Biologics

Introduction

Three categories of biologics, drugs manufactured from biological sources, are currently Food and Drug Administration (FDA)-approved for the treatment of ulcerative colitis (UC): tumor necrosis factor (TNF) blockers, integrin blockers and anti-interleukin (IL)-12 and -23 antagonists (Table 11-1). The approved TNF blockers available for the treatment of patients with UC include infliximab, adalimumab and golimumab, which target and bind TNFa, a cytokine involved in systemic inflammation. Vedolizumab, the only currently approved integrin inhibitor, prevents the migration of specific inflammatory cells into inflamed gastrointestinal parenchymal tissue. The most recent biologics to gain regulatory approval for UC ar ustekinumab, an IL-12/23 antagonist which binds to the p40 subunit present in both IL-12 and IL-23 and mirikizumab, an IL-23 antagonist that binds to the IL-23-specific p19 subunit.

Historically, biologics have been indicated for patients with moderately to severely active UC when other treatments have failed. This was the case for many years, until recently, where we now assess disease severity and patient prognosis at the time of presentation to help guide therapeutic treatment decisions. There are many variables which are evaluated when defining the patient’s severity of disease, including:

• Patient reported outcomes (e.g., rectal bleeding, stool frequency)
• Disease inflammatory burden, including endoscopic extent, severity of disease and serologic markers (e.g., noncardiac c-reactive protein (CRP), serum albumin, hemoglobin, fecal markers of disease [e.g., fecal calprotectin])
• Impact of disease on the patient (e.g., quality of life, patient functionality)
• Disease course (e.g., need for steroids, response to prior medications, need for being hospitalized).

Thus, treatment selection is chosen not only on the basis of the inflammatory activity, but also on the basis of the patient’s disease prognosis.

Specific indications for the approved biologic agents, per their prescribing information, are as follows:

• Infliximab for adult and pediatric (≥6 years of age) patients with moderately to severely active UC and with an inadequate response to conventional therapy.
• Adalimumab for adult and pediatric (≥5 years of age) patients with moderately to severely active UC.
• Golimumab for adult patients with moderate to severe UC and with an inadequate response or intolerance to prior treatment or requiring continuous steroid therapy.
• Vedolizumab for adult patients with moderately to severely active UC.
• Ustekinumab for adult patients with moderately to severely active UC.
• Mirikizumab for adult patients with moderately to severely active UC.

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TNFa Blockers

Infliximab, adalimumab and golimumab are TNFa blockers with similar mechanisms of action. Whereas adalimumab and golimumab are recombinant fully human monoclonal antibodies, infliximab is a chimeric monoclonal antibody, composed of human constant and murine variable regions. All three biologics target and bind both soluble and transmembrane forms of human TNFa, which prevents the binding of TNFa to its receptors (Figure 11-1). Biological activities normally affected by TNFa include the induction of pro­inflammatory cytokines, enhancement of leukocyte migration, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins and others. Although elevated TNFa levels are implicated in the pathogenesis of several chronic inflammatory disease, the exact mechanism by which these biologics exert their clinical effects in UC is unknown.

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Infliximab (Remicade)

Infliximab was first approved by the FDA in 1998 and is currently approved for the treatment for a variety of conditions, including Crohn’s disease, pediatric Crohn’s disease, UC, pediatric UC, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. The therapeutic indications of infliximab in UC are as follows:

• UC: Infliximab is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active UC who have had an inadequate response to conventional therapy.
• Pediatric UC: Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active UC who have had an inadequate response to conventional therapy.

In October 2023, an SC formulation of the infliximab biosimilar infliximab-dyyb received FDA approval for the treatment of moderately to severely active UC following treatment with an infliximab product administered by IV.

Efficacy in Adult UC

The safety and efficacy of infliximab for the treatment of adults with UC were assessed in two randomized clinical trials, ACT 1 and ACT 2, which enrolled a total of 728 patients. Eligible patients had moderately to severely active UC with an inadequate response to conventional oral therapies. Patients in ACT 1 had failed to respond or were intolerant to oral corticosteroids, 6­-mercaptopurine, or azathioprine, whereas patients in ACT 2 had failed to respond or were intolerant to the above treatments and/or aminosalicylates. Eligible patients were randomized to receive either placebo, infliximab 5 mg/kg, or infliximab 10 mg/kg at Weeks 0, 2, 6 and every 8 weeks thereafter.

Patients were permitted to receive concomitant treatment with stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents; corticosteroid taper was permitted after Week 8. Treatment was administered until Week 46 and Week 22 in ACT 1 and ACT 2, respectively. In ACT 2, patients could continue blinded therapy to Week 46 at the investigator’s discretion. The primary endpoint of the trials was clinical response, defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1. Key secondary endpoints included clinical remission, mucosal healing and others.

In both ACT 1 and ACT 2, a greater proportion of infliximab-treated patients achieved clinical response, clinical remission and mucosal healing compared to the placebo group, with benefits being maintained through the end of each trial (Figure 11-2; Table 11-2). A greater proportion of infliximab-treated patients also demonstrated sustained response and sustained remission. Improvements across all Mayo subscores were also observed with infliximab through Week 54. Efficacy was generally similar in the infliximab 5 mg/kg and 10 mg/kg treatment groups.

In patients who were on corticosteroids at baseline, a greater proportion of those receiving infliximab were in clinical remission and able to discontinue corticosteroids at Week 30 compared to patients receiving placebo (ACT 1: 22% infliximab vs 10% placebo; ACT 2: 23% infliximab vs 3% placebo). This effect was maintained through Week 54 in ACT 1 (21% infliximab vs 9% placebo).

As in Crohn’s disease, the efficacy of combination therapy with infliximab plus azathioprine has been studied. In a landmark study by Panaccione and colleagues, anti–TNF-naïve patients with moderate to severe UC treated with infliximab plus azathioprine were more likely to achieve remission at 16 weeks, and demonstrate mucosal healing compared to patients treated with infliximab alone.

The efficacy of the SC formulation of the biosimilar infliximab-dyyb was assessed in the LIBERTY UC trial. In this study, a total of 438 patients with moderately to severely active UC were randomized (2:1) to receive open-label SC infliximab-dyyb or a placebo every 2 weeks. At Week 54, compared to patients in the placebo group, significantly more patients who received SC infliximab-dyyb achieved the primary endpoint of clinical remission (43.2% vs 20.8%; P <0.0001) and the secondary endpoint of clinical response (53.7% vs 31.3%; P <0.0001), endoscopic-histologic mucosal improvement (35.7% vs 16.7%; P <0.0001), and corticosteroid-free remission (36.7% vs 18.0%; P = 0.0127). Another trial of 131 adult patients with IBD (of which 78 had UC) established that, following a 6-week IV infliximab-dyyb induction period, the pharmacokinetics of SC infliximab-dyyb were noninferior to those of IV infliximab-dyyb, and that the immunogenicity, safety, and efficacy profiles of the two administration groups were comparable. The efficacy of switching from IV to SC infliximab was assessed in the REMSWITCH study. In this observational study of IBD patients in clinical remission on IV infliximab, switching to SC infliximab (120 mg every other week) was safe and generally effective, with relapse rates of 10.2% (6/59 patients), 7.3% (3/38 patients), 16.7% (3/18 patients), and 66.7% (10/15 patients) in the baseline IV infliximab 5 mg/kg/8 weeks, 10 mg/kg/8 weeks, 10 mg/kg/6 weeks, and 10 mg/kg/4 weeks groups, respectively. Among the patients who relapsed, 15/22 received a dose escalation to 240 mg SC infliximab every 2 weeks, which resulted in remission recapture in 14/15 patients.

