criteria: 

1. Member is hospitalized with fulminant ulcerative colitis (i.e., persons with severe ulcerative colitis who have more than 10 stools per day, continuous bleeding, abdominal pain, and distension, and acute, severe toxic symptoms including fever and anoxia); or
2. Member has moderate-to-severe active ulcerative colitis and meets all of the following criteria:
    
   1. Member is refractory to or requires continuous immunosuppression with corticosteroids (e.g., methylprednisolone, prednisone) at a dose of prednisone 40 to 60 mg/day (or equivalent) for 30 days for oral therapy or 7 to 10 days for IV therapy); and
   2. Member is refractory to or has a contraindication to 5-aminosalicylic acid agents (e.g., balsalazide, mesalamine, sulfasalazine); and
   3. Member is refractory to or has a contraindication to immunosuppressants (azathioprine and 6-mercaptopurine). 

Aetna considers vedolizumab (Entyvio) medically necessary for the treatment of adult members 18 years of age or older with moderately-to-severely active Crohn's disease as manifested by any of the following signs/symptoms:

1. Abdominal pain;
2. Bleeding;
3. Diarrhea;
4. Internal fistulae;
5. Intestinal obstruction;
6. Megacolon;
7. Perianal disease;
8. Weight loss;
9. Extra-intestinal manifestations: arthritis or spondylitis; and

Crohn's disease has remained active despite treatment with one of the following: 

1. 6-mercaptopurine/azathioprine; or
2. Corticosteroids.

Note: There are several brands of targeted immune modulators on the market.  There is a lack of reliable evidence that any one brand of targeted immune modulator is superior to other brands for medically necessary indications.  Enbrel (etanercept), Humira (adalimumab), Remicade (infliximab), Simponi (golimumab), Simponi Aria (golimumab intravneous), and Stelara (ustekinumab) brands of targeted immune modulators ("least cost brands of targeted immune modulators") are less costly to Aetna.  Consequently, because other brands (e.g., Actemra (tocilizumab), Cimzia (certolizumab), Entyvio (vedolizumab), Kineret (anakinra), Orencia (abatacept), Rituxan (rituximab) and Xeljanz (tofacitinib)) of injectables are more costly than these least cost brands of targeted immune modulators, and least cost brands of targeted immune modulators are at least as likely to produce equivalent therapeutic results, no other brands of targeted immune modulator will be considered medically necessary unless the member has a contraindication, intolerance or incomplete response to at least 2 of the least cost brands of targeted immune modulator: Enbrel, Humira, Remicade, Simponi, Simponi Aria, or Stelara, for the same medically necessary indication.  If the least costly targeted immune modulator does not have the labeled indication (see Appendix), then Aetna considers medically necessary another brand of targeted immune modulator that has the required labeling indication.

Note: * Precertification of vedolizumab (Entyvio) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of vedolizumab, call (866) 503-0857, or fax (866) 267-3277.

See also CPB 0314 - Rituximab (Rituxan), CPB 0315 - Enbrel (Etanercept), CPB 0341- Remicade (Infliximab), CPB 0595 - Kineret (Anakinra), CPB 0655 - Adalimumab (Humira), CPB 0720 - Abatacept (Orencia), CPB 0751 - Natalizumab (Tysabri), CPB 0761 - Certolizumab Pegol (Cimzia), and CPB 0790 - Golimumab (Simponi).

Crohn's disease (CD) and ulcerative colitis (UC) are 2 chronic inflammatory bowel diseases (IBDs).  Current biologic therapies are limited to blocking tumor necrosis factor (TNF)-alpha.  However, some patients are primary non-responders; they experience a loss of response, intolerance or side effects defining the urgent unmet need for novel treatments.  Vedolizumab (VDZ), a α4 integrin inhibitor, is a humanized monoclonal antibody for the treatment of IBD.  It binds to the α 4β 7 integrin complex and inhibits its binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thus preventing lymphocyte extravasation to gut mucosal tissues.  It is the first gut-specific immunomodulator for the treatment of IBD.

To understand whether VDZ has additional effects that may affect its overall safety as a therapeutic molecule, Wyant et al (2013) examined other potential actions of VDZ.  In-vitro assays with human peripheral blood lymphocytes demonstrated that VDZ fails to elicit cytotoxicity, lymphocyte activation, and cytokine production from memory T-lymphocytes and does not interfere with the suppressive ability of regulatory T-cells.  Furthermore, these investigators demonstrated that VDZ induces internalization of α 4β 7 and that the integrin is rapidly re-expressed and fully functional after VDZ withdrawal.  These studies provided insight into the mechanisms underlying the observed safety profile of VDZ in clinical trials.

