Vedolizumab (Entyvio)

Number: 0885

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

Scope of Policy

This Clinical Policy Bulletin addresses vedolizumab (Entyvio) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

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 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

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.

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with one of the following:

   1. Crohn’s disease and ulcerative colitis: gastroenterologist;
   2. Immune checkpoint inhibitor-related toxicity: gastroenterologist, hematologist or oncologist.

2. Criteria for Initial Approval

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

   1. Crohn’s disease (CD)

      For treatment of moderately to severely active CD in adult members;

   2. Ulcerative colitis (UC)

      For treatment of moderately to severely active UC in adult members;

   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 or infliximab.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

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

   1. Crohn’s disease (CD)

      1. For all adult members (including new members) who are using the requested medication for moderately to severely active Crohn’s disease and who achieve or maintain remission; or
      2. For all adult members (including new members) who are using the requested medication for moderately to severely active Crohn’s disease and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline:
         
         
         1. Abdominal pain or tenderness; or
         2. Diarrhea; or
         3. Body weight; or
         4. Abdominal mass; or
         5. Hematocrit; or
         6. Appearance of the mucosa on endoscopy, computed tomography enterography (CTE), magnetic resonance enterography (MRE), or intestinal ultrasound; or
         7. Improvement on a disease activity scoring tool (e.g., Crohn’s Disease Activity Index [CDAI] score);

   2. Ulcerative colitis (UC)

      1. For all adult members (including new members) who are using the requested medication for moderately to severely active ulcerative colitis and who achieve or maintain remission; or
      2. For all adult members (including new members) who are using the requested medication for moderately to severely active ulcerative colitis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline: 
         
         
         1. Stool frequency; or
         2. Rectal bleeding; or
         3. Urgency of defecation; or
         4. C-reactive protein (CRP); or
         5. Fecal calprotectin (FC); or
         6. Appearance of the mucosa on endoscopy, computed tomography enterography (CTE), magnetic resonance enterography (MRE), or intestinal ultrasound; or
         7. Improvement on a disease activity scoring tool (e.g., Ulcerative Colitis Endoscopic Index of Severity [UCEIS], Mayo score);

   3. Immune checkpoint inhibitor-related toxicity

      All members (including new members) requesting authorization for continuation of therapy must meet all initial authorization criteria.

4. Other

   For all indications: Member cannot use the requested medication concomitantly with any other biologic drug or targeted synthetic drug.

5. Related Policies

   1. CPB 0314 - Rituximab
   2. CPB 0315 - Etanercept
   3. CPB 0341 - Infliximab
   4. CPB 0655 - Adalimumab
   5. CPB 0720 - Abatacept (Orencia)
   6. CPB 0751 - Natalizumab
   7. CPB 0761 - Certolizumab Pegol (Cimzia)
   8. CPB 0790 - Golimumab (Simponi and Simponi Aria)

Dosage and Administration

Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. See Medical Specialty Medication Quantity Limits for more information.

Below includes dosing recommendations as per the FDA-approved prescribing information.

Entyvio (vedolizumab) is supplied in the following dosage forms and strengths:

• Intravenous (IV) infusion administered by a healthcare provider:

  • 300 mg vedolizumab in a single-dose vial

• Subcutaneous (SC) injection for use under the guidance and supervision of a healthcare professional. A person may self-inject or caregiver may inject after proper training:

  • 108 mg/0.68 mL solution in a single-dose prefilled syringe with needle safety device
  • 108 mg/0.68 mL solution in a single-dose prefilled pen (Entyvio Pen).

Recommended dosage in adults with Crohn's disease or ulcerative colitis:

• Week 0: 300 mg is administered by IV infusion over approximately 30 minutes;
• Week 2: 300 mg is administered by IV infusion over approximately 30 minutes;
• Week 6: persons may remain on Entyvio IV therapy or switch to SC injection after receiving two Entyvio IV doses administered at Week 0 and Week 2:
  • IV infusion: 300 mg administered by IV infusion over approximately 30 minutes and then every 8 weeks therafter; or
  • SC injection: 108 mg administered SC once every 2 weeks.
• Therapy is discontinued in person who show no evidence of therapeutic benefit by Week 14.
• Persons currently receiving and responding to Entyvio IV therapy after Week 6 may also be switched to SC injection. The first SC dose is administered in place of the next scheduled IV infusion and every 2 weeks thereafter.