Efficacy in Pediatric UC

Safety and efficacy data for the use of infliximab in reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients were obtained from a phase 3, randomized, open-label trial (NCT00336492). Eligible patients were 6 to 17 years of age with moderately to severely active UC and had an inadequate response to conventional therapies. At baseline, 53% of patients were receiving immunomodulator therapy with azathioprine, 6-mercaptopurine, or methotrexate and 62% were receiving corticosteroids at a median dose of 0.5 mg/kg/day in prednisone equivalents. All patients received induction dosing of infliximab 5 mg/kg at Weeks 0, 2 and 6. Nonresponders at Week 8 discontinued treatment. Responders were randomized to receive a maintenance regimen of either infliximab 5 mg/kg Q8W through Week 46 or Q12W through Week 42. If a loss of response was experienced, patients could switch to a higher dose or a more frequent dosing schedule.

Clinical response was defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, including a decrease in the rectal bleeding subscore by ≥1 points or achievement of a rectal bleeding subscore of 0 or 1. At Week 8, 44 of 60 patients were in clinical response; 23 of 32 patients taking concomitant immunomodulators at baseline achieved clinical response, compared to 21 of 28 patients who were not taking concomitant immunomodulators at baseline.

Clinical remission was assessed at Week 8 and Week 54 and defined by a PUCAI score of <10 points. At Week 8, 17 of 51 patients were in clinical remission. At Week 54, 8 of 21 patients in the Q8W group and 4 of 22 patients in the Q12W group achieved remission.

During maintenance, 23 of 45 randomized patients required an increase in dose or frequency of administration due to loss of response; 9 of these 23 patients achieved remission at Week 54.

Safety

In ACT 1 and 2, the proportion of patients with AEs were similar across treatment groups (Table 11-3). In ACT 1, serious adverse events occurred in 25.6% of patients in the placebo group, compared to 21.5% and 23.8% of patients receiving infliximab 5 mg and 10 mg, respectively. The corresponding rates in ACT 2 were 19.5%, 10.7% and 9.2%, respectively. A similar number of patients across treatment groups discontinued treatment due to AEs in ACT 1; a greater proportion of placebo-treated patients discontinued treatment in ACT 2 compared to those treated with infliximab (P=0.01). Three neurologic events occurred, all in infliximab-treated patients. Rates of infection were similar among treatment groups in both studies. Infusion reactions occurred in 10.7% of placebo-treated patients of ACT 1 compared to 9.9% and 12.3% of patients receiving infliximab 5 mg and 10 mg, respectively. Corresponding rates in ACT 2 were 8.1%, 11.6% and 11.7%, respectively.

In pediatric patients, infliximab was generally well tolerated and had a safety profile consistent with that reported in ACT 1 and 2. In NCT00336492, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever and headache. The safety profile of SC infliximab in LIBERTY UC was generally comparable to that of the placebo, with no new safety signals emerging in this or other trials of SC infliximab.

Dosage and Administration

The prescribing information for infliximab recommends that it be administered by intravenous injection over a period of no less than 2 hours. However, it should be noted that there are studies demonstrating that it can be administered safely over shorter infusion periods of ≤1 hour. It is intended for use under the guidance and supervision of a physician. In adults with moderately to severely active UC, the recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter. In pediatric patients 6 years and older with moderately to severely active UC, the recommended dose is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks. Frequently, dose escalation from 5 mg/kg to 10 mg/kg every 4 weeks is performed to treat patients with active disease. These commonly used doses, however, are not FDA approved. The concomitant use of infliximab with other biologics is not currently recommended due to the possibility of an increased risk of infection.

The biosimilar infliximab-dyyb is available for SC administration, at a recommended dose of 120 mg every other week; this formulation is intended as maintenance treatment, after at least 10 weeks of IV infliximab (or infliximab biosimilar). It is available in the form of a pre-filled, single-dose (120 mg) syringe, syringe with needle guard, or pen. The first 120 mg dose of SC infliximab is administered in place of the next scheduled IV infliximab dose, and every 2 weeks thereafter. The SC injection is usually given by a healthcare professional, but, if deemed appropriate by the healthcare provider, may also be administered by a caretaker or the patient him- or herself, following training. Appropriate injection areas include the front of the thighs, the abdomen except for the 2 inches around the navel, or the outer area of the upper arms (healthcare professional or caregiver only).

Approximately 20% of infliximab-treated patients experienced an infusion reaction in clinical trials compared to 10% of placebo-treated patients. Prior to intravenous administration of infliximab, premedication (e.g., antihistamines, acetaminophen and/or corticosteroids) may be administered at the physician’s discretion. Mild or moderate infusion reactions may improve following slowing of the infusion rate. The infusion can also be suspended until the infusion reaction is resolved, followed by reinitiation at a lower infusion rate and/or with premedication. If patients do not tolerate infliximab following these interventions, then treatment should be discontinued. In patients who experience severe infusion-related hypersensitivity, treatment with infliximab should also be discontinued.

In a study evaluating infliximab in patients with moderate-to-severe congestive heart failure, infliximab 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening congestive heart failure. As such, infliximab use in patients with moderate-to-severe heart failure should be discussed in detail with the patient’s cardiologist to review the risk vs benefit of infliximab use in this scenario.

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Adalimumab (Humira)

Adalimumab was originally approved by the FDA in 2002 and is currently indicated for a range of conditions, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease (CD), pediatric CD, ulcerative colitis (UC), plaque psoriasis, Hidradenitis Suppurativa and uveitis. It is indicated for treatment of moderately to severely active ulcerative colitis in adults and pediatric patients 5 years of age and older. The effectiveness of adalimumab has not been established in patients who have lost response to or were intolerant to TNF blockers.

Efficacy

The safety and efficacy of adalimumab were assessed in two randomized, placebo-controlled trials: ULTRA 1 and 2. The trials enrolled adult patients with moderately to severely active UC despite concurrent or prior treatment with immunosuppressants. Patients in ULTRA 1 were TNF-blocker–naïve, whereas ULTRA 2 permitted enrollment of patients who lost response to, or were intolerant to, TNF-blockers. Concomitant treatment with stable doses of aminosalicylates and immunosuppressants was permitted in both trials.

