Vedolizumab (Entyvio) [Medicare]

Number: 0885m

Commercial CPB  |  Medicare CPB

Medicare Part B Step Therapy Criteria

For Medicare Advantage plans that do not offer prescription drug coverage (MA)

Entyvio, for the indication listed below:

• Crohn’s Disease (CD)

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Remicade or Renflexis
  2. Intolerable adverse event to Remicade or Renflexis
  3. Remicade or Renflexis is contraindicated for the member.

For Medicare Advantage plans that offer prescription drug coverage (MAPD)

Entyvio, for the indication listed below:

• Crohn’s Disease (CD)

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Humira
  2. Intolerable adverse event to Humira
  3. Humira is contraindicated for the member.

For Medicare Advantage plans that do not offer prescription drug coverage (MA) and Medicare Advantage plans that offer prescription drug coverage (MAPD)

Entyvio, for the indication listed below:

• Ulcerative Colitis (UC)

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Remicade or Renflexis
  2. Intolerable adverse event to Remicade or Renflexis
  3. Remicade or Renflexis is contraindicated for the member.

Policy

Note: Requires Precertification. Precertification of vedolizumab (Entyvio) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of vedolizumab, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies.  For information on site of service for Entyvio (vedolizumab), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Aetna considers vedolizumab (Entyvio) medically necessary for the following indications:

1. Moderately to severely active Crohn’s disease (CD)

   1. For members who have previously received a biologic indicated for the treatment of moderately to severely active Crohn’s disease; or
   2. For the treatment of moderately to severely active CD in members who had an inadequate response, intolerance or contraindication to at least one conventional therapy option (see Appendix); or
   3. For the treatment of fistulizing CD.

2. Moderately to severely active ulcerative colitis (UC)

   1. For members who have previously received a biologic or targeted synthetic DMARD (e.g., Xeljanz) indicated for moderately to severely active ulcerative colitis; or
   2. For the treatment of moderately to severely active UC for members who had an inadequate response, intolerance or contraindication to at least one conventional therapy option (see Appendix); or
   3. For members who have been hospitalized for acute, severe UC (e.g., continuous bleeding, severe toxic symptoms, including fever and anorexia).

3. Immune checkpoint inhibitor-related toxicity

   For the treatment of immune checkpoint inhibitor-related diarrhea or colitis when the member has experienced an inadequate response, intolerance, or contraindication to systemic corticosteroids.

4. Continuation of therapy

   1. Immune checkpoint inhibitor-related toxicity: all members (including new members) requesting authorization for continuation of therapy must meet all initial authorization criteria. 
   2. All other indications: all members (including new members) who are using the requested drug for an indication outlined in section I or II and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition. 

Aetna considers use of vedolizumab with other biologic disease-modifying antirheumatic drugs (bioDMARDS) experimental and investigational because the safety and effectiveness of these combinations has not been established. 

Aetna considers vedolizumab experimental and investigational for the following indications (not an al-inclusive list) because its effectiveness for these indications has not been established:

• Collagenous colitis
• Gastro-intestinal graft-versus-host disease
• Primary sclerosing cholangitis
• Spondyloarthritis.

Aetna considers measurement of serum levels of vedolizumab and antibodies to vedolizumab (ATV) (e.g. Anser VDZ [Prometheus Lab]) experimental and investigational because the clinical value of this measurement for individuals receiving vedolizumab therapy has not been established.

Background

Crohn's disease (CD) and ulcerative colitis (UC) are 2 chronic inflammatory bowel diseases (IBDs). Ulcerative colitis (UC) is a disease in which the lining of the colon becomes inflamed and develops ulcers, leading to bleeding and diarrhea. The inflammation almost always affects the rectum and lower part of the colon, but it can affect the entire colon. Two main goals of treatment for UC are to achieve remission and maintain remission. About 15% of people who have an initial attack will remain in remission without medications. The treatment of UC relies on initial medical management with corticosteroids and antiinflammatory agents, such as sulfasalazine, in conjunction with symptomatic treament with antidiarrheal agents and rehydration.