Source: Takeda Pharmaceuticals America, 2024b

Experimental, Investigational, or Unproven

Aetna considers concomitant use of vedolizumab with any other biologic drug or targeted synthetic drug experimental, investigational, or unproven because the safety and effectiveness of these combinations has not been established. 

Aetna considers vedolizumab experimental, investigational, or unproven for the following indications (not an all-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, investigational, or unproven because the clinical value of this measurement for individuals receiving vedolizumab therapy has not been established.

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
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:
Mesalamine, balsalazide –no specific code
J0129	Injection, abatacept, 10 mg
J0139	Injection, adalimumab, 1 mg
J0702	Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J0717	Injection, certolizumab pegol, 1 mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1mg
J1438	Injection, etanercept, 25 mg
J1602	Injection, golimumab, 1 mg, for intravenous use
J1620	Injection, gonadorelin HCl, per 100 mcg
J1700	Injection, hydrocortisone acetate, up to 25 mg
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J1745	Injection infliximab, 10 mg
J2650	Injection, prednisolone acetate, up to 1 ml
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg
J3245	Injection, tildrakizumab, 1 mg
J3262	Injection, tocilizumab, 1 mg
J3357	Injection, ustekinumab, 1 mg
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J7509	Methylprednisolone oral, per 4 mg
J7510	Prednisolone oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J8540	Dexamethasone, oral, 0.25 mg
J8610	Methotrexate; oral, 2.5 mg
J8611	Methotrexate (jylamvo), oral, 2.5 mg
J8612	Methotrexate (xatmep), oral, 2.5 mg
J9250	Methotrexate sodium, 5 mg
J9255	Injection, methotrexate (accord) not therapeutically equivalent to j9250 or j9260, 50 mg
J9260	Methotrexate sodium, 50 mg
J9312	Injection, rituximab, 10 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
Q5133	Injection, tocilizumab-bavi (tofidence), biosimilar, 1 mg
Q5135	Injection, tocilizumab-aazg (tyenne), biosimilar, 1 mg
Q5140	Injection, adalimumab-fkjp, biosimilar, 1 mg
Q5141	Injection, adalimumab-aaty, biosimilar, 1 mg
Q5142	Injection, adalimumab-ryvk biosimilar, 1 mg
Q5143	Injection, adalimumab-adbm, biosimilar, 1 mg
Q5144	Injection, adalimumab-aacf (idacio), biosimilar, 1 mg
Q5145	Injection, adalimumab-afzb (abrilada), biosimilar, 1 mg
S0108	Mercaptopurine, oral, 50 mg
ICD-10 codes covered if selection criteria are met:
D89.9	Disorder involving the immune mechanism, unspecified [immune checkpoint inhibitor-related toxicity]
K50.00 - K50.919	Crohn's disease [regional enteritis] [Adult]
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] [Adult]
T45.1X5A - T45.1X5S	Adverse effect of antineoplastic and immunosuppressive drugs [immune checkpoint inhibitor-related toxicity]
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

---

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Adult patients with moderately to severely active ulcerative colitis (UC)
• Adult patients with moderately to severely active Crohn’s disease (CD)

Compendial Uses

• Immune checkpoint inhibitor-related toxicity

Vedolizumab is branded as Entyvio (Takeda Pharmaceuticals U.S.A., Inc.). Vedolizumab is an integrin receptor antagonist, in which humanized monoclonal antibody specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Thus, inhibiting the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1). According to the mechanism of action, 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 implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn’s disease.