In ULTRA 1, 390 TNF-blocker naïve patients were randomized to the following treatment groups:

• Placebo Q2W
• Adalimumab 160 mg at Week 0, 80 mg at Week 2, followed by 40 mg Q2W
• Adalimumab 80 mg at Week 0, 40 mg at Week 2, followed by 40 mg Q2W

In ULTRA 2, 518 patients were randomized to the following treatment groups:

• Placebo Q2W
• Adalimumab 160 mg at Week 0, 80 mg at Week 2, followed by 40 mg Q2W

The primary efficacy endpoint in both trials was the proportion of patients achieving clinical remission, defined as Mayo score ≤2 with no individual subscores >1, assessed at Week 8 in ULTRA 1 and at Weeks 8 and 52 in ULTRA 2. Sustained clinical remission was also evaluated in ULTRA 2.

In both studies, a significantly greater proportion of patients treated with adalimumab 160/80 mg achieved clinical remission at Week 8 and at Week 52 in ULTRA 2, compared with placebo (Figure 11-3). In ULTRA 1, a significant improvement in clinical remission was not reached in the adalimumab 80/40 mg group at Week 8. In ULTRA 2, sustained clinical remission (clinical remission at both Weeks 8 and 52) was achieved by a significantly greater proportion of patients treated with adalimumab 160/80 mg compared to placebo (8.5% vs 4.1%).

In the TNF-blocker–experienced subgroup of patients in ULTRA 2, the effect of adalimumab on clinical remission was less pronounced at Week 8 (9% vs 7% for placebo). Treatment effects were similar in this subgroup compared to the overall population at Week 52 for clinical remission (10% vs 3% for placebo) and sustained clinical remission (5% vs 1% for placebo).

Safety

Selected safety results for ULTRA 1 and 2 are shown in Table 11-4. In the 52-week ULTRA 2 trial, adalimumab was generally well-tolerated, with an overall safety profile comparable to that of placebo. However, a significantly greater proportion of adalimumab-treated patients did report injection site-related and hematologic-related adverse events compared to placebo-treated patients. The hematologic-related adverse events were reported in patients who were all taking concomitant immunosuppressants at baseline and these resolved by the end of the study. There were numerical, but nonsignificant, increases in the incidence of serious adverse events, severe adverse events, infectious adverse events and adverse events leading to discontinuation in the placebo-treated group. Two adalimumab-treated patients experienced malignancies: one squamous cell carcinoma and one gastric cancer. No deaths, lymphoma, or tuberculosis were reported in ULTRA 2.

Dosage and Administration

Adalimumab is administered by subcutaneous injection. The recommended adalimumab dosing regimen for adult patients with UC is:

• Day 1: 160 mg, given in one day or split over two consecutive days
• Day 15 (2 weeks later): 80 mg
• Day 29 (2 weeks later): 40 mg Q2W

It has been suggested that treatment with adalimumab should only be continued in patients who have shown evidence of clinical remission by Day 57 (Week 8) of therapy.

Adalimumab is intended for use under the guidance and supervision of a physician. However, a patient may self-inject or a caregiver may inject it if a physician determines it to be appropriate after proper training and with medical follow-up as necessary. Adalimumab is available in several dosage strengths in single-use prefilled pens, syringes and glass vials. Prefilled glass vials are for administration within an institution setting only, such as a hospital, physician’s office, or clinic. Injections should be given at separate sites in the thigh or abdomen. Injection sites should be rotated and should not be injected into areas that are tender, bruised, red, or hard.

Continued treatment with aminosalicylates and/or corticosteroids is permitted during treatment with adalimumab. Treatment with azathioprine and 6-mercaptopurine may be continued if necessary.

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Golimumab (Simponi)

Golimumab was first approved in 2009 and currently has indications for the treatment of UC, rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. In UC, golimumab is indicated in adult patients with moderately to severely active UC who have demonstrated corticosteroid dependence or who have had an inadequate response to or failed to tolerate oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine. It is indicated for:

• Inducing and maintaining clinical response
• Improving endoscopic appearance of the mucosa during induction
• Inducing clinical remission
• Achieving and sustaining clinical remission in induction responders.

Efficacy

The safety and efficacy of golimumab were assessed in two randomized, double-blind, placebo-controlled clinical trials: PURSUIT-SC and PURSUIT-Maintenance.

PURSUIT-SC was an induction trial that enrolled patients ≥18 years of age with moderately to severely active UC and a baseline endoscopy subscore of 2 or 3 on a 3-point scale. Patients were also corticosteroid dependent or had an inadequate response to, or had failed to tolerate, at least one of the following therapies: oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine. TNF-inhibitor–experienced patients were ineligible.

In the dose-finding part of PURSUIT-SC, patients were randomized to one of four treatment groups: golimumab 400 mg at Week 0 and 200 mg at Week 2 (400/200); golimumab 200 mg at Week 0 and 100 mg at Week 2 (200/100); golimumab 100 mg at Week 0 and 50 mg at Week 2 (100/50); or placebo at Weeks 0 and 2. In the dose-confirming part of PURSUIT-SC, efficacy was evaluated in 761 patients randomized to the 400/200, 200/100 and placebo groups. Patients were permitted concomitant use of oral aminosalicylates, oral corticosteroids (<40 mg/day), azathioprine, 6-mercaptopurine and/or methotrexate. The primary endpoint of the trial was the proportion of patients in clinical response at Week 6, defined as a decrease from baseline in the Mayo score of ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1.

At Week 6 of PURSUIT-SC, a greater proportion of patients in the golimumab 200/100 mg group achieved clinical response, clinical remission (Mayo score ≤2 points, with no individual subscore >1), and demonstrated improvement in the endoscopic appearance of the mucosa (Mayo endoscopy subscore of 0 or 1) compared to placebo-treated patients (Table 11-5; Figure 11-4). No additional clinical benefit was achieved in the golimumab 400/200 mg group.

PURSUIT-Maintenance was a randomized-withdrawal maintenance trial that enrolled patients who had completed one of two induction studies: PURSUIT-SC or PURSUIT-IV. Patients who had achieved clinical response following golimumab induction and tolerated treatment were randomized to receive subcutaneous golimumab 50 mg, golimumab 100 mg, or placebo every 4 weeks. Concomitant treatment with stable doses of oral aminosalicylates, azathioprine, 6-mercaptopurine, and/or methotrexate were permitted, but corticosteroids were tapered at the start of the maintenance trial. The primary endpoint was the proportion of patients maintaining clinical response through Week 54.

Compared to placebo, a greater proportion of patients in the golimumab 100-mg group maintained clinical response through Week 54 in PURSUIT-Maintenance (Table 11-5; Figure 11-5). A greater proportion of golimumab-treated patients also achieved clinical remission at both Week 30 and Week 54, without demonstrating a loss of response at any time point through Week 54.