Crohn's disease (CD) is an idiopathic, chronic inflammatory process of the gastrointestinal (GI) tract that can affect any part of the tract from the mouth to the anus.For colon and small bowel inflammation in CD, anti‐inflammatory drugs (e.g., sulfasalazine) or antibiotics are helpful. Biologic therapy may provide benefits in patients who have moderate to severe debilitating symptoms of CD, who have documented active inflammation, or who are dependent on corticosteroids and unable to taper without return of symptoms.

Current biologic therapies have been 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 inhibiting the migration of memory T‐lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. The interaction of the α4β7 integrin with MAdCAM‐1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn’s disease.

Entyvio (vedolizumab) has been approved by the U.S. Food and Drug Administration (FDA) for inducing and maintaining clinical response, inducing and maintaining clinical remission, improving endoscopic appearance of the mucosa, and achieving corticosteroid free remission in adult patients with moderately to severely active ulcerative colitis 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 approved by the FDA for achieving clinical response, achieving clinical remission, and achieving corticosteroid‐free remission in adult patients with moderately to severely active Crohn’s disease 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.

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. 

Warnings and Precautions

Infusion-related reactions and hypersensitivity reactions (including anaphylaxis)

Discontinue Entyvio and initiate appropriate treatment if anaphylaxis or other serious allergic reactions occur.

Infections

Treatment with Entyvio is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding Entyvio in patients who develop a severe infection while on treatment with Entyvio.

Progressive Multifocal Leukoencephalopathy (PML)

Progressive Multifocal Leukoencephalopathy (PML): Although no cases have been observed in Entyvio clinical trials, John Cunningham virus(JCV) infection resulting in PML and death has occurred in patients treated with another integrin receptor antagonist. Although unlikely, a risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs or symptoms. If PML is suspected, withhold dosing with Entyvio and refer to a neurologist; if confirmed, discontinue dosing permanently.

Collagenous Colitis

An UpToDate review on "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management" (Dietrich, 2018) does not mention vedolizumab as a therapeutic option.

Gastro-Intestinal Graft-Versus-Host Disease

Floisand and colleagues (2017) noted that steroid refractory acute graft-versus-host-disease (aGVHD) of the gut is a serious complication associated with high mortality after allogeneic stem cell transplantation (ASCT).  Therapeutic options are limited and not predictably effective.  These researchers described the treatment of steroid-refractory aGVHD with vedolizumab in 6 patients.  All patients responded, and 4 of 6 patients were alive with a median follow-up of 10 months.  This was a small (n = 6), case-series, proof-of-concept study; these investigators stated that “these observations need to be confirmed in a larger prospective trial”.

In a retrospective case-series study, Coltoff and associates (2018) examined the use of vedolizumab for the treatment of steroid-refractory lower gastro-intestinal (LGI) aGVHD (n = 9; 2 were dead at 10-day follow-up; and only 3 were alive at 30-day follow-up).  The authors stated that “further research, including the ongoing phase II study at our institution focused on vedolizumab incorporation for steroid-refractory disease, will help elucidate the role of vedolizumab for LGI-aGVHD“.

Furthermore, UpToDate reviews on “Treatment of acute graft-versus-host disease” (Chao, 2020a) and “Treatment of chronic graft-versus-host disease” (Chao, 2020b)” do not mention vedolizumab as a therapeutic option.

Immune Checkpoint Inhibitor-Related Toxicity

Hsieh and colleagues (2016) noted that the use of the immune checkpoint inhibitors (ICPIs) (e.g., ipilimumab, nivolumab and pembrolizumab) has revolutionized treatment in patients with metastatic melanoma.  However, these drugs can cause an autoimmune enterocolitis, with diarrhea as the presenting symptom.  This is conventionally managed by prompt institution of corticosteroid therapy if moderate diarrhea (3 to 6 times/day; grade 2) is present for more than 5 days or if diarrhea is severe (more than 6 times/day; grade 3).  These investigators reported a case of steroid-dependent ipilimumab-induced colitis successfully treated with vedolizumab, after which complete withdrawal of corticosteroid was achieved.  The authors concluded that vedolizumab warrants further evaluation as a potential novel treatment of iICP{Is-induced colitis.