Jovani and Danese (2013) noted that IBD is characterized by a persistent recruitment of large quantities of leucocytes from the blood to the gut mucosa.  Adhesion molecules, such as integrins and their ligands, are the main players in this complex process.  Leucocyte traffic control using specific integrin inhibitors, such as natalizumab, has been plagued by severe systemic effects.  The α4β7 - integrin and its ligand, the MadCAM-1, have been of special interest, since they are found exclusively on the gut-homing lymphocyte subpopulations and in the intestinal mucosa respectively.  It follows that inhibition of such molecules should offer gut-specific immunosuppression, without the systemic effects of aspecific integrin-antagonists.  These investigators reviewed the role of VDZ, a humanized antibody against the α4β7 integrin, in both UC and CD.  Results from clinical trials showed that VDZ is effective in the induction and maintenance of remission in active CD and UC and has a very good safety profile.  The authors concluded that these data allowed them to confidently prospect that VDZ will be an important therapeutic option in the future of IBD treatment.

Parikh et al (2013) reported long-term experience with VDZ for active UC and CD.  After a placebo-controlled study, 38 patients with UC were randomized to a loading regimen of VDZ 2, 6, or 10 mg/kg on days 1, 15, and 43, followed by maintenance dosing every 8 weeks.  Thirty-four VDZ-naive patients (15 UC; 19 CD) were randomized to VDZ 2, 6, or 10 mg/kg on the same schedule.  Roll-over patients were treated up to 630 days and treatment-naive patients were treated up to 547 days.  A total of 72 patients were dosed; 52 (72 %) completed the study.  In exploratory analyses, 28 of 72 (39 %; UC: 21 of 53, CD: 7 of 19) achieved clinical response and 42 of 72 (58.3 %; UC: 38 of 53, CD: 4 of 19) achieved clinical remission.  Mean partial Mayo scores declined from baseline through day 155 in both treatment-naive patients with UC (5.4 to 1.7, respectively) and roll-over patients with UC (2.3 to 1.4, respectively), leveling off thereafter. Mean Crohn's Disease Activity Index (CDAI) scores decreased from 295 (baseline) to 238 at day 43, continued to trend downward through day 155, and remained below baseline through day 491.  Mean Inflammatory Bowel Disease Questionnaire scores increased in all treatment groups.  No deaths or systemic opportunistic infections were reported.  The authors concluded that VDZ every 8 weeks for up to 78 weeks had an adverse event profile similar to that previously observed.  Mean disease activity indices (partial Mayo score and CDAI score) improved with all 3 doses investigated.

Feagan and associates (2013) conducted 2 integrated randomized, double-blind, placebo-controlled trials of VDZ in patients with active UC.  In the trial of induction therapy, 374 patients (cohort 1) received VDZ (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label VDZ at weeks 0 and 2, with disease evaluation at week 6.  In the trial of maintenance therapy, patients in either cohort who had a response to VDZ at week 6 were randomly assigned to continue receiving VDZ every 8 or 4 weeks or to switch to placebo for up to 52 weeks.  A response was defined as a reduction in the Mayo Clinic score (range of 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30 % from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.  Response rates at week 6 were 47.1 % and 25.5 % among patients in the VDZ group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95 % confidence interval [CI]: 11.6 to 31.7; p < 0.001).  At week 52, 41.8 % of patients who continued to receive VDZ every 8 weeks and 44.8 % of patients who continued to receive VDZ every 4 weeks were in clinical remission (Mayo Clinic score less than or equal to 2 and no subscore greater than 1), as compared with 15.9 % of patients who switched to placebo (adjusted difference, 26.1 percentage points for VDZ every 8 weeks versus placebo [95 % CI: 14.9 to 37.2; p < 0.001] and 29.1 percentage points for VDZ every 4 weeks versus placebo [95 % CI: 17.9 to 40.4; p < 0.001]).  The frequency of adverse events was similar in the VDZ and placebo groups.  The authors concluded that VDZ was more effective than placebo as induction and maintenance therapy for UC.