Safety

In PURSUIT-Maintenance, 66.0%, 72.7% and 73.4% of patients in the placebo, golimumab 50 mg and golimumab 100-mg groups reported one or more treatment-emergent AE, respectively (Table 11-6). Serious adverse events were reported in 7.7%, 8.4% and 14.3% in the corresponding treatment groups. Infection rates were 28.2%, 39.0%, and 39.0%, and serious infection rates were 1.9%, 3.2%, and 3.2%, respectively. Discontinuation rates due to adverse events through Week 54 were 6.4%, 5.2% and 9.1%, respectively. Injection site reactions occurred in 1.9%, 1.9%, and 7.1% of patients in the corresponding treatment groups, with none being serious and no anaphylactic reactions being reported.

Dosage and Administration

Golimumab is available in 50 mg and 100 mg strengths, in either prefilled SmartJect^â autoinjectors or syringes. The recommended golimumab induction dosage regimen is 200 mg administered subcutaneously at Week 0, followed by 100 mg at Week 2, then maintenance therapy with 100 mg every 4 weeks. Golimumab is intended to be used under the guidance and supervision of a healthcare provider. A patient may self-inject with golimumab only after a patient has received proper training in subcutaneous injection technique and a healthcare provider determines that it is appropriate.

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Warning and Precautions with TNF Blockers

The prescribing information for infliximab, golimumab and adalimumab all contain boxed warnings for serious infections and malignancy, in addition to several other shared warnings and precautions (Table 11-1).

Therapeutic Drug Monitoring

When using anti-TNF agents such as infliximab and adalimumab in the treatment of UC, reactive drug monitoring has been recommended to guide treatment changes. Trough values should be obtained just prior to the next administration, with the target trough concentrations of ≥5 ug/ml of infliximab and ≥7.5 ug/ml for adalimumab. High antibody values along with low or no serum drug concentrations may indicate a reason to change to an alternative agent. There are no clear recommendations on proactive drug monitoring and further study is needed in this area to guide this therapeutic maneuvering going forward. Intense study is underway regarding measuring drug concentrations and antibody development with the newer biologic agents with various mechanisms of action.

Infections

Patients treated with TNF blockers are at an in­creased risk for developing serious infections that may lead to hospitalization or death. Most patients who develop these infections were taking concomitant immunosuppressants. Patients older than 65 years of age, with comorbid conditions and/or taking concomitant immunosuppressants may be at greater risk for infection. TNF blockers should not be given during an active infection and should be discontinued if a patient develops a serious infection or sepsis. Cases of reactivation of tuberculosis or new tuberculosis infections have been reported in patients receiving TNF blockers. Patients should therefore be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating infliximab and periodically during therapy. All patients should be monitored for active tuberculosis during treatment, even if initial latent tuberculosis tests were negative. Treatment for tuberculosis should be started before initiating anti-TNF therapy. Due to a greater risk of serious infections, the concomitant use of TNF blockers with abatacept or anakinra is not recommended.

Malignancies

Malignancies have been reported among patients who received treatment with TNF blockers, including lymphoma melanoma and others. Among pediatric and young adult patients, approximately half of the malignancies were lymphomas, with the others representing a variety of types, including melanoma as well as rare malignancies typically associated with immunosuppression and those not typically observed in children and adolescents. Most malignancies were reported in patients who were receiving concomitant immunosuppressants. Rare cases of hepatosplenic T­cell lymphoma (HSTCL), a type of T-cell lymphoma that has a very aggressive disease course, have been reported in postmarketing studies of patients treated with TNF-blocking agents. Nearly all cases of HSTCL occurred in patients with CD or UC, with the majority in adolescent and young adult males who had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. The risks and benefits of TNF-blocker treatment should be considered prior to initiating therapy in patients with a known malignancy (other than a successfully treated nonmelanoma skin cancer) or when continuing treatment in a patient who develops a malignancy.

Hypersensitivity Reactions

Hypersensitivity reactions have been reported with TNF blockers, some occurring following the first administration of the drug. If an anaphylactic or other serious allergic reaction occurs, administration of TNF blockers should be discontinued immediately and appropriate therapy instituted.

Live Vaccines

Live vaccines or therapeutic infectious agents should not be given concurrently with TNF blockers. Patients should be brought up to date with all vaccinations prior to initiating therapy whenever possible. A waiting period of at least 6 months is recommended prior to administration of live vaccines in newborns exposed to infliximab in utero. Screening for latent tuberculosis and hepatitis B status is advised in all patients prior to initiating anti TNF therapy.

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Integrin a4b7 Blockers

Vedolizumab (Entyvio)

Vedolizumab is a humanized monoclonal antibody that targets a4b7 integrin, blocking its interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Integrins are a group of heterodimeric cell adhesion proteins, composed of one a and one b subunit, which are expressed on the cell surface. Integrins play a crucial role in cell migration as they are capable of binding to molecules in the extracellular matrix, such as MAdCAM-1, to allow adhesion and movement. The a4b7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. The interaction of the a4b7 integrin with MAdCAM-1 is an important contributor to chronic inflammation that is a hallmark of UC and CD. Vedolizumab inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue by blocking the interaction of integrins on the leukocyte surface with the intestinal vasculature (Figure 11-6). Vedolizumab does not bind to a4b1 or aEb7 integrins and does not antagonize the interaction of a4 integrins with vascular cell adhesion molecule-1 (VCAM-1).

Vedolizumab was approved by the FDA in 2014 for CD and UC. In September 2023 and April 2024, a formulation of vedolizumab intended for SC administration was approved by the FDA for the treatment of UC and CD, respectively. Vedolizumab is currently indicated in adults for the treatment of. It is currently indicated in adults for the treatment of:

• Moderately to severely active UC
• Moderately to severely active CD

Efficacy

The safety and efficacy of vedolizumab in UC was evaluated in a randomized, double-blind, placebo-controlled trial: GEMINI 1, which consisted of two separate trials of induction (UC Trial 1) and maintenance therapy (UC Trial 2). The GEMINI 1 trial enrolled adult patients with moderately to severely active UC. Additional criteria for patients enrolled in the United States included prior inadequate response or intolerance to immunomodulator therapy over a 5-year period and/or inadequate response, loss of response, or intolerance to a TNF blocker. Patients enrolled outside the United States were required to have been corticosteroid dependent or to have had an inadequate response with, or intolerance to, corticosteroids over the previous 5-year period. Exclusion criteria included prior treatment with natalizumab, another integrin inhibitor, or treatment with a TNF blocker within the past 60 days.

In UC Trial 1, 374 patients were randomized to receive vedolizumab 300 mg or placebo at Week 0 and Week 2. Concomitant stable doses of aminosalicylates, corticosteroids (prednisone ≤30 mg/day or equivalent) and immunomodulators (azathioprine and 6-mercaptopurine) were permitted through Week 6. The primary efficacy endpoint of UC Trial 1 was clinical response at Week 6, defined as a reduction in the Mayo Clinic score of ≥3 points and a decrease of ≥30% from the baseline score, with a decrease of ≥1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1. Secondary outcomes included clinical remission at Week 6 (defined as complete Mayo score of ≤2 points and no individual subscore >1 point) and improvement of endoscopic appearance of the mucosa at Week 6 (defined as a Mayo endoscopy subscore of 0 or 1).