Bergqvist and associates (2017) stated that ICPIs improve survival in several cancer types.  Since inhibition of cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death protein-1 (PD-1) leads to non-selective activation of the immune system, immune-related adverse events (irAEs) are frequent.  Enterocolitis is a common irAE, currently managed with corticosteroids and, if necessary, anti-TNF-α therapy.  Such a regimen carries a risk of serious side effects including infections, and may potentially imply impaired anti-tumor effects.  Vedolizumab is an anti-integrin α4β7 antibody with gut-specific immunosuppressive effects, approved for CD and UC.  These investigators reported a case series of 7 patients with metastatic melanoma or lung cancer, treated with vedolizumab off-label for ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October 2016.  Clinical, laboratory, endoscopic, and histologic data were analyzed.  Patients initially received corticosteroids but were steroid-dependent and/or partially refractory; 1 patient was administered infliximab but was refractory.  The median time from onset of enterocolitis to start of vedolizumab therapy was 79 days.  Following vedolizumab therapy, all patients but 1 experienced steroid-free enterocolitis remission, with normalized fecal calprotectin.  This was achieved after a median of 56 days from vedolizumab start, without any vedolizumab-related side effects noted.  The patient in whom vedolizumab was not successful, due to active UC, received vedolizumab prophylactically.  The authors concluded that this was the 1st case series to suggest that vedolizumab is an effective and well-tolerated therapeutic for steroid-dependent or partially refractory ICPI-induced enterocolitis.  Moreover, they stated that a larger prospective study is needed to evaluate vedolizumab in this indication.

Abu-Sbeih et al. (2018) assessed clinical outcomes of vedolizumab as an alternative treatment for immune-mediated diarrhea and colitis (IMDC). The authors analyzed a retrospective case series of 28 adults who were IMDC refractory to steroids and/or infliximab and who received vedolizumab. The median time from immune checkpoint inhibitors (ICI) therapy to IMDC onset was 10 weeks. Fifteen patients (54%) had grade 2 and 13 patients (46%) had grade 3 or 4 IMDC. Mucosal ulceration was present in 8 patients (29%) and nonulcerative inflammation was present in 13 patients (46%). All patients had features of active histologic inflammation; 14 patients (50%) had features of chronicity, and 10 patients (36%) had features of microscopic colitis concurrently. The mean duration of steroid therapy was 96 days (standard deviation 74 days). Nine patients received infliximab in addition to steroids and their IMDC was refractory to it. Among these, the duration of steroid use was 131 days compared with 85 days in patients who did not receive infliximab. Likewise, patients who failed infliximab before vedolizumab had a clinical success rate of 67% compared to 95% for patients that did not receive infliximab. The median number of vedolizumab infusions was 3 (interquartile range 1-4). The mean duration of follow-up was 15 months. Twenty-four patients (86%) achieved and sustained clinical remission. Repeat endoscopic evaluation was performed in 17 patients. Endoscopic remission was attained in 7 (54%) of the 13 patients who had abnormal endoscopic findings initially; 5 of the 17 patients (29%) reached histologic remission as well. The authors concluded that vedolizumab can be appropriate for the treatment of steroid-refractory IMDC, with favorable outcomes and a good safety profile.

An UpToDate review on "Toxicities associated with checkpoint inhibitor immunotherapy" (Postow, 2020) states for cases refractory to infliximab, mycophenolate or vedolizumab may be helpful. 

The National Comprehensive Cancer Network Drugs & Biologics Compendium (NCCN, 2020) states to consider adding vedolizumab (Entyvio) for management of immunotherapy-related moderate (G2) and strongly consider for severe (G3-4) diarrhea or colitis [category 2A].