In an integrated study with separate induction and maintenance trials, Sanborn et al (2013) evaluated intravenous VDZ therapy (300 mg) in adults with active CD.  In the induction trial, 368 patients were randomly assigned to receive VDZ or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label VDZ at weeks 0 and 2 (cohort 2); disease status was assessed at week 6.  In the maintenance trial, 461 patients who had had a response to VDZ were randomly assigned to receive placebo or VDZ every 8 or 4 weeks until week 52.  At week 6, a total of 14.5 % of the patients in cohort 1 who received VDZ and 6.8 % who received placebo were in clinical remission (i.e., had a score on the CDAI of less than or equal to 150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (p = 0.02); a total of 31.4 % and 25.7 % of the patients, respectively, had a CDAI-100 response (greater than or equal to 100-point decrease in the CDAI score) (p = 0.23).  Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0 % and 36.4 % of those assigned to VDZ every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6 % assigned to placebo (p < 0.001 and p = 0.004 for the 2 VDZ groups, respectively, versus placebo).  Antibodies against VDZ developed in 4.0 % of the patients.  Naso-pharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving VDZ than in patients receiving placebo.  Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4 % versus 15.3 %), infections (44.1 % versus 40.2 %), and serious infections (5.5 % versus 3.0 %).  The authors concluded that VDZ-treated patients with active CD were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive VDZ (rather than switching to placebo) were more likely to be in remission at week 52.  Adverse events were more common with VDZ.

Cohen et al (2014) stated that IBD, including UC and CD, is characterized by the destructive inflammation of the intestinal tract.  Biologics represent a class of therapeutics with immune intervention potential.  These agents block the pro-inflammatory cascade that triggers the activation and proliferation of T-lymphocytes at the level of the intestine, thus re-establishing the balance between the pro- and anti-inflammatory messages.  All 7 biologics showing clinical benefits in IBD are monoclonal antibodies.  The authors discussed the pharmacokinetics and effectiveness of the TNF blockers infliximab, adalimumab, certolizumab pegol, and golimumab.  In addition, they described the α4 integrin inhibitors natalizumab and VDZ, which are directed against cell adhesion molecules, as well as the interleukin 12/23 blocker ustekinumab.

Lobaton and colleagues (2014) noted that a high proportion of patients with IBD do not achieve clinical remission with the current therapies including mesalazine (mesalamine), immunosuppresants (IMS) and anti-TNF agents.  Moreover, IMS and anti-TNF involve a non-negligible risk for infections and/or malignancies.  The anti-adhesion molecules are one of the most interesting new treatments because of their gut-selectivity.  These researchers reviewed the physiopathology of the adhesion molecules and the current drugs targeting this mechanism.  They performed a literature review in PubMed and in clinicaltrials.gov using the terms “anti-adhesion molecules”, “inflammatory bowel disease”, “natalizumab”, “vedolizumab”, “AMG181”, “etrolizumab”, “PF-00547659”, “AJM300”, “Alicaforsen” and “CCX282-B” up to November 2013.  A total of 8 drugs were found including those targeting the α4β1, α4β7 or αEβ7 integrins as well as the ICAM-1 and MAdCAM-1 addressins and the chemokine receptor 9.  The rationale for these drugs is the blockade of gut-homing T-lymphocytes and the ones targeting the α4β7/MAdCAM-1 interaction presented the most promising results in luminal disease.  Vedolizumab, an α4β7 antibody, has completed phase III trials with very positive results especially for UC.  However, many questions remain unanswered such as the effect of these therapies in perianal disease and extra-intestinal manifestations.  The authors concluded that the blockade of the α4β7/MAdCAM-1 interaction and especially VDZ is a safe and effective gut-specific treatment for IBD.

On May 20, 2014, the Food and Drug Administration (FDA) approved vedolizumab (Entyvio) injection for the treatment of adults with moderate-to-severe UC and adults with moderate-to-severe CD who have not fully responded to treatment with steroids, immunomodulators, or tumor necrosis factor inhibitors.  The most common adverse events observed with vedolizumab were fever, headache, nausea, and joint pains, while serious events have included hepatotoxicity, infections, and hypersensitivity reactions.  The recommended dosage of vedolizumab in UC and CD is 300 mg infused intravenously over approximately 30 minutes at 0, 2 and 6 weeks, then every 8 weeks thereafter.

Appendix

Table: Targeted Immune Modulators