At Week 6, a greater proportion of patients in the vedolizumab group achieved clinical response vs placebo (47% vs 26%; P <0.001; Table 11-7). A greater percentage of patients treated with vedolizumab also achieved clinical remission (17% vs 5%; P = 0.001) and had improvement of endoscopic appearance of the mucosa (41% vs 25%; P = 0.001).

UC Trial 2 enrolled patients who had received vedolizumab and were in clinical response at Week 6. Patients could have come from UC Trial 1 or, to meet the sample size requirements in the maintenance part of the trial, a group that received vedolizumab open-label. Starting at Week 6, 373 patients were randomized to receive vedolizumab 300 mg every 8 weeks, vedolizumab 300 mg every 4 weeks, or placebo every 4 weeks. Patients who achieved clinical response at Week 6 and were receiving corticosteroids were required to initiate a corticosteroid-tapering regimen. Concomitant corticosteroids and aminosalicylates were permitted through Week 52; however, concomitant immunomodulators were not allowed beyond Week 6 in the United States. The primary endpoint of UC Trial 2 was clinical remission at Week 52. Secondary endpoints included durable clinical response (response at both Week 6 and 52), durable clinical remission (remission at both Week 6 and 52), mucosal healing at Week 52, and corticosteroid-free remission at Week 52 in patients receiving glucocorticoids at baseline.

At Week 52 of UC Trial 2, a greater proportion of patients treated with vedolizumab every 8 weeks achieved clinical remission (42% vs 16%, P <0.001; Table 11-7). In addition, a great proportion of patients treated with vedolizumab every 8 weeks maintained clinical response (57% vs 24%; P <0.001) were in clinical remission at both Weeks 6 and 52 (21% vs 9%; P=0.008) and had improvement of endoscopic appearance of the mucosa at Week 52 (52% vs 20%; P <0.001). Among patients who received glucocorticoids at baseline, more patients treated with vedolizumab every 8 weeks achieved glucocorticoids-free remission at Week 52 compared to placebo-treated patients (31% vs 14%; P = 0.012). No additional treatment benefits were obtained in patients receiving vedolizumab every 4 weeks, so this treatment regimen is not recommended.

In the EARNEST trial, a phase 4, double-blind, randomized study, vedolizumab also demonstrated good efficacy for the treatment of pouchitis. This inflammation of the ileal pouch is the most common postoperative complication of proctocolectomy with ileal-pouch anal anastomosis (IPAA), itself the most common surgery for UC (see SURGERY). A total of 101 adult patients with post-IPAA pouchitis were randomized to vedolizumab 300 mg (n=51) or placebo (n=51) at day 1 and at weeks 2, 6, 14, 22 and 30; patients in both groups received ciprofloxacin 500 mg twice daily through week 4. At Week 14, 31% of patients in the vedolizumab group and 10% of patients in the placebo group (unadjusted between-group difference: 21%; P=0.01) achieved the primary endpoint of modified Pouchitis Disease Activity Index (mPDAI) remission (defined as an mPDAI score of ≤4 [scores range from 0 to 12, with higher scores indicating greater disease severity] and a reduction from baseline of ≥2 points).

The safety and efficacy of SC vedolizumab for UC treatment was assessed in a phase 3, randomized, double-blind trial in a total of 383 patients with moderate to severe UC. After a two open-label IV vedolizumab injections on week 0 and 2, patients with a clinical response were randomized (2:1:1) at week 6 to vedolizumab SC 108 mg every 2 weeks (with an IV placebo every 8 weeks), vedolizumab IV 300 mg every 8 weeks (with an SC placebo every 2 weeks), or a double placebo (SC every 2 weeks and IV every 8 weeks). The primary endpoint was clinical remission at week 52, which was achieved by 46.2% of patients in the SC vedolizumab group, which was similar to the patients in the IV vedolizumab group (42.6%), and significantly higher than in the placebo group (14.3%; P <0.001). Compared to the placebo group, significantly more patients in the SC vedolizumab group achieved endoscopic improvement and durable clinical remission at week 52 (P <0.001 for both comparisons).

The approval of SC vedolizumab for CD was based on positive results from the randomized, double-blind, placebo-controlled, phase 3 trial, VISIBLE 2. In this trial of 410 patient randomized (2:1) to SC vedolizumab or placebo after induction with IV vedolizumab, 48.0% of patients in the SC vedolizumab group maintained clinical remission, compared to 34.3% of those in the placebo group (P = 0.008).

Safety

Key safety results from UC Trial 2 are shown in Table 11-8. Frequencies of common adverse events were similar across treatment groups. Serious infections were not more common with vedolizumab than with placebo. Unlike other anti-integrin therapies, treatment with vedolizumab did not increase peripheral blood total lymphocyte counts. Few clinically important infusion reactions occurred with vedolizumab. The safety profile of SC vedolizumab was generally similar to that of IV vedolizumab in clinical trials, with only an increased frequency of injection-site reactions noted as a new safety signal. In the UC trial, injection-site reactions occurred in 10.4% of patients in the SC vedolizumab group, compared to 1.9% of patients who received IV vedolizumab.

Warnings and Precautions

The prescribing information for vedolizumab lists warnings and precautions for infusion-related reactions and hypersensitivity reactions, infections, progressive multifocal leukoencephalopathy, liver injury and for live and oral vaccines.

Hypersensitivity reactions occurred in clinical trials of vedolizumab, including a case of anaphylaxis (0.07%). Treatment with vedolizumab should be discontinued immediately if anaphylaxis or another serious allergic reaction occurs. The use of vedolizumab is contraindicated in patients who have previously had a severe or serious hypersensitivity reaction to either vedolizumab or any excipients of vedolizumab-containing products.

Clinical trials and real-world cohorts indicate an exposure-efficacy relationship for vedolizumab in UC. A post-hoc analysis of data from the GEMINI trials revealed that trough levels of less than 17 μg/mL showed clinical remission rates comparable to the placebo, while higher concentrations were associated with higher clinical remission rates. Data from a large retrospective Belgian study similarly demonstrated a link between higher vedolizumab exposure and increased efficacy.

Patients treated with vedolizumab have an increased risk of developing infections. Upper respiratory and nasal mucosa infections were the most commonly reported infections in clinical trials occurring at a rate greater with vedolizumab than placebo. Vedolizumab is not recommended in patients with active, severe infections until they are controlled. Caution is particularly recommended in patients with a history of recurring severe infections.