Primary Sclerosing Cholangitis

Halilbasic and co-workers (2015) stated that primary sclerosing cholangitis (PSC) represents a fibro-obliterative bile duct disease with unpredictable individual clinical course that may progress to liver cirrhosis and malignancy.  Due to incomplete understanding of the etiology and pathogenesis of this disease, the therapeutic options are still rather limited.  Bile acids play a key role in mediating cholangio-cellular and hepato-cellular injury in cholangiopathies such as PSC.  Thus, strategies targeting bile composition and homeostasis are valid approaches in PSC.  Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and its role in medical therapy of PSC is still under debate.  Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid (norUDCA), a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g., obeticholic acid).  Other nuclear receptors such as fatty acid-activated peroxisome proliferator-activated receptors, vitamin D receptor and vitamin A receptors (retinoic acid receptor, retinoid X receptor) are also of potential interest and can be targeted by already available drugs.  Furthermore, drugs targeting the gut-liver axis (e.g., intregrin blockers such as vedolizumab, antibiotics) appear promising, based on the close link of PSC to IBD and the emerging relevance of the gut microbiome for the development of PSC. 

Tse and colleagues (2018) noted that PSC is a chronic, progressive cholestatic biliary disease associated with IBD with no known cure.  These investigators examined the effect of biological therapies on PSC progression in IBD patients.  They performed a retrospective cohort study of 88 cases (75 unique patients with 12 patients treated with more than 1 biologics) of IBD (48 UC, 24 CD and 3 indeterminate colitis) with concomitant PSC who received biological therapy (42 infliximab, 19 adalimumab, 27 vedolizumab) between June 2002 and October 2017.  Hepatic biochemistries were compared using the paired t-test (patients served as their own controls) less than or equal to 3 months before and 6 to 8 and 12 to 14 months after biological initiation.  Radiographic information of biliary stenosis and liver fibrosis were obtained via abdominal ultrasound (US), abdominal magnetic resonance imaging (MRI) and magnetic resonance elastography.  Use of adalimumab was associated with a significant decrease in alkaline phosphatase (ALP) after 6 to 8 months (p = 0.03; mean change of -70 U/L, standard deviation [SD] 88 U/L) compared to vedolizumab (mean change of +50 U/L, SD 142 U/L) or infliximab (mean change of +37 U/L, SD 183 U/L) but the change was not significant after 12 to 14 months (p = 0.24).  No significant decreases were observed with, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total or direct bilirubin, elastography score or radiographic imaging of biliary tree dilation/strictures with any biological therapy after 6 to 8 or 12 to 14 months.  The authors concluded that current evidence suggested that biological therapies used for the treatment of IBD were not effective treatments for PSC.  They stated that further investigation is needed to elucidate any potential beneficial effect of adalimumab on PSC.

In a retrospective, multi-center study, Christensen and associates (2018) described the effect of vedolizumab on liver biochemistry and disease activity in patients with PSC and IBD.  This trial included adult patients with a diagnosis of both IBD and PSC.  The primary outcome was change in serum ALP level at weeks 14 and 30.  Secondary outcomes included changes in other liver biochemistries and in clinical outcomes for the bowel disease.  A safety analysis for AEs was performed.  A total of 34 patients (16 CD, 18 UC) were included; 9 (26 %) had a history of liver transplant.  Median follow-up on vedolizumab was 9 months (inter-quartile range [IQR]: 7 to 16).  There was no overall change in serum ALP level with vedolizumab therapy (median of 268 [IQR: 105 to 551] IU/L at baseline versus 249 [IQR: 183 to 634] IU/L, p = 0.99 at week 30).  No significant changes in other liver biochemistries or the Mayo PSC Risk Score were demonstrated at week 30.  Clinical remission was achieved at week 30 in 55 % of CD and 29% of UC; 7 (21 %) patients ceased vedolizumab; 6 patients stopped therapy due to persistent IBD activity and 1 for worsening of liver biochemistries.  The authors concluded that vedolizumab treatment in patients with PSC and IBD did not improve liver biochemistry but was associated with improvement in bowel disease and a favorable safety profile.  Moreover, they stated that future registry studies should focus more on whether vedolizumab can improve long‐term clinical outcomes in PSC patients including decreasing the development of new biliary strictures, cirrhosis, need for transplantation and cancer incidence.