Entyvio carries the following warnings and precautions: infusion-related reactions and hypersensitivity reactions (including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, increased blood pressure and heart rate), infections, and risk of progressive multifocal leukoencephalopathy (PML). The most commonly reported infections in clinical trials occurring at a rate greater on Entyvio than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection). Serious infections have also been reported in patients treated with Entyvio, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis. Per the label, Entyvio is not recommended in patients with active, severe infections until the infections are controlled. PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an Entyvio-treated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out.

The most common adverse reactions (incidence of 3% or more, and greater than or equal to 1% higher, than placebo) include nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.

In September 2023, the FDA approved subcutaneous (SC) administration of Entyvio for maintenance therapy in adults with moderately to severely active ulcerative colitis (UC) after induction therapy with intravenous Entyvio. Approval is based on the VISIBLE 1 study (SC UC Trial), which was a randomized, double-blind, placebo-controlled phase 3 trial that assessed the safety and efficacy of an SC formulation of Entyvio as maintenance therapy in adult patients with moderately to severely active UC who achieved clinical response at Week 6 following two doses of open-label vedolizumab intravenous therapy at Weeks 0 and 2. A total of 162 patients were randomized at Week 6 in a double-blind fashion (2:1) to one of the following regimens: Entyvio SC 108 mg or placebo by subcutaneous injection every 2 weeks. Eligible patients included patients who had demonstrated an inadequate response to, loss of response to, or intolerance to at least one 12-week regimen of azathioprine or 6-mercaptopurine, induction with a tumor necrosis factor (TNF) blocker, or corticosteroids. The primary endpoint was clinical remission at Week 52, which was defined as a total Mayo score of less than or equal to 2 and no individual subscore greater than 1. The trial results demonstrated a statistically significant proportion of patients who received Entyvio SC 108 mg maintenance therapy administered every 2 weeks achieved clinical remission compared to patients who received placebo (46% vs. 14%; p<0.001) at Week 52. In clinical studies, the Entyvio SC safety profile was generally consistent with the known safety profile of intravenous Entyvio with the exception of injection site reactions reported with the subcutaneous formulation.

In April 2024, the FDA approved a label expansion for subcutaneous (SC) administration for maintenance therapy in adults with moderately to severely active Crohn’s disease (CD) after induction therapy with intravenous (IV) Entyvio (vedolizumab). FDA approval was based on the VISIBLE 2 Study (SC CD Trial), a Phase 3, randomized, double-blind, placebo-controlled trial, which assessed the safety and efficacy of a SC formulation of vedolizumab as maintenance therapy in adult patients with moderately to severely active CD who had clinical response (defined as a ≥70-point decrease in Crohn’s Disease Activity Index [CDAI] score from baseline [Week 0]) at Week 6 following two doses of open-label vedolizumab IV therapy at Weeks 0 and 2. The primary endpoint was clinical remission at Week 52, which was defined as a total CDAI score of less than or equal to 150 (Takeda, 2024a).

In VISIBLE 2 trial, a total of 409 patients were randomized at Week 6 in a double-blind fashion (2:1) to vedolizumab 108 mg administered by SC injection or placebo every 2 weeks. Study results at Week 52 showed that a statistically significant proportion of patients receiving vedolizumab SC 108 mg maintenance therapy administered every 2 weeks achieved clinical remission compared to patients receiving placebo (48% vs. 34%; p<0.01). Moreover, the safety profile of SC vedolizumab was generally consistent with the known safety profile of IV vedolizumab, with the addition of injection site reactions (including injection site erythema, rash, pruritus, swelling, bruising, hematoma, pain, urticaria and edema) as an adverse reaction for vedolizumab SC (Takeda, 2024a).

Crohn's Disease and Ulcerative Colitis

Crohn's disease (CD) and ulcerative colitis (UC) are 2 chronic inflammatory bowel diseases (IBDs). 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 anti-inflammatory agents, such as sulfasalazine, in conjunction with symptomatic treatment 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), immunosuppressants (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.  

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.