Another integrin receptor antagonist natalizumab (Tysabri) is associated with a rare and often fatal opportunistic infection of the central nervous system called progressive multifocal leukoencephalopathy (PML). In trials of vedolizumab, patients were monitored for PML, with no cases identified among patients with at least 23 months of exposure in the trials. However, a risk for PML cannot be dismissed. Patients receiving vedolizumab should therefore be monitored for any new onset or worsening of neurological signs and symptoms related to progressive PML, including progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision and changes in thinking, memory and orientation leading to confusion and personality changes. If PML is suspected, vedolizumab should be withheld and the patient should be referred to a neurologist. If PML is confirmed, vedolizumab should be discontinued permanently.

Prior to initiating treatment with vedolizumab, patients should be brought up to date with all immunizations according to current immunization guidelines. Patients may receive non-live vaccines during treatment and may receive live vaccines only if the benefits outweigh the risks.

Dosage and Administration

Vedolizumab for IV infusion is available in single-use vials containing 300 mg lyophilized powder. The recommended dose of vedolizumab in adults with UC is 300 mg administered by intravenous infusion over 30 minutes at Week 0, 2, and 6, then then every 8 weeks thereafter. In clinical practice, 300-mg vedolizumab IV every 4 to 6 weeks is used as a non–FDA-approved dosing regimen. Vedolizumab for SC injection is available in the form of a 108 mg single-dose pre-filled syringe or pen. The recommended dosage is 108 mg every 2 weeks. Vedolizumab SC should be administered by a healthcare professional, or, following proper training, a caregiver or the patient him- or herself. The dose should be injected in the thigh, any quadrant of abdomen, or upper arms (the patient should not self-administer in the upper arm). Vedolizumab therapy should be discontinued in patients who show no evidence of therapeutic benefit by Week 14. Vedolizumab is contraindication in patients who have had a known serious or severe hypersensitivity reaction to vedolizumab or any excipients of vedolizumab-containing medicinal products.

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Interleukin-12/23 Antagonists

Ustekinumab (Stelara)

Ustekinumab is a monoclonal antibody targeting the p40 subunit of IL-12 and IL-23 cytokines. Approved for the treatment of CD in 2016, followed by plaque psoriasis in 2017, ustekinumab more recently gained regulatory approval for UC in 2019 based on positive data from the phase 3 UNIFI trial. Ustekinumab is indicated for the treatment of adult patients with moderately to severely active UC.

IL-12 and IL-13 have both been identified as important contributors to the chronic inflammation characteristic of CD and UC. They are involved in inflammatory and immune responses, including natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab has been shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by interfering with the interaction of these cytokines with a shared cell-surface receptor, IL-12Rβ1 (Figure 11-7).

Efficacy

The efficacy of ustekinumab in the treatment of UC was assessed in the UNIFI trial, which included an 8-week randomized induction trial and a 44-week randomized maintenance trial. UNIFI included adult patients with UC for three or more months before screening, moderate-to-severe disease and an inadequate response to or intolerance to TNF antagonists, vedolizumab, or conventional therapy. Aminosalicylates and immunomodulators were maintained at stable doses through week 44 of the maintenance trial. Oral corticosteroids were maintained during the induction trial but tapered during the maintenance trial.

During the induction trial, patients were randomized 1:1:1 to receive 130 mg of IV ustekinumab, 6 mg/kg IV ustekinumab, or placebo. Patients with a clinical response to IV ustekinumab at week 8 (defined as a decrease in the total Mayo score of ≥30% and of ≥3 points from baseline, with a decrease of ≥1 point on the rectal bleeding component of the Mayo scale or a rectal bleeding subscore of 0 or 1) then entered the maintenance trial. Patients who did not respond to IV placebo and who then received an induction dose of 6 mg/kg IV ustekinumab at week 8 and had a response at week 16 also entered the maintenance trial. In the maintenance trial, patients were randomized 1:1:1 to 90 mg subcutaneous ustekinumab every 12 weeks, 90 mg of subcutaneous ustekinumab every 8 weeks, or placebo through week 40. Patients were monitored for clinical flairs during maintenance therapy. The primary endpoint of the induction trial was clinical remission at week 8, defined as a total Mayo score of ≤2 and no subscore >1. The primary end point in the maintenance trial was clinical remission at week 44.

At week 8, 5.3% of placebo-treated patients reached clinical remission compared to 15.6% of 130 mg ustekinumab-treated patients (P<0.001) and 15.5% 6 mg/kg ustekinumab-treated patients (P<0.001; Figure 11-8). Among those who had a clinical response to induction treatment with ustekinumab, 24.0% of placebo-treated patients reached clinical remission at week 44 compared to 38.4% of patients treated with 90 mg ustekinumab Q12W (P=0.002) and 43.8% of patients treated with 90 mg ustekinumab Q8W (P<0.001).

Safety

Adverse reactions reported in at least 3% of ustekinumab-treated patients and at a higher rate than with placebo were nasopharyngitis (7% vs 4%) in the induction trial and nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs. 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%) and nausea (3% vs 2%) in the maintenance trial.

Serious or other clinically significant infections included gastroenteritis and pneumonia. Additionally, listeriosis and ophthalmic herpes zoster were reported in one patient each.

Following up to one year of treatment with ustekinumab in the UNIFI trial, 0.4% of ustekinumab-treated patients (0.48 events per hundred patient-years) and 0.0% of placebo-treated patients (0.00 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated patients and 0.2% of placebo-treated.

Warnings and Precautions

The prescribing information for ustekinumab lists warnings and precautions for infections, malignancies, hypersensitivity reactions, reversible posterior leukoencephalopathy syndrome (RPLS), noninfectious pneumonia and others.

Ustekinumab may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal and viral infections have been observed in patients receiving ustekinumab. Clinically significant infections reported in UC clinical studies included gastroenteritis, ophthalmic herpes zoster, pneumonia and listeriosis. Treatment with ustekinumab should not be initiated in patients with any clinically important active infection until it resolves or is adequately treated.

Ustekinumab is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received ustekinumab in clinical trials and there have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients with pre-existing risk factors for developing non-melanoma skin cancer. All patients receiving ustekinumab should be monitored for the appearance of non-melanoma skin cancer. Patients >60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment should be followed closely.

In clinical studies of psoriasis and psoriatic arthritis, one case of reversible RPLS was observed. RPLS is a neurological disorder and can present with headache, seizures, confusion and visual disturbances. The affected patient fully recovered with appropriate treatment. No cases of RPLS were observed in clinical studies of CD or UC.

Dosage and Administration

The approved dosage regimen of ustekinumab is the same for both UC and CD patients: a single IV induction dose followed by subcutaneous maintenance doses every 8 weeks. The IV induction dose is based on weight, with patients 55 kg or less given 260 mg, patients more than 55 kg to 85 kg given 390 mg, and patients more than 85 kg given 520 mg. The recommended maintenance dose is 90 mg administered subcutaneously 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. Each injection should be administered at a different anatomical location than the previous injection and should not be injected into areas where skin is tender, bruised, erythematous, or indurated.