The authors stated that this study had several drawbacks.  First, all data collection was performed retrospectively, but, since the included centers were all major referral centers for IBD and liver disease, these researchers were able to collect data obtained from routine clinic visits.  Although these investigators strengthened the data quality using objective outcome assessments where possible, there may still be bias present in the clinical follow‐up of patients.  Second, the sample size was small (n = 34), which may have contributed, for example, to the failure to observe statistical significance in changes in liver biochemistry, particularly at week 30 outcomes where large IQRs were observed.  However, the absolute difference in the primary outcomes of ALP levels did not appear to be clinically significant even if larger patient numbers were able to demonstrate a statistically significant difference.  The small sample size, however, also did not allow comparison of liver biochemistry improvement between different sub‐groups including those with intra- versus extra-hepatic PSC or history of liver transplant to be adequately explored.  The patients included in this study were also more likely to have CD than UC, which was not reflective of the ratios of CD versus UC in the general PSC population.  This was likely secondary to the fact that at the time of this study vedolizumab was primarily used to treat the intestinal disease activity rather than the PSC and in some centers, including the University of Chicago, the majority of patients commenced on vedolizumab had CD.  There was also the possibility that changes in ALP were secondary to other causes like low vitamin D status.  Unfortunately, vitamin D levels were not assessed in this study but it was felt the likelihood of this altering the results significantly was low as all patients were treated at large academic centers where vitamin D levels were routinely assessed and aggressively replaced.  Finally, this study was limited by its short duration of follow‐up.  Changes in liver biochemistries were only assessed to week 30 of therapy and, therefore, longer term outcomes such as need for liver transplantation, development of cirrhosis or cancer incidence were unable to be assessed.  These researchers stated that larger, prospective, multi‐center studies are needed to examine this question in more detail.

Spondylarthritis

Bethge and colleagues (2017) stated that IBD is frequently associated with spondylarthritis (SpA).  It has been discussed that α4/β7 expressing lymphocytes are involved in the pathogenesis of SpA.  These investigators reported a case of a successful combination therapy of vedolizumab (VDZ) and etanercept (ETA) in a patient with UC with pouchitis and SpA.  The authors concluded that VDZ was effective for pouchitis and ineffective for SpA.  The combination with ETA might be a useful treatment strategy to control both diseases and first indications suggested that it is safe; α4/β7 Expressing lymphocytes are most likely not associated in the etiology of SpA.

Vedolizumab Serum Levels and Antibodies

Rosario et al (2016) stated that vedolizumab is indicated for treatment of moderately-to-severely active ulcerative colitis (UC) or Crohn's disease (CD). In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers.  A total of 49 participants (in 5 cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo.  Blood samples were collected for measurement of vedolizumab serum concentrations and α4β7 saturation on peripheral blood lymphocytes by vedolizumab.  Pharmacokinetic parameters were computed using a non-compartmental approach.  Adverse events (AEs) were monitored.  Vedolizumab maximum observed serum concentration (C max) demonstrated dose proportionality over the dose range tested.  Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC0-inf) and shorter terminal elimination half-life (t 1/2) were observed from 0.2 to 2.0 mg/kg, suggestive of non-linear pharmacokinetics at lower doses.  At doses higher than 2.0 mg/kg, these parameters increased dose proportionally.  Saturation of α4β7 was at or near maximal levels (greater than 90 %) at all doses and time-points when vedolizumab was measurable in serum.  A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no AE signals, including serious infections or malignancies, were apparent.  The authors concluded that vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, non-linear elimination process at low concentrations and a slower linear elimination process at higher concentrations; nearly complete α4β7 saturation was observed at all doses.  A single intravenous infusion of vedolizumab was well-tolerated by healthy volunteers.