In a systematic review and meta-analysis, Li et al (2022) examined the safety and effectiveness of vedolizumab for the prophylaxis and treatment of GI involvement of aGVHD.  These investigators carried out literature search within PubMed, Embase, Web of Science, and Cochrane Library for observational studies and clinical trials that examined the effect of vedolizumab on GI-aGVHD through May 17, 2022.  A bi-variate and random-effect meta-analysis derived the pooled observational percentages and pooled risk ratios (RRs) from baseline of primary endpoints including overall response, complete response, mortality, and AEs.  There was a total of 122 participants in 8 eligible studies, including 1 study on the prophylactic use of vedolizumab and 7 studies on vedolizumab for the treatment of GI-aGVHD.  Of the 7 studies that reported details on baseline grades of GI-aGVHD, a total of 47 patients (47.95 %) were of stage-4, 31 patients (31.63 %) were of stage-3, 10 patients (10.2 %) were of stage-2, and 10 patients (10.2 %) were of stage-1.  The use of vedolizumab for the treatment of GI-aGVHD yielded a significantly improved objective response rate (ORR) at 14 days (pooled ORR = 60.53 %, pooled RR = 14.14, 95 % CI: 2.95 to 67.71), 28 days (pooled ORR = 50 %, RR = 7.36, 95 % CI: 2.14 to 25.37), and 12 months (pooled ORR = 76.92 %, RR = 13.66, 95 % CI: 3.5 to 53.35) from baseline.  Similarly, the use of vedolizumab was followed by a significantly improved complete response (CR) at 12 months (pooled CR = 27.27%, RR = 5.50, 95 % CI: 1.01 to 29.95), yet the CR at 14 days and 28 days did not reach statistical significance.  A total of 57 out of 87 (pooled overall survival, OS = 34.5 %) and 46 out of 65 (pooled OS = 29.2 %) patients expired at 6 and 12 months after the use of vedolizumab, respectively.  Prophylactic use of vedolizumab was not associated with any specific type of reported AEs, while patients with GI-aGVHD on vedolizumab presented with significantly increased risks of AEs including infections (RR = 7.55) and impaired metabolism or nutritional complications (RR = 9.00).  All analyses were of a low heterogeneity (all I-squares = 0 %).  The authors concluded that vedolizumab was safe and effective for the prophylaxis and management of early grade GI-aGVHD.  However, these researchers stated that more clinical evidence is needed to validate these findings.

The authors stated that this meta-analysis had several drawbacks.  First, the lack of unified definition of steroid-refractory aGVHD across studies, which resulted in different criteria for the initiation of vedolizumab treatment.  Second, due to the limited quantity of existing studies, not only clinical trials but also real-world studies and case series were included in the meta-analysis, which might compromise the external validity of the estimation on the effect of vedolizumab.  Third, due to the limited sample size of each study, underlying conditions of aGVHD such as the primary disease, conditioning regimen, the status of human leukocyte antigen (HLA) matching, as well as co-morbidities were not matched in the included studies, with which the lack of information might have resulted in residual confounding bias.

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, 2022) 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).

Comparison of Vedolizumab and Infliximab in Patients with Inflammatory Bowel Disease

Peyrin-Biroulet et al (2022) stated that there are limited comparative data for infliximab and vedolizumab in patients with IBD.  In a systematic review and meta-analysis, these investigators compared safety and effectiveness of infliximab and vedolizumab in adult patients with moderate-to-severe CD or UC.  They identified 6 eligible CD and 7 eligible UC studies that randomized over 1,900 participants per disease cohort to infliximab or vedolizumab.  In the CD and UC cohorts, infliximab yielded better effectiveness than vedolizumab for all analyzed outcomes (CDAI-70, CDAI-100 responses, and clinical remission for CD and clinical response and clinical remission for UC) during the induction phase, with non-overlapping 95 % CIs.  In the maintenance phase, similar proportions of infliximab- or vedolizumab-treated patients achieved clinical response, clinical remission, or mucosal healing in both CD and UC.  For the safety outcomes, rates of AEs, serious AEs, and discontinuations due to AEs were similar in infliximab- and vedolizumab-treated patients in both diseases.  The infection rate was higher in infliximab for CD and higher in vedolizumab when treating patients with UC.  There was no difference between the treatments in the proportions of patients who reported serious infections in both indications.  The authors concluded that indirect comparison of infliximab and vedolizumab trials in adult patients with moderate-to-severe CD or UC demonstrated that infliximab exhibited better effectiveness in the induction phase and comparable effectiveness during the maintenance phase and overall safety profile compared to vedolizumab.

Comparison of Vedolizumab and Tofacitinib in Patients with Ulcerative Colitis

Buisson et al (2023) stated that data comparing tofacitinib and vedolizumab in UC are lacking.  In a multi-center study, these investigators compared the effectiveness of tofacitinib and vedolizumab in patients with UC who had prior exposure to anti-TNF therapy.  They included consecutive UC patients (18 years of age or older) with partial Mayo score greater than 2 and prior anti-TNF exposure, who started tofacitinib or vedolizumab between January 2019 and June 2021.  Comparisons were carried out using propensity score analyses (inverse probability of treatment weighting).  A total of 126 and 178 patients received tofacitinib and vedolizumab, respectively.  Intensified induction (vedolizumab infusion at week 10 or tofacitinib 10 mg twice-daily until week 16) was performed in 28.5 % and 41.5 % of patients, respectively.  After propensity-score analysis, corticosteroid-free clinical remission (partial Mayo score of 2 or less) was achieved at week 16 in 45.1 % and 40.2 % of patients receiving tofacitinib and vedolizumab, respectively (aOR = 0.82 [0.35 to 1.91], p = 0.64).  Endoscopic improvement (corticosteroid-free clinical remission and endoscopic Mayo score of 1 or less) (aOR = 0.23 [0.08 to 0.65], p = 0.0032) and histological healing (endoscopic improvement + Nancy histological index of 1 or less) (13.4 % versus 3.2 %, aOR = 0.21 [0.05 to 0.91], p = 0.023) were higher at week 16 in patients treated with tofacitinib.  No factor was predictive of tofacitinib effectiveness.  At least 1 primary failure to a biologic (OR = 0.46 [0.22 to 0.99], p = 0.049), partial Mayo score of greater than 6 (OR = 0.39 [0.17 to 0.90], p = 0.029) and CRP level of greater than 30 mg/L at baseline (OR = 0.08 [0.01 to 0.85], p = 0.036) were associated with vedolizumab failure.  The authors concluded that tofacitinib and vedolizumab were effective in UC following failure of anti-TNF agents; however, tofacitinib appeared more effective, especially in severe disease and primary failure to biologics.

Comparison of Vedolizumab and Ustekinumab in Patients with Crohn's Disease

Kappelman et al (2023) noted that many patients with CD lose response or become intolerant to anti-TNF therapy and subsequently switch out of class.  In a retrospective, cohort study, these investigators compared the safety and effectiveness of ustekinumab to vedolizumab in a large, geographically diverse U.S. population of TNF-experienced patients with CD.  They used longitudinal claims data from a large U.S. insurer (Anthem, Inc.).  These researchers identified patients with CD initiating vedolizumab or ustekinumab with anti-TNF treatment in the prior 6 months.  The primary outcome was treatment persistence for more than 52 weeks.  Secondary outcomes included all-cause hospitalization, hospitalization for CD with surgery, hospitalization for CD without surgery, and hospitalization for infection.  Propensity score fine stratification was used to control for demographic and baseline clinical characteristics and prior treatments.  Among 885 new users of ustekinumab and 490 new users of vedolizumab, these investigators observed no difference in treatment persistence (adjusted RR of 1.09; 95 % CI: 0.95 to 1.25).  Ustekinumab was associated with a lower rate of all-cause hospitalization (adjusted hazard ratio 0.73 [0.59 to 0.91]), nonsurgical CD hospitalization (adjusted hazard ratio [HR] of 0.58 [0.40 to 0.83]), and hospitalization for infection (adjusted HR of 0.56 [0.34 to 0.92]).  The authors concluded that this real-world comparative effectiveness study of anti-TNF-experienced patients with CD initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalizations, non-surgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation.  These investigators advocated for individualized decision-making in this medically refractory population, considering patient preference and other factors such as cost and route of administration.

Switching from Intravenous to Subcutaneous Vedolizumab Maintenance Treatment for Inflammatory Bowel Diseases

Volkers et al (2022) noted that subcutaneous (SC) vedolizumab is effective in the treatment of IBD when administered following induction with 2 infusions.  In a prospective, cohort study, these investigators examined the safety, effectiveness, and pharmacokinetics of a switch from intravenous (IV) to SC maintenance vedolizumab in patients with IBD.  Patients with IBD who had 4 months or longer IV vedolizumab were switched to SC vedolizumab.  These researchers studied the time to discontinuation of SC vedolizumab, AEs, changes in clinical and biochemical outcomes and vedolizumab concentrations at baseline, and weeks 12 and 24.  This trial included 82 patients with CD and 53 with UC; 11 (13.4 %) patients with CD and 5 (9.4 %) with UC discontinued SC vedolizumab after a median of 18 (inter-quartile range [IQR] of 8 to 22) and 6 weeks (IQR of 5 to 10), respectively.  A total of 4 patients with CD switched to a different drug due to loss of response, 9 switched back to IV vedolizumab due to AEs, and 3 due to needle fear.  Common AEs were injection site reactions (n = 15) and headache (n = 6).  Median clinical and biochemical disease activity remained stable after the switch.  Median serum vedolizumab concentrations increased from 19 μg/ml at the time of the switch to 31 μg/ml 12 weeks after the switch (p < 0.005).  The authors concluded that switching from IV to SC vedolizumab maintenance treatment was effective in patients with CD or UC; however, 9 % of patients were switched back to IV vedolizumab due to AEs or fear of needles.

---

Appendix

Brands of Targeted Immune Modulators and FDA-approved Indications

Table: Brands of Targeted Immune Modulators and FDA-approved Indications (not an all-inclusive list)

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Cytokine release syndrome (CRS) Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Systemic sclerosis-associated interstitial lung disease (SSc-ILD)
Arcalyst	rilonacept	Cryopyrin-associated periodic syndromes Deficiency of interleukin-1 receptor antagonist (DIRA) Recurrent pericarditis
Cimzia	certolizumab	Ankylosing spondylitis or axial spondyloarthritis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis or axial spondyloarthritis Enthesitis-related arthritis 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 (for Humira biosimilars, see CPB 0655 - Adalimumab	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
Kevzara	sarilumab	Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Deficiency of interleukin-1 receptor antagonist (DIRA) Rheumatoid arthritis
Olumiant	baricitinib	Alopecia areata COVID-19 in hospitalized adults Rheumatoid arthritis
Orencia	abatacept	Acute graft versus host disease Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Oral ulcers associated with Behcet's disease Plaque psoriasis Psoriatic arthritis
Remicade (for Remicade biosimilars, see CPB 0341 - Infliximab)	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Rinvoq	upadacitinib	Atopic dermatitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Rituxan (for Rituxan biosimilars, see CPB 0314 - Rituximab	rituximab	Chronic lymphocytic leukemia Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis Various subtypes of non-Hodgkin's lymphoma
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Crohn's disease Plaque psoriasis Psoriatic arthritis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis Ulcerative colitis
Taltz	ixekinumab	Ankylosing spondylitis or axial spondyloarthritis  Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis Psoriatic arthritis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Ankylosing spondylitis Polyarticular Course Juvenile Idiopathic Arthritis Psoriatic arthritis Rheumatoid arthritis Ulcerative Colitis
Xeljanz XR	tofacitinib, extended release	Ankylosing spondylitis Polyarticular Course Juvenile Idiopathic Arthritis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis

---

References