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Mirikizumab (Omvoh)

Mirikizumab, an immunoglobulin G4 (IgG4) monoclonal antibody that specifically binds to subunit p19 of IL-23, received FDA approval in October 2023 based on results from two phase 3 trials – LUCENT 1 and LUCENT 2. Mirikizumab is currently indicated for the treatment of moderate to severe UC in adults.

Efficacy

LUCENT-1 was a 12-week induction trial that enrolled adult patients with moderate to severe UC (Mayo score of 4-9, with endoscopic subscore of 2-3); LUCENT-2 was a 40-week maintenance trial. Patients were eligible for inclusion into these trials if they exhibited an inadequate response to, a loss of response to, or an inability to tolerate one or more glucocorticoids, immunomodulators, biologic therapies, or JAK inhibitors. Throughout the trial, patients were permitted to receive stable doses of oral mesalamine, oral glucocorticoids, or the immunomodulators azathioprine, 6-mercaptopurine, and methotrexate. During LUCENT-1, oral glucocorticoids were maintained at stable doses, with tapering initiated during LUCENT-2 for patients who had exhibited a response during the induction phase.

Entering the LUCENT-1 induction trial, patients were randomized (3:1) to mirikizumab IV 300 mg or placebo IV Q4W. Those who demonstrated a clinical response to mirikizumab therapy at week 12 (defined as a modified Mayo score [MMS] decrease of ≥2 points, with ≥30% decrease from baseline, plus ≥1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1) were re-randomized for the LUCENT-2 maintenance trial. Patients who did not respond to mirikizumab or placebo during the initial trial received an extended induction therapy consisting of 3 additional doses of mirikizumab IV 300 mg Q4W. Those who showed a clinical response at week 12 (ie, week 24 since trial start) were transitioned to maintenance therapy. In LUCENT-2, patients were re-randomized (2:1) to receive subcutaneous mirikizumab 200 mg or subcutaneous placebo (mirikizumab withdrawal) Q4W to week 52. The primary end point in LUCENT-1 was clinical remission (defined as a modified Mayo stool-frequency subscore of 0 or a stool-frequency subscore of 1 with ≤1 point decrease from baseline, a rectal-bleeding subscore of 0, and an endoscopic subscore of 0 or 1) at week 12. The primary end point in LUCENT-2 was clinical remission at week 40.

Compared to the placebo, a greater portion of patients in the mirikizumab group achieved the primary endpoints in both trials. At week 12 in LUCENT-1, 24.2% and 13.3% of patients achieved clinical remission with mirikizumab and placebo, respectively (P<0.001; Figure 11-9A). At week 52 in LUCENT-2, 49.9% of mirikizumab-treated patients and 25.1% of placebo-treated patients achieved clinical remission (P<0.001; Figure 11-9B).

Safety

The rates of AEs throughout the two LUCENT trials was similar between the mirikizumab and placebo groups. Adverse reactions reported in at least 3% of mirikizumab-treated patients and at a higher rate than with placebo were nasopharyngitis (4.1% vs 3.1%), and headache (3.3% vs 2.8%) in the induction trial and nasopharyngitis (7.2% vs 5.7%), arthralgia (6.7% vs 4.2%), injection-site pain (4.4% vs 3.1%), headache (4.1% vs 1.0%%), rash (3.6% vs 0.0%) and pyrexia (3.3% vs 2.6%) in the maintenance trial (Table 11.9).

Clinically significant infections were present in similar rates in both groups during both trials (Table 11.9). Serious infections among those receiving mirikizumab included intestinal sepsis, listeria sepsis, and pneumonia in LUCENT-1, and one case of COVID-19 pneumonia in LUCENT-2.

During the 52 weeks of LUCENT-1 and LUCENT-2 trials, 8 cases of cancer were reported (Table 11.9). Adenocarcinoma of the colon was observed in 0.2% of mirikizumab-treated patients and 0.0% of placebo-treated patients during the induction trial. Within the initial 12 weeks of the maintenance trial, gastric cancer was reported in 0.3% of mirikizumab-treated patients and 0.0% of placebo-treated patients. Over the subsequent 28 weeks of the maintenance trial, squamous-cell carcinoma was observed in 2 patients, while adenocarcinoma of the colon, rectal cancer, and Kaposi’s sarcoma were reported in 1 patient each.

Warnings and Precautions

The prescribing information for mirikizumab contains warnings and precautions for hypersensitivity reactions, infections, hepatotoxicity, and immunizations.

Serious hypersensitivity reactions (including anaphylaxis) have been reported in patients receiving mirikizumab. In the event of a severe hypersensitivity reaction, mirikizumab should be discontinued immediately and appropriate treatment should be initiated.

Mirikizumab may increase the risk of infection, including candidiasis, cytomegalovirus disease, herpes zoster infection, and tuberculosis. Therefore, initiation of mirikizumab treatment should be avoided in patients with clinically significant active infections until they are resolved or adequately treated. For patients with chronic infections or a history of recurrent infections, the decision to initiate mirikizumab therapy should carefully weigh the potential risks and benefits. Patients should be evaluated for tuberculosis before starting mirikizumab treatment, and continuously monitored for signs and symptoms of active tuberculosis throughout and following mirikizumab treatment. If a patient has active tuberculosis, administration of mirikizumab should be postponed until the infection is treated and resolved.

Mirikizumab may induce liver injury; a case of hepatotoxicity was reported in one study participant who underwent a mirikizumab induction regimen for longer than recommended. Liver enzymes and bilirubin levels should be assessed before treatment initiation and continuously monitored for at least 24 hours afterward. If a patient presents evidence of liver cirrhosis, alternative treatment options should be considered.

Given the potential interaction between medications affecting the immune system and live vaccines, administration of live vaccines should be avoided in individuals undergoing mirikizumab treatment. All appropriate vaccinations (based on the patient’s age) should be completed according to current immunization guidelines before starting mirikizumab therapy.

Dosage and Administration

The approved dosage regimen of mirikizumab is a 300 mg IV induction dose (given over at least 30 minutes) at week 0, week 4, and week 8. The recommended maintenance dosage is two 100 mg subcutaneous injections at week 12, and Q4W thereafter. Each injection should be administered at a different anatomical location from the previous injection and should not be injected into areas where the skin is tender, bruised, erythematous, or indurated.

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Head-to-head Comparison of Biologics

Limited non-observational data is currently available on the comparative safety and efficacy of biologics for the treatment of UC. The first study in this area was the VARSITY trial, which assessed the superiority of vedolizumab over adalimumab in patients with moderate to severe UC. Adult (age 18 to 85) patients with moderately to severely active UC (Mayo scale 6-12 with an endoscopic subscore of ≥2) with colonic involvement of ≥15 cm who were diagnosed ≥3 months prior to screening were eligible for recruitment. Both TNF blocker-naïve patients and those who discontinued a TNF blocker (other than adalimumab) for reasons other than safety were eligible, with TNF-experienced patients capped at 25%. A total of 769 eligible patients were randomized (1:1) to receive either vedolizumab (300 mg by intravenous [IV] infusion on Day 1 and Week 2, 6, 14, 22, 30, 38 and 46) or adalimumab (by 40 mg subcutaneous [SC] injection; four injections on Day 1 or two injections on Day 1 and two injections on Day 2, followed by two injections at Week 2 and single weekly injections thereafter until Week 50). In both groups, a corresponding IV or SC placebo was administered on appropriate days. The primary endpoint was clinical remission (Mayo score ≤2 with no subscore >1) at Week 52. Other endpoints, tested in a hierarchical procedure, included endoscopic improvement (Mayo endoscopic subscore of 0 or 1) and corticosteroid-free remission at Week 52.

Significantly more patients in the vedolizumab group (31.3%) achieved the primary endpoint at Week 52 compared to patients in the adalimumab group (22.5%, P=0.006). A significantly higher proportion of vedolizumab-treated patients (39.7%) also achieved endoscopic improvement compared to patients who received adalimumab (27.7%; P <0.001). However, vedolizumab failed to demonstrate superiority in corticosteroid-free remission, with 12.6% of patients achieving this endpoint, compared to 21.8% of adalimumab-treated patients. The two groups had comparable rates of adverse events, with numerically lower incidence rates of infection in the vedolizumab group (23.4 events per 100 patient-years) than in the adalimumab group (34.6 events per 100 patient-years).

The EVOLVE study, a 24-month retrospective medical chart study in 1095 adult patients with UC and CD treated with vedolizumab or anti-TNFa, found similar clinical effectiveness (clinical remission and mucosal healing) between treatment groups. However, rates of serious AEs and serious infections were significantly lower with vedolizumab than with anti-TNFa agents.

A registry study from the Netherlands compared the efficacy and safety of vedolizumab (83 patients) and tofacitinib (65 patients), finding that tofacitinib was more effective than vedolizumab in achieving corticosteroid-free clinical remission at week 12, 24, and 52 (P <0.01 for each). While AEs were more common in vedolizumab-treated patients, no difference in infection or severe AE rates was detected.

Owing to a general lack of direct head-to-head comparison trials of biologics, several network meta-analyses have been performed to compare the safety and efficacy of the various biologic treatments. One NMA found that infliximab was superior to adalimumab in clinical remission, clinical response, and mucosal healing, and superior to golimumab for clinical response and mucosal healing. Another NMA found that vedolizumab was superior to adalimumab for clinical remission but inferior to infliximab for clinical remission and clinical response, and that vedolizumab 300 mg every 8 weeks was superior as a maintenance treatment to adalimumab 40 mg, golimumab 50 mg, and ustekinumab 90 mg every 12 weeks for clinical remission (with similar clinical response rates). Infliximab was ranked highest for clinical remission and endoscopic improvement induction in biologic-naïve patients in another NMA, with ustekinumab and tofacitinib being the highest ranked agents for clinical remission induction among patients with prior exposure to anti-TNFa medications. Finally, another NMA of 29 studies (of which 4 were head-to-head trials), found upadacitinib to be superior to infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, etrolizumab, tofacitinib, filgotinib, and ozanimod for the induction of clinical remission. However, upadacitinib was also the worst-ranked agent with respect to AEs, with vedolizumab being the highest ranked for safety.

Biosimilars

A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorized reference biologic (also called originator biologic). The active substance of a biosimilar and its reference medicine are essentially the same biological substance, though there may be minor differences since they are made in living systems and their exact characteristics and properties are highly dependent on the manufacturing process. In contrast, generics are small-molecule chemical medications that are structurally and therapeutically equivalent to an originator product. Before a biosimilar can be marketed and sold, the patent for the reference biologic must expire and similarity to the reference medicinal product in terms of quality characteristics, biological activity, development of antidrug antibodies, safety, and efficacy must be established. Regulatory approval of biosimilar products depends on the principle of extrapolation, i.e., if a biosimilar product satisfies FDA criteria for similarity to the originator product, it may be approved for indications based on the approved indications of the originator product. It is important to note that a biosimilar is not necessarily interchangeable with the reference product. To establish interchangeability, switching studies with at least 3 switches between the biosimilar and the originator product for at least 2 exposure periods are required. Once classified as interchangeable, the biosimilar can be substituted for the originator product without consulting the prescribing healthcare professional (ie, it can be substituted by the pharmacist). Biosimilars have a great potential to decrease overall healthcare costs and increase healthcare access; however, lack of long term safety data and data on cross-switching between biosimilars, lack of practice guidelines, and US-specific factors including regulatory delay, patent litigation, federal reimbursement rules, represent roadblocks to wider adoption of biosimilars.

Infliximab was the first biologic used in the treatment of IBD and its patent expired in 2015, permitting other companies to produce their own versions of the same drug. So far, four biosimilars to infliximab have been approved in the United States: Renflexis (infliximab-abda), Ixifi (infliximab-qbtx), Inflectra (infliximab-dyyb), and Avsola (infliximab-axxq), all of which are given as an intravenous infusion at the same dose and frequency as infliximab. One systematic review on the safety and efficacy of switching between reference and biosimilar infliximab products analyzed 70 articles, of which only 13 were from randomized controlled trials (6 trials). Two trials (NOR-SWITCH and NOR-SWITCH OLE) included patients with UC. No clinically important efficacy or safety signals were observed in this review; however, most studies only reported on single switches. Ten biosimilars to adalimumab have also received FDA approval: Abrilada (adalimumab-afzb), Amjevita (adalimumab-atto), Cyltezo (adalimumab-adbm), Hadlima (adalimumab-bwwd), Hulio (adalimumab-fkjp), Hymiroz (adalimumab-adaz), Idacio (adalimumab-aacf), Simlandi (adalimumab-ryvk), Yuflyma (adalimumab-aaty), and Yusimry (adalimumab-aqvh). Ustekinumab has one FDA-approved biosimilar: Wezlana (ustekinumab-auub).

Drugs in Development

Given that remission rates for most biologic therapies range from up to 40%, there is still a large unmet need for effective treatment of UC. Several novel biologic agents are in various stages of development, including an anti-TNFa agent (OPRX-106), JAK inhibitors (ivarmacitinib, brepocitinib, ritlecitinib, peficitinib, izencitinib, and deucravacitinib), anti-trafficking agents (etrolizumab, carotegrast methyl, ontamalimab, abrilumab, PN-943, and PTG-100), IL-23 inhibitors (risankizumab, brazikumab, and guselkumab), S1P receptor modulators (CBP-307, amiselimod), a PDE4 inhibitor (apremilast), and a TLR9 agonist (cobitolimod). Although several novel options have recently been approved and many are in the pipeline, a “therapeutic ceiling” appears to have emerged, with no individual treatment showing efficacy in more than 30% of patients. Several combination therapies are currently under investigation to address this need.