Unger et al. (2017) conducted a prospective study to evaluate the association of vedolizumab level, anti-drug antibodies, and α4β7 occupancy with response in patients with IBD. The study included 106 patients with IBD (67 Crohn’s, 39 UC) who were treated with vedolizumab from September 2014 through March 2017 at 2 tertiary medical centers in Israel. Clinical remission was defined as Harvey-Bradshaw index scores below 5 or as Simple Clinical Colitis Activity Index scores of 3 or less. Serum levels of vedolizumab, AVAs, and markers of inflammation were measured. Peripheral blood mononuclear cells were obtained from some patients at designated trough time points and CD3+ CD45RO+ T cells were isolated from 36 samples. Flow cytometry was used to quantify α4β7 integrin saturation and provide analyses of CD3+ CD45RO+ lamina propria T cells isolated from intestinal mucosa of patients without IBD ( n = 6), patients with IBD not treated with vedolizumab (n = 8), and patients with IBD treated with vedolizumab (n = 15). The investigators found that clinical remission was achieved in 45% of patients by week 6, and 48% by week 14 of treatment. The median level of vedolizumab at week 6 was higher in patients in clinical remission than in patients with active disease (P = .05). The median serum level of vedolizumab was significantly higher in patients with a normal level of C-reactive protein vs the level in those with a high level of C-reactive protein during maintenance treatment (P = .0006). The other clinical outcomes measured were not associated with median serum level of vedolizumab at any time point examined. AVAs were detected in 17% of patients during induction therapy and 3% of patients during maintenance therapy, but did not correlate with clinical outcomes. Flow-cytometry analysis of peripheral blood memory T cells (n = 36) showed near-complete occupancy of α4β7 integrin at weeks 2 and 14 and during the maintenance phase, regardless of response status or drug levels. Most intestinal CD3+CD45RO+ memory T cells of healthy and IBD controls expressed α4β7 (72%). In contrast, free α4β7 was detectable on only 5.6% of intestinal memory cells (P < .0001) from vedolizumab-treated patients, regardless of response. The authors concluded that these findings indicate a need to explore alternative mechanisms that prevent response to vedolizumab.

The Prescribing Information of Entyvio does not mention the need of measuring serum anti-vedolizumab antibodies for patients receiving the drug and in non-responders (Takeda Pharmaceuticals America, 2020).

Appendix

1. Mild to moderate disease – induction of remission:

   1. Oral budesonide
   2. Alternatives: metronidazole, ciprofloxacin, rifaximin

2. Mild to moderate disease – maintenance of remission:

   1. Azathioprine, mercaptopurine
   2. Alternatives: oral budesonide, methotrexate intramuscularly (IM) or subcutaneously (SC), sulfasalazine

3. Moderate to severe disease – induction of remission:

   1. Prednisone, methylprednisolone intravenously (IV)
   2. Alternatives: methotrexate IM or SC

4. Moderate to severe disease – maintenance of remission:

   1. Azathioprine, mercaptopurine
   2. Alternative: methotrexate IM or SC

5. Perianal and fistulizing disease – induction of remission:

   Metronidazole ± ciprofloxacin, tacrolimus 

6. Perianal and fistulizing disease – maintenance of remission

   1. Azathioprine, mercaptopurine
   2. Alternative: methotrexate IM or SC.

1. Mild to moderate disease – induction of remission:

   1. Oral mesalamine (e.g.,  Asacol, Asacol HD, Lialda, Pentasa), balsalazide, olsalazine
   2. Rectal mesalamine (e.g.,  Canasa, Rowasa)
   3. Rectal hydrocortisone (e.g.,  Colocort, Cortifoam)
   4. Alternatives: prednisone, azathioprine, mercaptopurine, sulfasalazine

2.  Mild to moderate disease – maintenance of remission:

   1. Oral mesalamine, balsalazide, olsalazine, rectal mesalamine
   2. Alternatives: azathioprine, mercaptopurine, sulfasalazine

3. Severe disease – induction of remission:

   1. Prednisone, hydrocortisone IV, methylprednisolone IV
   2. Alternatives: cyclosporine IV, tacrolimus, sulfasalazine

4. Severe disease – maintenance of remission:

   1. Azathioprine, mercaptopurine
   2. Alternative: sulfasalazine

5. Pouchitis: Metronidazole, ciprofloxacin

   1. Alternative: rectal mesalamine.

Brands of Targeted Immune Modulators and FDA-approved Indications

Table: Brands of Targeted Immune Modulators and FDA-approved Indications

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Cytokine release syndrome (CRS)
Cimzia	certolizumab	Ankylosing spondylitis or axial spondyloarthritis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis or axial spondyloarthritis Plaque psoriasis Psoriatic arthritis
Enbrel	etanercept	Ankylosing spondylitis Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Entyvio	vedolizumab	Crohn's disease Ulcerative colitis
Humira	adalimumab	Ankylosing spondylitis Crohn's disease Hidradenitis suppurativa Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis Uveitis
Ilaris	canakinumab	Adult-onset Still's disease Periodic fever syndromes   Systemic juvenile idiopathic arthritis
Ilumya	tildrakizumab-asmn	Plaque psoriasis
Inflectra	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Kevzara	sarilumab	Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Rheumatoid arthritis
Orencia	abatacept	Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Oral ulcers associated with Behcet's disease Plaque psoriasis Psoriatic arthritis
Remicade	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Rinvoq	upadacitinib	Rheumatoid arthritis
Rituxan	rituximab	Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Plaque psoriasis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis
Taltz	ixekinumab	Ankylosing spondylitis or axial spondyloarthritis  Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Rheumatoid arthritis Psoriatic arthritis Ulcerative Colitis
Xeljanz XR	tofacitinib, extended release	Rheumatoid arthritis Psoriatic arthritis Ulcerative colitis

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
CPT codes not covered for indications listed in the CPB:
Measurement of serum levels of vedolizumab and antibodies to vedolizumab - no specific code :
Other CPT codes related to the CPB:
71045 - 71048	Radiologic examination, chest
80280	Vedolizumab
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96413	Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
HCPCS codes covered if selection criteria are met:
J3380	Injection, vedolizumab, 1 mg
Other HCPCS codes related to the CPB:
J0129	Injection, abatacept, 10 mg
J0135	Injection, adalimumab, 20 mg
J0717	Injection, certolizumab pegol, 1 mg
J1438	Injection, etanercept, 25 mg
J1602	Injection, golimumab, 1 mg, for intravenous use
J1620	Injection, gonadorelin HCl, per 100 mcg
J1745	Injection infliximab, 10 mg
J3245	Injection, tildrakizumab, 1 mg
J3262	Injection, tocilizumab, 1 mg
J3357	Injection, ustekinumab, 1 mg
J9312	Injection, rituximab, 10 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
ICD-10 codes covered if selection criteria are met:
K50.00 - K50.919	Crohn's disease [regional enteritis]
K51.00 - K51.919	Ulcerative colitis [for the treatment of adult members 18 years of age or older with moderate-to-severe active ulcerative colitis]
K52.1	Toxic gastroenteritis and colitis [immune check point inhibitor-related diarrhea or colitis]
K55.011 - K55.069	Acute vascular disorders of intestine [Member is hospitalized with fulminant ulcerative colitis]
ICD-10 not codes covered if selection criteria are met:
D89.810 - D89.813	Graft-versus-host disease [gastrointestinal]
K52.831	Collagenous colitis
K52.89	Other specified noninfective gastroenteritis and colitis [immune checkpoint inhibitor-induced enterocolitis]
K83.01	Primary sclerosing cholangitis
M47.011 - M47.896	Spondylosis

The above policy is based on the following references: